Metampicillin is a cyclic aminal produced by reaction of ampicillin with formaldehyde

Raphael Reinbold, Tobias John, Paolo Spingardi, Akane Kawamura, Christopher J. Schofield, Richard J. Hopkinson

Wellcome Trust, Wellcome Trust, Wellcome Trust, Wellcome Trust, Biotechnology and Biological Sciences Research Council, Biotechnology and Biological Sciences Research Council, Biotechnology and Biological Sciences Research Council, Biotechnology and Biological Sciences Research Council, Cancer Research UK, Cancer Research UK, Cancer Research UK, Cancer Research UK, Engineering and Physical Sciences Research Council

Abstract: AbstractMetampicillin is a β-lactam antibiotic that is prepared by the reaction of ampicillin with formaldehyde. Although metampicillin has been studied for treatment of infections in animals and humans, its structure has been unclear. We report NMR studies revealing that metampicillin contains a formaldehyde-derived cyclic aminal. NMR time-course experiments with excess formaldehyde in solution show formation of another product with an additional exocyclic hemiaminal group formed by reaction with the cyclic aminal nitrogen. The exocyclic hemiaminal group is readily removed by reaction with the formaldehyde scavenger 1,3-cyclohexanedione, whereas the cyclic aminal methylene exhibits greater stability. The overall results assign the structure of metampicillin as containing a cyclic aminal and further reveal the potential for complexity in the reaction of formaldehyde with biomedicinally relevant molecules.


Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle?

Wellcome Trust, MOH | National Medical Research Council, MOH | National Medical Research Council, UKRI | Medical Research Council, British Heart Foundation, Fondation Leducq

Abstract: Abstract Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Irrespective of the underlying profibrotic condition (e.g. ageing, diabetes, hypertension), maladaptive cardiac fibrosis is defined by the transformation of resident fibroblasts to matrix‐secreting myofibroblasts. Numerous profibrotic factors have been identified at the molecular level (e.g. TGFβ, IL11, AngII), which activate gene expression programs for myofibroblast activation. A number of existing HF therapies indirectly target fibrotic pathways; however, despite multiple clinical trials in HFpEF, a specific clinically effective antifibrotic therapy remains elusive. Therapeutic inhibition of TGFβ, the master‐regulator of fibrosis, has unfortunately proven toxic and ineffective in clinical trials to date, and new approaches are needed. In this review, we discuss the pathophysiology and clinical implications of interstitial fibrosis in HFpEF. We provide an overview of trials targeting fibrosis in HFpEF to date and discuss the promise of potential new therapeutic approaches and targets in the context of underlying molecular mechanisms.


Electrophysiology Measurements of Metal Transport by MntH2 from Enterococcus faecalis

Matthias Gantner, Theodoros Laftsoglou, Honglin Rong, Vincent L. G. Postis, Lars J. C. Jeuken

School of Biomedical Sciences and the Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK

Wellcome Trust, European Research Council

Abstract: Transition metals are essential trace elements and their high-affinity uptake is required for many organisms. Metal transporters are often characterised using metal-sensitive fluorescent dyes, limiting the metals and experimental conditions that can be studied. Here, we have tested whether metal transport by Enterococcus faecalis MntH2 can be measured with an electrophysiology method that is based on the solid-supported membrane technology. E. faecalis MntH2 belongs to the Natural Resistance-Associated Macrophage Protein (Nramp) family of proton-coupled transporters, which transport divalent transition metals and do not transport the earth metals. Electrophysiology confirms transport of Mn(II), Co(II), Zn(II) and Cd(II) by MntH2. However, no uptake responses for Cu(II), Fe(II) and Ni(II) were observed, while the presence of these metals abolishes the uptake signals for Mn(II). Fluorescence assays confirm that Ni(II) is transported. The data are discussed with respect to properties and structures of Nramp-type family members and the ability of electrophysiology to measure charge transport and not directly substrate transport.


Mitochondrial Translation Occurs Preferentially in the Peri-Nuclear Mitochondrial Network of Cultured Human Cells

Christin A. Albus, Rolando Berlinguer-Palmini, Caroline Hewison, Fiona McFarlane, Elisabeta-Ana Savu, Robert N. Lightowlers, Zofia M. Chrzanowska-Lightowlers, Matthew Zorkau

Wellcome Centre for Mitochondrial Research, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK

Abstract: Human mitochondria are highly dynamic organelles, fusing and budding to maintain reticular networks throughout many cell types. Although extending to the extremities of the cell, the majority of the network is concentrated around the nucleus in most of the commonly cultured cell lines. This organelle harbours its own genome, mtDNA, with a different gene content to the nucleus, but the expression of which is critical for maintaining oxidative phosphorylation. Recent advances in click chemistry have allowed us to visualise sites of mitochondrial protein synthesis in intact cultured cells. We show that the majority of translation occurs in the peri-nuclear region of the network. Further analysis reveals that whilst there is a slight peri-nuclear enrichment in the levels of mitoribosomal protein and mitochondrial rRNA, it is not sufficient to explain this substantial heterogeneity in the distribution of translation. Finally, we also show that in contrast, a mitochondrial mRNA does not show such a distinct gradient in distribution. These data suggest that the relative lack of translation in the peripheral mitochondrial network is not due to an absence of mitoribosomes or an insufficient supply of the mt-mRNA transcripts.


Surveillance of travel-associated isolates elucidates the diversity of non-pandemic Vibrio cholerae

Lia Bote, Alyce Taylor-Brown, Mailis Maes, Danielle J. Ingle, Mary Valcanis, Benjamin P. Howden, Nicholas R. Thomson

Wellcome Trust, Wellcome Trust, Wellcome Trust, Wellcome Trust

Abstract: Vibrio cholerae is a Gram-negative bacterium found in aquatic environments and is the aetiological agent of cholera, characterized by acute watery diarrhoea and severe dehydration. Cholera presents a significant global health burden of an estimated 1.3–5 million annual cases, with the current pandemic caused by a toxigenic lineage of the O1 El Tor biotype called seventh pandemic El Tor (7PET) that is still ongoing. Whilst it is known that non-7PET lineages can cause sporadic disease, little is known about the transmission of these non-epidemic lineages. Thirty-four V. cholerae isolates were obtained from travellers returning from Indonesia to Australia between 2005 and 2017. These were whole genome sequenced, placed into a global phylogenetic context with 883 isolates, and screened for known genes associated with antimicrobial resistance and virulence. This analysis revealed that 30 isolates fell within non-7PET lineages and four within the 7PET lineage. Both 7PET and non-7PET isolates carried genes for resistance to antibiotics that are commonly used in cholera treatment such as tetracyclines and fluoroquinolones. Diverse virulence factors were also present in non-7PET isolates, with two isolates notably carrying toxin-coregulated pilus genes, which are primarily responsible for intestinal colonization in 7PET V. cholerae. This study demonstrates the role of travel in long-range carriage of epidemic and non-epidemic lineages of V. cholerae, and how sentinel travel surveillance can enrich our knowledge of V. cholerae diversity, reveal new biology about the spread of diverse lineages with differing disease potential and illuminate disease presence in endemic regions with limited surveillance data.


The Natural History of Antibiotic-Treated Lower Limb Cellulitis: Analysis of Data Extracted From a Multicenter Clinical Trial

O Martin Williams, Fergus Hamilton, Richard Brindle

UK Health Security Agency Microbiology Laboratory Services Bristol, Bristol Royal Infirmary , Bristol , UK

National Institute for Health Research, Wellcome Trust

Abstract: Abstract Background Although cellulitis is a relatively common skin infection, there remains uncertainty about management, particularly the length and route of antimicrobials required. Further information on the symptomatology and biomarker changes associated with cellulitis over time would guide clinicians and patients as to the expected natural history. Methods We extracted data from a randomized clinical trial (NCT01876628) of clindamycin as adjunctive therapy in cellulitis to illustrate the evolution of local parameters (pain, swelling, local erythema, and warmth) and the resolution of biomarkers over time. Results Data from 247 individuals with mild to moderate unilateral lower limb cellulitis, who attended at least 1 face-to-face interview following recruitment, were used to examine response dynamics. Although there was a local improvement in swelling, warmth, erythema, and pain by day 5 compared with baseline, some individuals still had evidence of local inflammation at 10 days. Most biomarkers demonstrated a return to normal by day 3, although the initial fall in albumin only returned to baseline by day 10. Conclusions Although there was initial resolution, a significant number of individuals still had local symptoms persisting to day 10 and beyond. Clinicians can use these data to reassure themselves and their patients that ongoing local symptoms and signs after completion of antibiotic treatment do not indicate treatment failure or warrant extension of the initial antibiotic treatment or a change in antibiotic class or mode of administration.


Neuromodulatory Control and Language Recovery in Bilingual Aphasia: An Active Inference Approach

Noor Sajid, Karl Friston, Justyna Ekert, Cathy Price, David Green

Wellcome Centre for Human Neuroimaging, University College London, 12 Queen Square, London WC1N 3AR, UK

Medical Research Council, Wellcome Trust

Abstract: Understanding the aetiology of the diverse recovery patterns in bilingual aphasia is a theoretical challenge with implications for treatment. Loss of control over intact language networks provides a parsimonious starting point that can be tested using in-silico lesions. We simulated a complex recovery pattern (alternate antagonism and paradoxical translation) to test the hypothesis—from an established hierarchical control model—that loss of control was mediated by constraints on neuromodulatory resources. We used active (Bayesian) inference to simulate a selective loss of sensory precision; i.e., confidence in the causes of sensations. This in-silico lesion altered the precision of beliefs about task relevant states, including appropriate actions, and reproduced exactly the recovery pattern of interest. As sensory precision has been linked to acetylcholine release, these simulations endorse the conjecture that loss of neuromodulatory control can explain this atypical recovery pattern. We discuss the relevance of this finding for other recovery patterns.


Non‐enzymatic glycolysis and pentose phosphate pathway‐like reactions in a plausible Archean ocean

Markus A Keller, Alexandra V Turchyn, Markus Ralser

Isaac Newton Trust, Wellcome Trust, Royal Society, ERC, ERC

Abstract: Abstract The reaction sequences of central metabolism, glycolysis and the pentose phosphate pathway provide essential precursors for nucleic acids, amino acids and lipids. However, their evolutionary origins are not yet understood. Here, we provide evidence that their structure could have been fundamentally shaped by the general chemical environments in earth's earliest oceans. We reconstructed potential scenarios for oceans of the prebiotic Archean based on the composition of early sediments. We report that the resultant reaction milieu catalyses the interconversion of metabolites that in modern organisms constitute glycolysis and the pentose phosphate pathway. The 29 observed reactions include the formation and/or interconversion of glucose, pyruvate, the nucleic acid precursor ribose‐5‐phosphate and the amino acid precursor erythrose‐4‐phosphate, antedating reactions sequences similar to that used by the metabolic pathways. Moreover, the Archean ocean mimetic increased the stability of the phosphorylated intermediates and accelerated the rate of intermediate reactions and pyruvate production. The catalytic capacity of the reconstructed ocean milieu was attributable to its metal content. The reactions were particularly sensitive to ferrous iron Fe(II), which is understood to have had high concentrations in the Archean oceans. These observations reveal that reaction sequences that constitute central carbon metabolism could have been constrained by the iron‐rich oceanic environment of the early Archean. The origin of metabolism could thus date back to the prebiotic world.


Multiscale mobility patterns and the restriction of human movement

Juni Schindler, Jonathan Clarke, Mauricio Barahona

Engineering and Physical Sciences Research Council, Engineering and Physical Sciences Research Council, Wellcome Trust

Abstract: From the perspective of human mobility, the COVID-19 pandemic constituted a natural experiment of enormous reach in space and time. Here, we analyse the inherent multiple scales of human mobility using Facebook Movement maps collected before and during the first UK lockdown. Firstly, we obtain the pre-lockdown UK mobility graph and employ multiscale community detection to extract, in an unsupervised manner, a set of robust partitions into flow communities at different levels of coarseness. The partitions so obtained capture intrinsic mobility scales with better coverage than nomenclature of territorial units for statistics (NUTS) regions, which suffer from mismatches between human mobility and administrative divisions. Furthermore, the flow communities in the fine-scale partition not only match well the UK travel to work areas but also capture mobility patterns beyond commuting to work. We also examine the evolution of mobility under lockdown and show that mobility first reverted towards fine-scale flow communities already found in the pre-lockdown data, and then expanded back towards coarser flow communities as restrictions were lifted. The improved coverage induced by lockdown is well captured by a linear decay shock model, which allows us to quantify regional differences in both the strength of the effect and the recovery time from the lockdown shock.


Triaging of respiratory protective equipment on the assumed risk of SARS-CoV-2 aerosol exposure in patient-facing healthcare workers delivering secondary care: a rapid review

Prashanth Ramaraj, Jonathan Super, Ruben Doyle, Christopher Aylwin, Shehan Hettiaratchy

Major Trauma Centre, Imperial College Healthcare NHS Trust, London, UK

Abstract: Objectives In patient-facing healthcare workers delivering secondary care, what is the evidence behind UK Government personal protective equipment (PPE) guidance on surgical masks versus respirators for SARS-CoV-2 protection? Design Two independent reviewers performed a rapid review. Appraisal was performed using Critical Appraisal Skills Programme checklists and Grading of Recommendations, Assessment, Development and Evaluations methodology. Results were synthesised by comparison of findings and appraisals. Data sources MEDLINE, Google Scholar, UK Government COVID-19 website and grey literature. Eligibility criteria Studies published on any date containing primary data comparing surgical facemasks and respirators specific to SARS-CoV-2, and studies underpinning UK Government PPE guidance, were included. Results Of 30 identified, only 3 laboratory studies of 14 different respirators and 12 surgical facemasks were found. In all three, respirators were significantly more effective than facemasks when comparing protection factors, reduction factors, filter penetrations, total inspiratory leakages at differing particle sizes, mean inspiratory flows and breathing rates. Tests included live viruses and inert particles on dummies and humans. In the six clinical studies (6502 participants) included the only statistically significant result found continuous use of respirators more effective in clinical respiratory illness compared with targeted use or surgical facemasks. There was no consistent definition of ‘exposure’ to determine the efficacy of respiratory protective equipment (RPE). It is difficult to define ‘safe’. Conclusions There is a paucity of evidence on the comparison of facemasks and respirators specific to SARS-CoV-2, and poor-quality evidence in other contexts. The use of surrogates results in extrapolation of non-SARS-CoV-2 specific data to guide UK Government PPE guidance. The appropriateness of this is unknown given the uncertainty over the transmission of SARS-CoV-2. This means that the evidence base for UK Government PPE guidelines is not based on SARS-CoV-2 and requires generalisation from low-quality evidence of other pathogens/particles. There is a paucity of high-quality evidence regarding the efficacy of RPE specific to SARS-CoV-2. UK Government PPE guidelines are underpinned by the assumption of droplet transmission of SARS-CoV-2. These factors suggest that the triaging of filtering face piece class 3 respirators might increase the risk of COVID-19 faced by some.


Distinct properties of semiquinone species detected at the ubiquinol oxidation Qo site of cytochrome <i>bc</i> 1 and their mechanistic implications

Rafał Pietras, Marcin Sarewicz, Artur Osyczka

Abstract: Abstract The two-electron ubiquinol oxidation or ubiquinone reduction typically involves semiquinone (SQ) intermediates. Natural engineering of ubiquinone binding sites of bioenergetic enzymes secures that SQ is sufficiently stabilized, so that it does not leave the site to membranous environment before full oxidation/reduction is completed. The ubiquinol oxidation Qo site of cytochrome bc1 (mitochondrial complex III, cytochrome b6f in plants) has been considered an exception with catalytic reactions assumed to involve highly unstable SQ or not to involve any SQ intermediate. This view seemed consistent with long-standing difficulty in detecting any reaction intermediates at the Qo site. New perspective on this issue is now offered by recent, independent reports on detection of SQ in this site. Each of the described SQs seems to have different spectroscopic properties leaving space for various interpretations and mechanistic considerations. Here, we comparatively reflect on those properties and their consequences on the SQ stabilization, the involvement of SQ in catalytic reactions, including proton transfers, and the reactivity of SQ with oxygen associated with superoxide generation activity of the Qo site.


Severe malaria

Abstract: AbstractSevere malaria is a medical emergency. It is a major cause of preventable childhood death in tropical countries. Severe malaria justifies considerable global investment in malaria control and elimination yet, increasingly, international agencies, funders and policy makers are unfamiliar with it, and so it is overlooked. In sub-Saharan Africa, severe malaria is overdiagnosed in clinical practice. Approximately one third of children diagnosed with severe malaria have another condition, usually sepsis, as the cause of their severe illness. But these children have a high mortality, contributing substantially to the number of deaths attributed to ‘severe malaria’. Simple well-established tests, such as examination of the thin blood smear and the full blood count, improve the specificity of diagnosis and provide prognostic information in severe malaria. They should be performed more widely. Early administration of artesunate and broad-spectrum antibiotics to all children with suspected severe malaria would reduce global malaria mortality.


Molecular Epidemiology of Human Rhinovirus From 1-Year Surveillance Within a School Setting in Rural Coastal Kenya

Martha M Luka, Everlyn Kamau, Irene Adema, Patrick K Munywoki, Grieven P Otieno, Elijah Gicheru, Alex Gichuki, Nelson Kibinge, Charles N Agoti, D James Nokes

Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine Research – Coast, Kilifi, Kenya

Abstract: Abstract Background Human rhinovirus (HRV) is the most common cause of the common cold but may also lead to more severe respiratory illness in vulnerable populations. The epidemiology and genetic diversity of HRV within a school setting have not been previously described. The objective of this study was to characterize HRV molecular epidemiology in a primary school in a rural location of Kenya. Methods Between May 2017 and April 2018, over 3 school terms, we collected 1859 nasopharyngeal swabs (NPS) from pupils and teachers with symptoms of acute respiratory infection in a public primary school in Kilifi County, coastal Kenya. The samples were tested for HRV using real-time reverse transcription polymerase chain reaction. HRV-positive samples were sequenced in the VP4/VP2 coding region for species and genotype classification. Results A total of 307 NPS (16.4%) from 164 individuals were HRV positive, and 253 (82.4%) were successfully sequenced. The proportion of HRV in the lower primary classes was higher (19.8%) than upper primary classes (12.2%; P &lt; .001). HRV-A was the most common species (134/253; 53.0%), followed by HRV-C (73/253; 28.9%) and HRV-B (46/253; 18.2%). Phylogenetic analysis identified 47 HRV genotypes. The most common genotypes were A2 and B70. Numerous (up to 22 in 1 school term) genotypes circulated simultaneously, there was no individual re-infection with the same genotype, and no genotype was detected in all 3 school terms. Conclusions HRV was frequently detected among school-going children with mild acute respiratory illness symptoms, particularly in the younger age groups (&lt;5-year-olds). Multiple HRV introductions were observed that were characterized by considerable genotype diversity.


Stakeholder analysis for ‘One Health’ approach to tackle antimicrobial resistance

Sanjib Adhikari, Komal Raj Rijal, Daniel M Parker, Prakash Ghimire, Phaik Yeong Cheah, Bipin Adhikari

Central Department of Microbiology, Tribhuvan University, Kirtipur, Nepal

Global Health Bioethics Network (GHBN), UK, Wellcome Trust

Abstract: Antimicrobial resistance (AMR) and interventions to mitigate it are multisectoral, exhibiting super-wicked features that require intersectoral collaboration and synergy. Although AMR and mitigation strategies are pressing issues, their solutions are complex, ethically challenging, multilayered and often conflict at various levels and among diverse stakeholders. The main objective of this study was to identify the values and potential contributions of stakeholder analysis related to AMR and potential interventions from a case study that is being undertaken in Nepal using a ‘One Health’ approach. A total of 33 representatives from human, animal, agricultural and environmental sectors attended a stakeholder meeting in Kathmandu to discuss AMR, its ethical and practical challenges, opportunities and potential interventions. Using a five-pillar framework for stakeholder analysis, we demonstrate its relevance for addressing AMR and propose practical considerations for implementing effective interventions in Nepal. Beyond the practical discussions on AMR and its interventions at the policy, implementation and practice levels, this study underscores the critical value of its methodological reflections for informing ongoing interventions both within Nepal and in similar contexts globally.


Epithelial Cells and Inflammation in Pulmonary Wound Repair

Amanda Croasdell Lucchini, Naomi N. Gachanja, Adriano G. Rossi, David A. Dorward, Christopher D. Lucas

University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh Bioquarter, Edinburgh EH16 4TJ, UK

Wellcome Trust, Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund, Pathological Society Award

Abstract: Respiratory diseases are frequently characterised by epithelial injury, airway inflammation, defective tissue repair, and airway remodelling. This may occur in a subacute or chronic context, such as asthma and chronic obstructive pulmonary disease, or occur acutely as in pathogen challenge and acute respiratory distress syndrome (ARDS). Despite the frequent challenge of lung homeostasis, not all pulmonary insults lead to disease. Traditionally thought of as a quiescent organ, emerging evidence highlights that the lung has significant capacity to respond to injury by repairing and replacing damaged cells. This occurs with the appropriate and timely resolution of inflammation and concurrent initiation of tissue repair programmes. Airway epithelial cells are key effectors in lung homeostasis and host defence; continual exposure to pathogens, toxins, and particulate matter challenge homeostasis, requiring robust defence and repair mechanisms. As such, the epithelium is critically involved in the return to homeostasis, orchestrating the resolution of inflammation and initiating tissue repair. This review examines the pivotal role of pulmonary airway epithelial cells in initiating and moderating tissue repair and restitution. We discuss emerging evidence of the interactions between airway epithelial cells and candidate stem or progenitor cells to initiate tissue repair as well as with cells of the innate and adaptive immune systems in driving successful tissue regeneration. Understanding the mechanisms of intercellular communication is rapidly increasing, and a major focus of this review includes the various mediators involved, including growth factors, extracellular vesicles, soluble lipid mediators, cytokines, and chemokines. Understanding these areas will ultimately identify potential cells, mediators, and interactions for therapeutic targeting.


Sleep, circadian rhythms and health

Abstract: Abstract At the core of human thought, for the majority of individuals in the developed nations at least, there is the tacit assumption that as a species we are unfettered by the demands imposed by our biology and that we can do what we want, at whatever time we choose, whereas in reality every aspect of our physiology and behaviour is constrained by a 24 h beat arising from deep within our evolution. Our daily circadian rhythms and sleep/wake cycle allow us to function optimally in a dynamic world, adjusting our biology to the demands imposed by the day/night cycle. The themes developed in this review focus upon the growing realization that we ignore the circadian and sleep systems at our peril, and this paper considers the mechanisms that generate and regulate circadian and sleep systems; what happens mechanistically when these systems collapse as a result of societal pressures and disease; how sleep disruption and stress are linked; why sleep disruption and mental illness invariably occur together; and how individuals and employers can attempt to mitigate some of the problems associated with working against our internal temporal biology. While some of the health costs of sleep disruption can be reduced, in the short-term at least, there will always be significant negative consequences associated with shift work and sleep loss. With this in mind, society needs to address this issue and decide when the consequences of sleep disruption are justified in the workplace.


Anterior-enriched filopodia create the appearance of asymmetric membrane microdomains in polarizing <i>C. elegans</i> zygotes

Nisha Hirani, Rukshala Illukkumbura, Tom Bland, Grégoire Mathonnet, Delphine Suhner, Anne-Cecile Reymann, Nathan W. Goehring

The Francis Crick Institute 1 , 1 Midland Road, London NW1 1AT , UK

Francis Crick Institute, Cancer Research UK, Medical Research Council, Wellcome Trust, H2020 Marie Skłodowska-Curie Actions, Agence Nationale de la Recherche, LabEx, European Cooperation in Science and Technology, European Molecular Biology Organization

Abstract: ABSTRACT The association of molecules within membrane microdomains is critical for the intracellular organization of cells. During polarization of the C. elegans zygote, both polarity proteins and actomyosin regulators associate within dynamic membrane-associated foci. Recently, a novel class of asymmetric membrane-associated structures was described that appeared to be enriched in phosphatidylinositol 4,5-bisphosphate (PIP2), suggesting that PIP2 domains could constitute signaling hubs to promote cell polarization and actin nucleation. Here, we probe the nature of these domains using a variety of membrane- and actin cortex-associated probes. These data demonstrate that these domains are filopodia, which are stimulated transiently during polarity establishment and accumulate in the zygote anterior. The resulting membrane protrusions create local membrane topology that quantitatively accounts for observed local increases in the fluorescence signal of membrane-associated molecules, suggesting molecules are not selectively enriched in these domains relative to bulk membrane and that the PIP2 pool as revealed by PHPLCδ1 simply reflects plasma membrane localization. Given the ubiquity of 3D membrane structures in cells, including filopodia, microvilli and membrane folds, similar caveats are likely to apply to analysis of membrane-associated molecules in a broad range of systems.


Immune response to vaccination in people with psychotic disorders relative to healthy controls: prospective study of SARS-CoV-2 vaccination

Oisín O'Brien, Atheeshaan Arumuham, Yuya Mizuno, Luke Baxter, Maria Lobo, Sita Parmar, Stephen Jolles, Oliver D. Howes

Medical Research Council, Maudsley Charity, Wellcome Trust

Abstract: Summary This prospective study examines the immune response to SARS-CoV-2 vaccination in patients with psychotic disorders compared with healthy volunteers. Participants were recruited naturalistically as part of the UK's COVID-19 vaccination programme. Prior to receiving their first COVID-19 vaccine, blood samples were provided by participants to examine anti-SARS-CoV-2 immunoglobulins (IgG) at baseline, followed by a repeat assay 1 month after receiving their first vaccine to assess vaccine response. The increase of IgG levels from baseline to 1 month post-vaccination was significantly lower in patients compared with controls, supporting evidence of impaired vaccine response in people with psychotic disorders. When excluding patients treated with clozapine from the analysis, this difference was no longer significant, suggesting that effects may be particularly marked in people taking clozapine.


Increase in brain glycogen levels ameliorates Huntington's disease phenotype and rescues neurodegeneration in <i>Drosophila</i>

Akanksha Onkar, Deepashree Sheshadri, Anupama Rai, Arjit Kant Gupta, Nitin Gupta, Subramaniam Ganesh

Indian Institute of Technology 1 Department of Biological Sciences and Bioengineering , (IIT), Kanpur 208016 , India

University Grants Commission, Wellcome Trust, Indian Institute of Technology

Abstract: ABSTRACT Under normal physiological conditions, the mammalian brain contains very little glycogen, most of which is stored in astrocytes. However, the aging brain and the subareas of the brain in patients with neurodegenerative disorders tend to accumulate glycogen, the cause and significance of which remain largely unexplored. Using cellular models, we have recently demonstrated a neuroprotective role for neuronal glycogen and glycogen synthase in the context of Huntington's disease. To gain insight into the role of brain glycogen in regulating proteotoxicity, we utilized a Drosophila model of Huntington's disease, in which glycogen synthase is either knocked down or expressed ectopically. Enhancing glycogen synthesis in the brains of flies with Huntington's disease decreased mutant Huntingtin aggregation and reduced oxidative stress by activating auto-lysosomal functions. Further, overexpression of glycogen synthase in the brain rescues photoreceptor degeneration, improves locomotor deficits and increases fitness traits in this Huntington's disease model. We, thus, provide in vivo evidence for the neuroprotective functions of glycogen synthase and glycogen in neurodegenerative conditions, and their role in the neuronal autophagy process.


Age-related changes in working memory and the ability to ignore distraction

Proceedings of the National Academy of Sciences

Fiona McNab, Peter Zeidman, Robb B. Rutledge, Peter Smittenaar, Harriet R. Brown, Rick A. Adams, Raymond J. Dolan

School of Psychology, University of Birmingham, Birmingham, B15 2TT, United Kingdom;

The Wellcome Trust, The Wellcome Trust, The Wellcome Trust, The Brain Research Trust, The Wellcome Trust, The Wellcome Trust

Abstract: Significance We reveal a novel and highly significant change in how items are held in mind in healthy aging. Using smartphones, data were collected from 29,631 participants, between the ages of 18–69 y. We compare the ability to exclude distractors when items are entered into working memory (WM) (encoding distraction, ED) and when items are held in mind (delay distraction, DD). In older adults, WM in the absence of distraction was more similar to ED exclusion than DD exclusion. A greater reliance on focused attention during encoding may reflect compensation for the more pronounced deterioration we observed in DD exclusion in older age. This can inform other areas of cognition and strategies to ameliorate or manage debilitating age-related cognitive decline.


A framework for managing health research capacity strengthening consortia: addressing tensions and enhancing capacity outcomes

Nadia Tagoe, Justin Pulford, Sam Kinyanjui, Sassy Molyneux

Office of Grants and Research, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Wellcome Trust, Wellcome Trust, UK government, DELTAS Africa Initiative

Abstract: There has been a steady increase in health research capacity strengthening (HRCS) consortia and programmes. However, their structures and management practices and the effect on the capacity strengthening outcomes have been underexamined. We conducted a case study involving three HRCS consortia where we critically examined the consortia’s decision-making processes, strategies for resolving management tensions and the potential implications for consortia outcomes. We conducted 44 in-depth interviews with a range of consortia members and employed the framework method to analyse the data. We assessed the extent to which consortia’s management practices and strategies enabled or hindered research capacity strengthening using a capacity development lens. At the heart of consortium management is how tensions are navigated and the resolution strategies adopted. This study demonstrates that the management strategies adopted by consortia have capacity strengthening consequences. When deciding on tension management strategies, trade-offs often occur, sometimes to the detriment of capacity strengthening aims. When management strategies align with capacity development principles, consortium management processes become capacity strengthening mechanisms for participating individuals and institutions. Such alignment enhances programme effectiveness and value for money. Drawing on these findings, we propose an evidence-informed management framework that consortia leaders can use in practice to support decision-making to optimise research capacity gains. Considering the increasing investment in HRCS consortia, leveraging all consortium processes towards capacity strengthening will maximise the returns on investments made.


Status of Insecticide Resistance and Its Mechanisms in Anopheles gambiae and Anopheles coluzzii Populations from Forest Settings in South Cameroon

Roland Bamou, Nadège Sonhafouo-Chiana, Konstantinos Mavridis, Timoléon Tchuinkam, Charles S. Wondji, John Vontas, Christophe Antonio-Nkondjio

Vector Borne Diseases Laboratory of the Applied Biology and Ecology Research Unit (VBID-URBEA), Department of Animal Biology, Faculty of Science of the University of Dschang, Dschang P.O. Box 067, Cameroon

Wellcome Trust, European Union’s Horizon 2020 research and innovation programme

Abstract: A key factor affecting malaria vector control efforts in Cameroon is the rapid expansion of insecticide resistance in Anopheles gambiae s.l (An. gambiae) populations; however, mechanisms involved in insecticide resistance in forest mosquito populations are still not well documented yet. The present study was conducted to screen molecular mechanisms conferring insecticide resistance in An. gambiae s.l. populations from the South Cameroon forest region. WHO bioassays were conducted with F0 An. gambiae females aged three to four days from forest (Sangmelima, Nyabessan, and Mbandjock) and urban sites (Yaoundé (Bastos and Nkolondom)), against pyrethroids (permethrin 0.75% and deltamethrin 0.05%) and carbamates (bendiocarb 0.1%). Members of the An. Gambiae s.l. species complex were identified using molecular diagnostic tools. TaqMan assays were used to screen for target site mutations. The expression profiles of eight genes implicated in insecticide resistance were assessed using RT-qPCR. Cuticle hydrocarbon lipids were measured to assess their potential implication in insecticide resistance. Both An. Gambiae and An. coluzzii were detected. An. gambiae was highly prevalent in Sangmelima, Nyabessan, Mbandjock, and Nkolondom. An. coluzzii was the only species found in the Yaoundé city center (Bastos). Low mortality rate to both pyrethroids and bendiocarb was recorded in all sites. High frequency of L1014F allele (75.32–95.82%) and low frequencies of L1014S (1.71–23.05%) and N1575Y (5.28–12.87%) were recorded. The G119S mutation (14.22–35.5%) was detected for the first time in An. gambiae populations from Cameroon. This mutation was rather absent from An. coluzzii populations. The detoxification genes Cyp6m2, Cyp9k1, Cyp6p4, Cyp6z1, as well as Cyp4g16 which catalyzes epicuticular hydrocarbon biosynthesis, were found to be overexpressed in at least one population. The total cuticular hydrocarvbon content, a proxy of cuticular resistance, did not show a pattern associated with pyrethroid resistance in these populations. The rapid emergence of multiple resistance mechanisms in An. Gambiae s.l. population from the South Cameroon forest region is of big concern and could deeply affect the sustainability of insecticide-based interventions strategies in this region.


Glycyrrhizin Blocks the Detrimental Effects of HMGB1 on Cortical Neurogenesis after Traumatic Neuronal Injury

Susruta Manivannan, Balkis Harari, Maryam Muzaffar, Omar Elalfy, Sameera Hettipathirannahelage, Zoe James, Feras Sharouf, Chloe Ormonde, Mouhamed Alsaqati, William Gray, Malik Zaben

Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cathays, Cardiff CF24 4HQ, UK

Royal College of Surgeons of England, Wellcome Trust, Rhiannon Jade-Smith Trust

Abstract: Despite medical advances, neurological recovery after severe traumatic brain injury (TBI) remains poor. Elevated levels of high mobility group box protein-1 (HMGB1) are associated with poor outcomes; likely via interaction with receptors for advanced-glycation-end-products (RAGE). We examined the hypothesis that HMGB1 post-TBI is anti-neurogenic and whether this is pharmacologically reversible. Post-natal rat cortical mixed neuro-glial cell cultures were subjected to needle-scratch injury and examined for HMGB1-activation/neuroinflammation. HMGB1-related genes/networks were examined using genome-wide RNA-seq studies in cortical perilesional tissue samples from adult mice. Post-natal rat cortical neural stem/progenitor cell cultures were generated to quantify effects of injury-condition medium (ICM) on neurogenesis with/without RAGE antagonist glycyrrhizin. Needle-injury upregulated TNF-α/NOS-2 mRNA-expressions at 6 h, increased proportions of activated microglia, and caused neuronal loss at 24 h. Transcriptome analysis revealed activation of HMGB1 pathway genes/canonical pathways in vivo at 24 h. A 50% increase in HMGB1 protein expression, and nuclear-to-cytoplasmic translocation of HMGB1 in neurons and microglia at 24 h post-injury was demonstrated in vitro. ICM reduced total numbers/proportions of neuronal cells, but reversed by 0.5 μM glycyrrhizin. HMGB1 is activated following in vivo post mechanical injury, and glycyrrhizin alleviates detrimental effects of ICM on cortical neurogenesis. Our findings highlight glycyrrhizin as a potential therapeutic agent post-TBI.


Serum Exosomal miRNAs Are Associated with Active Pulmonary Tuberculosis

Shamila D. Alipoor, Payam Tabarsi, Mohammad Varahram, Mehrnaz Movassaghi, Mehdi Kazempour Dizaji, Gert Folkerts, Johan Garssen, Ian M. Adcock, Esmaeil Mortaz

Institute of Medical Biotechnology, Molecular Medicine Department, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran

Iran National Science Foundation, Iran National Science Foundation, Welcome Trust, Welcome Trust

Abstract: Introduction. Tuberculosis (TB) remains a major threat to human health. Due to the limited accuracy of the current TB diagnostic tests, it is critical to determine novel biomarkers for this disease. Circulating exosomes have been used as diagnostic biomarkers in various diseases. Objective of the Study. In this pilot study, we examined the expression of miRNAs as biomarker candidates for the diagnosis of TB infection. Methods. Serum-derived exosomes were isolated from TB patients and matched control subjects. The expression of miR-484, miR-425, and miR-96 was examined by RT-PCR methods. Results. The expression of miR-484, miR-425, and miR-96 were significantly increased in serum of TB patients which correlated with the TB infection level. A receiver operating characteristic (ROC) curve analysis showed the diagnostic potency of each individual serum exosomal miRNA with an area under the curve AUC=0.72 for miR-484 (p<0.05), 0.66 for miR-425 (p<0.05), and 0.62 for miR-96 (p<0.05). Conclusion. These results demonstrate that exosomal miRNAs have diagnostic potential in active tuberculosis. The diagnostic power may be improved when combined with conventional diagnostic markers.


11βHSD1 Inhibition with AZD4017 Improves Lipid Profiles and Lean Muscle Mass in Idiopathic Intracranial Hypertension

The Journal of Clinical Endocrinology & Metabolism

Rowan S Hardy, Hannah Botfield, Keira Markey, James L Mitchell, Zerin Alimajstorovic, Connar S J Westgate, Michael Sagmeister, Rebecca J Fairclough, Ryan S Ottridge, Andreas Yiangou, Karl-Heinz H Storbeck, Angela E Taylor, Lorna C Gilligan, Wiebke Arlt, Paul M Stewart, Jeremy W Tomlinson, Susan P Mollan, Gareth G Lavery, Alexandra J Sinclair

Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

Medical Research Council Asset Sharing Scheme, UK, Medical Research Council Asset Sharing Scheme, UK, National Institute for Health Research, Wellcome Trust, Academy of Medical Sciences UK, Versus Arthritis, National Institute for Health Research

Abstract: Abstract Background The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11β-HSD1 inhibitors. We examined the impact of the reversible competitive 11β-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension (IIH). Methods We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry. Results Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P &lt; .001). No changes in body mass index, fat mass, and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass. Conclusions These beneficial metabolic changes represent a reduction in risk factors associated with raised intracranial pressure and represent further beneficial therapeutic outcomes of 11β-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia.


Digital mental health interventions for adolescents and young people (10–24 years) in Africa: A protocol for a systematic review of mental health outcomes, engagement, and equity considerations

Aggrey Gisiora Mokaya, Nondumiso Michelle Dlamini, Syethemba Nkosi, Mpilonhle Thembinkosi Nzuza, Thandeka Smith, Grace Nduku Wambua, Xanthe Hunt, Alan Stein, Nothando Ngwenya

Abstract: Background Adolescents and young people (AYP) aged 10–24 years in Africa experience a high burden of mental health disorders but face significant barriers to accessing care, including a severe shortage of mental health professionals, stigma, and limited integration of mental health services into primary healthcare. Digital mental health interventions (DMHIs) offer a promising avenue to bridge these gaps by providing accessible, scalable, and potentially equitable support. However, little is known about the effectiveness, acceptability, and equity impacts of these interventions among African AYP. Objective This systematic review aims to identify, characterize, and synthesize evidence on DMHIs targeting adolescents and young people in Africa, focusing on mental health outcomes, engagement, feasibility, and equity considerations. Methods We will search PubMed, Scopus, Web of Science, and EBSCOhost databases, as well as the PsyberGuide repository, for empirical studies published between January 1, 2015, and April 3, 2025. Eligible studies must evaluate a digital mental health intervention among AYP aged 10–24 years living in Africa. Study designs will include randomized controlled trials, quasi-experimental studies, observational studies, and mixed-methods studies. Outcomes of interest include mental health symptom reduction (depression, anxiety, stress), psychological well-being, engagement, feasibility, acceptability, and equity-related factors such as gender inclusivity and digital access. Risk of bias will be assessed using RoB 2 and ROBINS-I tools, and evidence quality will be rated using the GRADE approach. Quantitative synthesis will be conducted where feasible, otherwise narrative synthesis will be employed. Conclusion This review will provide a comprehensive synthesis of available evidence on DMHIs for adolescents and young people in Africa, offering critical insights into their effectiveness, feasibility, and contribution to promoting mental health equity. The findings aim to inform the development, implementation, and policy integration of digital mental health strategies tailored to young populations in diverse African contexts.


Prognostic models for predicting in-hospital paediatric mortality in resource-limited countries: a systematic review

Morris Ogero, Rachel Jelagat Sarguta, Lucas Malla, Jalemba Aluvaala, Ambrose Agweyu, Mike English, Nelson Owuor Onyango, Samuel Akech

School of Mathematics, University of Nairobi College of Biological and Physical Sciences, Nairobi, Kenya

The Wellcome Trust, The Wellcome Trust, The Wellcome Trust, The Wellcome Trust

Abstract: Objectives To identify and appraise the methodological rigour of multivariable prognostic models predicting in-hospital paediatric mortality in low-income and middle-income countries (LMICs). Design Systematic review of peer-reviewed journals. Data sources MEDLINE, CINAHL, Google Scholar and Web of Science electronic databases since inception to August 2019. Eligibility criteria We included model development studies predicting in-hospital paediatric mortality in LMIC. Data extraction and synthesis This systematic review followed the Checklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies framework. The risk of bias assessment was conducted using Prediction model Risk of Bias Assessment Tool (PROBAST). No quantitative summary was conducted due to substantial heterogeneity that was observed after assessing the studies included. Results Our search strategy identified a total of 4054 unique articles. Among these, 3545 articles were excluded after review of titles and abstracts as they covered non-relevant topics. Full texts of 509 articles were screened for eligibility, of which 15 studies reporting 21 models met the eligibility criteria. Based on the PROBAST tool, risk of bias was assessed in four domains; participant, predictors, outcome and analyses. The domain of statistical analyses was the main area of concern where none of the included models was judged to be of low risk of bias. Conclusion This review identified 21 models predicting in-hospital paediatric mortality in LMIC. However, most reports characterising these models are of poor quality when judged against recent reporting standards due to a high risk of bias. Future studies should adhere to standardised methodological criteria and progress from identifying new risk scores to validating or adapting existing scores. PROSPERO registration number CRD42018088599.


The Drosophila orthologue of the primary ciliary dyskinesia-associated gene, DNAAF3 , is required for axonemal dynein assembly

Petra zur Lage, Zhiyan Xi, Jennifer Lennon, Iain Hunter, Wai Kit Chan, Alfonso Bolado Carrancio, Alex von Kriegsheim, Andrew P. Jarman

Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK EH8 9XD, UK

Biotechnology and Biological Sciences Research Council, Wellcome Trust

Abstract: ABSTRACT Ciliary motility is powered by a suite of highly conserved axoneme-specific dynein motor complexes. In humans, the impairment of these motors through mutation results in the disease primary ciliary dyskinesia (PCD). Studies in Drosophila have helped to validate several PCD genes whose products are required for cytoplasmic pre-assembly of axonemal dynein motors. Here we report the characterisation of the Drosophila orthologue of the less-known assembly factor DNAAF3. This gene, CG17669 (Dnaaf3), is expressed exclusively in developing mechanosensory chordotonal (Ch) neurons and the cells that generate spermatozoa, The only two Drosophila cell types bearing cilia/flagella containing dynein motors. Mutation of Dnaaf3 results in larvae that are deaf and adults that are uncoordinated, indicating defective Ch neuron function. The mutant Ch neuron cilia of the antenna specifically lack dynein arms, while Ca imaging in larvae reveals a complete loss of Ch neuron response to vibration stimulus, confirming that mechanotransduction relies on ciliary dynein motors. Mutant males are infertile with immotile sperm whose flagella lack dynein arms and show axoneme disruption. Analysis of proteomic changes suggest a reduction in heavy chains of all axonemal dynein forms, consistent with an impairment of dynein pre-assembly.


The G119S Acetylcholinesterase (Ace-1) Target Site Mutation Confers Carbamate Resistance in the Major Malaria Vector Anopheles gambiae from Cameroon: A Challenge for the Coming IRS Implementation

Emmanuel Elanga-Ndille, Lynda Nouage, Cyrille Ndo, Achille Binyang, Tatiane Assatse, Daniel Nguiffo-Nguete, Doumani Djonabaye, Helen Irving, Billy Tene-Fossog, Charles S. Wondji

Centre for Research in Infectious Diseases (CRID), P.O. BOX 13591 Yaoundé, Cameroon

Abstract: Growing resistance is reported to carbamate insecticides in malaria vectors in Cameroon. However, the contribution of acetylcholinesterase (Ace-1) to this resistance remains uncharacterised. Here, we established that the G119S mutation is driving resistance to carbamates in Anopheles gambiae populations from Cameroon. Insecticide bioassay on field-collected mosquitoes from Bankeng, a locality in southern Cameroon, showed high resistance to the carbamates bendiocarb (64.8% ± 3.5% mortality) and propoxur (55.71% ± 2.9%) but a full susceptibility to the organophosphate fenitrothion. The TaqMan genotyping of the G119S mutation in field-collected adults revealed the presence of this resistance allele (39%). A significant correlation was observed between the Ace-1R and carbamate resistance at allelic ((bendiocarb; odds ratio (OR) = 75.9; p < 0.0001) and (propoxur; OR = 1514; p < 0.0001)) and genotypic (homozygote resistant vs. homozygote susceptible (bendiocarb; OR = 120.8; p < 0.0001) and (propoxur; OR = 3277; p < 0.0001)) levels. Furthermore, the presence of the mutation was confirmed by sequencing an Ace-1 portion flanking codon 119. The cloning of this fragment revealed a likely duplication of Ace-1 in Cameroon as mosquitoes exhibited at least three distinct haplotypes. Phylogenetic analyses showed that the predominant Ace-1R allele is identical to that from West Africa suggesting a recent introduction of this allele in Central Africa from the West. The spread of this Ace-1R represents a serious challenge to future implementation of indoor residual spraying (IRS)-based interventions using carbamates or organophosphates in Cameroon.


Patterns and drivers of vector-borne microparasites in a classic metapopulation

Laura S. Mackenzie, Xavier Lambin, Emma Bryce, Claire L. Davies, Richard Hassall, Ali A. M. Shati, Chris Sutherland, Sandra E. Telfer

Wellcome Trust, Wellcome Trust, Biotechnology and Biological Sciences Research Council

Abstract: AbstractMany organisms live in fragmented populations, which has profound consequences on the dynamics of associated parasites. Metapopulation theory offers a canonical framework for predicting the effects of fragmentation on spatiotemporal host–parasite dynamics. However, empirical studies of parasites in classical metapopulations remain rare, particularly for vector-borne parasites. Here, we quantify spatiotemporal patterns and possible drivers of infection probability for several ectoparasites (fleas, Ixodes trianguliceps and Ixodes ricinus) and vector-borne microparasites (Babesia microti, Bartonella spp., Hepatozoon spp.) in a classically functioning metapopulation of water vole hosts. Results suggest that the relative importance of vector or host dynamics on microparasite infection probabilities is related to parasite life-histories. Bartonella, a microparasite with a fast life-history, was positively associated with both host and vector abundances at several spatial and temporal scales. In contrast, B. microti, a tick-borne parasite with a slow life-history, was only associated with vector dynamics. Further, we provide evidence that life-history shaped parasite dynamics, including occupancy and colonization rates, in the metapopulation. Lastly, our findings were consistent with the hypothesis that landscape connectivity was determined by distance-based dispersal of the focal hosts. We provide essential empirical evidence that contributes to the development of a comprehensive theory of metapopulation processes of vector-borne parasites.


Assessment of the pharmacodynamic properties of antimalarial drugs

Abstract: Abstract Quantifying therapeutic responses in clinical malaria is easier than for most other infections as the intraerythrocytic parasites can be counted by microscopy or estimated using quantitative PCR. In treating the blood-stage of malaria, between 107 and 1013 parasites undergo a first-order decline in densities at a rate determined by the concentrations and potency of the antimalarial drug. A simple conceptual framework based on total intravascular parasite biomass and standard sigmoid concentration–effect relationships for parasite killing explains most, but not all, aspects of antimalarial therapeutic responses, and it has proved very useful in designing chemoprevention and treatment regimens and in understanding the selection and spread of resistance. Drugs acting on younger circulating ring-stage asexual parasites (artemisinins, cipargamin, ganaplacide) provide rapid parasite clearance, which translates into faster clinical recoveries and a life-saving benefit in severe malaria. Artemisinin-sensitive Plasmodium falciparum densities decline with a half-life (PC1/2) of usually less than 5 h. Many antimalarial drugs are eliminated slowly and provide protracted exposures, which allows full treatment to be administered in 3 days, and also provides chemosuppression of newly acquired infections for 1 month. Greater availability of drug measurement in malaria-endemic areas would facilitate the field assessment of antimalarial drugs. This article is part of the Theo Murphy meeting issue ‘Evaluating anti-infective drugs’.


Nrf2 in Cancer, Detoxifying Enzymes and Cell Death Programs

Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1E 7HX, UK

Abstract: Reactive oxygen species (ROS) play an important role in cell proliferation and differentiation. They are also by-products of aerobic living conditions. Their inherent reactivity poses a threat for all cellular components. Cells have, therefore, evolved complex pathways to sense and maintain the redox balance. Among them, Nrf2 (Nuclear factor erythroid 2-related factor 2) plays a crucial role: it is activated under oxidative conditions and is responsible for the expression of the detoxification machinery and antiapoptotic factors. It is, however, a double edge sword: whilst it prevents tumorigenesis in healthy cells, its constitutive activation in cancer promotes tumour growth and metastasis. In addition, recent data have highlighted the importance of Nrf2 in evading programmed cell death. In this review, we will focus on the activation of the Nrf2 pathway in the cytoplasm, the molecular basis underlying Nrf2 binding to the DNA, and the dysregulation of this pathway in cancer, before discussing how Nrf2 contributes to the prevention of apoptosis and ferroptosis in cancer and how it is likely to be linked to detoxifying enzymes containing selenium.


Combined analysis of host IFN-γ, IL-2 and IP-10 as potential LTBI biomarkers in ESAT-6/CFP-10 stimulated blood

Antony M. Rapulana, Thabo Mpotje, Omolara O. Baiyegunhi, Hlumani Ndlovu, Theresa K. Smit, Timothy D. McHugh, Mohlopheni J. Marakalala

Bill and Melinda Gates Foundation, Wellcome Trust, National Research Foundation, South African Medical Research Council

Abstract: Background: Accurate diagnosis of latent tuberculosis infected (LTBI) individuals is important in identifying individuals at risk of developing active tuberculosis. Current diagnosis of LTBI routinely relies on the detection and measurement of immune responses using the Tuberculin Skin Test (TST) and interferon gamma release assays (IGRAs). However, IGRA, which detects Mycobacterium tuberculosis specific IFN-γ, is associated with frequent indeterminate results, particularly in immunosuppressed patients. There is a need to identify more sensitive LTBI point of care diagnostic biomarkers. The aim of this study was to assess the validity of early secreted antigen target 6 kDa (ESAT-6) and culture filtrate protein 10 (CFP-10) stimulated plasma to identify additional cytokines and chemokines as potential biomarkers of LTBI.Method: The levels of 27 cytokines and chemokines were measured by Bio-Plex Pro cytokine, chemokine and growth factor assay in ESAT-6 and CFP-10 co-stimulated plasma from 20 LTBI participants with positive IGRA (Quantiferon TB Gold plus) and 20 healthy controls with negative IGRA. Traditional ELISA was used to validate the abundance of the best performing markers in 70 LTBI and 72 healthy participants. All participants were HIV negative.Results: We found that Interleukin 1 receptor antagonist (IL1ra) (p = 0.0056), Interleukin 2 (IL-2) (p &lt; 0.0001), Interleukin 13 (IL-13) (p &lt; 0.0001), Interferon gamma-induced protein 10 (IP-10) (p &lt; 0.0001), and Macrophage inflammatory protein-1 beta (MIP1b) (p = 0.0010) were significantly higher in stimulated plasma of LTBI compared to healthy individuals. Stimulated plasma IL-2 (cutoff 100 pg/mL), IP-10 (cutoff 300 pg/mL) and IL-13 (5 pg/mL) showed potential in diagnosing LTBI with PPV = 100%, 0.89.4%, and 80.9% and NPV = 86.9%, 0.85.7%, and 84.2%, respectively.Conclusion: Our data shows that co-stimulating whole blood with ESAT-6 and CFP-10 may help distinguish LTBI from healthy individuals. We also identified IL-2 and IP-10 as potential biomarkers that could be added to the currently used IFN-γ release assays in detection of LTBI.


Neuroendocrine Evaluation in Kleine-Levin Syndrome: Evidence of Reduced Doparrlinergic Tone during Periods of Hypersomnolence


Addition of a Homologous Internal Control to a Real-Time PCR Assay for Detection of Bordetella pertussis

Christoph Koidl, Michael Bozic, Jörg Berg, Markus Stöcher, Gerhard Mühlbauer, Egon Marth, Harald H Kessler

Molecular Diagnostics Laboratory, Institute of Hygiene, Medical University of Graz, Graz, Austria


For the Better: The Reform of the Finnish Competition Act

Journal of European Competition Law & Practice


New Federalism and the cities: a double cross


226Ra, 232Th and 40K radionuclides enhancement rate and dose assessment for residues of lignite-fired thermal power plants in Turkey

A. Parmaksiz, P. Arikan, M. Vural, E. Yeltepe, I. Tukenmez


MANUSCRIPT TEXTS OF POEMS BY THE EARL OF DORSET AND WILLIAM CONGREVE


Notes on the 'Oxford English Dictionary.'


The Origin of Privacy as a Legal Value: A Reflection on Roman and English Law


Round towers at Bhaugulpore


A214 A COMPARISON OF REAL-WORLD UTILIZATION PATTERNS OF INNOVATOR AND BIOSIMILAR INFLIXIMAB: A PRESCRIPTION CLAIMS DATA SUBGROUP ANALYSIS OF GERMAN GASTROENTEROLOGISTS

Journal of the Canadian Association of Gastroenterology

E Ewara, V Jairath, M Marrache, X Baraliakos


STUDIES ON SYPHILIS IN THE EASTERN HEALTH DISTRICT OF BALTIMORE CITY

THOMAS B. TURNER, ROBERT DYAR, E. GURNEY CLARK, MARY FOOTNER BIRKHEAD


Authors of quotations wanted


Review: Frontiers of Dental and Facial Esthetics


P4186Paradoxical effects of cholesterol in first-ever ischemic stroke patients: data from Lund Stroke Register

Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden; Resource Education Center “Center of Medical Accreditation”, St. Petersburg State University, St. Petersburg, Russian Federation


Short Notices


New York before Chinatown: Orientalism and the Shaping of American Culture, 1776-1882. By John Kuo Wei Tchen (Baltimore & London: Johns Hopkins University Press, 1999. xxiv plus 385pp.)


Information processing time adds useful information to traditional recall measures


Thomas Warton


VIOLENCE IN THE STREETS. Edited by Shalom Endleman. Chicago: Quadrangle Books, 1968. 471 pp. $10.00


Dictionary of Quotations (French)


Editorial: Church-State Relations in the Modern World


Place-name Wideopen


Book Reviews

Journal of the American Academy of Religion


St. Cuthbert


American Physical Therapy Association


P. S.


LANGLAND'S ‘BOOK OF CONSCIENCE’ AND ALANUS DE INSULIS


REVIEWS


CROPPER<i>V.</i>SMITH

Reports of Patent, Design and Trade Mark Cases


Notes on the Presence of Tachyglossus and Ornithorhynchus in Northern and North-eastern Queensland.

Journal of the Linnean Society of London, Zoology


Correlation and Machine Calculation

G. W. Forster, H. A. Wallace, George W. Snedecor


Instructions to Authors


Power, Politics, and Crime


COUNTERPOINT: Can CQI Really Work in Health Care? For How Long?

International Journal for Quality in Health Care


Book Reviews


Sir George Monoux


The British oak


ARCHIV F. D. GESAMTE PSYCHOLOGIE


Enhancement of Burkholderia cepacia antimicrobial susceptibility by cationic compounds


Stejneger on a 'Lost Species' of Murrelet On Brachyramphus Perdix (Pall.) and Its Nearest Allies Leonhard Stejneger


Visual compatibility of idarubicin hydrochloride with selected drugs during simulated Y-site injection

American Journal of Health-System Pharmacy

Robert C. Turowski, Jeffrey M. Durthaler

The Ohio State University Hospitals, Columbus, OH


INTERNATIONAL TELESIS GROUP SERVICE MARK


P187. Hearing loss in patients with Inflammatory Bowel Disease


Descartes' Revision of the Cartesian Dualism


Spectroscopic and photometric observations of six possible Seyfert galaxies

Monthly Notices of the Royal Astronomical Society


0587 Sleep Problems are Associated with Treatment for Anemia in the US Population

Sayani Shah, Brooke Mason, Chloe Wills, Andrew Tubbs, William Killgore, Michael Grandner

Abstract: Abstract Introduction Anemia is characterized as low circulating hemoglobin and is often treated with an increase in iron consumption. Previous studies have linked anemia with Restless Legs Syndrome. Regarding other sleep disorders, Insomnia has been found to be associated with anemia in children, but the relationship has been understudied in adults. Methods A multinomial logistic regression was conducted on the data collected from 2017 to March 2020 for the National Health and Nutrition Examination Survey, to explore a relationship between those with self-assessed sleep problems and whether the participant was treated for anemia. Sleep problems were assessed using a item asking participants how often they have been bothered by difficulties “falling asleep, staying asleep, or sleeping too much,” categorized as “Never,” “Several Days,” “More Than Half the Days” and “Nearly Every Day” in the past 2 weeks. Anemia treatment was characterized as “yes” or “no” based on self-report, with any form of treatment in the past 3 months was considered as “yes.” Reported results were unweighted; weighted results forthcoming. Results Unadjusted results indicate that those being treated for anemia show an increased likelihood of sleep difficulties several days (OR:1.36, [1.07,1.73] p=0.011), more than half the days (OR: 1.59, [1.13,2.25] p=0.008), and nearly every day (OR: 1.85, [1.37,2.50] p&lt;0.001), compared to those who report that they never have sleep difficulties. When adjusted for sex, age, race/ethnicity, education, and marital status, those being treated for anemia show significant increased odds of sleep problems several days (OR: 1.29, [1.01,1.65] p=0.041), more than half the days (OR: 1.50, [1.06,2.14] p=0.024), and nearly every day (OR: 1.55, [1.13,2.13] p=0.006), compared to never. Those being treated for anemia also had a higher likelihood of having short sleep (≤ 6 hours) during the week (OR: 1.56, [1.13,2.15], p=0.007) as well as long sleep( ≥ 9 hours) (OR: 1.75, [1.30,2.36], p&lt;0.001) compared to those that slept a healthy amount, 6.5-8.5 hours a night. Conclusion There was a significant relationship between those treated for anemia the presence of sleep difficulties, as well as short and long sleep. Future studies should assess the associations between anemia and specific sleep characteristics, as sleep problems may be a cause, a consequence, or a marker of anemia. Also, the degree to which these sleep difficulties represent overlap with Restless Legs symptoms should be explored at the population level. Support (If Any)


0359 Clinical Performance Quality of a Precision Oral Appliance Made from Novel Medical Grade Class VI Material

Mark Murphy, Len Liptak, Sung Kim, Yoann Ojeda

Abstract: Abstract Introduction Oral appliance therapy device quality is an important factor for successful, efficient treatment of Obstructive Sleep Apnea. Poor device quality, defined in this investigation as the remake rate, is costly. A previous investigation reports that 13% of oral appliance therapy devices required remakes, each costing an estimated $300 in lost productivity, fees for remakes, and three weeks of lost therapy. Other investigations associate poor quality with even higher costs and an increased propensity for the patient to discontinue treatment. Methods In this retrospective study design, quality data for 34,261 consecutively manufactured oral appliance therapy devices made from a novel medical grade class VI material was collected. Quality data was analyzed in total, and with 30-day and 60-day lag periods. The purpose of the lag periods was to account for the time between manufacture and delivery. Results Total remake rates were 1.2% (416/34,261). Total remake rates with a 30-day lag period were 1.3% (416/30,946). Total remakes with a 60-day lag period were 1.5% (416/26,964). Conclusion The clinical performance quality for a new precision oral appliance made from a novel medical grade class VI material is encouraging. Remake rates were between 1.2% and 1.5% depending on the lag period, which is directionally favorable in comparison with previously reported remake data. Support (If Any) Data provided by ProSomnus Sleep Technologies.


0634 Symptoms of insomnia and depression among individuals with Multiple Sclerosis before and during the COVID-19 – results from a prospective longitudinal study

Dena Sadeghi-Bahmani, Youkhabeh Mohammadian, Nahid Piri, Laleh Sadeghi Bahmani, Serge Brand, Andrea Goldstein-Piekarski, Habibollah Khazaie, James Gross

Department of Psychology, Stanford University

Abstract: Abstract Introduction There is some -- but inconsistent -- evidence that sleep and psychological health have deteriorated in the general population as a result of the COVID-19-pandemic and its related social restrictions. In the present study, we investigated whether and to what extent symptoms of insomnia, depression, fatigue, and paresthesia changed from before to during the COVID-19-pandemic among women diagnosed with multiple sclerosis (MS). Methods A total of 90 women with MS (mean age; 37.62 (SD = 8.61) years; EDSS score: median: 2.5 (range: 0-6.50)) completed a series of self-rating scales at two time-points: Nine months before the COVID-19-outbreak in May 2019 (baseline) and during the COVID-19-pandemic (study end; 12 months after baseline: May 2020). Self-rating questionnaires covered sociodemographic and disease-related information, symptoms of insomnia, depression, fatigue, and paresthesia. Results Symptoms of depression increased over time (medium effect size: Cohen’s d = 0.53), while symptoms of insomnia (small effect size: Cohen’s d = 0.43), fatigue (trivial effect size: Cohen’s d = 0.19), and paresthesia (trivial effect size: Cohen’s d = 0.08) did not. The only predictor for insomnia during the COVID-19-pandemic was insomnia before the COVID-19-pandemic (β = 0.36; p = 0.001); the only predictor for depression during the COVID-19-pandemic was insomnia before the COVID-19-pandemic (β = 0.66; p = 0.001). Conclusion Overall, among a sample of female individuals with MS the COVID-19-pandemic and its related social restrictions may have had a modest influence on participants’ core concerns of insomnia, depression, fatigue, and paresthesia. Support (If Any)


0563 Association between actigraphic sleep measures and lymphocyte subsets in people with chronic HIV infection

Malvika Sharma, Priya Borker, Bernard Macatangay, Naresh Punjabi, Charles Rinaldo, Steven Wolinsky, Joshua Hyong-Jin Cho, Heather McKay, Sanjay Patel

Abstract: Abstract Introduction While inadequate sleep is known to increase inflammation in immunocompetent individuals, it is unknown if poor sleep worsens inflammation in people living with HIV. The ratio of CD4+/CD8+ T cells is a readily derived measure of chronic inflammation in people living with HIV. We sought to investigate the association between lymphocyte subsets and actigraphy-derived sleep measures in a cohort of HIV seropositive men. Methods HIV seropositive men on antiretroviral therapy for &gt; 1 year and with undetectable (&lt; 20 copies/mL) plasma HIV-1 RNA participating in the Multicenter AIDS Cohort Study underwent a sleep evaluation with 1 week of wrist actigraphy. Data from 287 participants with ≥ 5 days of actigraphy were analyzed. We evaluated three dimensions of sleep: mean nocturnal sleep duration, sleep onset latency, and sleep maintenance efficiency. Linear regression was used to assess the association between each sleep dimension with CD4+ and CD8+ T-cell counts. Because of a U-shaped association, nocturnal sleep duration was also modelled dichotomously as a normal (6-8 hrs) vs. abnormal duration (&lt;6 or &gt;8 hrs). Results Participants had a mean (±SD) age of 55 ± 12 years, mean CD4+ count of 723 ± 293 cells/ml, and 7.0 ± 1.7 days of actigraphy data. None of the sleep measures were associated with CD4+ counts. However, participants with abnormal sleep duration had 129 ± 31 cells/mL higher CD8+ counts compared to those with normal sleep duration (p=0.01). There were also nonsignificant trends whereby every 30-minute increase in sleep latency was associated with a 138 cells/ml increase in CD8+ count (p=0.07) while every 10% reduction in sleep efficiency was associated with a 56 cells/ml increase in CD8+ count (p=0.12). These findings were unchanged after adjusting for age and body mass index. Conclusion Among men with treated HIV infection, abnormal sleep duration (both short and long) is associated with increased circulating CD8+ T cell count, suggesting increased chronic inflammation. Support (If Any) NIH AI0355041, HL082610 and American Thoracic Society ASPIRE Fellowship


Biotechnology Notables


Biotechnology Shorts


Biotechnology Journal


Industrial Biotechnology

Abstract: AbstractCover illustrationIndustrial biotechnology. Renewable biomass can be used as a raw material for the production of various chemicals, fuels and materials in a cost‐effective manner by employing metabolically engineered high performance microorganisms. This cover art shows production of biobutanol from renewable biomass by employing engineered clostridia (see the article by Jang et al. http://dx.doi.org/10.1002/biot.201100059). The cover picture was created by Prof. Sang Yup Lee and Dr. Yu Sin Jang at KAIST, Korea.


Contents: Biotechnology Journal 5/2014


Editorial: Biotechnology Journal's diverse coverage of biotechnology


International Biotechnology

Abstract: AbstractCover illustrationSpecial Issue: International Biotechnology. Efforts to develop biotechnological strategies for various applications have reached a global scale as indicated by the diverse international representation at the IBS2012 organized by the Asian Federation of Biotechnology (AFOB). For this special issue's cover, one such useful technique – the rapid gene knockout method – is schematically shown: a series of outer grey arrows represent the multiple steps required for conventional gene knockout experiments, while the inner green arrow represents the rapid gene knockout method; the steam‐engine and the bullet train are used to further illustrate the difference. Image provided by Sang Yup Lee and Chan Woo Song (KAIST, Korea).


Plant Biotechnology

Abstract: AbstractCover illustrationThis Special Issue of Biotechnology Journal is edited by Prof. Eva Stöger and covers the latest breakthroughs in plant biotechnology. The cover image shows genetically modified corn producing an anti‐HIV antibody along with DsRed as a visual marker. Image courtesy of Dr. Thomas Rademacher (RWTH and Fraunhofer IME, Aachen, Germany). Border around image: © boulemon – Fotolia.com.


Abstract: AbstractCover illustration: This issue is the first official special issue of Biotechnology Journal with the Asian Federation of Biotechnology (AFOB). In the cover, we use the grain as a symbol and analogy for biotechnology, as both the grain and biotechnology are common and uniting factors that link the member countries of the AFOB. Gran image credit: © Myimagine– Fotolia.com.


Biotechnology in Asia

Abstract: AbstractCover illustration:The Asian Federation of Biotechnology (AFOB, http://www.afob.org) was established to promote cooperation between all those interested in biotechnology in Asia and stimulate innovation and technology transfer with the goal of advancing biotechnology in Asia and the rest of the world. BTJ continues its cooperation with AFOB and Asian Congress on Biotechnology (ACB‐2011), with a special issue of articles from selected invited speakers at the congress, edited by Jian‐Jiang Zhong (Chair ACB‐2011 Organizing Committee; SJTU, China), and Sang Yup Lee (BTJ's Editor‐in‐Chief; KAIST, Korea). Read the Editorial: http://dx.doi.org/10.1002/201100445


Editorial Board: Biotechnology Journal 9/2018


Editorial Board: Biotechnology Journal 12/2009


Editorial Board: Biotechnology Journal 10/2023


Editorial Board: Biotechnology Journal 9/2020


Biotechnology Journal 3/2008

Abstract: AbstractCover illustration: Spectral karyotype of chromosomes. The BTJ special issue on Methods and Advances in Biotech is not only covering DNA‐based methods but also exciting highlights in the fields of imaging, bioluminescent screening methods, plant transformation assays, stem cell differentiation on chips and much more. Image copyright USA Federal Government. http://www.genome.gov, http://doi.wiley.com/biot.200800042


Cover Picture: Biotechnology Journal 03/2015

Abstract: AbstractSpecial issue: Protein Stabilization. This Special issue edited by Marina Lotti and Francesco Secundo includes contributions on protein stability concerning protein production and purification, screening for more stable proteins and the impact of protein aggregation. The articles were presented at the 10th International Conference on Protein Stabilisation (7–9 May 2014) in Stresa (Lake Maggiore, Italy). The cover illustrates the difficult balance between stability and other properties of the proteins. Image: © styf Fotolia.com


Editorial Board: Biotechnology Journal 8/2017


Editorial Board: Biotechnology Journal 6/2019


Editorial Board: Biotechnology Journal 9/2022


Cover Picture: Biotechnology Journal 4/2019


Editorial Board: Biotechnology Journal 4/2017


Issue Information: Biotechnology Journal 6/2026


Biotechnology Journal 2014 Cover Gallery


Biotechnology Journal 2013 Cover Gallery


Issue Information: Biotechnology Journal 10/2025


Cover Picture: Biotechnology Journal 3/2014

Abstract: AbstractThis “regular” issue of Biotechnology Journal gathers the state‐of‐the‐art in biotechnology, including articles on CHO cells, plant biotechnology and tissue engineering. The cover image shows immunohistochemical staining of tissue sections using antibodies recognizing different target proteins (www.proteinatlas.org) and is provided by Sophia Hober et al., authors of “Antibody performance in western blot applications is context‐dependent” (http://dx.doi.org/10.1002/biot.201300341)


Editorial Board: Biotechnology Journal 5/2022


Editorial Board: Biotechnology Journal 12/2020


Editorial Board: Biotechnology Journal 5/2020


Issue Information: Biotechnology Journal 9/2024


Cover Picture: Biotechnology Journal 7/2015

Abstract: AbstractSpecial issue: Mammalian Production Systems. This special issue is edited by Nicole Borth and Lars Nielsen. It focuses on the use of CHO cells and their improvement to produce recombinant proteins. The articles cover the application of CRISPR technology, systems biology and modeling approaches as well as bioinformatics methods. The cover visualizes the highly interconnected metabolic pathway map of CHO cells based on a genome‐scale metabolic reconstruction (blue: reactions, red: molecular species). Image by Michael Hanscho.


Editorial Board: Biotechnology Journal 4/2014


Cover Picture: Biotechnology Journal 11/2015

Abstract: AbstractThis regular issue of BTJ features articles on the production of biofuels, small molecules and recombinant proteins. The cover is inspired by an article describing increased expression levels of recombinant proteins in potato tubers upon post‐harvest light treatment. © Lenslife – Fotolia.com


Cover Picture: Biotechnology Journal 11/2017


Editorial Board: Biotechnology Journal 9/2012


Cover Picture: Biotechnology Journal 2/2016

Abstract: AbstractFocus: Synthetic biology. This Focus issue is edited by George Chen and Michael Jewett features articles from the Cold Spring Harbor Asia Synthetic Biology Meeting in Suzhou, China. It includes articles on cell‐free protein synthesis, genome mining, and a method for a rapid production of protein biologics. The cover shows the development of a high‐yielding bacterial cell‐free protein synthesis for the production of active proteins containing copper cofactors. It specifically demonstrates a simple method for producing multicoppper oxidases (MCOs). By decoupling catalyst synthesis from catalyst utilization, advantages are gained for synthesizing hard to express proteins. Image by Jessica Stark, Tom Lawton, and Michael Jewett.


Intentionalism

Encyclopedia of the Philosophy of Law and Social Philosophy


Group Representations

Crystallographic Texture and Group Representations


Italian Legal Institutionalism


Applications of the Bergelson–Leibman and the Mordell–Faltings Theorems


Microfluidic Approach for Modeling Coupled Circadian Clock


Stigma and Discrimination in Relation to People with Mental Health Conditions and Psychiatric Institutions

Maria Milenova, Sarah Parry, Nisha Mehta, Graham Thornicroft


Burlamaqui, Jean-Jacques


Culturing of Airway Stem Cells Obtained from COPD Patients to Assess the Effects of Rhinovirus Infection

Mohsen Tabasi, Tyler Markward, Umadevi Sajjan


Conclusion and Recommendation for Future Research

New Frontiers in Regional Science: Asian Perspectives


Proteomic Identification and Label-Free Quantification of Proteins Implicated in Neurite and Spine Formation

Kanika Sharma, Prashant Kaushal, Vikas Kumar


Just War in the Catholic Tradition


Harvesting of Postbiotics and Its Assessment

T. Pushpa, G. Sentilkumar, Varatharaju Ambikapathy, Annamalai Panneerselvam


Unbiased Quantitative Proteomics of Organoid Models of Pancreatic Cancer

Ronnie Ren Jie Low, Ka Yee Fung, Laura F. Dagley, Jumana Yousef, Samantha J. Emery-Corbin, Tracy L. Putoczki


Generation of Human Induced Pluripotent Stem Cells Using Episomal Vectors


Whose Conjecture Did Van der Waerden Prove? Two Lives Between Two Wars: Issai Schur and Pierre Joseph Henry Baudet


Calvin, John (Jehan)


The Hippocratic Tradition and the Development of Medical Knowledge and Practice


Using High-Throughput Measurements to Identify Principles of Transcriptional and Epigenetic Regulators


Methods for Characterizing Flavobacterium in Fish

Yamini Gopi, Sakthinarenderan Sai, Mirunalini Ganesan, Ravi Mani


Unrevealing the Role of TLRs in the Pathogenesis of Autoimmune Disease by Using Mouse Model of Diabetes

Eleonora Panfili, Elena Orecchini, Giada Mondanelli


Peace


Spencer, Herbert


Phagekines: Directed Evolution and Characterization of Functional Cytokines Displayed on Phages

Gertrudis Rojas, Tania Carmenate, Gisela García-Pérez, Dayana Pérez-Martínez


Clustering from Data Streams

Encyclopedia of Machine Learning and Data Science


Quantification of Sympathetic Nerve Traffic to the Heart: Electrophysiological Recording of Cardiac Sympathetic Nerve Activity in a Rodent Model


Precise Mapping of Physiological DSBs Using In-Suspension Break Labeling In Situ and Sequencing (sBLISS)

Osama Hidmi, Sara Oster, Diala Shatleh, Jonathan Monin, Rami I. Aqeilan


Social Motility Assays of Flavobacterium johnsoniae


Mirandola, Pico della


Walzer, Michael: Political Theory


Natural Law: Protestant


Critical Quality Attributes of Biomass that Affect Downstream Conversion

Handbook of Biorefinery Research and Technology: Biomass Logistics to Saccharification

Onyinye Okonkwo, Chang Dou, James Gardner


Access Control for XML Big Data Applications

Encyclopedia of Complexity and Systems Science Series

Alberto De la Rosa Algarin, Steven A. Demurjian, Eric Jackson


Legal Science


Herbig, George Howard

Biographical Encyclopedia of Astronomers


Ethics of Law

Ruwen Fritsche, Philipp Gisbertz-Astolfi


Analyzing the Interaction of Arginylated Proteins and Nt-Arg-Mimicking Chemical Compounds to N-Recognins

Chang Hoon Ji, Min Ju Lee, Su Bin Kim, Yong Tae Kwon


Assays and Utilization of Enzymes Involved in Glycolipid Metabolism in Bacteria and Fungi

Makoto Ito, Yohei Ishibashi, Takashi Watanabe, Jun Iwaki, Toyohisa Kurita, Nozomu Okino


In Vitro Methods for the Investigation of sRNA-mRNA Interactions in Bacillus subtilis

Inam Ul Haq, Peter Müller, Sabine Brantl


TUNEL-n-DIFL Method for Detection and Estimation of Apoptosis Specifically in Neurons and Glial Cells in Mixed Culture and Animal Models of Central Nervous System Diseases and Injuries


A Deep Learning and PSSM Profile Approach for Accurate SNARE Protein Prediction

Quang Hien Kha, Huu Phuc Lam Nguyen, Nguyen Quoc Khanh Le


Liquid Chromatography-Tandem Mass Spectrometry Method for the Quantification of Plasma Busulfan

Uttam Garg, Ada Munar, C. Clinton Frazee


Korsgaard, Christine


Liver Carcinogenesis


Patient-Derived Glioblastoma Explants Empower Rapid and Personalized Drug Assessment: Harnessing the Potential of 3D Perfusion Bioreactors in Glioblastoma Drug Discovery

Nazanin Tatari, Manuele G. Muraro, Hayget Mohamed Seid Hedad, Gregor Hutter


Tagging and Manipulation of Fear Engrams

Marie-Theres Wittmann, Asim J. Rashid, Sheena A. Josselyn, Paul W. Frankland


GeF-seq: A Simple Procedure for Base-Pair Resolution ChIP-seq

Onuma Chumsakul, Kensuke Nakamura, Kazuki Fukamachi, Shu Ishikawa, Taku Oshima


Leveraging DNA Origami to Study Phagocytosis

Wyatt D. Miller, Nadja Kern, Shawn M. Douglas, Meghan A. Morrissey


Measurements of Phagocytosis in Trabecular Meshwork Cells

Jennifer A. Faralli, Mark S. Filla, Caleigh Dunn, Donna M. Peters


Chromogenic Factor VIII Assay for Patients with Hemophilia A and on Emicizumab Therapy


Rights: Claim Rights


Welcome to Artificial Intelligence Science and Engineering

Institute of Electrical and Electronics Engineers (IEEE)


Artificial Intelligence and Human Society (Artificial Intelligence and Education)

Abstract: The impact of AI technologies on different sectors has been profound, and one area where significant changes have occurred is education. In this abstract the integration of artificial intelligence technologies in education is explored, highlighting their potential advantages, challenges and ethical considerations. There are a wide range of tools and techniques in use for the application of AI to education, e.g. Intelligent Coaching Systems, Personalized Learning Platforms, Automated Scoreboards or Virtual Classrooms.


Contents


Front Cover


IEEE Transactions on Artificial Intelligence


IEEE Transactions on Artificial Intelligence Publication Information


2025 Index IEEE Transactions on Artificial Intelligence


Exploring Scientific Principles and Laws of Artificial Intelligence, World Model, and Artificial General Intelligence (AGI) in Future Intelligence Networking: Paradigms, Architectures, and Innovations

School of Information Technology, Carleton University

Abstract: Intelligence Networking (IN) is an emerging paradigm that seeks to embed intelligence into every layer of the network, enabling intelligent decision-making and service delivery to be as seamless and efficient as accessing conventional information. This survey offers a comprehensive overview of IN, focusing on its evolution, foundational technologies, architectural frameworks, core applications, and theoretical underpinnings of intelligence. It aims to serve as a valuable reference for researchers exploring the principles, structures, and mathematical modeling of IN. We begin by tracing the evolution of networking paradigms to highlight the growing interdependence between networking and intelligence, establishing the basic logic for IN's emergence. We then introduce a layered IN architecture and examine enabling technologies and applications across each layer. In addition, we explore the definition of intelligence within the context of networking, discuss relevant world models, analyze first principles derived from this definition, and explore the intrinsic connections between network intelligence and Artificial General Intelligence (AGI). The survey concludes with a discussion of future research directions and potential technological breakthroughs needed to realize the full promise of IN.


IEEE Transactions on Artificial Intelligence [Front cover]


Editorial: From Explainable Artificial Intelligence (xAI) to Understandable Artificial Intelligence (uAI)

Hussein Abbass, Keeley Crockett, Jonathan Garibaldi, Alexander Gegov, Uzay Kaymak, Joao Miguel C. Sousa

School of Systems and Computing, University of New South Wales, Canberra, ACT, Australia


Editorial: Artificial Intelligence: A New Transactions

University of New South Wales, Canberra, ACT, Australia


Abstract: Intelligence Networking (IN) is an emerging paradigm that seeks to embed intelligence into every layer of the network, enabling intelligent decision-making and service delivery to be as seamless and efficient as accessing conventional information. This survey offers a comprehensive overview of IN, focusing on its evolution, foundational technologies, architectural frameworks, core applications, and theoretical underpinnings of intelligence. It aims to serve as a valuable reference for researchers exploring the principles, structures, and mathematical modeling of IN. We begin by tracing the evolution of networking paradigms to highlight the growing interdependence between networking and intelligence, establishing the basic logic for IN’s emergence. We then introduce a layered IN architecture and analyze enabling technologies and applications across each layer. In addition, we explore the definition of intelligence within the context of networking, discuss relevant world models, analyze first principles derived from this definition, and explore the intrinsic connections between network intelligence and Artificial General Intelligence (AGI). The survey concludes with a discussion of future research directions.


"Teaching Sociology" on Teaching Sociology


The Sociology of Sociology

International Journal of Comparative Sociology


Sociology versus Religion?: The Case of the 1973 Introductory Sociology Texts


Enduring Issues in Sociology: Opposing Viewpoints for Teaching Sociology


John Holmwood: Sociology of Structure, Sociology as Structure


The Phenomenon of Sociology: A Reader in the Sociology of Sociology


Social Epistemology: A Philosophy for Sociology or a Sociology of Philosophy?

Department of Sociology University of Warwick


Ambivalent Sociology


Sociology.


The Sociology of Sociology


Sociology after Postmodernism


Errata: Introductory Sociology: A Behavioral Objectives Approach


Rural Sociology


Teaching Applied Sociology: Development of a Graduate-Level Seminar in Clinical Medical Sociology


`Make Way for Professional Sociology!'

European University at St Petersburg and Centre for Independent Social Research, St Petersburg

Abstract: This article presents the context of the current debate on the status of sociology in Russia, maps the controversy between professional and public sociology and locates the public sociology agenda in the context of a fight for professional sociology using the case of sociological education. To test the thesis of sociological internationalism, it is necessary to take into account local contexts, especially three aspects: the political opportunities for the public sociology manifesto; the situation with respect to civil society (as `a natural location of sociology'); and the level of institutionalization of sociology. All three contexts frame the cultural translation of the public sociology manifesto to the Russian sociological scene.


Introductory Sociology through Literature


The Sociology of Power.


Towards Postsecular Sociology?

Abstract: This article identifies four articulations of the growing `postsecular' condition of social and political thought, and places the idea of sociology in relation to them. I identify and critically engage with those aspects of poststructuralist vitalism, transcendental realism, multiculturalist thinking, and the recent `dialogical' sentiments of Habermas that might undermine sociology's definitive (but broadly conceived) secularism/naturalism. This implies that if we are concerned about advancing the role of `public sociology' then we should be actively engaged in countering anti-secular and anti-naturalistic elements of the postsecular climate.Yet we must avoid anthropomorphizing sociology as a public player, and accept too that the postsecular reconsideration of `faith versus reason' stretches beyond the confines of epistemological and explanatory considerations per se.


Elements of Sociology


Philosophy and Sociology.


Sociology and Utopia

Abstract: The theme of this paper is that the content, form, location and social role of utopia vary with the material conditions in which people live. These variations have been obscured by definitions of utopia in terms of its function in catalysing social change, which has also produced the illusion that the contemporary Western world lacks utopias. By defining utopia with reference to its meaning to author and audience as an expression of their desires and aspirations, it is possible to trace a series of shifts in the English utopia, to relate these to one another and to the social context, and to show that the `absence' of contemporary utopias is simply another transformation of this kind. From being a spatially-located wish-fantasy, utopia moved through the function of social criticism to being a temporally-located catalyst of social change. These changes depended on perceptions of society-in-time as increasingly malleable and open to human control, culminating in the nineteenth century belief in progress. Utopia now appears to have reverted to the role of wish-fantasy as a result of a prevalent fatalism and a shift away from an evolutionary perspective, a change which, paradoxically, allows it to be more utopian by tying it less closely to reality. Utopia as a catalyst of social change depends on an optimism which is now absent.


Solution-Centered Sociology: Addressing Problems through Applied Sociology

Jay Weinstein, Stephen F. Steele, AnneMarie Scarisbrick-Hauser, William J. Hauser


Canadian Sociology


Sociology


Sociology and Survival 101


Introductory Sociology

Roger Steinhauer, Edward Lehman, Dorothy Mariner


Sociology in Israel.


Soviet Sociology, Past and Present


Book Review: Political Sociology


Teaching the Sociology of Japan


Trying Sociology.


Industrial Sociology.


The Sociology of Science


Studies in Sociology


Urban Sociology in France

Abstract: Prior to the period 1940-54, to which this bibliography is restricted, various types of surveys of some sociological interest had, for a hundred years or so, been carried out in a number of French towns. But despite the large number of individual studies inspired by France's increasing urbanization, no real urban sociology had been built up. This is now gradually coming into existence through an accumulation of recent or current studies, some directed towards theoretical research, others guided by more immediate practical considerations (such as the problems of town-planning). In actual fact, urban sociology seems unlikely to develop, in France, into a specialized branch of sociology. The position is, rather, that town-dwellers offer a common field of investigation to experts in many different subjects. These experts progress thanks to mutual support and—what chiefly interests us—in proportion to the extent that adopt a sociological viewpoint.


The Sociology of Futurelessness

Abstract: This article contributes to ‘sociologies of the future’ by discussing the concept of ‘futurelessness’. I provide a conceptual elaboration of what is meant by ‘futurelessness’, beginning with its use in the psychological literature of the 1980s concerned with the effect of a constant threat of nuclear war. I argue that this concept is of value to ongoing sociological debates about the relationship between imagined futures, power and social change. I further discuss the extent to which ‘futurelessness’ is a particular mode of relating to and feeling about the future that is characteristic of contemporary European societies. I discuss how this ‘futurelessness’ must be understood in relation to political and cultural developments of the past 50 years and consider its significance for sociological debates about contemporary futurity.


Using Student Journals in Sociology Courses


Sociology Laboratory: Computer Simulations for Learning Sociology


Key Ideas in Sociology


The sociology of law

Abstract: Intensified efforts to determine the subject matter and research aims of the sociology of law have clarified ideas in the last 12 years. These ideas were, at the beginning, rather diffuse and abstract, as can be seen in Friedmann's report. Admittedly, there is much room for subjective opinions even now for in actuality every important author still creates his own sociology of the law. Yet, by and large, some consensus seems to have been established on certain points. Therefore, at the beginning of our report, a brief résumé of current opinions must be given. This cannot be done without subjectivity, but on the other hand it is necessary to avoid an endless discussion of the different conceptions of what sociology of law can be.


Medical Sociology.


The Sociology of Law.


Images of Sociology and Sociologists in Fiction


Using Art and Architectural Slides in Sociology


International Perspectives in Rural Sociology


The Scope of Sociology


The Sociology of Dissent.


Intellectuals, Not Professionals: Sociology in France


Looking at Sociology


Teaching Medical Sociology.

Rodney M. Coe, Yvo Nuyens., Janin Vansteenkiste


Volumes in Series


Preface

Advances in Biomembranes and Lipid Self-Assembly

Aleš Iglič, Michael Rappolt, Ana J. García-Sáez


Multilevel Dynamical Models for Polydisperse Systems: a Volume Averaging Approach


Flipping the Capstone Process Design Course


Contents

Progress in Nucleic Acid Research and Molecular Biology


Energy Efficient Hybrid Gas Separation with Ionic Liquids

Xinyan Liu, Xiaodong Liang, Rafiqul Gani, Xiangping Zhang, Suojiang Zhang


Preface


Front Matter


Acknowledgements


Contents of Volumes in This Series


The DNA Code


Series Editors

Handbook of Natural Resource and Energy Economics


The Epistemological Problem of Natural Science


Keyword Index