bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel role for ESCRT-III component CHMP4C in the integrity of the endocytic network utilized for herpes simplex virus envelopment
Authors: Russell Tiffany , Samolej Jerzy , Hollinshead Michael , Smith Geoffrey L. , Kite Joanne , Elliott Gillian 
Published: August 2020

SummaryEnveloped viruses exploit cellular trafficking pathways for their morphogenesis, providing potential scope for the development of new antiviral therapies. We have previously shown that herpes simplex virus 1 (HSV1) utilises recycling endocytic membranes as the source of its envelope, in a process involving four Rab GTPases. To identify novel factors involved in HSV1 envelopment, we have screened an siRNA library targeting over eighty human trafficking proteins including coat proteins, adaptor proteins, fusion factors, fission factors and Rab effectors. Depletion of eleven factors reduced virus yield by 20- to 100-fold, including three early secretory pathway proteins; four late secretory pathway proteins; and four endocytic pathway proteins, three of which are membrane fission factors. Five of the eleven targets were chosen for further analysis in virus infection where it was found that the absence of only one, the fission factor CHMP4C, known for its role in the cytokinesis checkpoint, specifically reduced virus production at the final stage of morphogenesis. Ultrastructural and confocal microscopy of CHMP4C-depleted, HSV1-infected cells, showed an accumulation of endocytic membranes; extensive tubulation of recycling, transferrin receptor-positive endosomes indicative of aberrant fission; and a failure in virus envelopment. No effect on the late endocytic pathway was detected, while exogenous CHMP4C was shown to localise to recycling endosomes. Taken together, these data reveal a novel role for the CHMP4C fission factor in the integrity of the recycling endosomal network, which has been unveiled through the dependence of HSV1 on these membranes for the acquisition of their envelopes.ImportanceCellular transport pathways play a fundamental role in secretion and membrane biogenesis. Enveloped viruses exploit these pathways to direct their membrane proteins to sites of envelopment, and as such, are powerful tools for unravelling subtle activities of trafficking factors, potentially pinpointing therapeutic targets. Using the sensitive biological readout of virus production, over eighty trafficking factors involved in diverse and poorly defined cellular processes have been screened for involvement in the complex process of HSV1 envelopment. Out of eleven potential targets, CHMP4C – a key component in the cell-cycle abscission checkpoint – stood out as being required for the physical process of virus wrapping in endocytic tubules, where it was shown to localise. In the absence of CHMP4C, recycling endocytic membranes failed to undergo scission, causing transient tubulation and accumulation of membranes and unwrapped virus. These data reveal a new role for this important cellular factor in the biogenesis of recycling endocytic membranes.
Object manifold geometry across the mouse cortical visual hierarchy
Authors: Froudarakis Emmanouil , Cohen Uri , Diamantaki Maria , Walker Edgar Y. , Reimer Jacob , Berens Philipp , Sompolinsky Haim , Tolias Andreas S. 
Published: August 2020

AbstractDespite variations in appearance we robustly recognize objects. Neuronal populations responding to objects presented under varying conditions form object manifolds and hierarchically organized visual areas untangle pixel intensities into linearly decodable object representations. However, the associated changes in the geometry of object manifolds along the cortex remain unknown. Using home cage training we showed that mice are capable of invariant object recognition. We simultaneously recorded the responses of thousands of neurons to measure the information about object identity across the visual cortex and found that lateral areas LM, LI and AL carry more linearly decodable object information compared to other visual areas. We applied the theory of linear separability of manifolds, and found that the increase in classification capacity is associated with a decrease in the dimension and radius of the object manifold, identifying the key features in the geometry of the population neural code that enable invariant object coding.
Dissecting serotype-specific contributions to live oral cholera vaccine efficacy
Authors: Sit Brandon , Fakoya Bolutife , Zhang Ting , Billings Gabriel , Waldor Matthew K. 
Published: August 2020

AbstractThe O1 serogroup ofVibrio choleraecauses pandemic cholera and is divided into Ogawa and Inaba serotypes. The O-antigen isV. cholerae’simmunodominant antigen, and the two serotypes, which differ by the presence or absence of a terminally methylated O-antigen, likely influence development of immunity to cholera and oral cholera vaccines (OCVs). However, there is no consensus regarding the relative immunological potency of each serotype, in part because previous studies relied on genetically heterogenous strains. Here, we engineered matched serotype variants of a live OCV candidate, HaitiV, and used a germ-free mouse model to evaluate the immunogenicity and protective efficacy of each vaccine serotype. By combining vibriocidal antibody quantification with single and mixed strain infection assays, we found that all three HaitiV variants - InabaV, OgawaV, and HikoV(bivalent Inaba/Ogawa) - were immunogenic and protective, suggesting the impact of O1 serotype variation on OCV function may be minimal. The potency of OCVs was found to be challenge strain-dependent, emphasizing the importance of appropriate strain selection for cholera challenge studies. Our findings and experimental approaches will be valuable for guiding the development of live OCVs and oral vaccines for additional pathogens.
Inhibitory control of frontal metastability sets the temporal signature of cognition
Authors: Fontanier Vincent , Sarazin Matthieu , Stoll Frederic M. , Delord Bruno , Procyk Emmanuel 
Published: August 2020

AbstractCortical neural dynamics organizes over multiple anatomical and temporal scales. The mechanistic origin of the temporal organization and its contribution to cognition remain unknown. Here we demonstrate the cause of this organization by studying a specific temporal signature (autocorrelogram time constant and latency) of neural activity. In monkey frontal areas, recorded during flexible cognitive decisions, temporal signatures display highly specific area-dependent ranges, as well as anatomical and cell-type distributions. Moreover, temporal signatures are functionally adapted to behaviorally relevant timescales. Fine-grained biophysical network models, constrained to account for temporal signatures, reveal that after-hyperpolarization potassium and inhibitory GABA-B conductances critically determine areas’ specificity. They mechanistically account for temporal signatures by organizing activity into metastable states, with inhibition controlling state stability and transitions. As predicted by models, state durations non-linearly scale with temporal signatures in monkey, matching behavioral timescales. Thus, local inhibitory-controlled metastability constitutes the dynamical core specifying the temporal organization of cognitive functions in frontal areas.
Frontal theta and posterior alpha oscillations reflect the reactivation of working memory representations following interruptions
Authors: Zickerick Bianca , Rösner Marlene , Sabo Melinda , Schneider Daniel 
Published: August 2020

AbstractInterruptions (secondary tasks) have been frequently investigated in behavioral studies leading to a deterioration of working memory performance. Yet, the underlying attentional control processes are not sufficiently understood. A lateralized working memory task was frequently interrupted by either a high- or low-demanding arithmetic task and a subsequent retroactive cue indicated the working memory item required for later report. We examined the role of frontal theta (4-7 Hz) and posterior alpha power (8-14 Hz) as correlates for retroactive attentional switches between working memory representations. In particular, highly demanding interruptions decreased primary task performance compared to a control condition without interruption. This was also reflected in decreased frontal theta power and higher posterior alpha power after retro-cue presentation, suggesting decreased attentional control resources. Moreover, reduced alpha lateralization indicated an impaired refocusing on primary task information following the interruption. These results highlight oscillatory mechanisms required for successfully handling the detrimental effects of interruptions.
Proteomics characterisation of the L929 cell supernatant and its role in BMDM differentiation
Authors: Heap Rachel E. , Marín-Rubio José Luis , Peltier Julien , Heunis Tiaan , Dannoura Abeer , Moore Adam , Trost Matthias 
Published: August 2020

AbstractBone marrow-derived macrophages (BMDMs) are a key model system to study macrophage biologyin vitro. Commonly used methods to differentiate macrophages from bone marrow are treatment with either recombinant M-CSF or the supernatant of L929 cells, which secrete M-CSF. However, little is known about the composition of L929 cell conditioned media (LCCM) and how it affects BMDM phenotype. Here, we used quantitative mass spectrometry to characterise the kinetics of protein secretion from L929 cells over a two-week period, identifying 2,193 proteins. While M-CSF is very abundant in LCCM, we identified several other immune-regulatory proteins such as macrophage migration inhibitory factor (MIF), osteopontin and chemokines such as Ccl2 and Ccl7 at surprisingly high abundance levels. We therefore further characterised the proteomes of BMDMs after differentiation with M-CSF, M-CSF + MIF or LCCM, respectively. Interestingly, macrophages differentiated with LCCM induced a stronger anti-inflammatory M1 phenotype that those differentiated with M-CSF. This resource will be valuable to all researchers using LCCM for the differentiation of BMDMs.
Temporal Metabolic Characteristics and Transcriptomic Landscape of Islets and Liver Reveal Dynamic Pathophysiology and Interorgan Crosstalk in High-fat Diet-induced Diabetes
Authors: Gao Rui , Fu Qi , Jiang He-Min , Shen Min , Zhao Rui-Ling , Qian Yu , He Yun-Qiang , Xu Kuan-Feng , Xu Xin-Yu , Chen Heng , Zhang Quan , Yang Tao 
Published: August 2020

AbstractObjectiveHyperinsulinemia and insulin resistance are co-existing characteristics of type 2 diabetes, whereas the molecular mechanism underlying this deleterious cycle remains elusive. The temporal transcriptomic landscape of core organs responsible for insulin secretion (islets) and insulin action (liver) could provide new insights.MethodsThe longitudinal profiling of glucose metabolism, insulin sensitivity, islet architecture and secretion were conducted in C57BL/6N mice fed a high-fat diet (HFD) or chow diet for 24 weeks. RNA-sequencing of islets and liver were performed once every 4 weeks. Weighted gene co-expression network analysis and Ingenuity Pathway Analysis were applied to construct networks and evaluate co-ordinated molecular interactions between islets and liver.ResultsMice exhibited progressively deteriorated glucose homeostasis with hyperinsulinemia but impaired first-phase insulin secretion after 4 weeks on HFD. Insulin, glucagon and somatostatin secretion in response to glucose with or without palmitate gradually deteriorated from dysregulation to failure. Systemic insulin resistance developed over 24 weeks with variable time course in tissue-specific insulin action. Our transcriptomic datasets outlined the impact of HFD on dynamics of islet and liver molecular network at different stages. Correlation analyses revealed that both organs jointly programmed β-cell compensatory adaption via cell proliferation at early phase and irreversible islet dysfunction by inappropriate immune response at later stage. Alternations of T cell subpopulations validated the participation of adaptive immune response through priming and amplification phases in diabetic progression.ConclusionOur data provide a comprehensive landscape of crosstalk between islets and liver in diet-induced diabetes, elucidating the development of islet dysfunction and insulin resistance.HighlightsDiet-induced diabetes is featured by transition from islet dysfunction to failureInsulin resistance develops with variable time course in different tissuesDynamics of islet and liver molecular network interplay at different stagesCell proliferation and improper immune reaction mediated interorgan crosstalkAdaptive immune response participated via priming and amplification phases
Dengue in western Uganda: A prospective cohort of children presenting with undifferentiated febrile illness
Authors: Boyce Ross M. , Collins Matthew , Muhindo Rabbison , Nakakande Regina , Ciccone Emily J. , Grounds Samantha , Espinoza Daniel , Zhu Yerun , Matte Michael , Ntaro Moses , Nyehangane Dan , Juliano Jonathan J. , Mulogo Edgar M. 
Published: August 2020

ABSTRACTBackgroundThe spatial distribution and burden of dengue in sub-Saharan Africa remains highly uncertain, despite high levels of ecological suitability. The goal of this study was to describe the epidemiology of dengue among a cohort of febrile children presenting to outpatient facilities located in areas of western Uganda with differing levels of urbanicity and malaria transmission intensity.MethodsEligible children were first screened for malaria using rapid diagnostic tests. Children with a negative malaria result were tested for dengue using a combination NS1/IgM/IgG rapid test (SD Bioline Dengue Duo). Confirmatory testing by RT-PCR was performed in a subset of participants. Antigen-capture ELISA was performed to estimate seroprevalence.ResultsOnly 6 of 1,416 (0.42%) children had a positive dengue rapid test, while none of the RT-PCR results were positive. ELISA testing demonstrated reactive IgG antibodies in 28 (2.2%) participants with the highest prevalence seen at the urban site in Mbarara (19 of 392, 4.9%, p< 0.001).ConclusionsOverall, these findings suggest that dengue, while present, is an uncommon cause of non-malarial, pediatric febrile illness in western Uganda. Further investigation into the eocological factors that sustain low-level transmission in urban settings are urgently needed to reduce the risk of epidemics.
Correlation of National and Healthcare Workers COVID-19 Infection Data; Implications for Large-scale Viral Testing Programs
Authors: Wu Dan , Aonghusa Pól Mac , O’Shea Donal F. 
Published: August 2020

AbstractTime analysis of the course of an infectious disease epidemic is a critical way to understand the dynamics of pathogen transmission and the effect of population scale interventions. Computational methods have been applied to the progression of the COVID-19 outbreak in five different countries (Ireland, Germany, UK, South Korea and Iceland) using their reported daily infection data. A Gaussian convolution smoothing function constructed a continuous epidemic line profile that was segmented into longitudinal time series of mathematically fitted individual logistic curves. The time series of fitted curves allowed comparison of disease progression with differences in decreasing daily infection numbers following the epidemic peak being of specific interest. A positive relationship between rate of declining infections and countries with comprehensive COVID-19 testing regimes existed. In contrast, extended epidemic timeframes were recorded for those least prepared for large scale testing and contact tracing. As many countries continue to struggle to implement population wide testing it is prudent to explore additional measures that could be employed. Comparative analysis of healthcare worker (HCW) infection data from Ireland shows it closely related to that of the entire population with respect to trends of daily infection numbers and growth rates over a 57-day period. With 31.6% of all test-confirmed infections in healthcare workers (all employees of healthcare facilities), they represent a concentrated 3% subset of the national population which if exhaustively tested (regardless of symptom status) could provide valuable information on disease progression in the entire population (or set). Mathematically, national population and HCWs can be viewed as a set and subset with significant influences on each other, with solidarity between both an essential ingredient for ending this crisis.
How often do symptoms return after unsuccessful drug treatment for malaria? A systematic review and meta-analysis
Authors: Mumtaz Rida , Okell Lucy C. , Challenger Joseph D. 
Published: August 2020

AbstractBackgroundIn clinical trials of therapies for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures are categorised as ‘clinical’ or ‘parasitological’ failures, the latter indicating that recrudescence of the infection has occurred without inducing the return of symptoms. Asymptomatic treatment failure has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of treatment failures in an individual trial is often low, it is difficult to assess how commonplace asymptomatic treatment failure is, and with what factors it is associated.MethodsA systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude reinfections. Using a multivariable Bayesian regression model, we explored factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in our study.ResultsAcross 60 published trials including 9137 malaria patients we found that 40.8% (95% CIs [35.9-45.8%]) of late treatment failures were symptomatic. We found a positive association between transmission intensity and the observed proportion of treatment failures that were asymptomatic. We also found that symptoms were more likely to return in trials that only enrolled children aged < 72 months (odds ratio =1.62, 95% CIs [1.01,2.59]). However, 84 studies had to be excluded from our analysis, as treatment failures were not specified as symptomatic or asymptomatic.ConclusionsAL, the most widely used treatment for uncomplicated Plasmodium falciparum in Africa, remains a highly efficacious drug in most endemic countries. However in the small proportion of patients where AL does not clear parasitaemia, the majority of patients do not develop symptoms again and thus would be unlikely to seek another course of treatment. This continued asymptomatic parasite carriage in patients who have been treated may have implications for drug-resistant parasites being introduced into high-transmissions settings.
Evidence for treatment with estradiol for women with SARS-CoV-2 infection
Authors: Seeland Ute , Coluzzi Flaminia , Simmaco Maurizio , Mura Cameron , Bourne Philip E. , Heiland Max , Preissner Robert , Preissner Saskia 
Published: August 2020

AbstractBackgroundGiven that an individual’s age and gender are strongly predictive of COVID-19 outcomes, do such factors imply anything about preferable therapeutic options?MethodsAn analysis of electronic health records for a large (68,466-case), international COVID-19 cohort, in five-year age strata, revealed age-dependent sex differences. In particular, we surveyed the effects of systemic hormone administration in women. The primary outcome for estradiol therapy was death. Odds Ratios (ORs) and Kaplan-Meier survival curves were analyzed for 37,086 COVID-19 women in two age groups: pre- (15-49 years) and post-menopausal (>50 years).ResultsThe incidence of SARS-CoV-2 infection is higher in women than men (about +15%) and, in contrast, the fatality rate is higher in men (about +50%). Interestingly, the relationships between these quantities are also linked to age. Pre-adolescent girls had the same risk of infection and fatality rate as boys. Adult premenopausal women had a significantly higher risk of infection than men in the same five-year age stratum (about 16,000 vs. 12,000 cases). This ratio changed again in postmenopausal women, with infection susceptibility converging with men. While fatality rates increased continuously with age for both sexes, at 50 years there was a steeper increase for men. Thus far, these types of intricacies have been largely neglected. Because the hormone 17ß-estradiol has a positive effect on expression of the human ACE2 protein—which plays an essential role for SARS-CoV-2 cellular entry—propensity score matching was performed for the women’s sub-cohort, comparing users versus non-users of estradiol. This retrospective study of hormone therapy in female COVID-19 patients shows that the fatality risk for women >50 yrs receiving estradiol therapy (user group) is reduced by more than 50%; the OR was 0.33, 95 % CI [0.18, 0.62] and the Hazard Ratio was 0.29, 95% CI[0.11,0.76]. For younger, pre-menopausal women (15-49 yrs), the risk of COVID-19 fatality is the same irrespective of estradiol treatment, probably because of higher endogenous estradiol levels.ConclusionsAs of this writing, still no effective drug treatment is available for COVID-19; since estradiol shows such a strong improvement regarding fatality in COVID-19, we suggest prospective studies on the potentially more broadly protective roles of this naturally occurring hormone.