bluuebunny/crossref_metadata_2025 huggingface dataset:
Coordination between patterning and morphogenesis ensures robustness during mouse development
Authors: Saiz Néstor , Hadjantonakis Anna-Katerina
Published: August 2020

The mammalian preimplantation embryo is a highly tractable, self-organizing developmental system in which three cell types are consistently specified without the need for maternal factors or external signals. Studies in the mouse over the past decades have greatly improved our understanding of the cues that trigger symmetry breaking in the embryo, the transcription factors that control lineage specification and commitment, and the mechanical forces that drive morphogenesis and inform cell fate decisions. These studies have also uncovered how these multiple inputs are integrated to allocate the right number of cells to each lineage despite inherent biological noise, and as a response to perturbations. In this review, we summarize our current understanding of how these processes are coordinated to ensure a robust and precise developmental outcome during early mouse development.

This article is part of a discussion meeting issue ‘Contemporary morphogenesis'.
Digital otoscopy videos versus composite images: A reader study to compare the accuracy of ENT physicians
Authors: Binol Hamidullah , Niazi M. Khalid Khan , Essig Garth , Shah Jay , Mattingly Jameson K. , Harris Michael S. , Elmaraghy Charles , Teknos Theodoros , Taj-Schaal Nazhat , Yu Lianbo , Gurcan Metin N. , Moberly Aaron C.
Published: August 2020

Objectives

With the increasing emphasis on developing effective telemedicine approaches in Otolaryngology, this study explored whether a single composite image stitched from a digital otoscopy video provides acceptable diagnostic information to make an accurate diagnosis, as compared with that provided by the full video.

Methods

Five Ear, Nose, and Throat (ENT) physicians reviewed the same set of 78 digital otoscope eardrum videos from four eardrum conditions: normal, effusion, retraction, and tympanosclerosis, along with the composite images generated by aSelectStitchmethod that selectively uses video frames with computer-assisted selection, as well as aStitchmethod that incorporates all the video frames. Participants provided a diagnosis for each item along with a rating of diagnostic confidence. Diagnostic accuracy for each pathology ofSelectStitchwas compared with accuracy when reviewing the entire video clip and when reviewing theStitchimage.

Results

There were no significant differences in diagnostic accuracy for physicians reviewingSelectStitchimages and full video clips, but both provided better diagnostic accuracy thanStitchimages. The inter-reader agreement was moderate.

Conclusion

Equal to using full video clips, composite images of eardrums generated bySelectStitchprovided sufficient information for ENTs to make the correct diagnoses for most pathologies. These findings suggest that use of a composite eardrum image may be sufficient for telemedicine approaches to ear diagnosis, eliminating the need for storage and transmission of large video files, along with future applications for improved documentation in electronic medical record systems, patient/family counseling, and clinical training.

Level of Evidence

Level 3
Comparing the Fit of N95, KN95, Surgical, and Cloth Face Masks and Assessing the Accuracy of Fit Checking
Authors: O’Kelly Eugenia , Arora Anmol , Pirog Sophia , Ward James , Clarkson P. John
Published: August 2020

Introduction

The COVID-19 pandemic has made well-fitting face masks a critical piece of protective equipment for healthcare workers and civilians. While the importance of wearing face masks has been acknowledged, there remains a lack of understanding about the role of good fit in rendering protective equipment useful. In addition, supply chain constraints have caused some organizations to abandon traditional quantitative or qualitative fit testing, and instead, have implemented subjective fit checking. Our study seeks to quantitatively evaluate the level of fit offered by various types of masks, and most importantly, assess the accuracy of implementing fit checks by comparing fit check results to quantitative fit testing results.

Methods

Seven participants first evaluated N95 and KN95 masks by performing a fit check. Participants then underwent quantitative fit testing wearing five N95 masks, a KN95 mask, a surgical mask, and fabric masks.

Results

N95 masks offered higher degrees of protection than the other categories of masks tested; however, it should be noted that most N95 masks failed to fit the participants adequately. Fit check responses had poor correlation with quantitative fit scores. All non-N95 masks achieved low fit scores.

Conclusion

Fit is critical to the level of protection offered by masks. For an N95 mask to provide the promised protection, it must fit the participant. Performing a fit check was an unreliable way of determining fit.
NLRP3 inflammasome contributes to host defense againstTalaromyces marneffeiinfection
Authors: Ma Haiyan , Chan Jasper FW , Tan Yen Pei , Kui Lin , Tsang Chi-Ching , Pei Steven LC , Lau Yu-Lung , Woo Patrick CY , Lee Pamela P
Published: August 2020

Talaromyces marneffeiis an important thermally dimorphic pathogen causing disseminated mycoses in immunocompromised individuals in southeast Asia. Previous study has suggested that NLRP3 inflammasome plays a critical role in antifungal immunity. However, the mechanism underlying the role of NLRP3 inflammasome activation in host defense againstT. marneffeiremains unclear. We show thatT. marneffeiyeasts but not conidia induce potent IL-1β response, which is differentially regulated in discrete immune cell types. Dectin-1/Syk signaling pathway mediates pro-IL-1β production, and NLRP3 inflammasome is activated to trigger the processing of pro-IL-1β into IL-1β. The activated NLRP3 inflammasome partially promotes Th1 and Th17 immune responses againstT. marneffeiyeasts.In vivo, mice with NLRP3 or caspase-1 deficiency exhibit higher mortality rate and fungal load compared to wild-type mice. Herein, our study provides the first evidence that NLRP3 inflammasome contributes to host defense againstT. marneffeiinfection, which may have implications for future antifungal therapeutic designs.
Optogenetic activation of heterotrimeric Gi proteins by LOV2GIVe— a rationally engineered modular protein
Authors: Garcia-Marcos Mikel , Parag-Sharma Kshitij , Marivin Arthur , Maziarz Marcin , Luebbers Alex , Nguyen Lien T.
Published: August 2020

Heterotrimeric G-proteins are signal transducers that mediate the action of many natural extracellular stimuli as well as of many therapeutic agents. Non-invasive approaches to manipulate the activity of G-proteins with high precision are crucial to understand their regulation in space and time. Here, we engineered LOV2GIVe, a modular protein that allows the activation of Gi proteins with blue light. This optogenetic construct relies on a versatile design that differs from tools previously developed for similar purposes, i.e. metazoan opsins, which are light-activated GPCRs. To make LOV2GIVe, we fused a peptide derived from a non-GPCR protein that activates Gαi (but not Gαs, Gαq, or Gα12) to a small plant protein domain, such that light uncages the G-protein activating module. Targeting LOV2GIVe to cell membranes allowed for light-dependent activation of Gi proteins in different experimental systems. In summary, LOV2GIVe expands the armamentarium and versatility of tools available to manipulate heterotrimeric G-protein activity.

GRAPHICAL SUMMARY
Retrospective screening of routine respiratory samples revealed undetected community transmission and missed intervention opportunities for SARS-CoV-2 in the United Kingdom
Authors: Chappell Joseph G. , Tsoleridis Theocharis , Clark Gemma , Berry Louise , Holmes Nadine , Moore Christopher , Carlile Matthew , Sang Fei , Debebe Johnny , Wright Victoria , Irving William L. , Thomson Brian J. , Boswell Timothy C.J. , Willingham Iona , Joseph Amelia , Smith Wendy , Khakh Manjinder , Fleming Vicki M. , Lister Michelle M. , Howson-Wells Hannah C. , Holmes Edward C. , Loose Matthew W. , Ball Jonathan K. , McClure C. Patrick
Published: August 2020

In the early phases of the SARS coronavirus type 2 (SARS-CoV-2) pandemic, testing focused on individuals fitting a strict case definition involving a limited set of symptoms together with an identified epidemiological risk, such as contact with an infected individual or travel to a high-risk area. To assess whether this impaired our ability to detect and control early introductions of the virus into the UK, we PCR-tested archival specimens collected on admission to a large UK teaching hospital who retrospectively were identified as having a clinical presentation compatible with COVID-19. In addition, we screened available archival specimens submitted for respiratory virus diagnosis, and dating back to early January 2020, for the presence of SARS-CoV-2 RNA. Our data provides evidence for widespread community circulation of SARS-CoV2 in early February 2020 and into March that was undetected at the time due to restrictive case definitions informing testing policy. Genome sequence data showed that many of these early cases were infected with a distinct lineage of the virus. Sequences obtained from the first officially recorded case in Nottinghamshire - a traveller returning from Daegu, South Korea – also clustered with these early UK sequences suggesting acquisition of the virus occurred in the UK and not Daegu. Analysis of a larger sample of sequences obtained in the Nottinghamshire area revealed multiple viral introductions, mainly in late February and through March. These data highlight the importance of timely and extensive community testing to prevent future widespread transmission of the virus.
Clinical Characterisation of Eleven Lateral Flow Assays for Detection of COVID-19 Antibodies in a Population
Authors: Rudolf Fabian , Kaltenbach Hans-Michael , Linnik Janina , Ruf Marie-Therèse , Niederhauser Christoph , Nickel Beatrice , Gygax Daniel , Savic Miodrag
Published: August 2020

Importance

Serological assays can help diagnose and determine the rate of SARS-CoV-2 infections in a population.

Objective

We characterized and compared 11 different lateral flow assays for their performance in diagnostic or epidemiological settings.

Design, Setting, Participants

We used two cohorts to determine the specificity: (i) up to 350 blood donor samples from past influenza seasons and (ii) up to 110 samples which tested PCR negative for SARS-CoV-2 during the first wave of SARS-CoV-2 infections in Switzerland. The sensitivity was determined using up to 370 samples which tested PCR positive for SARS-CoV-2 during the same time and is representative for age distribution and severity.

Main Outcome

We found a single test usable for epidemiological studies in the current low-prevalence setting, all other tests showed lacking sensitivity or specificity for a usage in either epidemiological or diagnostic setting. However, orthogonal testing by combining two tests without common cross-reactivities makes testing in a low-prevalence setting feasible.

Results

Nine out of the eleven tests showed specificities below 99%, only five of eleven tests showed sensitivities comparable to established ELISAs, and only one fulfilled both criteria. Contrary to previous results from lab assays, five tests measured an IgM response in >80% of the samples. We found no common cross-reactivities, which allows orthogonal testing schemes for five tests of sufficient sensitivities.

Conclusions and Relevance

This study emphasizes the need for large and diverse negative cohorts when determining specificities, and for diverse and representative positive samples when determining sensitivities of lateral flow assays for SARS-CoV-2 infections. Failure to adhere to statistically relevant sample sizes or cohorts exclusively made up of hospitalised patients fails to accurately capture the performance of these assays in epidemiological settings. Our results allow a rational choice between tests for different use cases.
FinaleDB: a browser and database of cell-free DNA fragmentation patterns
Authors: Zheng Haizi , Zhu Michelle S , Liu Yaping
Published: August 2020

Circulating cell-free DNA (cfDNA) is a promising biomarker for the diagnosis and prognosis of many diseases, including cancer. The genome-wide non-random fragmentation patterns of cfDNA are associated with the nucleosomal protection, epigenetic environment, and gene expression in the cell types that contributed to cfDNA. However, current progress on the development of computational methods and understanding of molecular mechanisms behind cfDNA fragmentation patterns is significantly limited by the controlled-access of cfDNA whole-genome sequencing (WGS) dataset. Here, we present FinaleDB (FragmentatIoN AnaLysis of cEll-free DNA DataBase), a comprehensive database to host thousands of uniformly processed and curated de-identified cfDNA WGS datasets across different pathological conditions. Furthermore, FinaleDB comes with a fragmentation genome browser, from which users can seamlessly integrate thousands of other omics data in different cell types to experience a comprehensive view of both gene-regulatory landscape and cfDNA fragmentation patterns.

Availability and implementation

FinaleDB service:http://finaledb.research.cchmc.org/FinaleDB source code:https://github.com/epifluidlab/finaledb_portalandhttps://github.com/epifluidlab/finaledb_workflow.

Contact

lyping1986@gmail.com
Rescuing auditory temporal processing with a novel augmented acoustic environment in a mouse model of congenital SNHL
Authors: Dziorny Adam C. , Scott Luisa L. , Luebke Anne E. , Walton Joseph P.
Published: August 2020

Congenital sensorineural hearing loss (SNHL) affects thousands of infants each year and results in significant delays in speech and language development. Previous studies have shown that early exposure to a simple augmented acoustic environment (AAE) can limit the effects of progressive SNHL on hearing sensitivity. However, SNHL is also accompanied by “hidden hearing loss” that is not assessed on standard audiological exams, such as reduced temporal processing acuity. To assess whether sound therapy may improve these hidden deficits, a mouse model of congenital SNHL was exposed to simple or temporally complex AAE. Peripheral function and sound sensitivity in auditory midbrain neurons improved following exposure to both types of AAE. However, only exposure to a novel, temporally complex AAE significantly improved a measure of temporal processing acuity, neural gap-in-noise detection in the auditory midbrain. These experiments suggest that targeted sound therapy may improve hearing outcomes for children suffering from congenital SNHL.
Early life stress programming of NG2+ glia transcriptome alters functional properties of voltage gated sodium (Nav) channels and cognitive performance
Authors: Treccani Giulia , Yigit Hatice , Lingner Thomas , Schleuβner Vanessa , Wennström Malin , Herzog David P , Fricke Markus , Wegener Gregers , Mittmann Thomas , Trotter Jacqueline , Müller Marianne B
Published: August 2020

The precise mechanisms underlying the detrimental effects of early life stress (ELS) on adult mental health remain still elusive. To date, most studies have exclusively targeted neuronal populations and not considered neuron-glia crosstalk as a crucially important element for the integrity of stress-related brain function. Here, we have investigated the impact of ELS on a glial subpopulation with unique properties in brain homeostasis, the NG2+ cells. ELS shifted the NG2+ transcriptome towards more mature stages, and these transcriptional effects were dependent on stress-induced glucocorticoids. The functional relevance of one candidate gene, Scn7a, could be confirmed by an increase in the density of voltage-gated sodium (Nav) channel activated currents in hippocampal NG2+ cells. Scn7a remained upregulated until adulthood in ELS animals, and these same animals displayed impaired cognitive performance. Considering that Nav channels are important for NG2+ cell-to-neuron communication, our findings suggest novel insights into the pathophysiology of stress-related mental disorders.
Mechanical Activation of MscL Revealed by a Locally Distributed Tension Molecular Dynamics Approach
Authors: Tatikonda R. R. , Anishkin A. , Sukharev S. , Vanegas J. M.
Published: August 2020

Membrane tension perceived by mechanosensitive (MS) proteins mediates cellular responses to mechanical stimuli and osmotic stresses, and it also guides multiple biological functions including cardiovascular control and development. In bacteria, MS channels function as tension-activated pores limiting excessive turgor pressure, with MscL (MS channel of large conductance) acting as an emergency release valve preventing cell lysis. Previous attempts to simulate gating transitions in MscL by either directly applying steering forces to the protein or by increasing the whole system tension were not fully successful and often disrupted the integrity of the system. We present a novel locally distributed tension molecular dynamics (LDT-MD) simulation method that allows application of forces continuously distributed among lipids surrounding the channel using a specially constructed collective variable. We report reproducible and reversible transitions of MscL to the open state with measured parameters of lateral expansion and conductivity that exactly satisfy experimental values. The LDT-MD method enables exploration of the MscL gating process with different pulling velocities and variable tension asymmetry between the inner and outer membrane leaflets. We use LDT-MD in combination with well-tempered metadynamics to reconstruct the tension-dependent free energy landscape for the opening transition in MscL.

SIGNIFICANCE

Membrane-embedded mechanosensitive (MS) proteins are essential for numerous biological functions including cardiovascular control and development, osmotic regulation, touch and pain sensing. In this work, we present a novel molecular dynamics simulation method that allows rapid and systematic exploration of structure, dynamics, and energetics of the mechanical transduction process in MS proteins under tightly controlled local tension distributed in the lipid rim around the protein. We provide a detailed description of the gating transition for the tension-activated bacterial mechanosensitive channel of large conductance, MscL, which is the best characterized channel of this type. MscL functions as a tension-activated emergency osmolyte release valve that limits excessive turgor pressure, prevents cell lysis and thus imparts environmental stability to most free-living bacteria.
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

Enveloped 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.

Importance

Cellular 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

Despite 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

The 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

Cortical 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

Interruptions (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

Bone 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

Objective

Hyperinsulinemia 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.

Methods

The 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.

Results

Mice 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.

Conclusion

Our data provide a comprehensive landscape of crosstalk between islets and liver in diet-induced diabetes, elucidating the development of islet dysfunction and insulin resistance.

Highlights

Diet-induced diabetes is featured by transition from islet dysfunction to failure

Insulin resistance develops with variable time course in different tissues

Dynamics of islet and liver molecular network interplay at different stages

Cell proliferation and improper immune reaction mediated interorgan crosstalk

Adaptive 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

Background

The 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.

Methods

Eligible 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.

Results

Only 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).

Conclusions

Overall, 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

Time 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

Background

In 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.

Methods

A 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.

Results

Across 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.

Conclusions

AL, 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

Background

Given that an individual’s age and gender are strongly predictive of COVID-19 outcomes, do such factors imply anything about preferable therapeutic options?

Methods

An 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).

Results

The 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.

Conclusions

As 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.
Prevalence and Correlates of Diabetes: Inception Cohort of a Semi-Urban Population of Southern India
Authors: Singh Mandeep , Kotwal Atul , Mittal Chetan , Reddy PC , Subbanna J , Babu Ram , Kotwal Anupam
Published: August 2020

Introduction

India has the second highest number of people with diabetes, however few studies assessed true burden and ensured screening of pre-diabetics. This cross sectional survey (inception cohort) was conducted to estimate the burden and correlates of one of the common risk factors (hyperglycemia / diabetes) likely to impact the morbidity and mortality due to Non-communicable diseases.

Research Design and Methods

A cross sectional survey was conducted in villages under Chittoor District, Andhra Pradesh, India. 15,888 individuals (62.1% females and 37.9% males) above 15 years of age participated in the study.

Results

960 (6.04%) had a history of diabetes while 592 (3.67%) had high random capillary blood glucose (RCBG) ≥200 mg/dL. HbA1c and fasting blood sugar was tested in a subset of those with high RCBG (n = 248) but with no self-reported diabetes and 212 (85.48%) had HbA1c levels > 6.5 and fasting blood sugar ≥126 mg/dL. Thus, 85.48% (n = 506) with high RCBG were likely to be diabetic. The likely magnitude of diabetes in the community was 9.23%. Another 2,331 (14.67%) were found to be at a higher risk of developing diabetes (RCBG 140 to 200 mg/dL). Receiver Operator Characteristic analysis revealed waist circumference as the most important anthropometric measurement predicting high RCBG. Comparison of diabetes and non-diabetics by multivariate logistic regression showed that male gender, age, weight, history of hypertension, family history of diabetes and waist circumference played a significant role in the prevalence of diabetes.

Conclusions

There is high prevalence of diabetes in the rural and semi-urban India. Waist Circumference was the best predictor of Diabetes. RCBG can be considered as a easy, cheap, reliable and important tool for community diagnosis and management of diabetes.

Strengths and limitations of the study

A large planned cross-sectional survey to establish a cohort with community participation

Quality assurance and control measures at all levels for high internl validity

Follow up assurance for the entire community

These results are from Cross Sectional survey data and thus provides only associations

Generealizeability to similar populations

What is already known?

Global burden of disease projected India to have a manifold increase in diabetes between 1995–2025.

Diabetes threat is being under-prioritised with increasing pool of undiagnosed diabetes.

What are the new findings?

Total prevalence of Diabetes 9.77% and 14.67% were at risk of developing Diabetes

85.5 % individuals with RCBG≥200mg/dL conform to diabetes as per ADA criteria.

Waist Circumference was the best predictor of Diabetes.

What do the new findings imply?

RCBG can be a reliable, cheap and important tool for community diagnosis and management of diabetes.

Cohort established, interventions being implememted with follow up.
Consistent variations in personality traits and their potential for genetic improvement of biocontrol agents:Trichogramma evanescensas a case study
Authors: Silène Lartigue , Myriam Yalaoui , Jean Belliard , Claire Caravel , Louise Jeandroz , Géraldine Groussier , Vincent Calcagno , Philippe Louâpre , François-Xavier Dechaume-Moncharmont , Thibaut Malausa , Jérôme Moreau
Published: August 2020

Improvements in the biological control of agricultural pests require improvements in the phenotyping methods used by practitioners to select efficient biological control agent (BCA) populations in industrial rearing or field conditions. Consistent inter-individual variations in behaviour (i.e. animal personality) probably affect BCA efficiency, but have never been taken into account in the development of phenotyping methods, despite having characteristics useful for phenotyping: repeatable (by definition), often heritable, etc. We developed a video-tracking method targeting animal personality traits and evaluated the feasibility of its use for genetic improvement in the BCATrichogramma evanescens, by phenotyping 1,049 individuals from 24 isogenic lines. We found consistent individual variations in boldness, activity and exploration. Personality differences between the 24 isogenic lines suggested a genetic origin of the variations in activity and exploration (broad-sense heritability estimates of 0.06 to 0.11) and revealed a trade-off between exploration and fecundity.
Anin vitrografting method to quantify mechanical forces of adhering tissues
Authors: Kawakatsu Yaichi , Sawai Yu , Kurotani Ken-ichi , Shiratake Katsuhiro , Notaguchi Michitaka
Published: August 2020

Abstracts

Grafting is an indispensable agricultural technology for propagating useful tree varieties and obtaining beneficial traits of two varieties/species—as stock and scion—at the same time. Recent studies of molecular events during grafting have revealed dynamic physiological and transcriptomic changes. Strategies focused on specific grafting steps are needed to further associate each physiological and molecular event with those steps. In this study, we developed a method to investigate the tissue adhesion event, an early grafting step, by improving an artificialin vitrografting system in which two pieces of 1.5-mm thickNicotiana benthamianacut stem sections were combined and cultured on medium. We prepared a silicone sheet containing five special cutouts for adhesion of cut stem slices. We quantitatively measured the adhesive force at these grafting interfaces using a force gauge and found that graft adhesion started 2 days after grafting, with the adhesive force gradually increasing over time. After confirming the positive effect of auxin on grafting by this method, we tested the effect of cellulase treatment and observed significant enhancement of graft tissue adhesion. Compared with the addition of auxin or cellulase individually, the adhesive force was stronger when both auxin and cellulase were added simultaneously. Thein vitrografting method developed in this study is thus useful for examining the process of graft adhesion.