bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating the extent of asymptomatic COVID-19 and its potential for community transmission: systematic review and meta-analysis
Authors: Byambasuren Oyungerel , Cardona Magnolia , Bell Katy , Clark Justin , McLaws Mary-Louise , Glasziou Paul
Published: May 2020

Background

The prevalence of true asymptomatic COVID-19 cases is critical to policy makers considering the effectiveness of mitigation measures against the SARS-CoV-2 pandemic. We aimed to synthesize all available research on the asymptomatic rates and transmission rates where possible.

Methods

We searched PubMed, Embase, Cochrane COVID-19 trials, and Europe PMC (which covers pre-print platforms such as MedRxiv). We included primary studies reporting on asymptomatic prevalence where: (a) the sample frame includes at-risk population, and (b) there was sufficiently long follow up to identify pre-symptomatic cases. Meta-analysis used fixed effect and random effects models. We assessed risk of bias by combination of questions adapted from risk of bias tools for prevalence and diagnostic accuracy studies.

Results

We screened 2,454 articles and included 13 low risk-of-bias studies from seven countries that tested 21,708 at-risk people, of which 663 were positive and 111 were asymptomatic. Diagnosis in all studies was confirmed using a RT-PCR test. The proportion of asymptomatic cases ranged from 4% to 41%. Meta-analysis (fixed effect) found that the proportion of asymptomatic cases was 17% (95% CI: 14% - 20%) overall; higher in aged care 20% (14% - 27%), and lower in non-aged care 16% (13% - 20%). Five studies provided direct evidence of forward transmission of the infection by asymptomatic cases. Overall, there was a 42% lower relative risk of asymptomatic transmission compared to symptomatic transmission (combined Relative Risk: 0.58; 95% CI 0.335-0.994, p=0.047).

Discussion

Our estimates of the prevalence of asymptomatic COVID-19 cases and asymptomatic transmission rates are lower than many highly publicized studies, but still sufficient to warrant policy attention. Further robust epidemiological evidence is urgently needed, including in sub-populations such as children, to better understand the importance of asymptomatic cases for driving spread of the pandemic.

Funding

OB is supported by NHMRC Grant APP1106452. PG is supported by NHMRC Australian Fellowship grant 1080042. KB is supported by NHMRC Investigator grant 1174523. All authors had full access to all data and agreed to final manuscript to be submitted for publication. There was no funding source for this study.
Structure of a proton-powered molecular motor that drives protein transport and gliding motility
Authors: James Rory Hennell , Deme Justin C. , Kjӕr Andreas , Alcock Felicity , Silale Augustinas , Lauber Frédéric , Berks Ben C. , Lea Susan M.
Published: May 2020

Ion-driven motors are rare in biology. The archetypes of the three classes identified to date are ATP synthase, the bacterial flagellar motor, and a proton-driven motor that powers gliding motility and protein secretion inBacteroidetesbacteria. Whilst the molecular mechanism of ATP synthase is now well understood, structural information is lacking for the other two classes of motor. Here we present the structure of theBacteroidetesgliding motility motor determined by cryo-electron microscopy. The motor is an asymmetric inner membrane protein complex in which the single transmembrane helices of two periplasm-spanning GldM proteins are positioned within a ring of five GldL proteins. Combining mutagenesis and single-molecule tracking, we identify protonatable amino acid residues within the transmembrane domain of the complex that are important for motor function. Our data imply a mechanism in which proton flow leads the periplasm-spanning GldM dimer to rotate with respect to the intra-membrane GldL ring to drive processes at the bacterial outer membrane. This work provides a molecular basis for understanding how the gliding motility motor is able to transduce the energy of the inner membrane protonmotive force across the bacterial cell envelope.
Saliva is less sensitive than nasopharyngeal swabs for COVID-19 detection in the community setting
Authors: Becker David , Sandoval Efren , Amin Aakash , De Hoff Peter , Diets Amberly , Leonetti Nicole , Lim Yan Wei , Elliott Christie , Laurent Louise , Grzymski Joseph , Lu James
Published: May 2020

The use of saliva collection for SARS-CoV-2 diagnostics in the ambulatory setting provides several advantages when compared to nasopharyngeal swabs (NPS), including ease of self-collection and reduced use of personal protective equipment (PPE). In addition saliva collection could be advantageous in advising if a convalescent patient is able to return to work after a period of self-quarantine. We investigated the utility of saliva collection in the community setting at Renown Health in a prospective Diagnostic Cohort of 88 patients and in a Convalescent Cohort of 24 patients. In the Diagnostic Cohort, we find that saliva collection has reduced sensitivity (~30% less) relative than NPS. And in our convalescent cohort of patients greater than 8 days and less than 21 days from first symptom, we find that saliva has ~ 50% sensitivity relative to NPS. Our results suggest that rigorous studies in the intended populations should be performed before large-scale screening using saliva as the test matrix is initiated.
Risk assessment and prediction of severe or critical illness of COVID-19 in the elderly
Authors: Zhang Xiao-Yu , Zhang Lin , Zhao Yang , Li Wei-Xia , Wu Hai-Bing , Ling Yun , Qian Zhi-Ping , Jin Yin-Peng , Fu Qing-Chun , Li Xin-Yan , Zhang Yi , Huang Yu-Xian , Chen Liang
Published: May 2020

Background: This study aims to investigate the clinical characteristics and risk prediction of severe or critical events of COVID-19 in the elderly patients in China.

Methods: The clinical data of COVID-19 in the elderly patients admitted to the Shanghai Public Health Clinical Center during the period of January 20, 2020 to March 16, 2020 were collected. A retrospective cohort study design was conducted to screen out independent factors through Cox univariable regression analysis and multivariable regression analysis, and the efficacy of risk prediction of severe or critical illness was examined through the receiver operating characteristic (ROC) curve.

Results: A total of 110 elderly patients with COVID-19 were enrolled. 52 (47.3%) were males and 21 (19.1%) had severe or critical illness. Multivariable regression analysis showed that CD4 cells and D-dimer were independent risk factors. D-dimer, CD4 cells, and D-dimer/CD cells ratios with cut off values of 0.65 (mg/L), 268 (cell/ul) and 431 were in the prediction of severe or critical illness of the elderly COVID-19. The AUC value of D-dimer, CD4 cells, CD4 cells/D-dimer ratio, the tandem group and the parallel group were 0.703, 0.804, 0.794, 0.812 and 0.694, respectively.

Conclusions: D-dimer, CD4 cells and their combination have risk assessment value in predicting severe or critical illness of COVID-19 in the elderly.
Reappearance of Effector T Cells Predicts Successful Recovery from COVID-19
Authors: Odak Ivan , Barros-Martins Joana , Bosnjak Berislav , Stahl Klaus , David Sascha , Wiesner Olaf , Busch Markus , Hoeper Marius M , Pink Isabell , Welte Tobias , Cornberg Markus , Stoll Matthias , Goudeva Lilia , Blasczyk Rainer , Ganser Arnold , Prinz Immo , Foerster Reinhold , Koenecke Christian , Schultze-Florey Christian R
Published: May 2020

Background: Elucidating the role of T cell responses in COVID-19 is of utmost importance to understand the clearance of SARS-CoV-2 infection.
Methods: 90 individuals were enrolled in this study, 30 hospitalized COVID-19 patients and 60 age- and gender-matched healthy controls (HC). Using two comprehensive 11-color flow cytometric panels conforming to Good Laboratory Practice (GLP) and approved for clinical diagnostics, we longitudinally examined cell count differences in lymphocyte populations and T cell activation in COVID-19 patients.
Findings: Absolute numbers of lymphocyte subsets were differentially decreased in COVID-19 patients according to clinical severity. In severe disease (SD) patients, all lymphocyte subsets were reduced, whilst in mild disease (MD) NK, NKT and γδ T cells were at the level of HC. Additionally, we provide evidence of T cell activation in MD but not SD, when compared to HC. Interestingly, follow up samples revealed a marked increase in effector T cells and memory subsets in convalescing but not in non-convalescing patients.
Interpretation: Our data suggest that activation and expansion of innate and adaptive lymphocytes play a major role in COVID-19. Additionally, recovery is associated with formation of T cell memory as suggested by the missing formation of effector and central memory T cells in SD but not in MD. Our data imply that the presence of SARS-CoV-2 responsive T cells contributes to convalescence in MD. Thus, understanding the T cell-response in the context of clinical severity might serve as foundation to overcome the lack of effective anti-viral immune response in severely affected COVID-19 patients and can offer prognostic value as biomarker for disease outcome and control.
A one-year hospital-based prospective COVID-19 open-cohort in the Eastern Mediterranean region: The Khorshid COVID Cohort (KCC) study
Authors: Sami Ramin , Soltaninejad Forogh , Amra Babak , Naderi Zohreh , Javanmard Shaghayegh Haghjooy , Iraj Bijan , Ahmadi Somayeh Haji , Shayganfar Azin , Dehghan Mehrnegar , Khademi Nilufar , Hosseini Nastaran Sadat , Mortazavi Mojgan , Mansourian Marjan , Mañanas Miquel Angel , Marateb Hamid Reza , Adibi Peyman
Published: May 2020

The COVID-19 is rapidly scattering worldwide, and the number of cases in the Eastern Mediterranean Region is rising. Thus, there is a need for immediate targeted actions. We designed a longitudinal study in a hot outbreak zone to analyze the serial findings between infected patients for detecting temporal changes from February 2020. In a hospital-based open-cohort study, patients are followed from admission until one year from their discharge (the 1st, 4th, 12th weeks, and the first year). The patient recruitment phase finished at the end of August 2020, and the follow-up continues by the end of August 2021. The measurements included demographic, socio-economics, symptoms, health service diagnosis and treatment, contact history, and psychological variables. The signs improvement, death, length of stay in hospital were considered primary, and impaired pulmonary function and psychotic disorders were considered main secondary outcomes. Moreover, clinical symptoms and respiratory functions are being determined in such follow-ups. Among the first 600 COVID-19 cases, 490 patients with complete information (39% female; the average age of 57±15 years) were analyzed. Seven percent of these patients died. The three main leading causes of admission were: fever (77%), dry cough (73%), and fatigue (69%). The most prevalent comorbidities between COVID-19 patients were hypertension (35%), diabetes (28%), and ischemic heart disease (14%). The percentage of primary composite endpoints (PCEP), defined as death, the use of mechanical ventilation, or admission to an intensive care unit was 18%. The Cox proportional-hazards model for PCEP indicated the following significant risk factors: Oxygen saturation < 80% (HR= 6.3; [CI 95%: 2.5,15.5]), lymphopenia (HR= 3.5; [CI 95%: 2.2,5.5]), Oxygen saturation 80%-90% (HR= 2.5; [CI 95%: 1.1,5.8]), and thrombocytopenia (HR= 1.6; [CI 95%: 1.1,2.5]). This long-term prospective Cohort may support healthcare professionals in the management of resources following this pandemic.
Early estimation of the risk factors for hospitalisation and mortality by COVID-19 in Mexico
Authors: Carrillo-Vega Maria Fernanda , Salinas-Escudero Guillermo , Garcia-Peña Carmen , Gutierrez-Robledo Luis Miguel , Parra-Rodriguez Lorena
Published: May 2020

Background. With its high prevalence of chronic non-degenerative diseases, it is suspected that in Mexico there is a high risk of fatal complications from COVID-19. The present study aims to estimate the risk factors for hospitalisation and death in the Mexican population infected by SARS-CoV-2.
Methods and Findings. We used the publicly available data released by the Epidemiological Surveillance System for Viral Respiratory Diseases of the Mexican Ministry of Health (Secretaria de Salud, SS). All records of positive SARS-CoV-2 cases were included. Two multiple logistic regression models were fitted to estimate the association between the hospitalisation and mortality, with other covariables. Data on 10,544 individuals (57.68% men), with mean age 46.47 SD 15.62, were analysed. Men were about 1.54 times as likely to be hospitalized than women (p<0.001, 95% C.I. 1.37-1.74); individuals aged 50-74 and >=74 years were more likely to be hospitalized than people from 25-49 years (OR 2.05, p<0.001, 95% C.I. 1.81-2.32, and OR 23.84, p<0.001, 95% C.I. 2.90-5.15, respectively). People with hypertension, obesity, and diabetes were more likely to be hospitalised than people without these morbidities (p<0.01). Men had more risk of death in comparison to women (OR=1.53, p<0.001, 95% C.I. 1.30-1.81) and individuals aged 50-74 and ≥75 years were more likely to die than people from 25-49 years (OR 1.96, p<0.001, 95% C.I. 1.63-2.34, and OR 3.74, p<0.001, 95% C.I. 2.80-4.98, respectively). Hypertension, obesity, and diabetes presented in combination, provided a higher risk of dying in comparison to not having these diseases (OR=2.10; p<0.001, 95% C.I. 1.50-2.93). Hospitalisation, intubation and pneumonia conferred a higher risk of dying (OR 5.02, p<0.001, 95% C.I. 3.88-6.50; OR 4.27, p<0.001, 95% C.I. 3.26-5.59, and OR=2.57; p<0.001, 95% C.I. 2.11-3.13, respectively). The main limitation of our study is the lack of information on mild (asymptomatic) or moderate cases of COVID-19.
Conclusions. The present study points out that in Mexico, where an important proportion of the population develops two or more chronic conditions simultaneously, high mortality is a sever outcome for those infected by SARS-CoV-2.
Diagnosis of T-Cell-Mediated Kidney Rejection by Biopsy-Based Proteomics and Machine Learning
Authors: Fang Fei , Liu Peng , Zhao Yang , Mehta Rajil , Tseng George , Randhawa Parmjeet , Xiao Kunhong
Published: May 2020

Purpose: This study is aimed at developing a clinic-friendly proteomics protocol and a machine learning (ML)-based molecular diagnostic test for T-cell-mediated rejection (TCMR) using formalin-fixed, paraffin-embedded (FFPE) biopsies.
Experimental design: Based on the procedures we reported for proteomic profiling of FFPE biopsies using Tandem Mass Tag (TMT)-based technology, a label-free-based quantitative proteomics protocol was developed as a more clinical-practical and cost-efficient molecular diagnostic test for renal transplant injection. This new protocol was applied to a set of FFPE biopsies from renal allograft injury patients and normal controls, including 5 TCMR, 5 polyomavirus BK nephropathy (BKPyVN) and 5 stable graft function (STA). Three different machine learning algorithms, linear discriminant analysis (LDA), support vector machine (SVM) and random forests (RF), were tested to build a prediction model for TCMR.
Results: About 750-1250 proteins were identified and quantified in each sample with high confidence using the label-free-based proteomics protocol. 178, 450 and 281 proteins were defined as differential expression (DE) proteins for TCMR vs STA, BKPyVN vs STA and TCMR vs BKPyVN, respectively. By comparing the quantitative data from the TMT- and label-free-based proteomics profiling, a classifier panel comprised of 234 DE proteins commonly quantified by two methods was generated to test different ML algorithms. Leave-one-out cross-validation result suggested that the RF-based model achieved the best prediction power for TCMR at both proteome and transcriptome level.
Conclusions and clinical relevance: Proteomics profiling of FFPE biopsies using a platform integrated of label-free quantitative proteomics with ML-based predictive model can help to discover biomarker panels and provide clinical molecular diagnostic tests to enhance biopsy interpretation for renal allograft rejection.
Annexin-A1 tripeptide attenuates surgery-induced neuroinflammation and memory deficits through regulation of the NLRP3 inflammasome
Authors: Zhang Zhiquan , Ma Qing , Velagapudi Ravikanth , Barclay William E. , Rodriguiz Ramona M. , Wetsel William C. , Shinohara Mari L. , Terrando Niccolò
Published: May 2020

Neuroinflammation is a growing hallmark of perioperative neurocognitive disorders (PNDs), including delirium and longer-lasting cognitive deficits. We have developed a clinically-relevant orthopedic mouse model to study the impact of a common surgical procedure on the vulnerable brain. The mechanism underlying PNDs remain unknown. Here we evaluated the impact of surgical trauma on the NLRP3 inflammasome signaling, including the expression of apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and IL-1β in the hippocampus of C57BL6/J male mice, adult (3-months) and aged (>18-months). Surgery triggered ASC specks formation in CA1 hippocampal microglia, but without inducing significant morphological changes in NLRP3 and ASC knockout mice. Since no therapies are currently available to treat PNDs, we assessed the neuroprotective effects of a biomimetic peptide derived from the endogenous inflammation-ending molecule, Annexin-A1 (ANXA1). We tested the hypothesis that this peptide (ANXA1sp) inhibits NLRP3 inflammasome activation, thus preventing microglial activation and hippocampal-dependent memory deficits. Together these results uncover a previously underrecognized role of the NLRP3 inflammasome in triggering postoperative neuroinflammation and offer a new target for advancing treatment of PNDs through resolution of inflammation.
Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration
Authors: Morshed Nader , Ralvenius William T. , Nott Alexi , Watson L. Ashley , Rodriguez Felicia H. , Akay Leyla A. , Joughin Brian A. , Pao Ping-Chieh , Penney Jay , LaRocque Lauren , Mastroeni Diego , Tsai Li-Huei , White Forest M.
Published: May 2020

Alzheimer’s disease (AD) is characterized by the appearance of amyloid-β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV-2 cell line and human stem-cell derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells. Collectively, our results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration.

Highlights

Phosphoproteomics analysis of CK-p25, 5XFAD, and Tau P301S mouse models finds dysregulated signaling networks associated with Alzheimer’s disease pathologies.

A phosphorylation site on Siglec-F is found to be upregulated across all three models of disease.

Expression of Siglec-F and its human paralog Siglec-8 is increased in reactive microglia.

Overexpression of Siglec-F and Siglec-8in vitrodrives an endocytic and pyroptotic inflammatory response.

In Brief

Phosphoproteome signaling changes associated with Alzheimer’s disease (AD) are poorly characterized. Here, Morshed et al. apply phosphoproteomics to mouse models of AD to uncover a novel microglial receptor, Siglec-F, that is upregulated on a subset of inflammatory microglia across models of neurodegeneration. The human paralog, Siglec-8 is also found to be upregulated in late-onset AD microglia. Overexpression of Siglec-F and related human Siglecs activates pro-inflammatory signaling responses in BV-2 cells.
The longer the better? General skill but not probabilistic learning improves with the duration of short rest periods
Authors: Fanuel Lison , Plèche Claire , Vékony Teodóra , Quentin Romain , Janacsek Karolina , Nemeth Dezso
Published: May 2020

Memory consolidation has mainly been investigated for extended periods, from hours to days. Recent studies suggest that memory consolidation can also occur within shorter periods, from minutes to seconds. Our study aimed at determining (1) whether short rest periods lead to improvements in implicit probabilistic sequence learning and (2) whether length of rest duration influences such offline improvements. Participants performed an implicit probabilistic sequence learning task throughout 45 blocks. Between blocks, participants were allowed to rest and then to continue the task in their pace. The overall reaction times (general skill learning) shortened from pre- to post-rest periods, and this improvement was increased for longer rest durations. However, probabilistic sequences knowledge decreased in these periods, and this decrement was not related to the length of rest duration. These results suggest that (1) general skill learning but not probabilistic sequence knowledge benefits from short rest periods and, possibly, from memory consolidation, (2) ultra-fast offline improvements in general skills, but not forgetting in probabilistic sequence knowledge, are time-dependent. Overall, our findings highlight that ultra-fast consolidation differently affects distinct cognitive processes.
Disrupted object-scene semantics boost scene recall but diminish object recall in drawings from memory
Authors: Bainbridge Wilma A. , Kwok Wan Y. , Baker Chris I.
Published: May 2020

Humans are highly sensitive to the statistical relationships between features and objects within visual scenes. Inconsistent objects within scenes (e.g., a mailbox in a bedroom) instantly jump out to us, and are known to capture our attention. However, it is debated whether such semantic inconsistencies result in boosted memory for the scene, impaired memory, or have no influence on memory. Here, we examined the relationship of scene-object consistencies on memory representations measured through drawings made during recall. Participants (N=30) were eye-tracked while studying 12 real-world scene images with an added object that was either semantically consistent or inconsistent. After a 6-minute distractor task, they drew the scenes from memory while pen movements were tracked electronically. Online scorers (N=1,725) rated each drawing for diagnosticity, object detail, spatial detail, and memory errors. Inconsistent scenes were recalled more frequently, but contained less object detail. Further, inconsistent objects elicited more errors reflecting looser memory binding (e.g., migration across images). These results point to a dual effect in memory of boosted global (scene) but diminished local (object) information. Finally, we replicated prior effects showing that inconsistent objects captured eye fixations, but found that fixations during study were not correlated with recall performance, time, or drawing order. In sum, these results show a nuanced effect of scene inconsistencies on memory detail during recall.
Social hierarchy is established and maintained with distinct acts of aggression in maleDrosophila
Authors: Simon Jasper C. , Heberlein Ulrike
Published: May 2020

Social interactions pivot on an animal’s experiences, internal states, and feedback from others. This complexity drives the need for precise descriptions of behavior to dissect the fine detail of its genetic and neural circuit bases. In laboratory assays, maleDrosophila melanogasterreliably exhibit aggression, and its extent is generally measured by scoring lunges, a feature of aggression in which one male quickly thrusts onto his opponent. Here, we introduce an explicit approach to identify both the onset and reversals in hierarchical status among opponents and observe that distinct aggressive acts reproducibly precede, concur, or follow the establishment of dominance. We find that lunges are insufficient for establishing dominance. Rather, lunges appear to reflect the dominant state of a male and help in maintaining his social status. Lastly, we characterize the recurring and escalating structure of aggression that emerges through subsequent reversals in dominance. Collectively, this work provides a framework for studying the complexity of agonistic interactions in male flies enabling its neurogenetic basis to be understood with precision.
Preferred conformations in the disordered region of human CPEB3, a functional amyloid linked to memory consolidation
Authors: de Mingo D. Ramírez , Pantoja-Uceda D. , Hervás R. , Carrión-Vázquez M. , Laurents D. V.
Published: May 2020

While implicated in neurodegenerative diseases, amyloids are also essential to some physiological processes, including memory consolidation by neuronal-specific isoforms of the Cytoplasmic Polyadenylation Element Binding (CPEB) protein family. CPEB mediates memory persistence by the formation of self-sustaining amyloid assemblies through its intrinsically disordered region (IDR). Here, we characterize the atomic level conformation and ps-ns dynamics of the 426-residue IDR of human CPEB3 (hCPEB3), which has been associated with episodic memory in humans, by NMR spectroscopy. We found that the first 29 residues: M1QDDLLMDKSKTQPQPQQQQRQQQQPQP29, adopt a helical+disordered motif. Residues 86-93: P83QQPPPP93, and 166-175: P166PPPAPAPQP175form polyproline II (PPII) helices. While the (VG)5repeat motif is completely disordered, residues 200-250 adopt three partially populated α-helices. Residues 345–355, which comprise the nuclear localization signal (NLS), form a modestly populated α-helix and border a phosphoTyr which may mediate STAT5B binding. These findings allow us to suggest a model for nascent hCPEB3 structural transitions at single residue resolution, advancing that amyloid breaker residues, like proline, are a key difference between functional versus pathological amyloids. Besides revealing some aspects of the molecular basis of memory, these findings could aid the future development of treatments for post-traumatic stress disorder.

Areas:Biophysics, Structural Biology, Biochemistry & Neurosciences.
Working groups, gender and publication impact of Canada’s ecology and evolution faculty
Authors: Wei Qian , Lachapelle Francois , Fuller Sylvia , Corrigall-Brown Catherine , Srivastava Diane S.
Published: May 2020

A critical part of science is the extraction of general principles by synthesizing results from many different studies or disciplines. In the fields of ecology and evolution, a popular method to conduct synthesis science is in working groups – that is, research collaborations based around intensive week-long meetings. We present in this report an analysis of the impact of working group participation and gender on the publication impact of ecology and evolution faculty at Canadian universities who were research active over the last three decades (N=1408). Women are underrepresented in this research population relative to the general population, and even the Canadian faculty population. Participation in working groups not only benefits science, but also benefits the researchers involved by accelerating the temporal increase in their H-index. However, this benefit is particularly driven by senior male researchers. The effect is weaker for female researchers and even negative for researchers within 4 years of their PhD. However, gender does not affect current participation rates in working groups, nor reported indirect benefits – such as future collaborations, funding and data resources. The results of this study suggest that working groups can act as career catalysts for researchers, but that – as in many areas of science – there are challenging issues of equity that require action. Because the H-index is a cumulative measure, gender inequities from before the turn of the millenium may still be distorting the perceived publication impact of today’s research-active faculty.
The immunosuppression of macrophages underlies the cardioprotective effects of catestatin (CST)
Authors: Ying Wei , Tang Kechun , Avolio Ennio , Schilling Jan M. , Pasqua Teresa , Liu Matthew A. , Cheng Hongqiang , Gao Hong , Zhang Jing , Mahata Sumana , Ko Myung S. , Bandyopadhyay Gautam , Das Soumita , Roth David M. , Sahoo Debashis , Webster Nicholas J.G. , Sheikh Farah , Ghosh Gourisankar , Patel Hemal H. , Ghosh Pradipta , van den Bogaart Geert , Mahata Sushil K.
Published: May 2020

Hypertension (HTN) is associated with inflammation and excessive production of catecholamines. Hypertensive patients have reduced plasma levels of Catestatin (CST), a bioactive cleavage product of the prohormone Chromogranin A (CgA). In mouse models, HTN symptoms can be reduced by administration of CST, but the role of CST in the regulation of cardiovascular function is unknown. In this study, we generated mice with knockout (KO) of the region of the CgA gene coding for CST (CST-KO) and found that CST-KO mice are not only hypertensive as predicted, but also display left ventricular hypertrophy, have marked macrophage infiltration of the heart and adrenal gland, and have elevated levels of pro-inflammatory cytokines and catecholamines. Intraperitoneal injection with CST reversed these phenotypes, and ischemic pre-conditioning-induced cardioprotection was also abolished in CST-KO mice. Experiments with chlodronate depletion of macrophages and bone-marrow transfer showed that macrophages produce CST and that the anti-hypertensive effects of CST are mediated in part via CST’s immunosuppression of macrophages as a form of feedback inhibition. The data thus implicate CST as a key autocrine attenuator of the cardiac inflammation in HTN by reducing macrophage inflammation.
Uncovering the locus coeruleus: comparison of localization methods for functional analysis
Authors: Mäki-Marttunen Verónica , Espeseth Thomas
Published: May 2020

Functional neuroimaging of small brainstem structures in humans is gaining increasing interest due to their potential importance in aging and many clinical conditions. Researchers have used different methods to measure activity in the locus coeruleus (LC), the main noradrenergic nucleus in the brain. However, the reliability of the different methods for identifying this small structure is unclear. In the present article, we compared four different approaches to estimate localization of the LC in a large sample (N = 98): 1) a probabilistic map from a previous study, 2) masks segmented from neuromelanin-sensitive scans, 3) components from a masked-independent components analysis of the functional data, and 4) a mask from pupil regression of the functional data. The four methods have been used in the community and find some support as reliable ways of assessing the localization of LCin vivoin humans by using functional imaging. We report several measures of similarity between the LC masks obtained from the different methods. In addition, we compare the similarity between functional connectivity maps obtained from the different masks. We conclude that sample-specific masks appear more suitable than masks from a different sample, that masks based on structural versus functional methods may capture different portions of LC, and that, at the group level, the creation of a “consensus” mask using more than one approach may give a better estimate of LC localization.
A Novel Method of Immunomodulation of Endothelial cells Using Streptococcus Pyogenes and its Lysate
Authors: Arokiaraj Mark Christopher , Wilson Jarad
Published: May 2020

Background

Coronary artery diseases and autoimmune disorders are common in clinical practice. In this study, a novel method of immune-modulation to modify the endothelial function was studied to modulate the features of the endothelial cells, and thereby to reduce coronary artery disease and other disorders modulated by endothelium.

Methods

HUVEC cells were seeded in the cell culture, and streptococcus pyogenes were added to the cell culture, and the supernatant was studied for the secreted proteins. In the second phase, the bacterial lysate was synthesized, and the lysate was added to cell culture; and the proteins in the supernatant were studied at various time intervals.

Results

When streptococcus pyogenes alone was added to culture, E Cadherin, Angiostatin, EpCAM and PDGF-AB were some of the biomarkers elevated significantly. HCC1, IGFBP2 and TIMP were some of the biomarkers which showed a reduction. When the lysate was added, the cell-culture was maintained for a longer time, and it showed the synthesis of immune regulatory cytokines. Heatmap analysis showed a significant number of proteins/cytokines concerning the immune/pathways, and toll-like receptors superfamily were modified. BLC, IL 17, BMP 7, PARC, Contactin2, IL 10 Rb, NAP 2 (CXCL 7), Eotaxin 2 were maximally increased. By principal component analysis, the results observed were significant.

Conclusion

There is potential for a novel method of immunomodulation of the endothelial cells, which have pleiotropic functions, using streptococcus pyogenes and its lysates.
GEM: Scalable and flexible gene-environment interaction analysis in millions of samples
Authors: Westerman Kenneth E. , Pham Duy T. , Hong Liang , Chen Ye , Sevilla-González Magdalena , Sung Yun Ju , Sun Yan V. , Morrison Alanna C. , Chen Han , Manning Alisa K.
Published: May 2020

Motivation

Gene-environment interaction (GEI) studies are a general framework that can be used to identify genetic variants that modify the effects of environmental, physiological, lifestyle, or treatment effects on complex traits. Moreover, accounting for GEIs can enhance our understanding of the genetic architecture of complex diseases. However, commonly-used statistical software programs for GEI studies are either not applicable to testing certain types of GEI hypotheses or have not been optimized for use in large samples.

Results

Here, we develop a new software program, GEM (Gene-Environment interaction analysis in Millions of samples), which supports the inclusion of multiple GEI terms, adjustment for GEI covariates, and robust inference, while allowing multi-threading to reduce computation time. GEM can conduct GEI tests as well as joint tests of genetic effects for both continuous and binary phenotypes. Through simulations, we demonstrate that GEM scales to millions of samples while addressing limitations of existing software programs. We additionally conduct a gene-sex interaction analysis on waist-hip ratio in 352,768 unrelated individuals from the UK Biobank, identifying 39 novel loci in the joint test that have not previously been reported in combined or sex-specific analyses. Our results demonstrate that GEM can facilitate the next generation of large-scale GEI studies and help advance our understanding of genomic contributions to complex traits.

Availability

GEM is freely available as an open source project athttps://github.com/large-scale-gxe-methods/GEM.

Contact

akmanning@mgh.harvard.edu,Han.Chen.2@uth.tmc.edu

Supplementary information

Supplementary data are available atBioinformaticsonline.
Invariant chain with an AP3 interacting sorting signal is sorted to late endosomal compartments and may improve MHC class I loading and presentation
Authors: Kucera Ana , Mensali Nadia , Pati Niladri Busan , Inderberg Else Marit , Myhre Marit Renée , Gregers Tone Fredsvik , Wälchli Sébastien , Bakke Oddmund
Published: May 2020

Invariant chain (Ii) is traditionally known as the dedicated MHCII chaperone. Recent reports have broadened our understanding about various tasks that Ii plays including its physiological role in MHCI cross-presentation. Ii bound MHCI via the MHCII scaffolding CLIP peptide may facilitate MHCI trafficking to the endosomal pathway. The sorting function of Ii depends on two leucine-based sorting signals present in the cytoplasmic tail that acts as binding sites for the adaptor proteins AP-1/AP-2. Here we increased the Ii cross-presentation potency by replacing these with an AP3 motif resulting an efficient transport of Ii from TGN to late endosomes. We also replaced the CLIP region of li with a therapeutically relevant peptide, MART-1. We found the Ii AP3mutant-MART1 construct was capable of loading MHCI and stimulate specific T-cell response more efficiently than the wild type counterpart. The results show that Ii with an AP3 binding sorting motif carrying peptide epitope(s) can promote efficient antigen presentation to cytotoxic T cells (CTLs) independent of the ER located classical MHCI peptide loading machinery.
Commonalities in alpha and beta neural desynchronizations during prediction in language comprehension and production
Authors: Gastaldon Simone , Arcara Giorgio , Navarrete Eduardo , Peressotti Francesca
Published: May 2020

The present study investigates whether predictions during language comprehension are generated by engaging the production system. We recorded EEG from participants performing both a comprehension and a production task in two separate blocks. Participants listened to high and low constraint incomplete sentences and were asked either to name a picture to complete it (production) or to simply listen to the final word (comprehension). We found that in a silent gap before the final stimulus, predictable stimuli elicited alpha (8-10 Hz) and beta (13-30 Hz) desynchronization in both tasks. Source estimation highlighted not only the involvement of the left-lateralized language network, but also of temporo-parietal areas in the right hemisphere. Furthermore, correlations between the desynchronizations in comprehension and production showed spatiotemporal commonalities in language-relevant areas in the left hemisphere, especially in the temporal, lateral inferior and dorsal frontal, and inferior parietal corteces. As proposed by prediction-by-production models, our results show that comprehenders engage the production system while predicting upcoming words.
Statistics of nascent and mature RNA fluctuations in a stochastic model of transcriptional initiation, elongation, pausing, and termination
Authors: Filatova Tatiana , Popovic Nikola , Grima Ramon
Published: May 2020

Recent advances in fluorescence microscopy have made it possible to measure the fluctuations of nascent (actively transcribed) RNA. These closely reflect transcription kinetics, as opposed to conventional measurements of mature (cellular) RNA, whose kinetics is affected by additional processes downstream of transcription. Here, we formulate a stochastic model which describes promoter switching, initiation, elongation, premature detachment, pausing, and termination while being analytically tractable. By computational binning of the gene into smaller segments, we derive exact closed-form expressions for the mean and variance of nascent RNA fluctuations in each of these segments, as well as for the total nascent RNA on a gene. We also derive exact expressions for the first two moments of mature RNA fluctuations, and approximate distributions for total numbers of nascent and mature RNA. Our results, which are verified by stochastic simulation, uncover the explicit dependence of the statistics of both types of RNA on transcriptional parameters and potentially provide a means to estimate parameter values from experimental data.
Achieving High-Resolution Whole-Brain Slab1H-MRSI with Compressed-Sensing and Low-Rank Reconstruction at 7 Tesla
Authors: Klauser Antoine , Strasser Bernhard , Thapa Bijaya , Lazeyras Francois , Andronesi Ovidiu
Published: May 2020

Low sensitivity MR techniques such as magnetic resonance spectroscopic imaging (MRSI) greatly benefit from the gain in signal-to-noise (SNR) provided by ultra-high field MR. High-resolution and whole-brain slab MRSI remains however very challenging due to lengthy acquisition, low signal, lipid contamination and field inhomogeneity. In this study, we propose an acquisition-reconstruction scheme that combines a1H-FID-MRSI sequence with compressed sensing acceleration and low-rank modeling with total-generalized-variation constraint to achieve metabolite imaging in two and three dimensions at 7 Tesla. The resulting images and volumes reveal highly detailed distributions that are specific to each metabolite and follow the underlying brain anatomy. The MRSI method was validated in a high-resolution phantom containing fine metabolite structures, and in 3 healthy volunteers. This new application of compressed sensing acceleration paves the way for high-resolution MRSI in clinical setting with acquisition times of 5 min for 2D MRSI at 2.5 mm and of 20 min for 3D MRSI at 3.3 mm isotropic.
Dose-dependent and disease-modifying effects of striatal infusion of cholesterol in Huntington’s disease
Authors: Birolini Giulia , Valenza Marta , Di Paolo Eleonora , Vezzoli Elena , Talpo Francesca , Maniezzi Claudia , Caccia Claudio , Leoni Valerio , Bocchi Vittoria D. , Conforti Paola , Sogne Elisa , Petricca Lara , Cariulo Cristina , Verani Margherita , Caricasole Andrea , Falqui Andrea , Biella Gerardo , Cattaneo Elena
Published: May 2020

A variety of pathophysiological mechanisms are implicated in Huntington’s disease (HD). Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from pre-symptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In addition, systemic injection of cholesterol-loaded brain-permeable nanoparticles ameliorates synaptic and cognitive function in a transgenic mouse model of HD. To identify an appropriate treatment regimen and gain mechanistic insights into the beneficial activity of exogenous cholesterol in the HD brain, we employed osmotic mini-pumps to infuse three escalating doses of cholesterol directly into the striatum of HD mice in a continuous and rate-controlled manner. All tested doses prevented cognitive decline, while amelioration of disease-related motor defects was dose-dependent. In parallel, we found morphological and functional recovery of synaptic transmission involving both excitatory and inhibitory synapses of striatal medium spiny neurons. The treatment also enhanced endogenous cholesterol biosynthesis and clearance of mutant Huntingtin aggregates. These results indicate that cholesterol infusion to the striatum can exert a dose-dependent, disease-modifying effect and may be therapeutically relevant in HD.
Quantitative measurement of activity of JAK-STAT signaling pathways in blood samples and immune cells to predict innate and adaptive cellular immune response to viral infection and accelerate vaccine development
Authors: Bouwman Wilbert , Verhaegh Wim , Holtzer Laurent , van de Stolpe Anja
Published: May 2020

The host immune response determines the clinical course of a viral infection, for example in case of COVID-19 infection. The effectiveness of vaccination also depends on the induced immune response. Currently there is no method to measure the cellular immune response in blood samples. The functional activity of cells of innate and adaptive immune system is determined by coordinated activity of signaling pathways, especially the JAK-STAT pathways. Using a previously described approach we developed mRNA-based tests to measure activity of these signaling pathways, and show that they can be used to measure in a quantitative manner the cellular innate and adaptive immune response to a viral infection or vaccine in whole blood, PBMC, and specific immune cell type samples. Pathway activity level and range in healthy individuals was established, enabling interpretation of a pathway activity score on a patient sample without the need for a reference sample. Evidence is presented that the pathway activity analysis may also be useful for in vitro vaccine development and assessment of vaccine immunogenicity. Other envisioned applications lie in development of immunomodulatory drugs and drug response prediction and monitoring. Tests are expected to be of value in the COVID-19 crisis. In addition to the described Affymetrix microarray-based pathway tests for measuring host immune response, qPCR-based versions are in development; the latter can in principle be performed within three hours in routine hospital labs.
Anaplerotic pathways inHalomonas elongata: the role of the sodium gradient
Authors: Hobmeier Karina , Goëss Marie C. , Sehr Christiana , Kunte Hans Jörg , Kremling Andreas , Pflüger-Grau Katharina , Marin-Sanguino Alberto
Published: May 2020

Salt tolerance in theγ-proteobacteriumHalomonas elongatais linked to its ability to produce the compatible solute ectoine. The metabolism of ectoine production is of great interest since it can shed light on the biochemical basis of halotolerance as well as pave the way for the improvement of the biotechnological production of such compatible solute. The ectoine production pathway uses oxaloacetate as a precursor, thereby connecting ectoine production to the anaplerotic reactions that refill carbon into the TCA cycle. This places a high demand on these reactions and creates the need to regulate them not only in response to growth but also in response to extracellular salt concentration. In this work we combine modeling and experiments to analyze how these different needs shape the anaplerotic reactions inH. elongata. First, the stoichiometric and thermodynamic factors that condition the flux distributions are analyzed, then the optimal patterns of operation for oxaloacetate production are calculated. Finally, the phenotype of two deletion mutants lacking potentially relevant anaplerotic enzymes: Phosphoenolpyruvate carboxylase (Ppc) and Oxaloacetate decarboxylase (Oad) is experimentally characterized. The results show that the anaplerotic reactions inH. elongataare indeed subject to different evolutionary pressures than those of other gram-negative bacteria. Ectoine producing halophiles must meet a higher metabolic demand for oxaloacetate and the reliance of many marine bacteria on the Entner-Doudoroff pathway compromises the anaplerotic efficiency of Ppc, which is usually one of the main enzymes fulfilling this role. The anaplerotic flux inH. elongatais contributed not only by Ppc but also by Oad, an enzyme that has not yet been shown to play this rolein vivo. Ppc is necessary forH. elongatato grow normally at low salt concentrations but it is not required to achieve near maximal growth rates as long as there is a steep sodium gradient. On the other hand, the lack of Oad presents serious difficulties to grow at high salt concentrations. This points to a shared role of these two enzymes in guaranteeing the supply of OAA for biosynthetic reactions.