bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Nocturia Associated With Detrusor Underactivity?
Authors: Ryles Hannah T. , Sansone Stephanie A. , Levin Pamela J. , Andy Uduak U. , Harvie Heidi S. , Arya Lily A.
Published: March 2021

Objectives

Detrusor underactivity (DU) is diagnosed using urodynamic testing. We hypothesized that nocturia is associated with detrusor underactivity.

Methods

We performed a retrospective chart review of all women who underwent urodynamic testing at our institution between 2016 and 2018. Uroflowmetry and pressure-flow study parameters were compared between women with nocturia (≥2 voids/night) and without nocturia (0–1 void/night). Detrusor underactivity was diagnosed using 3 different criteria: (1) bladder voiding efficiency (BVE) of <90%, (2) bladder contractility index of <100, and (3) a composite of three urodynamic measures (Gammie criteria).

Results

Of 358 women, 172 (48%) were in the nocturia group and 186 (52%) were in the no nocturia group. On uroflowmetry, median postvoid residual volume was similar (20 mL) in both groups. Median maximum flow rate (15 vs 17 mL/s, P < 0.05) and average flow rate (6 mL/s vs 7 mL/s, P < 0.05) were significantly lower in the nocturia group compared with the no nocturia group. During pressure-flow study, a significantly greater proportion of women with nocturia were unable to void around the catheter (30% vs 27%, P < 0.01). The overall rate of DU varied with the criteria used: BVE (54%), bladder contractility index (41%), and Gammie criteria (7%). The rate of DU using the BVE criteria was significantly higher in the nocturia group (63% vs 48%, P < 0.01), but no significant differences were noted using the other criteria.

Conclusions

Nocturia is associated with reduced voiding efficiency in women. The diagnosis of DU using urodynamics is challenging.
The Genetic Architecture of Alzheimer’s Disease Risk: A Genomic Structural Equation Modelling Study
Authors: Foote Isabelle F , Jacobs Benjamin M , Mathlin Georgina , Watson Cameron J , Bothongo Phazha LK , Waters Sheena , Dobson Ruth , Noyce Alastair J , Bhui Kamaldeep S , Korszun Ania , Marshall Charles R
Published: March 2021

Background

Targeting modifiable risk factors may have a role in the prevention of Alzheimer’s disease. However, the mechanisms by which these risk factors influence Alzheimer’s risk remain incompletely understood. Genomic structural equation modelling can reveal patterns of shared genetic architecture that provide insight into the pathophysiology of complex traits.

Methods

We identified genome-wide association studies for Alzheimer’s disease and its major modifiable risk factors: less education, hearing loss, hypertension, high alcohol intake, obesity, smoking, depression, social isolation, physical inactivity, type 2 diabetes, sleep disturbance and socioeconomic deprivation. We performed linkage disequilibrium score regression among these traits, followed by exploratory factor analysis, confirmatory factor analysis and structural equation modelling.

Results

We identified complex networks of linkage disequilibrium among Alzheimer’s disease risk factors. The data were best explained by a bi-factor model, incorporating a Common Factor for Alzheimer’s risk, and three orthogonal sub-clusters of risk factors, which were validated across the two halves of the autosome. The first sub-cluster was characterised by risk factors related to sedentary lifestyle behaviours, the second by traits associated with reduced life expectancy and the third by traits that are possible prodromes of Alzheimer’s disease. Alzheimer’s disease was more genetically distinct and displayed minimal shared genetic architecture with its risk factors, which was robust to the exclusion ofAPOE.

Conclusion

Shared genetic architecture may contribute to epidemiological associations between Alzheimer’s disease and its risk factors. Understanding the biology reflected by this communality may provide novel mechanistic insights that could help to prioritise targets for dementia prevention.
On Cross-ancestry Cancer Polygenic Risk Scores
Authors: Fritsche Lars G. , Ma Ying , Zhang Daiwei , Salvatore Maxwell , Lee Seunggeun , Zhou Xiang , Mukherjee Bhramar
Published: March 2021

Polygenic risk scores (PRS) can provide useful information for personalized risk stratification and disease risk assessment, especially when combined with non-genetic risk factors. However, their construction depends on the availability of summary statistics from genome-wide association studies (GWAS) independent from the target sample. For best compatibility, it was reported that GWAS and the target sample should match in terms of ancestries. Yet, GWAS, especially in the field of cancer, often lack diversity and are predominated by European ancestry. This bias is a limiting factor in PRS research. By using electronic health records and genetic data from the UK Biobank, we contrast the utility of breast and prostate cancer PRS derived from external European-ancestry-based GWAS across African, East Asian, European, and South Asian ancestry groups. We highlight differences in the PRS distributions of these groups that are amplified when PRS methods condense hundreds of thousands of variants into a single score. While European-GWAS-derived PRS were not directly transferrable across ancestries on an absolute scale, we establish their predictive potential when considering them separately within each group. For example, the top 10% of the breast cancer PRS distributions within each ancestry group each revealed significant enrichments of breast cancer cases compared to the bottom 90% (odds ratio of 2.81 [95%CI: 2.69,2.93] in European, 2.88 [1.85, 4.48] in African, 2.60 [1.25, 5.40] in East Asian, and 2.33 [1.55, 3.51] in South Asian individuals). Our findings highlight a compromise solution for PRS research to compensate for the lack of diversity in well-powered European GWAS efforts while recruitment of diverse participants in the field catches up.
Systematic development of an mHealth app to prevent healthcare-associated infections by involving patients: Participatient
Authors: Bentvelsen R.G. , van der Vaart R. , Veldkamp K.E. , Chavannes N.H.
Published: March 2021

Introduction

In hospital care, urinary catheters are frequently used, causing a substantial risk for catheter-associated urinary tract infections (CAUTI). Patient awareness and evaluation of appropriateness of their catheter through mHealth could decrease these healthcare-associated infections. However, patient engagement via mHealth in infection prevention is still limited. Therefore, we describe the systematic development and usability evaluation of the mHealth intervention Participatient, to prevent CAUTI, aiming for optimal adoption of the app in the clinical setting.

Method

The CeHRes roadmap was used as development guideline, operationalizing phases for (1) contextual inquiry (observations and interviews), (2) value specification (interviews with probing) and (3) design in multiple steps and in co-creation with end-users. During phases 1 and 2, semi-structured interviews were conducted with fifteen patients and three nurses. The design phase was combined with the minimum viable product development strategy, with a focus on early cyclic steps of prototyping.

Results

In phase 1, patients acknowledged the risks of catheter use. Patients in phase 2 valued endorsement of a mHealth application by healthcare workers and reported to own a smartphone. Both patients and nurses recognized the need for useful modules in the app besides catheter care. Based on the needs and values as found in phase 2, the Participation app was developed. Based on usability tests in phase 3, content, text size, plain language, and navigation structures were further amended, and images were added.

Conclusion

This study provides real-world insight in the developmental strategy for mHealth interventions by involving both patients and care providers. Development of an app using thorough needs-assessment provided understanding for its content and design. By developing an app providing patients with reliable information and daily checklists, we aim to provide a tailored tool for communication and awareness on catheter use for the whole ward, and a potential blueprint for mHealth development.
High failure rate of ChAdOx1 in healthcare workers during Delta variant surge: A case for continued use of masks post-vaccination
Authors: Ujjainiya Rajat , Tyagi Akansha , Sardana Viren , Naushin Salwa , Bhatheja Nitin , Kumar Kartik , Barman Joydeb , Prakash Satyartha , Kutum Rintu , Bhaskar Akash K , Singh Prateek , Chaudhary Kumardeep , Loomba Menka , Khanna Yukti , Walecha Chestha , Ahmed Rizwan , Yadav Ashutosh , Bajaj Archana , Malik Gaurav , Qureshi Sahar , Waghdhare Swati , Siddiqui Samreen , Trehan Kamal Krishan , Mani Manju , Dang Rajiv , Das Poonam , Dougall Pankaj , Mahajan Monica , Sonar Sudipta , Jakhar Kamini , Kumar Reema , Tiwari Mahima , Mani Shailendra , Bhattacharyya Sankar , Budhiraja Sandeep , Agrawal Anurag , Dash Debasis , Jha Sujeet , Sengupta Shantanu
Published: March 2021

Immunization is expected to confer protection against infection and severe disease for vaccinees, while reducing risks to unimmunized populations by inhibiting transmission. Here, based on serial serological studies, we show that during a severe SARS-CoV2 Delta-variant outbreak in Delhi, 25.3% (95% CI 16.9 - 35.2) of previously uninfected, ChAdOx1-nCoV19 double vaccinated, healthcare-workers (HCW) were infected within a period of less than two months, based on serology. Induction of anti-spike response was similar between groups with breakthrough infection (541 U/ml, IQR 374) or not (342 U/ml, IQR 497), as was induction of neutralization activity to wildtype. Most infections were unrecognized. The Delta-variant thus causes frequent unrecognized breakthrough infections in adequately immunized subjects, reducing any herd-effect of immunity, and requiring reinstatement of preventive measures such as masking.
Prevalence of SARS-CoV-2 antibodies among workers of the public higher education institutions of Porto, Portugal
Authors: Meireles Paula , Amaro Joana , Costa Joana Pinto , Lopes Mariana Mendes , Varandas Tatiana , Norton Pedro , Guimarães João Tiago , Severo Milton , Barros Henrique
Published: March 2021

Objectives

To assess the prevalence of SARS-CoV-2 specific immunoglobulin (Ig) M and IgG antibodies among workers of the three public higher education institutions of Porto, Portugal, up to July 2020.

Methods

A rapid point of care test for specific IgM and IgG antibodies of SARS-CoV-2 was offered to all workers. Testing was performed to and a questionnaire was completed by 4592 workers on a voluntary basis. We computed the apparent IgM, IgG, and combined IgM or IgG prevalence, along with the true prevalence and 95% credible intervals (95% CI) using Bayesian inference.

Results

We found an apparent prevalence of 3.1% for IgM, 1.0% for IgG, and 3.9% for either antibody class. The estimated true prevalence was 2.0% (95% CI 0.1-4.3) for IgM, 0.6% (95% CI 0.0-1.3) for IgG and 2.5% (95% CI 0.1-5.3) for IgM or IgG. A SARS-CoV-2 molecular diagnosis was reported by 21 (0.5%) workers, and of these, 90.5% had a reactive IgG result. Seroprevalence was higher among those reporting known contacts with confirmed cases, having been quarantined, having a previous molecular negative test, or having had symptoms.

Conclusions

The seroprevalence among workers from the three public higher education institutions of Porto after the first wave of the SARS-CoV-2 infection was relatively low. However, the estimated true seroprevalence was approximately five times higher than the reported SARS-CoV-2 infection based on a molecular test result.
Instructor-learner neural synchronization during elaborated feedback predicts learning transfer
Authors: Zhu Yi , Leong Victoria , Hou Yingying , Zhang Dingning , Pan Yafeng , Hu Yi
Published: March 2021

The provision of feedback with complex information beyond the correct answer, i.e., elaborated feedback, can powerfully shape learning outcomes such as transfer, i.e., the ability to extend what has been learned in one context to new contexts. However, an understanding of neurocognitive processes of elaborated feedback during instructor-learner interactions remains elusive. Here, a two-person interactive design is used during simultaneous recording of functional near-infrared spectroscopy (fNIRS) signals from adult instructor-learner dyads. Instructors either provided elaborated feedback (i.e., correct answer and an example) or simple feedback (i.e., correct answer only) to learners during a concept learning task. Our results showed that elaborated feedback produced comparable levels of retention to simple feedback, however, transfer was significantly enhanced by elaboration. We also noted significant instructor-learner neural synchronization in frontoparietal regions during the provision of elaborated feedback, especially when examples were provided. Further, interpersonal neural synchronization in the parietal cortex successfully predicted transfer of knowledge to novel contexts. This prediction was retained for both learner-delayed and learner-preceding neural synchronization. These findings point toward transfer effects of elaborated feedback provided in a social context can be predictable through interpersonal neural synchronization, which may hold important implications for real-world learning and pedagogical efficacy.

Educational Impact and Implications Statement

Feedback provides learners with crucial information regarding the gap between what has currently been achieved and what remains to be achieved, and thus plays a critical role in any learning process. In real-world settings, feedback is typically provided and received through social interaction, and high-quality “elaborated feedback” contains complex information that goes beyond the correct answer. This study aims to elucidate the neurocognitive processes underpinning elaborated feedback during instructor-learner interactions. We detected significant instructor-learner neural synchronization in mutual frontoparietal brain regions during elaborated feedback, particularly during the provision of specific elaborated information (i.e., concrete examples). Moreover, this synchronization (including learner-delayed and learner-preceded synchronization) in the parietal region predicted whether the learners transferred learning to novel examples of learned psychology concepts. This study advances current understanding on the neural mechanisms for elaborated feedback and the role of social interaction in feedback effects. These results may have important implications for successful real-world learning and communication, and related pedagogical applications in educational settings.
The E3 Ubiquitin Ligase RNF5 Facilitates SARS-CoV-2 Membrane Protein-Mediated Virion Release
Authors: Yuan Zhen , Hu Bing , Wang Yulei , Tan Xuan , Xiao Hurong , Yue Mengzhen , Cai Kun , Tang Ke , Ding Binbin
Published: March 2021

As enveloped virus, SARS-CoV-2 membrane protein (M) mediates viral release from cellular membranes, but the molecular mechanisms of SARS-CoV-2 virions release remain poorly understood. Here, we performed RNAi screening and identified the E3 ligase RNF5 which mediates ubiquitination of SARS-CoV-2 M at residue K15 to enhance the interaction of viral envelope (E) with M. M-E complex ensures the uniform size of viral particles for viral maturation and mediates viral release. Moreover, overexpression of M induces complete autophagy which is dependent on RNF5-mediated ubiquitin modification. M inhibits the activity of lysosome protease, and uses autolysosomes for virion release. Consequently, all these results demonstrate that RNF5 mediates ubiquitin modification of SARS-CoV-2 M to stabilize the M-E complex and induce autophagy for virion release.
Persistence of G10P[11] neonatal rotavirus infections in southern India
Authors: Babji Sudhir , Sindhu Kulandaipalayam Natarajan , Selvarajan Sribal , Ramani Sasirekha , Venugopal Srinivasan , Khakha Shainey Alokit , Hemavathy Priya , Ganesan Santhosh Kumar , Giri Sidhartha , Reju Sudhabharathi , Gopalakrishnan Krithika , Ninan Binu , Iturriza-Gomara Miren , Srikanth Padma , Kang Gagandeep
Published: March 2021

Neonatal rotavirus infections are predominantly caused by distinct genotypes restricted to this age-group and are mostly asymptomatic. Stool samples from neonates admitted for >48 hours in neonatal intensive care units (NICUs) in Vellore (2014-2015) and Chennai (2015-2016) in southern India, and from neonates born at hospitals in Vellore but not admitted to NICUs (2015-2016) were tested for rotavirus by ELISA and genotyped by hemi-nested RT-PCR. Of the 791 neonates, 150 and 336 were recruited from Vellore and Chennai NICUs, and 305 were born in five hospitals in Vellore. The positivity rates in the three settings were 49.3% (74/150), 29.5% (99/336) and 54% (164/305), respectively. G10P[11] was the commonly identified genotype in 87.8% (65/74), 94.9% (94/99) and 98.2% (161/164) of the neonates in Vellore and Chennai NICUs, and those born at Vellore hospitals, respectively. Neonates delivered by lower segment caesarean section (LSCS) at Vellore hospitals, not admitted to NICUs, had a significantly higher odds of acquiring rotavirus infection compared to those delivered vaginally [p=0.002, OR=2.4 (1.4-4.3)]. This report demonstrates the persistence of G10P[11] strain in Vellore and Chennai, indicating widespread neonatal G10P[11] strain in southern India and their persistence over two decades, leading to interesting questions about strain stability.
Distinct systemic and mucosal immune responses to SARS-CoV-2
Authors: Smith Nikaïa , Goncalves Pedro , Charbit Bruno , Grzelak Ludivine , Beretta Maxime , Planchais Cyril , Bruel Timothée , Rouilly Vincent , Bondet Vincent , Hadjadj Jérôme , Yatim Nader , Pere Helene , Merkling Sarah H , Kernéis Solen , Rieux-Laucat Frederic , Terrier Benjamin , Schwartz Olivier , Mouquet Hugo , Duffy Darragh , Di Santo James P.
Published: March 2021

Coordinated local mucosal and systemic immune responses following SARS-CoV-2 infection protect against COVID-19 pathologies or fail leading to severe clinical outcomes. To understand this process, we performed an integrated analysis of SARS-CoV-2 spike-specific antibodies, cytokines, viral load and 16S bacterial communities in paired nasopharyngeal swabs and plasma samples from a cohort of clinically distinct COVID-19 patients during acute infection. Plasma viral load was associated with systemic inflammatory cytokines that were elevated in severe COVID-19, and also with spike-specific neutralizing antibodies. In contrast, nasopharyngeal viral load correlated with SARS-CoV-2 humoral responses but inversely with interferon responses, the latter associating with protective microbial communities. Potential pathogenic microrganisms, often implicated in secondary respiratory infections, were associated with mucosal inflammation and elevated in severe COVID-19. Our results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes.
AB12PHYLO: an integrated pipeline for Maximum Likelihood phylogenetic inference from ABI trace data
Authors: Kaindl Leo , Small Corinn , Stam Remco
Published: March 2021

Multi-gene phylogenies constructed from multiplexed and Sanger sequencing data are regularly used in mycology and other disciplines as a cost-effective way of species identification and as a first means to investigate genetic diversity samples.

Today, a number of tools exist for each of the steps in this analysis, including quality control and trimming, the generation of a multiple sequence alignment (MSA), extraction of informative sites, and the construction of the final phylogenetic tree. A BLAST search in a reference database is often performed to identify sequences of type specimens to compare the samples with in the phylogeny. Made over the past decades, these tools are all independent from and often not perfectly adapted to one another.

We present AB12PHYLO, an integrated pipeline that can perform all necessary steps from reading in raw Sanger sequencing data through visualizing and editing phylogenies. In addition, AB12PHYLO can calculate basic summary statistics for each gene in the phylogeny.

AB12PHYLO is designed as a wrapper of several open access and commonly used tools for each of the intermediate stages, and intended to simplify the phylogenetic pipeline while still allowing a high degree of access. It comes as a command-line version for the highest reproducibility and an intuitive graphical user interface (GUI) for easy adoption by IT-agnostic end-users. The use of AB12PHYLO significantly reduces the hands-on working time for these analyses.
Species-wide transposable element repertoires retrace the evolutionary history of theSaccharomyces cerevisiaehost
Authors: Bleykasten-Grosshans Claudine , Fabrizio Romeo , Friedrich Anne , Schacherer Joseph
Published: March 2021

Transposable elements (TE) are an important source of genetic variation with a dynamic and content that greatly differ in a wide range of species. The origin of the intraspecific content variation is not always clear and little is known about the precise nature of it. Here, we surveyed the species-wide content of the Ty LTR-retrotransposons in a broad collection of 1,011Saccharomyces cerevisiaenatural isolates to understand what can stand behind the variation of the repertoire,i.e.the type and number of Ty elements. We have compiled an exhaustive catalog of all TE variants present in theS. cerevisiaespecies by identifying a large set of new variants. The characterization of the TE content in each isolate clearly highlighted that each subpopulation exhibits a unique and specific repertoire, retracing the evolutionary history of the species. Most interestingly, we have shown that ancient interspecific hybridization events had a major impact in the birth of new variants and therefore in the shaping of the TE repertoires. We also investigated the transpositional activity of these elements in a large set of natural isolates, and we found a broad variability related to the level of ploidy as well as the genetic background. Overall, our results pointed out that the evolution of the Ty content is deeply impacted by clade-specific events such as introgressions and therefore follows the population structure. In addition, our study lays the foundation for future investigations to better understand the transpositional regulation and more broadly the TE-host interactions.

Authors summary

Mobile DNA elements are widely distributed in the genomes of many eukaryotes, but their contents greatly vary between species, populations and even individuals. In fact, little is known about the origin of this variation of transposable element (TE) content across individuals of the same species. Here, we surveyed the Ty LTR-retrotransposon content in a broad collection of 1,011Saccharomyces cerevisiaeyeast natural isolates. We have defined an exhaustive and precise catalog of the TE variants present in theS. cerevisiaespecies. We found that the TE content follows the evolutionary history of the species because each subpopulation has a unique and specific content. Interestingly, our results highlighted that ancient interspecific hybridization events led to the appearance of new TE variants and therefore had a strong impact on the variation of the TE repertoires in this species. We also investigated the transpositional activity of these elements and found a wide variability related to the genetic background diversity. Altogether, our results have led to a better understanding of the variability of TE content at a species level.
Social behaviour and vocalizations of the tent-roosting Honduran White Bat
Authors: Fernandez Ahana Aurora , Schmidt Christian , Schmidt Stefanie , Rodríguez-Herrera Bernal , Knörnschild Mirjam
Published: March 2021

Bats are highly gregarious animals, displaying a large spectrum of social systems with different organizational structures. One important factor shaping sociality is group stability. To maintain group cohesion and stability, bats often rely on social vocal communication. The Honduran white bat,Ectophylla albaexhibits an unusual social structure compared to other tent-roosting species. This small white-furred bat lives in perennial stable mixed-sex groups. Tent construction requires several individuals and, as the only tent roosting species so far, involves both sexes. The bats’ social system and ecology render this species an interesting candidate to study social behaviour and social vocal communication. In our study, we investigated the social behaviour and vocalizations ofE. albain the tent by observing two stable groups, including pups, in the wild. We documented 16 different behaviours, among others, play and fur chewing, a behaviour presumably used for scent-marking. Moreover, we found 10 distinct social call types in addition to echolocation calls, and, for seven call types, we were able to identify the corresponding behavioural context. Most of the social call types were affiliative, including two types of contact calls, maternal directives, pup isolation calls and a call type related to the fur-chewing behaviour. In sum, this study entails an ethogram and describes the first vocal repertoire of a tent-roosting phyllostomid bat, providing the basis for further in-depth studies about the sociality and vocal communication inE. alba.
ASSOCIATION STUDY OF SIX CANDIDATE GENES WITH MAJOR DEPRESSIVE DISORDER IN THE NORTH-WESTERN POPULATION OF PAKISTAN
Authors: Alam Naqash , Ali Sadiq , Akbar Nazia , Ilyas Muhammad , Ahmed Habib , Mustafa Arooj , Khurram Shehzada , Sajid Zeeshan , Ullah Najeeb , Qayyum Shumaila , Rahim Tariq , Usman Mian Syed , Ali Nawad , Khan Imad , Pervez Khola , Sumaira BiBi , Ali Nasir , Sultana Nighat , Tanoli Adeel Yunus , Islam Madiha
Published: March 2021

People around the world are currently affected by Major Depressive Disorder (MDD). Despite its many aspects, symptoms, manifestations and impacts, efforts have been made to identify the root causes of the disorder. In particular, genetic studies have concentrated on identifying candidate genes for MDD and exploring associations between these genes and some specific group of individuals. The aim of this research was to find out the association between single nucleotide polymorphisms in 6 candidate genes linked to the neurobiology of major depressive disorder in the North-Western population of Pakistan. We performed a case-control analysis, with 400 MDD and 232 controls. A trained psychiatrist or clinical psychologists evaluated the patients. Six polymorphisms were genotyped and tested for allele and genotype association with MDD. There were no statistical variations between MDD patients and healthy controls for genotypic and allelic distribution of all the polymorphisms observed. Thus, our analysis does not support the major role of these polymorphisms in contributing to MDD susceptibility, although it does not preclude minor impact. The statistically significant correlation between six polymorphisms and major depressive disorder in the studied population was not observed. There are inconsistencies in investigations around the world. Future research, including GWAS and association analysis on larger scale should be addressed for further validation and replication of the present findings.
The time to peak blood bicarbonate (HCO3−), pH, and strong ion difference (SID) following sodium bicarbonate (NaHCO3) ingestion in highly trained adolescent swimmers
Authors: Newbury Josh W. , Cole Matthew , Kelly Adam L. , Chessor Richard J. , Sparks S. Andy , McNaughton Lars R. , Gough Lewis A.
Published: March 2021

Background

Contemporary research suggests that the optimal timing of sodium bicarbonate (NaHCO3) should be based upon an individual time in which bicarbonate (HCO3−) or pH peaks within the blood. However, the mechanisms surrounding acidosis on exercise performance are contested, therefore it is plausible that the ergogenic effects of NaHCO3are instead a result of an increased strong ion difference (SID) following ingestion. Since the post-ingestion time course of the SID is currently unknown, the purpose of this study was to investigate the pharmacokinetics of the SID in direct comparison to HCO3−and pH.

Methods

Twelve highly trained, adolescent swimmers (age: 15.9 ± 1.0 yrs, body mass: 65.3 ± 9.6 kg) consumed their typical pre-competition nutrition before ingesting 0.3 g·kg BM-1NaHCO3in gelatine capsules. Capillary blood samples were then taken during quiet, seated rest on nine occasions (0, 60, 75, 90, 105, 120, 135, 150, and 165 min post-ingestion) for the assessment of time course changes in HCO3−, pH, and the SID.

Results

On a group mean level, no differences were found in the time in which each variable peaked within the blood (HCO3−= 130 ± 35 min, pH = 120 ± 38 min, SID = 96 ± 35 min; p = 0.06). A large effect size was calculated between the timing of peak HCO3−and the SID (g= 0.91), however, suggesting that a difference may occur between these two measures in practice.

Conclusions

A time difference between peak HCO3−and the SID presents an interesting avenue for further research since an approach based upon individual increases in extracellular SID has yet to be investigated. Future studies should therefore compare these dosing strategies directly to elucidate whether either one is more ergogenic for exercise performance.
Metacognitive Computations for Information Search: Confidence in Control
Authors: Schulz Lion , Fleming Stephen M. , Dayan Peter
Published: March 2021

The metacognitive sense of confidence can play a critical role in regulating decisionmaking. In particular, a lack of confidence can justify the explicit, potentially costly, instrumental acquisition of extra information that might resolve the underlying uncertainty. Recent work has suggested a statistically sophisticated tapestry behind the information governing both the making and monitoring of choices. Here, we extend this tapestry to reveal extra richness in the use of confidence for controlling information seeking. We thereby highlight how different models of metacognition can generate diverse relationships between action, confidence, and information search. More broadly, our work shows how crucial it can be to treat metacognitive monitoring and control together.
Copy number variant heterogeneity among cancer types reflects inconsistent concordance with diagnostic classifications
Authors: Carrio-Cordo Paula , Baudis Michael
Published: March 2021

Due to frequent genome instability and accumulation of mutations during the neoplastic process, malignant tumors present with patterns of somatic genome variants on diverse levels of heterogeneity. The delineation of pathophysiological consequences of these patterns remains one of the main challenges in cancer prognosis and treatment.

Although continuous efforts aim for better characterization of cancer entities through inclusion of molecular characteristics, current ontology systems still heavily rely on clinico-pathological features. Traditionally, malignant diseases have been classified using domain-specific or generalized classification systems, based on histopathological features and clinical gestalt. Aside from the general purpose “International Classification for Diseases in Oncology” (ICD-O; WHO), hierarchical terminologies such as NCIt promote data interoperability and ontology-driven computational analysis.

To evaluate two prominent, general cancer classification systems (NCIt and ICD-O) towards their concordance with genomic mutation patterns we have performed a data-driven meta-analysis of 83’505 curated cancer samples with genome-wide CNA (copy number aberration) profiles from our Progenetix database. The analysis provides a basis to assess the correspondence level of existing classification systems with respect to homogeneous molecular groups, and how individual codes represent an adequately detailed classification.
The aging DNA methylome reveals environment-by-aging interactions in a model teleost
Authors: Bertucci Emily M. , Mason Marilyn W. , Rhodes Olin E. , Parrott Benjamin B.
Published: March 2021

The rate at which individuals age underlies variation in life history and attendant health and disease trajectories. Age specific patterning of the DNA methylome (“epigenetic aging”) is strongly correlated with chronological age in humans and can be modeled to produce epigenetic age predictors. However, epigenetic age estimates vary among individuals of the same age, and this mismatch is correlated to the onset of age-related disease and all-cause mortality. Yet, the origins of epigenetic-to-chronological age discordance are not resolved. In an effort to develop a tractable model in which environmental drivers of epigenetic aging can be assessed, we investigate the relationship between aging and DNA methylation in a small teleost, medaka (Oryzias latipes). We find that age-associated DNA methylation patterning occurs broadly across the genome, with the majority of age-related changes occurring during early life. By modeling the stereotypical nature of age-associated DNA methylation dynamics, we built an epigenetic clock, which predicts chronological age with a mean error of 29.1 days (~4% of average lifespan). Characterization of clock loci suggests that aspects of epigenetic aging are functionally similar across vertebrates. To understand how environmental factors interact with epigenetic aging, we exposed medaka to four doses of ionizing radiation for seven weeks, hypothesizing that exposure to such an environmental stressor would accelerate epigenetic aging. While the epigenetic clock was not significantly affected, radiation exposure accelerated and decelerated patterns of normal epigenetic aging, with radiation-induced epigenetic alterations enriched at loci that become hypermethylated with age. Together, our findings advance ongoing research attempting to elucidate the functional role of DNA methylation in integrating environmental factors into the rate of biological aging.
MoBiFC: development of a modular bimolecular fluorescence complementation toolkit for the analysis of chloroplast protein-protein interactions
Authors: Velay Florent , Soula Melanie , Mehrez Marwa , D’Alessandro Stefano , Laloi Christophe , Crete Patrice , Field Ben
Published: March 2021

The bimolecular fluorescence complementation (BiFC) assay has emerged as one of the most popular methods for analysing protein-protein interactions (PPIs) in plant biology. This includes its increasing use as a tool for dissecting the molecular mechanisms of chloroplast function. However, the construction of chloroplast fusion proteins for BiFC can be difficult, and the availability and selection of appropriate controls is not trivial. Furthermore, the challenges of performing BiFC in restricted cellular compartments has not been specifically addressed. Here we describe the development of a flexible modular cloning-based toolkit (MoBiFC) for chloroplast BiFC and proximity labelling using synthetic biology principles. The approach facilitates the cloning process for chloroplast-targeted proteins, allows robust ratiometric quantification, and the toolkit comes with model positive and negative controls. Our study also highlights many potential pitfalls including the choice of fluorescent protein (FP) split, negative controls, cell type, and reference FP. Finally, we provide an example of how users can enrich the toolset by providing functional proximity labelling modules, and we discuss how MoBiFC could be further improved and extended to other compartments of the plant cell.
Acid sphingomyelinase deactivation post-ischemia/ reperfusion promotes cerebral angiogenesis and brain remodeling via small extracellular vesicles
Authors: Mohamud Yusuf A , Hagemann N , Zhang X , Zafar M , Hussner T , Bromkamp C , Martiny C , Tertel T , Börger V , Schumacher F , Solari FA , Hasenberg M , Kleinschnitz C , Doeppner TR , Kleuser B , Sickmann A , Gunzer M , Giebel B , Kolesnick R , Gulbins E , Hermann DM
Published: March 2021

Functional inhibitors of acid sphingomyelinase are clinically used as anti-depressants since ∼60 years. Here, we show that acid sphingomyelinase inhibition by the antidepressants amitriptyline, fluoxetine and desipramine protects from ischemia/reperfusion and elicits a profound brain remodeling response with increased angiogenesis, improved blood-brain barrier integrity, reduced brain leukocyte infiltration and increased neuronal survival. Angiogenesis is promoted by small extracellular vesicles withbona fidecharacteristics of exosomes, which are released from endothelial cells and which constitute an elegant target for the amplification of stroke recovery.
CD47 as a potential biomarker for the early diagnosis of severe COVID-19
Authors: McLaughlin Katie-May , Bojkova Denisa , Bechtel Marco , Kandler Joshua D. , Reus Philipp , Le Trang , Wagner Julian U. G. , Ciesek Sandra , Wass Mark N. , Michaelis Martin , Cinatl Jindrich
Published: March 2021

The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Most SARS-CoV-2 infections are mild or even asymptomatic. However, a small fraction of infected individuals develops severe, life-threatening disease, which is caused by an uncontrolled immune response resulting in hyperinflammation. Antiviral interventions are only effective prior to the onset of hyperinflammation. Hence, biomarkers are needed for the early identification and treatment of high-risk patients. Here, we show in a range of model systems and data from post mortem samples that SARS-CoV-2 infection results in increased levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells. Systematic literature searches also indicated that known risk factors such as older age and diabetes are associated with increased CD47 levels. High CD47 levels contribute to vascular disease, vasoconstriction, and hypertension, conditions which may predispose SARS-CoV-2-infected individuals to COVID-19-related complications such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury. Hence, CD47 is a candidate biomarker for severe COVID-19. Further research will have to show whether CD47 is a reliable diagnostic marker for the early identification of COVID-19 patients requiring antiviral therapy.
Acetylcholine boosts dendritic NMDA spikes in a CA3 pyramidal neuron model
Authors: Humphries Rachel , Mellor Jack R. , O’Donnell Cian
Published: March 2021

Acetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca2+influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of acetylcholine on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca2+-activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles.

Highlights

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Using biophysical computational models of CA3 pyramidal neurons we estimated the quantitative effects of acetylcholine on nonlinear synaptic integration.

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Nonlinear NMDA spikes can be triggered by fewer synapses in distal dendrites due to increased local input resistance.

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Acetylcholine broadly reduces the number of synapses needed to trigger NMDA spikes, but the magnitude of the effect varies across dendrite branches within a single neuron.

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No single potassium channel type is the dominant mediator of the excitability effects of acetylcholine.
Non-canonical Hedgehog signaling through L-type voltage gated Ca2+channels controls CD8+T cell killing
Authors: Hanna Joachim , Kapeni Chrysa , O’Brien Louise , Carbonaro Valentina , Beke Flavio , Chilamakuri Chandra , de la Roche Maike
Published: March 2021

Cytotoxic CD8+T lymphocytes (CTLs) are critical to the immune response against intracellular pathogens and cancer and act by eliminating infected and malignant cells through targeted secretion of cytotoxic granules. Hedgehog (Hh) signaling has been shown to be critical for CTL killing. Interestingly, Hh signaling in CD8+T cells is not induced by extracellular Hh ligands but is initiated upon T cell receptor (TCR) engagement. How the TCR induces the Hh pathway independently of extracellular Hh ligands is unknown. Here we show that the Hh transcription factor Gli1 is essential for efficient CTL function and is induced downstream of the TCR by an extracellular Ca2+influx selectively controlled by L-type voltage gated Ca2+channels localized at the plasma membrane. We demonstrate that this novel mode of Hh signaling induction is independent of the canonical Hh pathway and represents the primary mechanism of Gli1 induction in naïve CD8+T cells, while CTLs can also activate Gli1 via MAP Kinase signaling. Importantly, we show that this L-type voltage gated Ca2+channel-controlled Gli1 induction is functionally required for CTL killing in mice and humans. Gli inhibitors are currently in clinical trials against various cancers and our observations indicate that they likely inhibit the anti-tumor response.

Significance statement

Cytotoxic CD8+T cells (CTLs) kill infected and malignant cells by targeted secretion of cytotoxic granules. Hedgehog signaling is critical for effective CTL killing and is activated by the T cell receptor (TCR) independently of exogenous Hedgehog ligands. This study shows that Hedgehog transcription factor Gli1 is required for CTL killing and identifies L-type voltage gated Ca2+channels (Cav1) as essential regulators of CTL killing in mouse and human, by virtue of their ability to activate Gli1 downstream of the TCR. This Cav1-Gli1 axis operates independently of canonical Hedgehog signaling. Our work suggests that caution is required when using Gli inhibitors, currently in trials as anti-cancer therapeutics, since they may dampen the anti-tumor response.
Interaction of thyroid hormones and gonadotropin inhibitory hormone in the multifactorial control of zebrafish (Danio rerio) spermatogenesis
Authors: Rodrigues Maira S. , Fallah Hamideh P. , Zanardini Maya , Habibi Hamid R. , Nóbrega Rafael H.
Published: March 2021

Reproduction is under multifactorial control of neurohormones, pituitary gonadotropins, as well as a number of gonadal hormones including sex steroids and growth factors. Gonadotropin-inhibitory hormone (Gnih), a novel RFamide neuropeptide, was shown to be involved in the control of pituitary gonadotropin production, as well as being involved as a paracrine factor in the regulation of gonadal function. In this context, recent studies have demonstrated that Gnih inhibited gonadotropin-induced spermatogenesis in the zebrafish testicular explants. Thyroid hormones are known to interact with the reproductive axis, and are, in particular, involved in the regulation of testicular function. Based on this background, we investigated the interaction between Gnih and thyroid hormones in the control of zebrafish spermatogenesis. To this end, zebrafish adult males were treated with the goitrogen methimazole (1mM for 21 days) in order to generate a hypothyroid model organism. Subsequently, a factorial design using anex vivotestis culture system in combination with histomorphometrical and FACScan cell cycle analyses were adopted. Our results showed that methimazole treatment affected both basal and gonadotropin-induced spermatogenesis, in particular, meiosis and spermiogenesis. Moreover, the goitrogen treatment nullified the inhibitory actions of Gnih on the gonadotropin-induced spermatogenesis, specifically in the haploid cell population. We have demonstrated that thyroid hormones interaction with gonadotropin and Gnih are important components for the regulation of zebrafish spermatogenesis. The results provide a support for the hypothesis that thyroid hormones are important contributors in multifactorial control of spermatogenesis in zebrafish.
The spatiotemporal organization of experience dictates hippocampal involvement in primary visual cortical plasticity
Authors: Finnie Peter S. B. , Komorowski Robert W. , Bear Mark F.
Published: March 2021

The hippocampus and neocortex are theorized to be crucial partners in the formation of long-term memories. Here, we assess hippocampal involvement in two related forms of experience-dependent plasticity in the primary visual cortex (V1) of mice. Like control animals, those with hippocampal lesions exhibit potentiation of visually evoked potentials following passive daily exposure to a phase reversing oriented grating stimulus, which is accompanied by long-term habituation of a reflexive behavioral response. Thus, low-level recognition memory is formed independently of the hippocampus. However, response potentiation resulting from daily exposure to a fixed sequence of four oriented gratings is severely impaired in mice with hippocampal damage. A feature of sequence plasticity in V1 of controls, but absent in lesioned mice, is generation of predictive responses to an anticipated stimulus element when it is withheld or delayed. Thus, hippocampus is involved in encoding temporally structured experience, even in primary sensory cortex.
Deciphering enhancer sequence using thermodynamics-based models and convolutional neural networks
Authors: Dibaeinia Payam , Sinha Saurabh
Published: March 2021

Deciphering the sequence-function relationship encoded in enhancers holds the key to interpreting non-coding variants and understanding mechanisms of transcriptomic variation. Several quantitative models exist for predicting enhancer function and underlying mechanisms; however, there has been no systematic comparison of these models characterizing their relative strengths and shortcomings. Here, we interrogated a rich data set of neuroectodermal enhancers inDrosophila, representing cis- and trans- sources of expression variation, with a suite of biophysical and machine learning models. We performed rigorous comparisons of thermodynamics-based models implementing different mechanisms of activation, repression, and cooperativity. Moreover, we developed a convolutional neural network (CNN) model, called CoNSEPT, that learns enhancer “grammar” in an unbiased manner. CoNSEPT is the first general-purpose CNN tool for predicting enhancer function in varying conditions, and we show that such complex models can suggest interpretable mechanisms. We found model-based evidence for mechanisms previously established for the studied system, including cooperative activation and short-range repression. The data also favored one hypothesized activation mechanism over another and suggested an intriguing role for a direct, distance-independent repression mechanism. Our modeling shows that while fundamentally different models can yield similar fits to data, they vary in their utility for mechanistic inference. CoNSEPT is freely available at:https://github.com/PayamDiba/CoNSEPT.