bluuebunny/crossref_metadata_2025 huggingface dataset:
RISK OF ON JOB NON COMPLIANCE TOWARDS VARIOUS COVID-19 STANDARD & TRANSMISSION BASED INFECTION PREVENTION & CONTROL MEASURES/PRECAUTIONS AMONG THE HEALTHCARE WORKS WORKING IN OPD SETTINGs OF PUBLIC SECTOR TERTIORY CARE HOSPITALS OF QUETTA BALOCHISTAN
Authors: Arif Muhammad , Abdullah Muhammad , Chaudhary Ambreen , Hussain Zakir , Larik Ehsan
Published: July 2021

Background

COVID-19 Pandemic is still circulating within the human population and proving to be a deadlier disease with mortality rate ranging from 0.5 to 7%8. Since COVID-19 is a highly transmissible disease; there is always a probability for its out ward spread towards general public and community from the hospitals and healthcare facilities where they come to seek treatment.

Methodology

A prospective cohort study design was used, considering the limited available resources and time __ A total of 200 healthcare workers (Including Doctors, Nurses, Para-Medical staff, Janitorial staff, Reception staff & Pharmacists) working in the OPDs of the two major Public sector hospitals of Quetta were made part of this study. The study participants were selected using simple random sampling technique. The study participants from “Hospital-A” were first of all educated and trained on various COVID-19 IPC measures later on various COVID-19-IEC materials; written in simple Urdu language, were displayed clearly everywhere in the OPD. Similarly hand washing station along with Hand sanitizers/Soaps and surgical face masks were also made available free of cost for all the study participants of Hospital-A. More over the importance and effectiveness of COVID-19 IPC measures were continuously announced in the OPD gallery of Hospital-A, these announcements used Simple wording in local languages (i.e. Urdu, Pashto, Balochi & Brahvi). On the other hand in the OPD of “Hospital-B” no such interventions were made. The study participants of both the hospitals were followed for one month and observations like-which group showed more on-job non compliance towards various COVID-19 IPC measures were recorded. The data was recorded on daily bases (From 1stMay-to-31stMay 2021) after observing the study participants and checklist was used for recording various findings. Lastly all the data was analyzed using Microsoft Excel 2007 version.

Results

The major findings of this study are almost in line with the set objectives, the study results are clearly showing the Risk ratio (R.R) as 0.27, indicating that the intervention group participants were only 27% as likely to develop On-job non-compliance for various COVID-19 IPC measures compare to the non-intervention group.

Conclusion

The best suggestion and intervention for the developing countries that could at least address the spread of COVID-19 in a cost effective manner at health facility levels remains to be adoption of various Standard and Transmission based non-pharmacological measures of Infection prevention and Control (IPC)5.
In silico proof of principle of machine learning-based antibody design at unconstrained scale
Authors: Akbar Rahmad , Robert Philippe A. , Weber Cédric R. , Widrich Michael , Frank Robert , Pavlović Milena , Scheffer Lonneke , Chernigovskaya Maria , Snapkov Igor , Slabodkin Andrei , Mehta Brij Bhushan , Miho Enkelejda , Lund-Johansen Fridtjof , Andersen Jan Terje , Hochreiter Sepp , Haff Ingrid Hobæk , Klambauer Günter , Sandve Geir Kjetil , Greiff Victor
Published: July 2021

Generative machine learning (ML) has been postulated to be a major driver in the computational design of antigen-specific monoclonal antibodies (mAb). However, efforts to confirm this hypothesis have been hindered by the infeasibility of testing arbitrarily large numbers of antibody sequences for their most critical design parameters: paratope, epitope, affinity, and developability. To address this challenge, we leveraged a lattice-based antibody-antigen binding simulation framework, which incorporates a wide range of physiological antibody binding parameters. The simulation framework enables both the computation of antibody-antigen 3D-structures as well as functions as an oracle for unrestricted prospective evaluation of the antigen specificity of ML-generated antibody sequences. We found that a deep generative model, trained exclusively on antibody sequence (1D) data can be used to design native-like conformational (3D) epitope-specific antibodies, matching or exceeding the training dataset in affinity and developability variety. Furthermore, we show that transfer learning enables the generation of high-affinity antibody sequences from low-N training data. Finally, we validated that the antibody design insight gained from simulated antibody-antigen binding data is applicable to experimental real-world data. Our work establishes a priori feasibility and the theoretical foundation of high-throughput ML-based mAb design.

Highlights

A large-scale dataset of 70M [3 orders of magnitude larger than the current state of the art] synthetic antibody-antigen complexes, that reflect biological complexity, allows the prospective evaluation of antibody generative deep learning

Combination of generative learning, synthetic antibody-antigen binding data, and prospective evaluation shows that deep learning driven antibody design and discovery at an unconstrained level is feasible

Transfer learning (low-N learning) coupled to generative learning shows that antibody-binding rules may be transferred across unrelated antibody-antigen complexes

Experimental validation of antibody-design conclusions drawn from deep learning on synthetic antibody-antigen binding data

Graphical abstract

We leverage large synthetic ground-truth data to demonstrate the (A,B) unconstrained deep generative learning-based generation of native-like antibody sequences, (C) the prospective evaluation of conformational (3D) affinity, paratope-epitope pairs, and developability. (D) Finally, we show increased generation quality of low-N-based machine learning models via transfer learning.
Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology
Authors: Reifschneider Anika , Robinson Sophie , van Lengerich Bettina , Gnörich Johannes , Logan Todd , Heindl Steffanie , Vogt Miriam A , Weidinger Endy , Riedl Lina , Wind Karin , Zatcepin Artem , Haberl Sophie , Nuscher Brigitte , Kleinberger Gernot , Klimmt Julien , Götzl Julia K , Liesz Arthur , Bürger Katharina , Brendel Matthias , Levin Johannes , Diehl-Schmid Janine , Suh Jung , Di Paolo Gilbert , Lewcock Joseph W , Monroe Kathryn M , Paquet Dominik , Capell Anja , Haass Christian
Published: July 2021

GRNhaploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state.Trem2deficiency inGrnKO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages fromGRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism ofGrnKO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in theGrn/Trem2KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model.
Standardizing workflows in imaging transcriptomics with the abagen toolbox
Authors: Markello Ross D. , Arnatkevičiūtė Aurina , Poline Jean-Baptiste , Fulcher Ben D. , Fornito Alex , Misic Bratislav
Published: July 2021

Gene expression fundamentally shapes the structural and functional architecture of the human brain. Open-access transcriptomic datasets like the Allen Human Brain Atlas provide an unprecedented ability to examine these mechanisms in vivo; however, a lack of standardization across research groups has given rise to myriad processing pipelines for using these data. Here, we develop the abagen toolbox, an open-access software package for working with transcriptomic data, and use it to examine how methodological variability influences the outcomes of research using the Allen Human Brain Atlas. Applying three prototypical analyses to the outputs of 750,000 unique processing pipelines, we find that choice of pipeline has a large impact on research findings, with parameters commonly varied in the literature influencing correlations between derived gene expression and other imaging phenotypes by as much as ρ ≥ 1.0. Our results further reveal an ordering of parameter importance, with processing steps that influence gene normalization yielding the greatest impact on downstream statistical inferences and conclusions. The presented work and the development of the abagen toolbox lay the foundation for more standardized and systematic research in imaging transcriptomics, and will help to advance future understanding of the influence of gene expression in the human brain.
Microbiome divergence of marine gastropod species separated by the Isthmus of Panama
Authors: Neu Alexander T. , Torchin Mark E. , Allen Eric E. , Roy Kaustuv
Published: July 2021

The rise of the Isthmus of Panama ~3.5 mya separated populations of many marine organisms, which then diverged into new geminate sister species currently living in the Eastern Pacific Ocean and Caribbean Sea. However, we know very little about how such evolutionary divergences of host species have shaped their microbiomes. Here, we compared the microbiomes of whole-body and shell-surface samples of geminate species of marine gastropods in the genera Cerithium and Cerithideopsis to those of congeneric outgroups. Our results show that the effects of the Isthmus on microbiome composition varied among host genera and between sample types within the same hosts. In the whole-body samples, microbiome compositions of geminate species pairs in the focal genera tended to be similar, likely due to host filtering, although the strength of this relationship varied among the two groups and across similarity metrics. Shell-surface communities showed contrasting patterns, with co-divergence between the host taxa and a small number of microbial clades evident in Cerithideopsis, but not Cerithium. These results suggest that (i) the rise of the Isthmus of Panama affected microbiomes of geminate hosts in a complex and clade-specific manner and (ii) host-associated microbial taxa respond differently to vicariance events than the hosts themselves.
Unraveling patterns of disrupted gene expression across a complex tissue
Authors: Hunnicutt Kelsie E. , Good Jeffrey M. , Larson Erica L.
Published: July 2021

Whole tissue RNASeq is the standard approach for studying gene expression divergence in evolutionary biology and provides a snapshot of the comprehensive transcriptome for a given tissue. However, whole tissues consist of diverse cell types differing in expression profiles, and the cellular composition of these tissues can evolve across species. Here, we investigate the effects of different cellular composition on whole tissue expression profiles. We compared gene expression from whole testes and enriched spermatogenesis populations in two species of house mice, Mus musculus musculus and M. m. domesticus, and their sterile and fertile F1 hybrids, which differ in both cellular composition and regulatory dynamics. We found that cellular composition differences skewed expression profiles and differential gene expression in whole testes samples. Importantly, both approaches were able to detect large-scale patterns such as disrupted X chromosome expression although whole testes sampling resulted in decreased power to detect differentially expressed genes. We encourage researchers to account for histology in RNASeq and consider methods that reduce sample complexity whenever feasible. Ultimately, we show that differences in cellular composition between tissues can modify expression profiles, potentially altering inferred gene ontological processes, insights into gene network evolution, and processes governing gene expression evolution.
A specific relationship between musical sophistication and auditory working memory
Authors: Lad Meher , Billig Alexander J. , Kumar Sukhbinder , Griffiths Timothy D.
Published: July 2021

Musical engagement may be associated with better listening skills, such as the perception of and working memory for notes, in addition to the appreciation of musical rules. The nature and extent of this association is controversial. In this study we assessed the relationship between musical engagement and both sound perception and working memory.

We developed a task to measure auditory perception and working memory for sound using a behavioural measure for both, precision. We measured the correlation between these tasks and musical sophistication based on a validated measure (the Goldsmiths Musical Sophistication Index) that can be applied to populations of both musicians and non-musicians. The data show that musical sophistication accounts for 21% of the variance in the precision of working memory for frequency in an analysis that accounts for age and non-verbal intelligence. Musical sophistication was not significantly associated with the precision of working memory for amplitude modulation rate or with the precision of perception of either acoustic feature.

The work supports a specific association between musical sophistication and working memory for sound frequency.
Time-resolved structure-function coupling in brain networks
Authors: Liu Zhen-Qi , Vázquez-Rodríguez Bertha , Spreng R. Nathan , Bernhardt Boris C. , Betzel Richard F. , Misic Bratislav
Published: July 2021

The relationship between structural and functional connectivity in the brain is a key question in systems neuroscience. Modern accounts assume a single global structure-function relationship that persists over time. Here we show that structure-function coupling is dynamic and regionally heterogeneous. We use a temporal unwrapping procedure to identify moment-to-moment co-fluctuations in neural activity, and reconstruct time-resolved structure-function coupling patterns. We find that patterns of dynamic structure-function coupling are highly organized across the cortex. These patterns reflect cortical hierarchies, with stable coupling in unimodal and transmodal cortex, and dynamic coupling in intermediate regions, particularly in insular cortex (salience network) and frontal eye fields (dorsal attention network). Finally, we show that the variability of structure-function coupling is shaped by the distribution of connection lengths. The time-varying coupling of structural and functional connectivity points towards an informative feature of the brain that may reflect how cognitive functions are flexibly deployed and implemented.
Critical genetic program forDrosophilaimaginal disc regeneration revealed by single-cell analysis
Authors: Worley Melanie I. , Everetts Nicholas J. , Yasutomi Riku , Yosef Nir , Hariharan Iswar K.
Published: July 2021

Whether regeneration is primarily accomplished by re-activating gene regulatory networks used previously during development or by activating novel regeneration-specific transcriptional programs remains a longstanding question. Currently, most genes implicated in regeneration also function during development. Using single-cell transcriptomics in regeneratingDrosophilawing discs, we identified two regeneration-specific cell populations within the blastema. They are each composed of cells that upregulate multiple genes encoding secreted proteins that promote regeneration. In this regenerative secretory zone, the transcription factor Ets21C controls the expression of multiple regenerationpromoting genes. While eliminatingEts21Cfunction has no discernible effect on development, it severely compromises regeneration. This Ets21C-dependent gene regulatory network is also activated in blastema-like cells in tumorous discs, suggesting that pro-regenerative mechanisms can be co-opted by tumors to promote aberrant growth.
Knock-in tagging in zebrafish facilitated by insertion into non-coding regions
Authors: Levic Daniel S. , Yamaguchi Naoya , Wang Siyao , Knaut Holger , Bagnat Michel
Published: July 2021

Zebrafish provide an excellent model for in vivo cell biology studies due to their amenability to live imaging. Protein visualization in zebrafish has traditionally relied on overexpression of fluorescently tagged proteins from heterologous promoters, making it difficult to recapitulate endogenous expression patterns and protein function. One way to circumvent this problem is to tag the proteins by modifying their endogenous genomic loci. Such an approach is not widely available to zebrafish researchers due to inefficient homologous recombination and the error-prone nature of targeted integration in zebrafish. Here, we report a simple approach for tagging proteins in zebrafish on their N- or C termini with fluorescent markers by inserting PCR-generated donor amplicons into non-coding regions of the corresponding genes. Using this approach, we generated endogenously tagged alleles for several genes critical for epithelial biology and organ development including the tight junction components ZO-1 and Cldn15la, the trafficking effector Rab11a, and the ECM receptor β1 integrin. Our approach facilitates the generation of knock-in lines in zebrafish, opening the way for accurate quantitative imaging studies.

Summary statement

Generation of endogenously tagged stable zebrafish knock-in lines is simplified by the integration of fluorescent protein cassettes with mRNA splicing elements into non-coding regions of genes.
An Empirical Bayes Approach to Estimating Dynamic Models of Co-Regulated Gene Expression
Authors: Venkatraman Sara , Basu Sumanta , Clark Andrew G. , Delbare Sofie , Lee Myung Hee , Wells Martin T.
Published: July 2021

Time-course gene expression datasets provide insight into the dynamics of complex biological processes, such as immune response and organ development. It is of interest to identify genes with similar temporal expression patterns because such genes are often biologically related. However, this task is challenging due to the high dimensionality of these datasets and the nonlinearity of gene expression time dynamics. We propose an empirical Bayes approach to estimating ordinary differential equation (ODE) models of gene expression, from which we derive a similarity metric between genes called the Bayesian lead-lag R2 (LLR2). Importantly, the calculation of the LLR2 leverages biological databases that document known interactions amongst genes; this information is automatically used to define informative prior distributions on the ODE model’s parameters. As a result, the LLR2 is a biologically-informed metric that can be used to identify clusters or networks of functionally-related genes with co-moving or time-delayed expression patterns. We then derive data-driven shrinkage parameters from Stein’s unbiased risk estimate that optimally balance the ODE model’s fit to both data and external biological information. Using real gene expression data, we demonstrate that our methodology allows us to recover interpretable gene clusters and sparse networks. These results reveal new insights about the dynamics of biological systems.
Persistent autism-relevant phenotype produced by in utero and lactational exposure of female mice to the commercial PBDE mixture, DE-71
Authors: Kozlova Elena V. , Valdez Matthew C. , Denys Maximillian E. , Bishay Anthony E. , Krum Julia M. , Rabbani Kayhon M. , Carrillo Valeria , Gonzalez Gwendolyn M. , Lampel Gregory , Tran Jasmin D. , Vazquez Brigitte M. , Anchondo Laura M. , Uddin Syed A. , Huffman Nicole M. , Monarrez Eduardo , Olomi Duraan S. , Chinthirla Bhuvaneswari D. , Hartman Richard E. , Rao Kodavanti Prasada S. , Chompre Gladys , Phillips Allison L. , Stapleton Heather M. , Henkelmann Bernhard , Schramm Karl-Werner , Curras-Collazo Margarita C.
Published: July 2021

Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display altered short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.
Photoredox-catalyzed decarboxylative C-terminal differentiation for bulk and single molecule proteomics
Authors: Zhang Le , Floyd Brendan M. , Chilamari Maheshwerreddy , Mapes James , Swaminathan Jagannath , Bloom Steven , Marcotte Edward M. , Anslyn Eric V.
Published: July 2021

Methods for the selective labeling of biogenic functional groups on peptides are being developed and used in the workflow of both current and emerging proteomics technologies, such as single-molecule fluorosequencing. To achieve successful labeling with any one method requires that the peptide fragments contain the functional group for which the labeling chemistry is designed. In practice, only two functional groups are present on every peptide fragment regardless of the protein cleavage site, namely, an N-terminal amine and a C-terminal carboxylic acid. Developing a global-labeling technology, therefore, requires one to specifically target the N- and/or C-terminus of peptides. In this work, we showcase the first successful application of photocatalyzed C-terminal decarboxylative-alkylation for peptide mass-spectrometry and single molecule protein sequencing, that can be broadly applied to any proteome. We demonstrate that peptides in complex mixtures generated from enzymatic digests from bovine serum albumin, as well as protein mixtures from yeast and human cell extracts, can be site-specifically labeled at their C-terminal residue with a Michael acceptor. Using two distinct analytical approaches, we characterize C-terminal labeling efficiencies of greater than 50% across complete proteomes and document the proclivity of various C-terminal amino acid residues for decarboxylative-labeling, showing histidine and tryptophan to be the most disfavored. Finally, we combine C-terminal decarboxylative labeling with an orthogonal carboxylic acid labeling technology in tandem, to establish a new platform for fluorosequencing.
Lipopolysaccharide-induced neuroinflammation disrupts functional connectivity and community structure in primary cortical microtissues
Authors: Atherton Elaina , Brown Sophie , Papiez Emily , Restrepo Maria I. , Borton David A.
Published: July 2021

Three-dimensional (3D) neural microtissues are a powerful in vitro paradigm for studying brain development and disease under controlled conditions, while maintaining many key attributes of the in vivo environment. Here, we used primary cortical microtissues to study the effects of neuroinflammation on neural microcircuits. We demonstrated the use of a genetically encoded calcium indicator combined with a novel live-imaging platform to record spontaneous calcium transients in microtissues from day 14-34 in vitro. We implemented graph theory analysis of calcium activity to characterize underlying functional connectivity and community structure of microcircuits, which are capable of capturing subtle changes in network dynamics during early diseases states. We found that microtissues cultured for 34 days displayed functional remodeling of microcircuits and that community structure strengthened over time. Lipopolysaccharide, a neuroinflammatory agent, significantly increased functional connectivity and disrupted community structure 5-9 days after exposure. These microcircuit-level changes have broad implications for the role of neuroinflammation in functional dysregulation of neural networks.
Luminance and contrast of images in the THINGS database
Authors: Harrison William J
Published: July 2021

The THINGS database is a freely available stimulus set that has the potential to facilitate the generation of theory that bridges multiple areas within cognitive neuroscience. The database consists of 26,107 high quality digital photos that are sorted into 1,854 concepts. While a valuable resource, relatively few technical details relevant to the design of studies in cognitive neuroscience have been described. We present an analysis of two key low-level properties of THINGS images, luminance and luminance contrast. These image statistics are known to influence common physiological and neural correlates of perceptual and cognitive processes. In general, we found that the distributions of luminance and contrast are in close agreement with the statistics of natural images reported previously. However, we found that image concepts are separable in their luminance and contrast: we show that luminance and contrast alone are sufficient to classify images into their concepts with above chance accuracy. We describe how these factors may confound studies using the THINGS images, and suggest simple controls that can be implemented a priori or post-hoc. We discuss the importance of using such natural images as stimuli in psychological research.
caliPER: A software for blood-free parametric Patlak mapping using PET/MRI input function
Authors: Dassanayake Praveen , Cui Lumeng , Finger Elizabeth , Kewin Matthew , Hadaway Jennifer , Soddu Andrea , Jakoby Bjoern , Zuehlsdorf Sven , Lawrence Keith S St , Moran Gerald , Anazodo Udunna C
Published: July 2021

Routine clinical use of absolute PET quantification techniques is limited by the need for serial arterial blood sampling for input function and more importantly by the lack of automated pharmacokinetic analysis tools that can be readily implemented in clinic with minimal effort. PET/MRI provides the ability for absolute quantification of PET probes without the need for serial arterial blood sampling using image-derived input functions (IDIFs). Here we introduce caliPER, a modular and scalable software for simplified pharmacokinetic modelling of PET probes with irreversible uptake or binding based on PET/MR IDIFs and Patlak Plot analysis. caliPER generates regional values or parametric maps of net influx rate (Ki) using reconstructed dynamic PET images and anatomical MRI aligned to PET for IDIF vessel delineation. We evaluated the performance of caliPER for blood-free region-based and pixel-wise Patlak analyses of [18F] FDG by comparing caliPER IDIF to serial arterial blood input functions and its application in imaging brain glucose hypometabolism in Frontotemporal dementia. IDIFs corrected for partial volume errors including spill-out and spill-in effects were similar to arterial blood input functions with a general bias of around 6-8%, even for arteries <5 mm. The Ki and cerebral metabolic rate of glucose estimated using caliPER IDIF were similar to estimates using arterial blood sampling (<2%) and within limits of whole brain values reported in literature. Overall, caliPER is a promising tool for irreversible PET tracer quantification and can simplify the ability to perform parametric analysis in clinical settings without the need for blood sampling.

Highlights

caliPER is an adaptable image processing software for extracting image-derived input functions and generating parametric maps of irreversible PET tracer uptake.

Anatomical (T1-weighted/T2-weighted/time-of-flight angiography) MRI carefully aligned to PET provides a robust approach for delineation of vessels on PET, eliminating the need for serial blood sampling for input functions.

Application of caliPER in modelling glucose uptake in patients with Frontotemporal dementia, demonstrates the feasibility of absolute quantification of cerebral metabolic rate of glucose in clinical populations.
The mitochondrial Na+/Ca2+exchanger, NCLX, mediates PDE2 dependent neuronal survival and learning
Authors: Rozenfeld Maya , Azoulay Ivana Savic , Ben Kasus Nissim Tsipi , Stavsky Alexandra , Hershfinkel Michal , Kofman Ora , Sekler Israel
Published: July 2021

Impaired phosphodiesterase (PDE) function and mitochondrial Ca2+- [Ca2+]m signaling leads to cardiac failure, ischemic damage and dysfunctional learning and memory. Yet, a causative link between these pathways is unknown. Here, we fluorescently monitored [Ca2+]m transients in hippocampal neurons evoked by caffeine followed by depolarization. [Ca2+]m efflux was apparent in WT but diminished in neurons deficient in the mitochondrial Na+/Ca2+exchanger NCLX. Surprisingly, neuronal depolarization-induced Ca2+transients alone failed to evoke strong [Ca2+]m efflux in WT neurons. Caffeine is also a PDE inhibitor. Pretreatment with the PDE2 inhibitor Bay 60-7550 rescued [Ca2+]m efflux triggered by neuronal depolarization. Inhibition of PDE2 acted by diminishing the Ca2+dependent reduction of mitochondrial cAMP, thereby promoting NCLX phosphorylation. Selective PDE2 inhibition also enhanced [Ca2+]m efflux triggered by neuromodulators. We found that protection of neurons against excitotoxic insults, conferred by PDE2 inhibition, was diminished in NCLX KO neurons, thus is NCLX dependent. Finally, administration of Bay 60-7550 enhanced new object recognition learning in WT but not in NCLX KO mice. Our results identify a long-sought link between PDE and [Ca2+]m signaling thereby providing new therapeutic targets.
Instrumental aversion coding in the basolateral amygdala and its reversion by a benzodiazepine
Authors: Jean-Richard-dit-Bressel Philip , Tran Jenny , Didachos Angelos , McNally Gavan P.
Published: July 2021

Punishment involves learning the relationship between actions and their adverse consequences. Both the acquisition and expression of punishment learning depend on the basolateral amygdala (BLA), but how BLA supports punishment remains poorly understood. To address this, we measured calcium (Ca2+) transients in BLA principal neurons during punishment. Male rats were trained to press two individually presented levers for food; when one of these levers also yielded aversive footshock, responding on this punished lever decreased relative to the other, unpunished lever. In rats with the Ca2+indicator GCaMP6f targeted to BLA principal neurons, we observed excitatory activity transients to the footshock punisher and inhibitory transients to lever-presses. Critically, as rats learned punishment, activity around the punished response transformed from inhibitory to excitatory and similarity analyses showed that these punished lever-press transients resembled BLA transients to the punisher itself. Systemically administered benzodiazepine (midazolam) selectively alleviated punishment. Moreover, the degree to which midazolam alleviated punishment was associated with how much punished response-related BLA transients reverted to their pre-punishment state. Together, these findings show that punishment learning is supported by aversion-coding of instrumental responses in the BLA and that the anti-punishment effects of benzodiazepines are associated with a reversion of this aversion coding.
Long-distance migration was associated with increased prevalence of post-traumatic stress disorder in Syrian refugees
Authors: Eiset Andreas Halgreen , Aoun Michaelangelo P. , Stougaard Monica , Gottlieb Annemarie Graa , Haddad Ramzi S. , Frydenberg Morten , Naja Wadih J.
Published: July 2021

Background

Refugees are forced migrants but there is a large variation in the distance that refugees cover and there is a paucity in the evidence of how this may affect refugees’ health and health care needs. We investigated the association between long-distance migration and post-traumatic stress disorder (PTSD), a serious psychiatric disorder associated with deteriorating mental and somatic health.

Methods

Included from 2016-2019 were 712 adult Syrian refugees and asylum seekers in Lebanon and Denmark arrived up to 12 months prior. PTSD was assessed using the Harvard Trauma Questionnaire and the estimate of association was obtained by multiply imputing missing data and adjusting for confounding by propensity score-weighting with covariates age, sex, socioeconomic status, trauma experience and WHO-5-score, reporting the bootstrap 95-percentile confidence interval (95% CI). Additionally, a number of sensitivity analyses were performed.

Results

After multiply imputing missing data and propensity score-weighted adjustment for confounding, migration to Denmark instead of Lebanon was associated with an increase in PTSD prevalence of 9 percentage point (95% CI [-1; 19] percentage point).

Discussion

We found that long-distance migration was associated with an increase in the prevalence of PTSD suggesting that long-distance migration may be a factor to consider when assessing refugees’ and asylum seekers’ health. Practitioners should consider “long-distance migration” in refugee health screenings and in particular when assessing the risk of post-traumatic stress disorder. Future research should be designed to ultimately lead to studies of relevant interventions to lower the risk of post-traumatic stress disorder in refugees.
Genome-wide polygenic risk score method for diabetic kidney disease in patients with type 2 diabetes
Authors: Vy Ha My T. , Dellepiane Sergio , Chaudhary Kumardeep , Blair Alexander , Glicksberg Benjamin S , Coca Steven G , Chan Lili , He John Cijiang , Do Ron , Nadkarni Girish N
Published: July 2021

Diabetic kidney disease (DKD) is considered partially hereditary, but the genetic factors underlying disease remain largely unknown. A key barrier to our understanding stems from its heterogeneity, and likely polygenic etiology. Proteinuric and non-proteinuric DKD are two sub-classes of DKD, defined by high urinary albumin-to-creatinine ratio (UACR) and low creatinine estimated glomerular filtration rate (eGFR). Prior genome-wide association studies (GWAS) have identified multiple loci associated with eGFR and UACR. We aimed to combine summary statistics from previous GWAS’ for eGFR and UACR in one prediction model and associate it with DKD prevalence. We then tested this using genetic data from 18,841 individuals diagnosed with type 2 diabetes in UK Biobank. We computed two genome-wide polygenic risk scores (GPS) aggregating effects of common variants associated with the two measurements, eGFR and UACR. We show that including both GPS’ in a single model confers significant improvement in comparison with the single GPS model generated from GWAS summary statistics for DKD. We also find in replication analysis in 5,389 individuals in the multi-ethnic BioMe Biobank, that although the combined model had consistent direction of association, the lowest performance was in individuals with recent African ancestry. In summary, we show that joint modeling of polygenic associations of eGFR and UACR is more significantly associated with DKD than individual modeling as well as a GPS comprised of only DKD summary statistics and may be used to gain insights into biology and progression. However, efforts should be made to develop and validate polygenic approaches in diverse populations.
Investigating brain mechanisms underlying natural reading by co-registering eye tracking with combined EEG and MEG
Authors: Weiss Béla , Dreyer Felix , Fonteneau Elisabeth , van Casteren Maarten , Hauk Olaf
Published: July 2021

Linking brain and behavior is one of the great challenges in cognitive neuroscience. Ultimately, we want to understand how the brain processes information to guide every-day behavior. However, most neuroscientific studies employ very simplistic experimental paradigms whose ecological validity is doubtful. Reading is a case in point, since most neuroscientific studies to date have used unnatural word-by-word stimulus presentation and have often focused on single word processing. Previous research has therefore actively avoided factors that are important for natural reading, such as rapid self-paced voluntary saccadic eye movements. Recent methodological developments have made it possible to deal with associated problems such as eye movement artefacts and the overlap of brain responses to successive stimuli, using a combination of eye-tracking and neuroimaging. A growing number of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are successfully using this methodology. Here, we provide a proof-of-concept that this methodology can be applied to combined EEG and magnetoencephalography (MEG) data. Our participants naturally read 4-word sentences that could end in a plausible or implausible word while eye-tracking, EEG and MEG were being simultaneously recorded. Eye-movement artefacts were removed using independent-component analysis. Fixation-related potentials and fields for sentence-final words were subjected to minimum-norm source estimation. We detected an N400-type brain response in our EEG data starting around 200 ms after fixation of the sentence-final word. The brain sources of this effect, estimated from combined EEG and MEG data, were mostly located in left temporal lobe areas. We discuss the possible use of this method for future neuroscientific research on language and cognition.
Structural and mechanistic insight into CRISPR-Cas9 inhibition by anti-CRISPR protein AcrIIC4
Authors: Hwang Sungwon , Pan Chuxi , Garcia Bianca , Davidson Alan R. , Moraes Trevor F. , Maxwell Karen L.
Published: July 2021

Phages, plasmids, and other mobile genetic elements express inhibitors of CRISPR-Cas immune systems, known as anti-CRISPR proteins, to protect themselves from targeted destruction. These anti-CRISPRs have been shown to function through very diverse mechanisms. In this work we investigate the activity of an anti-CRISPR isolated from a prophage in Haemophilus parainfluenzae that blocks CRISPR-Cas9 DNA cleavage activity. We determine the three-dimensional crystal struture of AcrIIC4 and show that it binds to the Cas9 Recognition Domain. This binding does not prevent the Cas9-anti-CRISPR complex from interacting with target DNA but does inhibit DNA cleavage. AcrIIC4 likely acts by blocking the conformational changes that allow the HNH and RuvC endonuclease domains to contact the DNA sites to be nicked.
Myoparr-associated and -independent multiple roles of heterogeneous nuclear ribonucleoprotein K during skeletal muscle cell differentiation
Authors: Hitachi Keisuke , Kiyofuji Yuri , Nakatani Masashi , Tsuchida Kunihiro
Published: July 2021

RNA-binding proteins (RBPs) regulate cell physiology via the formation of ribonucleic-protein complexes with coding and non-coding RNAs. RBPs have multiple functions in the same cells; however, the precise mechanism through which their pleiotropic functions are determined remains unknown. In this study, we revealed the multiple inhibitory functions of heterogeneous nuclear ribonucleoprotein K (hnRNPK) for myogenic differentiation. We first identified hnRNPK as a lncRNAMyoparrbinding protein. Gain- and loss-of-function experiments showed that hnRNPK repressed the expression ofmyogeninat the transcriptional level. The hnRNPK-binding region ofMyoparrwas required to repressmyogeninexpression. Moreover, hnRNPK repressed the expression of a set of genes coding for aminoacyl-tRNA synthetases in aMyoparr-independent manner. Mechanistically, hnRNPK regulated the eIF2α/Atf4 pathway, one branch of the intrinsic pathways of the endoplasmic reticulum sensors, in differentiating myoblasts. Thus, our findings demonstrate that hnRNPK plays lncRNA-associated and - independent multiple roles during myogenic differentiation, indicating that the analysis of lncRNA-binding proteins will be useful for elucidating both the physiological functions of lncRNAs and the multiple functions of RBPs.
Co‑cultivation of the anaerobic fungusCaecomyces churroviswithMethanobacterium bryantiienhances transcription of carbohydrate binding modules
Authors: Brown Jennifer L. , Swift Candice L. , Mondo Stephen , Seppala Susanna , Salamov Asaf , Singan Vasanth , Henrissat Bernard , Henske John K. , Lee Samantha , He Guifen , Yan Mi , Barry Kerrie , Grigoriev Igor V. , O’Malley Michelle A.
Published: July 2021

Anaerobic fungi and methanogenic archaea are two classes of microorganisms found in the rumen microbiome that metabolically interact during lignocellulose breakdown. Here, stable synthetic co-cultures of the anaerobic fungusCaecomyces churrovisand the methanogenMethanobacterium bryantii(not native to the rumen) were formed, demonstrating that microbes from different environments can be paired based on metabolic ties. Transcriptional and metabolic changes induced by methanogen co-culture were evaluated inC. churrovisacross a variety of substrates to identify mechanisms that impact biomass breakdown and sugar uptake. A high-quality genome ofC. churroviswas obtained and annotated, which is the first sequenced genome of a non-rhizoid forming anaerobic fungus.C. churrovispossess an abundance of CAZymes and carbohydrate binding modules and, in agreement with previous studies of early-diverging fungal lineages, N6-methyldeoxyadenine (6mA) was associated with transcriptionally active genes. Co-culture with the methanogen increased overall transcription of CAZymes, carbohydrate binding modules, and dockerin domains in co-cultures grown on both lignocellulose and cellulose and caused upregulation of genes coding associated enzymatic machinery including carbohydrate binding modules in family 18 and dockerin domains across multiple growth substrates relative toC. churrovismonoculture. Two other fungal strains grown on a reed canary grass substrate in co-culture with the same methanogen also exhibited high log2fold change values for upregulation of genes encoding carbohydrate binding modules in families 1 and 18. Transcriptional upregulation indicated that co-culture of theC. churrovisstrain with a methanogen may enhance pyruvate formate lyase (PFL) function for growth on xylan and fructose and production of bottleneck enzymes in sugar utilization pathways, further supporting the hypothesis that co-culture with a methanogen may enhance certain fungal metabolic functions. Upregulation of CBM18 may play a role in fungal-methanogen physical associations and fungal cell wall development and remodeling.
Your head is there to move you around: Goal-driven models of the primate dorsal pathway
Authors: Mineault Patrick J , Bakhtiari Shahab , Richards Blake A , Pack Christopher C
Published: July 2021

Neurons in the dorsal visual pathway of the mammalian brain are selective for motion stimuli, with the complexity of stimulus representations increasing along the hierarchy. This progression is similar to that of the ventral visual pathway, which is well characterized by artificial neural networks (ANNs) optimized for object recognition. In contrast, there are no image-computable models of the dorsal stream with comparable explanatory power. We hypothesized that the properties of dorsal stream neurons could be explained by a simple learning objective: the need for an organism to orient itself during self-motion. To test this hypothesis, we trained a 3D ResNet to predict an agent’s self-motion parameters from visual stimuli in a simulated environment. We found that the responses in this network accounted well for the selectivity of neurons in a large database of single-neuron recordings from the dorsal visual stream of non-human primates. In contrast, ANNs trained on an action recognition dataset through supervised or self-supervised learning could not explain responses in the dorsal stream, despite also being trained on naturalistic videos with moving objects. These results demonstrate that an ecologically relevant cost function can account for dorsal stream properties in the primate brain.
Reduced neutralization of SARS-CoV-2 B.1.617 variant by inactivated and RBD-subunit vaccine
Authors: Hu Jie , Wei Xiao-yu , Xiang Jin , Peng Pai , Xu Feng-li , Wu Kang , Luo Fei-yang , Jin Ai-shun , Fang Liang , Liu Bei-zhong , Wang Kai , Tang Ni , Huang Ai-Long
Published: July 2021

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Spike protein that mediates coronavirus entry into host cells is a major target for COVID-19 vaccines and antibody therapeutics. However, multiple variants of SARS-CoV-2 have emerged, which may potentially compromise vaccine effectiveness. Using a pseudovirus-based assay, we evaluated SARS-CoV-2 cell entry mediated by the viral Spike B.1.617 and B.1.1.7 variants. We also compared the neutralization ability of monoclonal antibodies from convalescent sera and neutralizing antibodies (NAbs) elicited by CoronaVac (inactivated vaccine) and ZF2001 (RBD-subunit vaccine) against B.1.617 and B.1.1.7 variants. Our results showed that, compared to D614G and B.1.1.7 variants, B.1.617 shows enhanced viral entry and membrane fusion, as well as more resistant to antibody neutralization. These findings have important implications for understanding viral infectivity and for immunization policy against SARS-CoV-2 variants.