bluuebunny/crossref_metadata_2025 huggingface dataset:
Vaccination is Australia's most important COVID-19 public health action, even though herd immunity is unlikely
Authors: McBryde Emma S , Meehan Michael T , Sziklay Jamie , Adekunle Adeshina , Kuddus Abdul , Ogunlade Samson , Jayasundara Pavithra , Ragonnet Romain , Trauer James M , Cope Robert C
Published: July 2021

The Australian National Cabinet four-step plan to transition to post-pandemic re-opening begins with vaccination to achieve herd protection and protection of the health system against a surge in COVID-19 cases. Assuming a pre-vaccination reproduction number for the Delta variant of 5, we show that for the current Mixed program of vaccinating over 60s with AstraZeneca and 16-60s with Pfizer we would not achieve herd immunity. We would need to cover 85% of the population (including many 5-16 year-olds to achieve herd immunity).
At lower reproduction number of 3 and our current Mixed strategy, we can achieve herd immunity without vaccinating 5-15 year olds. This will be achieved at a 60% coverage pursuing a strategy targetting high transmitters or 70% coverage using a strategy targetting the vulnerable first. A reproduction number of 7 precludes achieving herd immunity, however vaccination is able to prevent 75% of deaths compared with no vaccination.
We also examine the impact of vaccination on death in the event that herd immunity is not achieved. Direct effects of vaccination on reducing death are very good for both Pfizer and AstraZeneca vaccines. However we estimate that the Mixed or Pfizer program performs better than the AstraZeneca program.
Furthermore, vaccination levels below the herd immunity threshold can lead to substantial (albeit incomplete) indirect protection for both vaccinated and unvaccinated populations. Given the potential for not reaching herd immunity, we need to consider what level of severe disease and death is acceptable, balanced against the consequences of ongoing aggressive control strategies.
Molecular evolution and structural analyses of the spike glycoprotein from Brazilian SARS-CoV-2 genomes: the impact of the fixation of selected mutations
Authors: Ferrareze Patrícia Aline Gröhs , Zimerman Ricardo Ariel , Franceschi Vinícius Bonetti , Caldana Gabriel Dickin , Netz Paulo Augusto , Thompson Claudia Elizabeth
Published: July 2021

The COVID-19 pandemic caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached by July 2021 almost 200 million cases and more than 4 million deaths worldwide since its beginning in late 2019, leading to enhanced concern in the scientific community and the general population. One of the most important pieces of this host-pathogen interaction is the spike protein, which binds to the human Angiotensin-converting enzyme 2 (hACE2) cell receptor, mediates the membrane fusion and is the major target of neutralizing antibodies against SARS-CoV-2. The multiple amino acid substitutions observed in this region, specially in the Receptor Binding Domain (RBD), mainly after almost one year of its emergence (late 2020), have enhanced the hACE2 binding affinity and led to several modifications in the mechanisms of SARS-CoV-2 pathogenesis, improving the viral fitness and/or promoting immune evasion, with potential impact in the vaccine development. In this way, the present work aimed to evaluate the effect of positively selected mutations fixed in the Brazilian SARS-CoV-2 lineages and to check for mutational evidence of coevolution. Additionally, we evaluated the impact of selected mutations identified in some of the VOC and VOI lineages (C.37, B.1.1.7, P.1, and P.2) of Brazilian samples on the structural stability of the spike protein, as well as their possible association with more aggressive infection profiles by estimating the binding affinity in the RBD-hACE2 complex. We identified 48 sites under selective pressure in Brazilian spike sequences, 17 of them with the strongest evidence by the HyPhy tests, including VOC related mutation sites 138, 142, 222, 262, 484, 681, and 845, among others. The coevolutionary analysis identified a number of 28 coevolving sites that were found not to be conditionally independent, such as the couple E484K - N501Y from P.1 and B.1.351 lineages. Finally, the molecular dynamics and free energy estimates showed the structural stabilizing effect and the higher impact of E484K for the improvement of the binding affinity between the spike RBD and the hACE2 in P.1 and P.2 lineages, as well as the stabilizing and destabilizing effects for the positively selected sites.
Spatio-temporal dynamics of stress-induced network reconfigurations reflect negative affectivity
Authors: Kühnel Anne , Czisch Michael , Sämann Philipp G. ,   BeCOME Study Team, Binder Elisabeth B. , Kroemer Nils B.
Published: July 2021

Background

Chronic stress is an important risk factor in the etiology of mood and anxiety disorders, but exact pathomechanisms remain to be understood. Mapping individual differences of acute stress-induced neurophysiological changes, especially on the level of neural activation and functional connectivity (FC), could provide important insights in how variation in the individual stress response is linked to disease risk.

Methods

Using an established psycho-social stress task flanked by two resting-state scans, we measured subjective, physiological, and brain responses to acute stress and recovery in 217 unmedicated participants with and without mood and anxiety disorders. To estimate block-wise changes in stress-induced brain activation and FC, we used hierarchical mixed-effects models based on denoised timeseries within a predefined stress network. We predicted inter- and intra-individual differences in stress phases (anticipation vs. acute stress vs. recovery) and transdiagnostic dimensions of stress reactivity using elastic net and support vector machines.

Results

We identified four subnetworks showing distinct changes in FC over time. Subnetwork trajectories predicted the stress phase (accuracy: 71%,pperm<.001) and increases in pulse rate (R2=.10,pperm<.001). Critically, individual spatio-temporal trajectories of changes across networks also predicted negative affectivity (ΔR2=.08,pperm=.009), but not the presence or absence of a mood and anxiety disorder.

Conclusions

Spatio-temporal dynamics of brain network reconfiguration induced by stress reflect individual differences in the psychopathology dimension negative affectivity. These results support the idea that vulnerability for mood and anxiety disorders can be conceptualized best at the level of network dynamics, which may pave the way for improved prediction of individual risk.
Radical pairs can explain magnetic field and lithium effects on the circadian clock
Authors: Zadeh-Haghighi Hadi , Simon Christoph
Published: July 2021

Abstract

Drosophila’s circadian clock can be perturbed by magnetic fields, as well as by lithium administration. Cryptochromes are critical for the circadian clock. Further, the radical pairs in cryptochrome also can explain magnetoreception in animals. Based on a simple radical pair mechanism model of the animal magnetic compass, we show that both magnetic fields and lithium can influence the spin dynamics of the naturally occurring radical pairs and hence modulate the circadian clock’s rhythms. Using a simple chemical oscillator model for the circadian clock, we show that the spin dynamics influence a rate in the chemical oscillator model, which translates into a change in the circadian period. Our model can reproduce the results of two independent experiments, magnetic fields and lithium effects on the circadian clock. Our model predicts that stronger magnetic fields would shorten the clock’s period. We also predict that lithium influences the clock in an isotope-dependent manner. Furthermore, our model also predicts that magnetic fields and hyperfine interactions modulate oxidative stress. The findings of this work suggest that quantum nature and entanglement of radical pairs might play roles in the brain, as another piece of evidence in addition to recent results on xenon anesthesia and lithium effects on hyperactivity.
Phosphorus availability and arbuscular mycorrhizal fungi limit soil C cycling and influence plant responses to elevated CO2 conditions
Authors: Castañeda-Gómez L. , Powell J.R. , Pendall E. , Carrillo Y.
Published: July 2021

Enhanced soil organic matter (SOM) decomposition and organic phosphorus (P) cycling may help sustain plant productivity under elevated CO2 (eCO2) and P-limiting conditions. P-acquisition by arbuscular mycorrhizal (AM) fungi and their impacts on SOM decomposition may become even more relevant in these conditions. Yet, experimental evidence of the interactive effect of AM fungi and P availability influencing altered SOM cycling under eCO2 is scarce and the mechanisms of this control are poorly understood. Here, we performed a pot experiment manipulating P availability, AM fungal presence and atmospheric CO2 levels and assessed their impacts on soil C cycling and plant growth. Plants were grown in chambers with a continuous 13C-input that allowed differentiation between plant- and SOM-derived fractions of respired CO2 (R), dissolved organic C (DOC) and microbial biomass (MBC) as relevant C pools in the soil C cycle. We hypothesised that under low P availability, increases in SOM cycling may support sustained plant growth under eCO2 and that AM fungi would intensify this effect. We found the impacts of CO2 enrichment and P availability on soil C cycling were generally independent of each other with higher root biomass and slight increases in soil C cycling under eCO2 occurring regardless of the P treatment. Contrary to our hypotheses, soil C cycling was enhanced with P addition suggesting that low P conditions were limiting soil C cycling. eCO2 conditions increased the fraction of SOM-derived DOC pointing to increased SOM decomposition with eCO2. Finally, AM fungi increased microbial biomass under eCO2 conditions and low-P without enhanced soil C cycling, probably due to competitive interactions with free-living microorganisms over nutrients. Our findings in this plant-soil system suggest that, contrary to what has been reported for N-limited systems, the impacts of eCO2 and P availability on soil C cycling are independent of each other.
Discovering cellular programs of intrinsic and extrinsic drivers of metabolic traits using LipocyteProfiler
Authors: Laber Samantha , Strobel Sophie , Mercader Josep-Maria , Dashti Hesam , Ainbinder Alina , Honecker Julius , Garborcauskas Garrett , Stirling David R. , Leong Aaron , Figueroa Katherine , Sinnott-Armstrong Nasa , Kost-Alimova Maria , Deodato Giacomo , Harney Alycen , Way Gregory P. , Saadat Alham , Harken Sierra , Reibe-Pal Saskia , Ebert Hannah , Zhang Yixin , Calabuig-Navarro Virtu , McGonagle Elizabeth , Stefek Adam , Dupuis Josée , Cimini Beth A. , Hauner Hans , Udler Miriam S. , Carpenter Anne E. , Florez Jose C. , Lindgren Cecilia M. , Jacobs Suzanne B. R. , Claussnitzer Melina
Published: July 2021

A primary obstacle in translating genetics and genomics data into therapeutic strategies is elucidating the cellular programs affected by genetic variants and genes associated with human diseases. Broadly applicable high-throughput, unbiased assays offer a path to rapidly characterize gene and variant function and thus illuminate disease mechanisms. Here, we report LipocyteProfiler, an unbiased high-throughput, high-content microscopy assay that is amenable to large-scale morphological and cellular profiling of lipid-accumulating cell types. We apply LipocyteProfiler to adipocytes and hepatocytes and demonstrate its ability to survey diverse cellular mechanisms by generating rich context-, and process-specific morphological and cellular profiles. We then use LipocyteProfiler to identify known and novel cellular programs altered by polygenic risk of metabolic disease, including insulin resistance, waist-to-hip ratio and the polygenic contribution to lipodystrophy. LipocyteProfiler paves the way for large-scale forward and reverse phenotypic profiling in lipid-storing cells, and provides a framework for the unbiased identification of causal relationships between genetic variants and cellular programs relevant to human disease.
A Sequence-based Antibody Paratope Prediction Model Through Combing Local-Global Information and Partner Features
Authors: Lu Shuai , Li Yuguang , Nan Xiaofei , Zhang Shoutao
Published: July 2021

Antibodies are proteins which play a vital role in the immune system by recognizing and neutralizing antigens. The region on the antibody binding to an antigen, known as paratope, mediates antibody-antigen interaction with high affinity and specificity. And the accurate prediction of those regions from antibody sequence contributes to the design of therapeutic antibodies and remains challenging. However, the experimental methods are time-consuming and expensive. In this article, we propose a sequence-based method for antibody paratope prediction by combing local and global information of antibody sequence and partner features from partner antigen sequence. Convolution Neural Networks(CNNs) and a sliding window approach on antibody sequence are used to extract local information. Attention-based Bidirectional Long Short-Term Memory (Att-BLSTM) on antibody sequence are used to extract global information. Also, the partner antigen is vital for paratope prediction, and we employ Att-BLSTM on the partner antigen sequence as well. The outputs of CNNs and Att-BLSTM networks are combined to predict antibody paratope by fully-connected networks. The experiments show that our proposed method achieves superior performance over the state-of-the-art sequenced-based antibody paratope prediction methods on benchmark datasets.
Assessing the polymer coil-globule state from the very first spectral modes
Authors: Földes Timothy , Lesage Antony , Barbi Maria
Published: July 2021

The determination of the coil-globule transition of a polymer is generally based on the reconstruction of scaling laws, implying the need for samples from a rather wide range of different polymer lengthsN. The spectral point of view developed in this work allows for a very parsimonious description of all the aspects of the finite-size coil-globule transition on the basis of the first two Rouse (cosine) modes only, shedding new light on polymer theory. Capturing the relevant configuration path features, the proposed approach enables to determine the state of a polymer without the need of any information about the polymer length or interaction strength. Importantly, we propose an experimental implementation of our analysis that can be easily performed with modern fluorescent imaging techniques, and would allow differentiation of coil or globule conformations by simply recording the positions of three discernible loci on the polymer.
SprayNPray: user-friendly taxonomic profiling of genome and metagenome contigs
Authors: Garber Arkadiy I. , Armbruster Catherine R. , Lee Stella E. , Cooper Vaughn S. , Bomberger Jennifer M. , McAllister Sean M.
Published: July 2021

Shotgun sequencing of cultured microbial isolates/individual eukaryotes (whole-genome sequencing) and microbial communities (metagenomics) has become commonplace in biology. Very often, sequenced samples encompass organisms spanning multiple domains of life, necessitating increasingly elaborate software for accurate taxonomic classification of assembled sequences. While many software tools for taxonomic classification exist, SprayNPray offers a quick and user-friendly, semiautomated approach, allowing users to separate contigs by taxonomy (and other metrics) of interest. Easy installation, usage, and intuitive output, which is amenable to visual inspection and/or further computational parsing, will reduce barriers for biologists beginning to analyze genomes and metagenomes. This approach can be used for broad-level overviews, preliminary analyses, or as a supplement to other taxonomic classification or binning software. SprayNPray profiles contigs using multiple metrics, including closest homologs from a user-specified reference database, gene density, read coverage, GC content, tetranucleotide frequency, and codon-usage bias. The output from this software is designed to allow users to spot-check metagenome-assembled genomes, identify, and remove contigs from putative contaminants in isolate assemblies, identify bacteria in eukaryotic assemblies (and vice-versa), and identify possible horizontal gene transfer events.
LENG8 regulation of mRNA processing, is responsible for the control of mitochondrial activity
Authors: Zhao Yongxu , Wang Xiaoting , Liu Yuenan , Li Niannian , Wang Shengming , Sun Zhigang , Gao Zhenfei , Zhang Xiaoxu , Mao Linfei , Tang Ru , Xue Wenyue , Li Chunyan , Guan Jian , Yi Hongliang , Zhang Nan , Ding Qiurong , Liu Feng
Published: July 2021

The processing of mRNA is essential for the maintenance of cellular and tissue homeostasis. However, the precise regulation of this process in mammalian cells, remains largely unknown. Here we have found that LENG8 represents the mammalian orthologue of the yeast mRNA processing factor Thp3 and Sac3. We go on to demonstrate that LENG8 binds to mRNAs, associates with components of mRNA processing machinery (the TREX complex) and contributes to mRNA nuclear export to the cytoplasm. Loss of LENG8, leads to aberrant accumulation of poly (A)+ RNA in the nucleus, in both Hela cells and murine fibroblasts. Furthermore, the precipitation of LENG8, is associated with an enrichment of both mRNAs and lncRNAs, and approximately half of these are also bound by the TREX component, THOC1. However, LENG8 preferentially binds mRNAs encoding for mitochondrial proteins and depletion of this processing factor, causes a dramatic breakdown in mitochondrial ultrastructure and a reduction in mitochondrial respiratory activity. Conditional deletion of Leng8 in mouse adipose tissues lead to a decreased body weight, and increased adipose thermogenesis. Our work has found an evolutionarily conserved mRNA processing factor that can control mitochondrial activity.
CoLoRd: Compressing long reads
Authors: Kokot Marek , Gudyś Adam , Li Heng , Deorowicz Sebastian
Published: July 2021

The costs of maintaining exabytes of data produced by sequencing experiments every year has become a major issue in today’s genomics. In spite of the increasing popularity of the third generation sequencing, the existing algorithms for compressing long reads exhibit minor advantage over general purpose gzip. We present CoLoRd, an algorithm able to reduce 3rd generation sequencing data by an order of magnitude without affecting the accuracy of downstream analyzes.
Dynamic surveillance of mosquitoes and their viromes in Wuhan during 2020
Authors: Ren Nanjie , Wang Shunlong , Shi Chenyan , Yu Ping , Zhao Lu , Huang Doudou , Ma Haixia , Xiao Shuqi , Wang Fei , Yuan Zhiming , Xia Han
Published: July 2021

Mosquitoes are medically important arthropod vectors and harbor a great variety of viruses. The population density, species and virome of mosquitoes varies according to geography and climate. To investigate the dynamic changes in the species composition and diversity of mosquitoes and their viromes in Wuhan, China, a total of 2,345 adult mosquitoes collected from different habitats including an urban residential area, two hospitals, a scenic area, and a pig farm in a rural region from April to October 2020 were subjected to morphological identification, RT-qPCR and metagenomic sequencing. The results indicated that the dominant presence of Culex mosquitoes was observed in both urban regions (90.32%, 1538/1703) and the pig farm (54.98%, 353/642). Viromes of Culex showed dynamic changes during the collection time. Several viruses, such as Culex flavivirus, Alphamesonivirus 1, Hubei mosquito virus 2 and Hubei mosquito virus 4, had seasonal changes and unimodal increases or declines. Other viruses, such as Wuhan mosquito virus 6, Hubei virga-like virus 2 and Zhejiang mosquito virus 3, were stable in all collected Culex and should be potential members of “core viromes”. This study improves the understanding of the dynamic composition of mosquitoes and the viromes they carry and provides useful information for informing mosquito control and mosquito-borne disease prevention strategies.
Pre-trauma memory contextualization as predictor for PTSD-like behavior in male rats
Authors: Sep Milou S.C. , Sarabdjitsingh R. Angela. , Geuze Elbert , Joёls Marian
Published: July 2021

While many people experience potentially threatening events during their life, only a minority develops posttraumatic stress disorder (PTSD). The identification of individuals at risk among those exposed to trauma is crucial for PTSD prevention in the future. Since re-experiencing trauma elements outside of the original trauma-context is a core feature of PTSD, we investigate if the ability to bind memories to their original encoding context (i.e. memory contextualisation) predicts PTSD vulnerability. We hypothesize that pre-trauma neutral memory contextualization (under stress) negatively relates to PTSD-like behavior, in a prospective design using the cut-off behavioral criteria rat model for PTSD. 72 male Sprague Dawley rats were divided in two experimental groups to assess the predictive value of 1) memory contextualization without acute stress (NS-group) and 2) memory contextualization during the recovery phase of the acute stress-response (S-group) for susceptibility to PTSD-like behavior. A powerful extension to regression analysis-path analysis-was used to test this specific hypothesis, together with secondary research questions. Following traumatic predator scent stress, 19.4% of the rats displayed PTSD-like behavior. Results showed a negative relation between pre-trauma memory contextualization and PTSD-like behavior, but only in the NS-group. Pre-trauma memory contextualization was positively related to fear association in the trauma environment, again only in the NS group. If the predictive value of pre-trauma contextualization of neutral information under non-stressful conditions for PTSD susceptibility is replicated in prospective studies in humans, this factor would supplement already known vulnerability factors for PTSD and improve the identification of individuals at risk among the trauma exposed, especially those at high trauma risk such as soldiers deployed on a mission.
A comparative in vitro and in vivo study of osteogenicity by using two biomaterials and two human mesenchymal stem cell subtypes
Authors: Fievet Lucile , Serratrice Nicolas , Brulin Bénédicte , Giraudo Laurent , Véran Julie , Degardin Nathalie , Sabatier Florence , Féron François , Layrolle Pierre
Published: July 2021

Bone repair induced by stem cells and biomaterials may represent an alternative to autologous bone grafting. Here, we compared the efficiency of two biomaterials - biphasic calcium phosphate (BCP) and bioactive glass (BG) - when loaded with either adult bone marrow mesenchymal stem cells (BM-MSCs) or newborn nasal ecto-mesenchymal stem cells (NE-MSCs), the latter being collected for further repair of lip cleft-associated bone loss. Both cell types display the typical stem cell surface markers CD73+/CD90+/CD105+/nestin, and exhibit the MSC-associated osteogenic, chondrogenic and adipogenic multipotency. NE-MSCs produce less collagen and alkaline phosphatase than BM-MSCs. At the transcript level, NE-MSCs express more abundantly three genes coding for bone sialoprotein, osteocalcin and osteopontin, while BM-MSCs produce extra copies of RUNX2. BM-MSCs and NE-MSCs adhere and survive on BCP and BG. In vivo experiments reveal that bone formation is only observed with BM-MSCs transplanted on BCP biomaterial.
Defining coarse-grainability in a model of structured microbial ecosystems
Authors: Moran Jacob , Tikhonov Mikhail
Published: July 2021

Despite their complexity, microbial ecosystems appear to be at least partially “coarse-grainable” in that some properties of interest can be adequately described by effective models of dimension much smaller than the number of interacting lineages (frequently in the dozens or hundreds). This is especially puzzling since recent studies demonstrate that a surprising amount of functionally relevant diversity is present at all levels of resolution, down to strains differing by 100 nucleotides or fewer. Rigorously defining coarse-grainability and understanding the conditions for its emergence is of critical importance for understanding microbial ecosystems. To begin addressing these questions, we propose a minimal model for investigating hierarchically structured ecosystems within the framework of resource competition. We use our model to operationally define coarse-graining quality based on reproducibility of the outcomes of a specified experiment and show that a coarse-graining can be operationally valid despite grouping together functionally diverse strains. We further show that, at least within our model, a high diversity of strains (while nominally more complex) may in fact facilitate coarse-grainability. However, this only applies if the pool of interacting strains is sampled from the appropriate “native” environment, as we discuss.
Echidna: integrated simulations of single-cell immune receptor repertoires and transcriptomes
Authors: Han Jiami , Kuhn Raphael , Papadopoulou Chrysa , Agrafiotis Andreas , Kreiner Victor , Shlesinger Danielle , Dizerens Raphael , Hong Kai-Lin , Weber Cédric , Greiff Victor , Oxenius Annette , Reddy Sai T. , Yermanos Alexander
Published: July 2021

Single-cell sequencing now enables the recovery of full-length immune repertoires [B cell receptor (BCR) and T cell receptor (TCR) repertoires], in addition to gene expression information. The feature-rich datasets produced from such experiments require extensive and diverse computational analyses, each of which can significantly influence the downstream immunological interpretations, such as clonal selection and expansion. Simulations produce validated standard datasets, where the underlying generative model can be precisely defined and furthermore perturbed to investigate specific questions of interest. Currently, there is no tool that can be used to simulate a comprehensive ground truth single-cell dataset that incorporates both immune receptor repertoires and gene expression. Therefore, we developed Echidna, an R package that simulates immune receptors and transcriptomes at single-cell resolution. Our simulation tool generates annotated single-cell sequencing data with user-tunable parameters controlling a wide range of features such as clonal expansion, germline gene usage, somatic hypermutation, and transcriptional phenotypes. Echidna can additionally simulate time-resolved B cell evolution, producing mutational networks with complex selection histories incorporating class-switching and B cell subtype information. Finally, we demonstrate the benchmarking potential of Echidna by simulating clonal lineages and comparing the known simulated networks with those inferred from only the BCR sequences as input. Together, Echidna provides a framework that can incorporate experimental data to simulate single-cell immune repertoires to aid software development and bioinformatic benchmarking of clonotyping, phylogenetics, transcriptomics and machine learning strategies.

Abstract Figure
Sex-Specific Computational Models of Kidney Function in Patients with Diabetes
Authors: Swapnasrita Sangita , Carlier Aurélie , Layton Anita T.
Published: July 2021

The kidney plays an essential role in homeostasis, accomplished through the regulation of pH, electrolytes and fluids, by the building blocks of the kidney, the nephrons. One of the important markers of the proper functioning of a kidney is the glomerular filtration rate. Diabetes is characterised by an enlargement of the glomerular and tubular size of the kidney, affecting the afferent and efferent arteriole resistance and hemodynamics, ultimately leading to chronic kidney disease. We postulate that the diabetes-induced changes in kidney may exhibit significant sex differences as the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, and (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes. The simulation results indicate that diabetes enhances Na+ transport, especially along the proximal tubules and thick ascending limbs, to similar extents in male and female patients, which can be explained by the diabetes-induced increase in glomerular filtration rate. Additionally, we conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons. Model simulations also suggest that SGLT2 inhibition, which constricts the afferent arteriole to attenuate glomerular hyperfiltration, can then limit Na+-glucose transport, consequently raising luminal [Cl-] at the macula densa and finally restoring the tubuloglomerular feedback signal. By inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis. Those effects on urinary excretion are blunted in women, in part due to their higher distal transport capacity.
gmxapi: a GROMACS-native Python interface for molecular dynamics with ensemble and plugin support
Authors: Irrgang M. Eric , Davis Caroline , Kasson Peter M.
Published: July 2021

Gmxapi provides an integrated, native Python API for both standard and advanced molecular dynamics simulations in GROMACS. The Python interface permits multiple levels of integration with the core GROMACS libraries, and legacy support is provided via an interface that mimics the command-line syntax, so that all GROMACS commands are fully available. Gmxapi has been officially supported since the GROMACS 2019 release and is enabled by default in current versions of the software. Here we describe gmxapi 0.3 and later. Beyond simply wrapping GROMACS library operations, the API permits several advanced operations that are not feasible using the prior command-line interface. First, the API allows custom user plugin code within the molecular dynamics force calculations, so users can execute custom algorithms without modifying the GROMACS source. Second, the Python interface allows tasks to be dynamically defined, so high-level algorithms for molecular dynamics simulation and analysis can be coordinated with loop and conditional operations. Gmxapi makes GROMACS more accessible to custom Python scripting while also providing support for high-level data-flow simulation algorithms that were previously feasible only in external packages.

Author Summary

The gmxapi software provides a Python interface for molecular dynamics simulations in GROMACS. In addition to simply wrapping GROMACS commands, it supports custom user plugin code, ensemble simulation, and data-flow chaining of commands. As such, gmxapi enables the writing and execution of high-level simulation algorithms. The software ships with GROMACS and is freely available under an LGPL2 license.
Lane-maze for preference testing in flies
Authors: Eckert Fabiola Boz , de Brittos Valdati Dhiozer , Neto José Marino , de Toni Daniela Cristina , de Oliveira Cilene Lino
Published: July 2021

Drosophila melanogaster is a candidate species to replace rodents in some neurobiological studies, encouraging attempts to develop behavioural tests for these flies. This study aimed to develop a behavioural test to simultaneously evaluate ethological (categorical) aspects of the motor and fluid intake activities, which may be used to assess sucrose preference in flies. For that, a lane-maze was 3D-printed to accommodate up to 14 individual flies in a single trial. Each lane had a capillary filled with 5% sucrose solution attached to one of the extremities. To validate a 5-min lane-maze test, male and female flies (adults, 5-6 days of age) underwent 0, 2, 8 or 20 h of food deprivation (FD, n=9-11/group) before testing. Duration of locomotion, immobility and grooming in the lane or capillary were scored from the video-recorded trials using EthoWatcher software. Minor effects of sex or FD were observed in the behaviours of flies. Independent of sex or FD, flies spent proportionally longer on the capillary than on the lane. Flies exhibited a significantly higher preference than expected for the capillary zone when food-deprived for 2h (males) or 20 h (females). Data suggest that short lane-maze test is a feasibly high throughput assessment of sucrose preference in flies, which may be sexually dimorphic as in other species studied so far.
A Reinforcement Meta-Learning Framework of Executive Function and Information Demand
Authors: Silvetti Massimo , Lasaponara Stefano , Horan Mattias , Gottlieb Jacqueline
Published: July 2021

Gathering information is crucial for maximizing fitness, but requires diverting resources from searching directly for primary rewards to actively exploring the environment. Optimal decision-making thus maximizes information while reducing effort costs, but little is known about the neural implementation of these tradeoffs. We present a Reinforcement Meta-Learning (RML) computational mechanism that solves the trade-offs between the value and costs of gathering information. We implement the RML in a biologically plausible architecture that links catecholaminergic neuromodulators, the medial prefrontal cortex and topographically organized visual maps and show that it accounts for neural and behavioral findings on information demand motivated by instrumental incentives and intrinsic utility. Moreover, the utility function used by the RML, encoded by dopamine, is an approximation of free-energy. Thus, the RML presents a biologically plausible mechanism through which coordinated motivational, executive and sensory systems generate visual information gathering policies that minimize free energy.
Experimental investigations of the human oesophagus: anisotropic properties of the muscular layer in large deformation
Authors: Durcan Ciara , Hossain Mokarram , Chagnon Grégory , Perić Djordje , Bsiesy Lara , Karam Georges , Girard Édouard
Published: July 2021

Technological advancements in the field of robotics have led to endoscopic biopsy devices able to extract diseased tissue from between the layers of the gastrointestinal tract. Despite this, the layer-dependent properties of these tissues have yet to be mechanically characterised using human tissue. In this study, the ex vivo mechanical properties of the passive muscularis propia layer of the human oesophagus were extensively investigated. For this, a series of uniaxial tensile tests were conducted. The results displayed hyperelastic behaviour, while the differences between loading the tissue in both the longitudinal and circumferential directions showcased its anisotropy. The anisotropy of the muscular layer was present at different strain rates, with the longitudinal direction being consistently stiffer than the circumferential one. The circumferential direction was found to have little strain-rate dependency, while the longitudinal direction results suggest pronounced strain-rate-dependent behaviour. The repeated trials showed larger variation in terms of stress for a given strain in the longitudinal direction compared to the circumferential direction. The possible causes of variation between trials are discussed, and the experimental findings are linked to the histological analysis which was carried out via various staining methods. Finally, the direction-dependent experimental data was simulated using an anisotropic, hyperelastic model.
Dynamic mechanisms of CRISPR interference by Escherichia coli CRISPR-Cas3
Authors: Yoshimi Kazuto , Takeshita Kohei , Kodera Noriyuki , Shibumura Satomi , Yamauchi Yuko , Omatsu Mine , Kunihiro Yayoi , Yamamoto Masaki , Mashimo Tomoji
Published: July 2021

Type I CRISPR-Cas3 uses an RNA-guided multi Cas-protein complex, Cascade, which detects and degrades foreign nucleic acids via the helicase-nuclease Cas3 protein. Despite many studies using cryoEM and smFRET, the precise mechanism of Cas3-mediated cleavage and degradation of target DNA remains elusive. Here we reconstitute the CRISPR-Cas3 system in vitro to show how the Escherichia coli Cas3 (EcoCas3) with EcoCascade exhibits collateral non-specific ssDNA cleavage and target specific DNA degradation. Partial binding of EcoCascade to target DNA with tolerated mismatches within the spacer sequence, but not the PAM, elicits collateral ssDNA cleavage activity of recruited EcoCas3. Conversely, stable binding with complete R-loop formation drives EcoCas3 to nick the non-target strand (NTS) in the bound DNA. Helicase-dependent unwinding then combines with trans ssDNA cleavage of the target strand and repetitive cis cleavage of the NTS to degrade the target dsDNA substrate. High-speed atomic force microscopy demonstrates that EcoCas3 bound to EcoCascade repeatedly reels and releases the target DNA, followed by target fragmentation. Together, these results provide a revised model for collateral ssDNA cleavage and target dsDNA degradation by CRISPR-Cas3, furthering understanding of type I CRISPR priming and interference and informing future genome editing tools.
Common molecular mechanisms underlie the transfer of alpha-synuclein, Tau and huntingtin and modulate spontaneous activity in neuronal cells
Authors: Brás Inês Caldeira , Khani Mohammad Hossein , Vasili Eftychia , Möbius Wiebke , Riedel Dietmar , Parfentev Iwan , Gerhardt Ellen , Fahlbusch Christiane , Urlaub Henning , Zweckstetter Markus , Gollisch Tim , Outeiro Tiago Fleming
Published: July 2021

The misfolding and accumulation of disease-related proteins are common hallmarks among several neurodegenerative diseases. Alpha-synuclein (aSyn), Tau and huntingtin (wild-type and mutant, 25QHtt and 103QHtt, respectively) were recently shown to be transferred from cell-to-cell through different cellular pathways, thereby contributing to disease progression and neurodegeneration. However, the relative contribution of each of these mechanisms towards the spreading of these different proteins and the overall effect on neuronal function is still unclear.

To address this, we exploited different cell-based systems to conduct a systematic comparison of the mechanisms of release of aSyn, Tau and Htt, and evaluated the effects of each protein upon internalization in microglial, astrocytic, and neuronal cells. In the models used, we demonstrate that 25QHtt, aSyn and Tau are released to the extracellular space at higher levels than 103QHtt, and their release can be further augmented with the co-expression of USP19. Furthermore, cortical neurons treated with recombinant monomeric 43QHtt exhibited alterations in neuronal activity that correlated with the toxicity of the polyglutamine expansion. Tau internalization resulted in an increase in neuronal activity, in contrast to slight effects observed with aSyn. Interestingly, all these disease-associated proteins were present at higher levels in ectosomes than in exosomes. The internalization of both types of extracellular vesicles (EVs) by microglial or astrocytic cells elicited the production of pro-inflammatory cytokines and promoted an increase in autophagy markers. Additionally, the uptake of the EVs modulated neuronal activity in cortical neurons.

Overall, our systematic study demonstrates the release of neurodegenerative disease-associated proteins through similar cellular pathways. Furthermore, it emphasizes that protein release, both in a free form or in EVs, might contribute to a variety of detrimental effects in receiving cells and to progression of pathology, suggesting they may be exploited as valid targets for therapeutic intervention in different neurodegenerative diseases.

Graphical abstract
Susceptibilities of human ACE2 genetic variants in coronavirus infection
Authors: Ren Wenlin , Zhu Yunkai , Lan Jun , Chen Hedi , Wang Yuyan , Shi Hongyang , Feng Fei , Chen Da-Yuan , Close Brianna , Zhao Xiaomin , Wu Jianping , Tian Boxue , Yuan Zhenghong , Zhou Dongming , Saeed Mohsan , Wang Xinquan , Zhang Rong , Ding Qiang
Published: July 2021

The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in more than 1603 million cases worldwide and 3.4 million deaths (as of May 2021), with varying incidences and death rates among regions/ethnicities. Human genetic variation can affect disease progression and outcome, but little is known about genetic risk factors for SARS-CoV-2 infection. The coronaviruses SARS-CoV, SARS-CoV-2 and HCoV-NL63 all utilize the human protein angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells. We hypothesized that the genetic variability in ACE2 may contribute to the variable clinical outcomes of COVID-19. To test this hypothesis, we first conducted an in silico investigation of single-nucleotide polymorphisms (SNPs) in the coding region of ACE2 gene. We then applied an integrated approach of genetics, biochemistry and virology to explore the capacity of select ACE2 variants to bind coronavirus spike protein and mediate viral entry. We identified the ACE2 D355N variant that restricts the spike protein-ACE2 interaction and consequently limits infection both in vitro and in vivo. In conclusion, ACE2 polymorphisms could modulate susceptibility to SARS-CoV-2, which may lead to variable disease severity.
3D molecular phenotyping of cleared human brain tissues with light-sheet fluorescence microscopy
Authors: Pesce Luca , Scardigli Marina , Gavryusev Vladislav , Laurino Annunziatina , Mazzamuto Giacomo , Sancataldo Giuseppe , Silvestri Ludovico , Destrieux Christophe , Hof Patrick R. , Costantini Irene , Pavone Francesco S.
Published: July 2021

The combination of optical tissue transparency with immunofluorescence allows the molecular characterization of biological tissues in 3D. However, adult human organs are particularly challenging to become transparent because of the autofluorescence contributions of aged tissues. To meet this challenge, we optimized SHORT (SWITCH - H2O2 - antigen Retrieval - TDE), a procedure based on standard histological treatments in combination with a refined clearing procedure to clear and label portions of the human brain. 3D histological characterization with multiple molecules is performed on cleared samples with a combination of multi-colors and multi-rounds labeling. By performing fast 3D imaging of the samples with a custom-made inverted light-sheet fluorescence microscope (LSFM), we reveal fine details of intact human brain slabs at subcellular resolution. Overall, we proposed a scalable and versatile technology that in combination with LSFM allows mapping the cellular and molecular architecture of the human brain, paving the way to reconstruct the entire organ.
Towards on-chip real-time classification of extra-cellular neural recordings
Authors: Ozdas Mehmet , Gronskaya Elena , von der Behrens Wolfger , Indiveri Giacomo
Published: July 2021

On-line classification of neural recordings can be extremely useful in brain-machine interface, prosthetic applications or therapeutic intervention. In this work we present a feasibility study for developing compact low-power VLSI systems able to classify neural recordings in real-time, using spike-based neuromorphic circuits. We developed a framework for classifying extra-cellular recordings made in rat auditory cortex in response to different auditory stimuli and porting the classification algorithm onto a spiking multi-neuron VLSI chip with programmable synaptic weights. We present recording methods and software classification algorithms; we demonstrate real-time classification in hardware and quantify the system performance; finally, we identify the potential sources of problems in developing such types of systems and propose strategies for overcoming them.
Prior Signal Acquisition Software Versions for Orbitrap Underestimate Low Isobaric Mass Tag Intensities, Without Detriment to Differential Abundance Experiments
Authors: Smith Tom S , Andrejeva Anna , Christopher Josie A. , Crook Oliver M. , Elzek Mohamed A. W. , Lilley Kathryn S
Published: July 2021

Tandem mass tags (TMT) enable simple and accurate quantitative proteomics for multiplexed samples by relative quantification of tag reporter ions. Orbitrap™ quantification of reporter ions has been associated with a characteristic notch region in intensity distribution, within which few reporter intensities are recorded. This has been resolved in version 3 of the instrument acquisition software, Tune. However, 53 % of Orbitrap Fusion, Lumos or Eclipse submissions to PRIDE were generated using prior software versions. To quantify the impact of the notch on existing quantitative proteomics data, we generated a mixed species benchmark and acquired quantitative data using Tune versions 2 and 3. Sub-notch intensities are systemically underestimated with Tune version 2, leading to over-estimation of the true differences in intensities between samples. However, when summarising reporter ion intensities to higher level features, such as peptides and proteins, few features are significantly affected. Targeted removal of spectra with reporter ion intensities below the notch is not beneficial for differential peptide or protein testing. Overall, we find the systematic quantification bias associated with the notch is not detrimental for a typical proteomics experiment.
Ankyrin2 is required for neuronal morphogenesis and long-term memory and interacts genetically with HDAC4
Authors: Schwartz Silvia , Wilson Sarah J , Hale Tracy K , Fitzsimons Helen L
Published: July 2021

Dysregulation ofHDAC4expression and/or subcellular distribution results in impaired neuronal morphogenesis and long-term memory inDrosophila melanogaster. A recent genetic screen for genes that interact in the same molecular pathway asHDAC4identified the cytoskeletal adapterAnkyrin2(Ank2). Here we sought to investigate the role ofAnk2in neuronal morphogenesis, learning and memory, and to examine the nature of interaction withHDAC4. We found that Ank2 is expressed widely throughout theDrosophilabrain where it localizes predominantly to axon tracts. Pan-neuronal knockdown ofAnk2in the mushroom body, a region critical for memory formation, resulted in defects in axon morphogenesis, and similarly reduction ofAnk2in lobular plate tangential neurons of the optic lobe disrupted dendritic branching and arborization. Conditional knockdown ofAnk2in the mushroom body of adultDrosophilasignificantly impaired long-term courtship memory, and this requirement forAnk2was isolated to gamma (γ) neurons of the mushroom body. As overexpression ofHDAC4in γ neurons also impairs the formation of long-term courtship memory, this suggests that any functional relationship between these proteins during LTM likely occurs in γ neurons. We determined that the genetic interaction requires the presence of nuclearHDAC4and is not dependent on a conserved putative ankyrin-binding motif present in HDAC4. In summary, we provide the first characterization of the expression pattern of Ank2 in the adultDrosophilabrain and demonstrate that Ank2 is critical for morphogenesis of the mushroom body and for the molecular processes required in the adult brain for formation of long-term memories.