bluuebunny/crossref_metadata_2025 huggingface dataset:
Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19
Authors: Ko Emily R. , Anstrom Kevin J. , Panettieri Reynold A. , Lachiewicz Anne M. , Maillo Martin , O’Halloran Jane A. , Boucher Cynthia , Smith P. Brian , McCarthy Matthew W. , Segura Nunez Patricia , Mendivil Tuchia de Tai Sabina , Khan Akram , Mena Lora Alfredo J. , Salathe Matthias , Kedar Eyal , Capo Gerardo , Rodríguez Gonzalez Daniel , Patterson Thomas F. , Palma Christopher , Ariza Horacio , Patelli Lima Maria , Blamoun John , Nannini Esteban C. , Sprinz Eduardo , Mykietiuk Analia , Wang Jennifer P. , Parra-Rodriguez Luis , Der Tatyana , Willsey Kate , Benjamin Daniel K. , Wen Jun , Zakroysky Pearl , Halabi Susan , Silverstein Adam , McNulty Steven E. , O’Brien Sean M. , Al-Khalidi Hussein R. , Butler Sandra , Atkinson Jane , Adam Stacey J. , Chang Soju , Maldonado Michael A. , Proscham Michael , LaVange Lisa , Bozzette Samuel A. , Powderly William G. ,   the ACTIV-1 IM study group members
Published: September 2022

Background

We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19.

Methods

We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality.

Results

Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00–1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41– 0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo).

Conclusions

Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality.

Trial registration

ClinicalTrials.gov(NCT04593940).
Development and validation of a methodology to measure exhaled carbon dioxide (CO2) and control indoor air renewal
Authors: Baselga Marta , Alba Juan J. , Schuhmacher Alberto J.
Published: September 2022

The measurement of CO2 has positioned itself as a low-cost and straightforward technique to indirectly control indoor air quality, allowing the reduction of the concentration of potentially pathogen-loaded aerosols to which we are exposed. However, on numerous occasions, bad practice limits the technique for CO2 level interpreting and does not apply methodologies that guarantee air renewal. This work proposes a new methodology for measuring and controlling CO2 levels for indoor air in shared spaces. The proposed methodology is based on three stages: diagnosis, correction protocols, and monitoring/control/surveillance (MCS). The procedure is explained using a cultural center as an actual base case study. Additionally, the procedure was validated by implementing 40 voluntary commercial spaces in Zaragoza (Spain). Standardization of methods is suggested so that the measurement of CO2 becomes an effective strategy to control the airborne transmission of pathogens and thus prevent future Covid-19 outbreaks and novel pandemics.
Evaluation of S/F94 as a proxy for COVID-19 severity
Authors: Swets Maaike C , Kerr Steven , Scott-Brown James , Brown Adam B , Gupta Rishi , Millar Jonathan E , Spata Enti , McCurrach Fiona , Bretherick Andrew D , Docherty Annemarie , Harrison David , Rowan Kathy , Young Neil ,   ISARIC4C Investigators, Groeneveld Geert H , Dunning Jake , Nguyen-Van-Tam Jonathan S , Openshaw Peter , Horby Peter W. , Harrison Ewen , Staplin Natalie , Semple Malcolm G , Lone Nazir , Baillie J Kenneth
Published: September 2022

Optimising statistical power in early-stage trials and observational studies accelerates discovery and improves the reliability of results. Ideally, intermediate outcomes should be continuously distributed and lie on the causal pathway between an intervention and a definitive outcome such as mortality. In order to optimise power for an intermediate outcome in the RECOVERY trial, we devised and evaluated a modification to a simple, pragmatic measure of oxygenation function - the SaO2/FIO2 (S/F) ratio.

We demonstrate that, because of the ceiling effect in oxyhaemoglobin saturation, S/F ceases to reflect pulmonary oxygenation function at high values of SaO2. Using synthetic and real data, we found that the correlation of S/F with a gold standard (PaO2/FIO2, P/F ratio) improved substantially when measurements with SaO2 ≥ 0.94 are excluded (Spearman r, synthetic data: S/F : 0.31; S/F94: 0.85). We refer to this measure as S/F94.

In order to test the underlying assumptions and validity of S/F94 as a predictor of a definitive outcome (mortality), we collected an observational dataset including over 39,000 hospitalised patients with COVID-19 in the ISARIC4C study. We first demonstrated that S/F94 is predictive of mortality in COVID-19. We then compared the sample sizes required for trials using different outcome measures (S/F94, the WHO ordinal scale, sustained improvement at day 28 and mortality at day 28) ensuring comparable effect sizes. The smallest sample size was needed when S/F94 on day 5 was used as an outcome measure.

To facilitate future study design, we provide an online user interface to quantify real-world power for a range of outcomes and inclusion criteria, using a synthetic dataset retaining the population-level clinical associations in real data accrued in ISARIC4C https://isaric4c.net/endpoints.

We demonstrated that S/F94 is superior to S/F as a measure of pulmonary oxygenation function and is an effective intermediate outcome measure in COVID-19. It is a simple and non-invasive measurement, representative of disease severity and provides greater statistical power to detect treatment differences than other intermediate endpoints.
Brain mechanism of foraging: reward-dependent synaptic plasticity or neural integration of values?
Authors: Pereira-Obilinovic Ulises , Hou Han , Svoboda Karel , Wang Xiao-Jing
Published: September 2022

During foraging behavior, action values are persistently encoded in neural activity and updated depending on the history of choice outcomes. What is the neural mechanism for action value maintenance and updating? Here we explore two contrasting network models: synaptic learning of action value versus neural integration. We show that both models can reproduce extant experimental data, but they yield distinct predictions about the underlying biological neural circuits. In particular, the neural integrator model but not the synaptic model requires that reward signals are mediated by neural pools selective for action alternatives and their projections are aligned with linear attractor axes in the valuation system. We demonstrate experimentally observable neural dynamical signatures and feasible perturbations to differentiate the two contrasting scenarios, suggesting that the synaptic model is a more robust candidate mechanism. Overall, this work provides a modeling framework to guide future experimental research on probabilistic foraging.
A Visual, Inexpensive, and Wireless Capillary Rheometer
Authors: Du Jianyi , Sinha Soham , Lee Stacey , Skylar-Scott Mark A.
Published: September 2022

Complex fluid systems can exhibit highly non-linear and time-dependent flow behaviors that arise from microscale reorganization. Rheological measurements to understand these flow-induced properties in soft condensed matter and biology are critical to optimize manufacturing processes that rely upon the use of complex fluids, such as the creation of viscoelastic bioinks for 3D bioprinting. While typical rheological characterizations are performed on bulky and expensive rheometers, these options do not readily enable in situ microscopic visualization of flow behavior, which can provide microstructural insights into the mechanisms and patterns of yielding. To address these limitations, we present a visual, inexpensive (approximately $200), and wireless capillary rheometer (VIEWR) assembled from chiefly 3D printed components. We validate the accuracy and reliability of the portable rheometer by comparing measurements of multiple rheological parameters, including viscosity and yield stress, with measurements obtained from a commercial oscillatory rheometer. At its core, VIEWR employs an easily interchangeable glass capillary channel to enable real-time microscopic observation under flow conditions. To facilitate various experimental conditions, a communication protocol based on Internet of Things (IoT) is adapted to support wireless transmission of data. This unique rheometer design can be used for characterizing and visualizing numerous living and non-living complex fluids.

Specifications table
Increase the flow rate and improve hydrogen deuterium exchange mass spectrometry
Authors: Peterle Daniele , DePice David , Wales Thomas E. , Engen John R.
Published: September 2022

Reversed-phase peptide separation in hydrogen deuterium exchange (HDX) mass spectrometry (MS) must be done with conditions where the back exchange is the slowest possible, the so-called quench conditions of low pH and low temperature. To retain maximum deuterium, separation must also be done as quickly as possible. The low temperature (0 °C) of quench conditions complicates the separation and leads primarily to a reduction in separation quality and an increase in chromatographic backpressure. To improve the separation in HDX MS, one could use a longer gradient, smaller particles, a different separation mechanism (for example, capillary electrophoresis), or multi-dimensional separations such as combining ion mobility separation with reversed-phase separation. Another way to improve separations under HDX MS quench conditions is to use a higher flow rate where separation efficiency at 0 °C is more ideal. Higher flow rates, however, require chromatographic systems (both pumps and fittings) with higher backpressure limits. We tested what improvements could be realized with a commercial UPLC/UHPLC system capable of ~20,000 psi backpressure. We found that a maximum flow rate of 225 μL/min (using a 1×50mm column packed with 1.8 μm particles) was possible and that higher flow rate clearly led to higher peak capacity. HDX MS analysis of both simple and particularly complex samples improved, permitting both shorter separation time, if desired, and providing more deuterium recovery.
IL-12-expressing highly immunogenic recombinant modified vaccinia virus Ankara reprograms tumor-infiltrating myeloid cells to overcome immune resistance
Authors: Liu Shuaitong , Mazo Gregory , Yang Ning , Zhang Tuo , Wang Yi , Tariq Shanza Baseer , Wang Yueqi , Hirschhorn-Cymerman Daniel , Ji Liangliang , Tan Adrian , Wang Jiahu , Yan Wei , Choi John , Xiang Jenny Zhaoying , Li Ming O. , Merghoub Taha , Wolchok Jedd D. , Deng Liang
Published: September 2022

Novel strategies to reprogram tumor-infiltrating myeloid cells for cancer immunotherapy are urgently needed, given that the primary and acquired resistance to immune checkpoint blockade (ICB) therapy has hindered the overall success of immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus and an approved vaccine against smallpox and monkeypox. Here we report rational engineering of recombinant MVA, MQ833, by removing three immune suppressive genes, E5R, E3L, and WR199, from the MVA genome and inserting three transgenes encoding Flt3L, OX40L, and IL-12. Intratumoral (IT) delivery of MQ833 generates potent antitumor responses dependent on CD8+T cells, neutrophils, and M1-like macrophages, the nucleic acid-sensing pathways mediated by MDA5/STING, and interferon feedback loop. IT MQ833 promotes the recruitment and activation of neutrophils and inflammatory monocytes into the injected tumors, depletion of M2-like macrophages, and expansion of M1-like macrophages, generating potent antitumor immunity against tumors resistant to ICB.
de novo diploid genome assembly using long noisy reads
Authors: Nie Fan , Ni Peng , Huang Neng , Zhang Jun , Wang Zhenyu , Xiao Chuan-Le , Luo Feng , Wang Jianxin
Published: September 2022

The high sequencing error rate has impeded the application of long noisy reads for diploid genome assembly. Most existing assemblers failed to generate high-quality phased assemblies using long noisy reads. Here, we present PECAT, a Phased Error Correction and Assembly Tool, for reconstructing diploid genomes from long noisy reads. We design a haplotype-aware error correction method that can retain heterozygote alleles while correcting sequencing errors. We combine a corrected read SNP caller and a raw read SNP caller to further improve the identification of inconsistent overlaps in the string graph. We use a grouping method to assign reads to different haplotype groups. PECAT efficiently assembles diploid genomes using Nanopore R9, PacBio CLR or Nanopore R10 reads only. PECAT generates more contiguous haplotype-specific contigs compared to other assemblers. Especially, PECAT achieves nearly haplotype-resolved assembly on B. taurus (Bison x Simmental) using Nanopore R9 reads and phase block NG50 with 59.4/58.0 Mb for HG002 using Nanopore R10 reads.
Effects of Simvastatin on RBL-2H3 cell degranulation
Authors: Yoshii Michiko , Kitazaki Ai , Ozawa Koichiro
Published: September 2022

Hypercholesterolemia is a major complication of arteriosclerosis. Mast cells in arteriosclerosis plaques induce inflammatory reactions, and promote arterial sclerosis. In this study, we evaluated the pharmacological effects of simvastatin (SV)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors on the degranulation of rat basophilic leukemia (RBL)-2H3 cells, which are commonly used as mast cell models. SV significantly decreased degranulation induced by three types of stimulation: antigen antibody reaction (Ag-Ab), thapsigargin (Tg) serosal endoplasmic reticulum calcium ATPase (SERCA) inhibitor, and A23187 calcium ionophore. SV had a stronger inhibitory effect on degranulation induced by Ag-Ab stimulation than the other two stimulations. However, SV had no effect on increases of intracellular Ca2+ concentrations. Mevalonate or geranylgeraniol co-treatment with SV completely prevented the inhibitory effect of SV on degranulation induced by these stimulations. Immunoblotting results showed that SV inhibited protein kinase C (PKC) delta translocation that was induced by Ag-Ab but not by Tg or A23187. SV induced a reduction in active Rac1, and actin filament rearrangements.

In conclusion, SV inhibits RBL-2H3 cell degranulation by inhibiting downstream signaling pathways, including the sequential degranulation pathway. These inhibitory effects were completely reversed by the addition of geranylgeraniol and might be induced by changes in the translocation of the small GTPase families Rab and Ras and Rho, which are related to vesicular transport and PKC delta activation, respectively. These changes are caused by the inhibition of HMG-CoA reductase by SV following the synthesis of farnesyl and geranylgeranyl pyrophosphates, which play important roles in the activation of small GTPases.
Genetic influences on the shape of brain ventricular and subcortical structures
Authors: Zhao Bingxin , Li Tengfei , Yang Xiaochen , Shu Juan , Wang Xifeng , Luo Tianyou , Yang Yue , Wu Zhenyi , Fan Zirui , Jiang Zhiwen , Chen Jie , Shan Yue , Tang Jiarui , Xiong Di , Zhu Ziliang , Gao Mufeng , Guan Wyliena , Tomlinson Chalmer E. , Dong Qunxi , Li Yun , Stein Jason L. , Wang Yalin , Zhu Hongtu
Published: September 2022

Brain ventricular and subcortical structures are heritable both in size and shape. Genetic influences on brain region size have been studied using conventional volumetric measures, but little is known about the genetic basis of ventricular and subcortical shapes. Here we developed pipelines to extract seven complementary shape measures for lateral ventricles, subcortical structures, and hippocampal subfields. Based on over 45,000 subjects in the UK Biobank and ABCD studies, 60 genetic loci were identified to be associated with brain shape features (P < 1.09 × 10-10), 19 of which were not detectable by volumetric measures of these brain structures. Ventricular and subcortical shape features were genetically related to cognitive functions, mental health traits, and multiple brain disorders, such as the attention-deficit/hyperactivity disorder. Vertex-based shape analysis was performed to precisely localize the brain regions with these shared genetic influences. Mendelian randomization suggests brain shape causally contributes to neurological and neuropsychiatric disorders, including Alzheimer’s disease and schizophrenia. Our results uncover the genetic architecture of brain shape for ventricular and subcortical structures and prioritize the genetic factors underlying disease-related shape variations.
Deep Learning Integration of Chest CT Imaging and Gene Expression Identifies Novel Aspects of COPD
Authors: Chen Junxiang , Zhonghui Xu , Sun Li , Yu Ke , Hersh Craig P. , Boueiz Adel , Hokanson John , Sciurba Frank C. , Silverman Edwin K. , Castaldi Peter J. , Batmanghelich Kayhan
Published: September 2022

Rationale

Chronic obstructive pulmonary disease (COPD) is characterized by pathologic changes in the airways, lung parenchyma, and persistent inflammation, but the links between lung structural changes and patterns of systemic inflammation have not been fully described.

Objectives

To identify novel relationships between lung structural changes measured by chest computed tomography (CT) and systemic inflammation measured by blood RNA sequencing.

Methods

CT scan images and blood RNA-seq gene expression from 1,223 subjects in the COPDGene study were jointly analyzed using deep learning to identify shared aspects of inflammation and lung structural changes that we refer to as Image-Expression Axes (IEAs). We related IEAs to COPD-related measurements and prospective health outcomes through regression and Cox proportional hazards models and tested them for biological pathway enrichment.

Measurements and Main Results

We identified two distinct IEAs: IEAemphcaptures an emphysema-predominant process with a strong positive correlation to CT emphysema and a negative correlation to FEV1and Body Mass Index (BMI); IEAairwaycaptures an airway-predominant process with a positive correlation to BMI and airway wall thickness and a negative correlation to emphysema. Pathway enrichment analysis identified 29 and 13 pathways significantly associated with IEAemphand IEAairway, respectively (adjusted p<0.001).

Conclusions

Integration of CT scans and gene expression data identified two IEAs that capture distinct inflammatory processes associated with emphysema and airway-predominant COPD.

At a Glance Commentary

Scientific Knowledge on the Subject

Chronic obstructive pulmonary disease (COPD) is characterized by lung structural changes and has a prominent systemic inflammatory component, but the links between lung structural changes and patterns of systemic inflammation in COPD have not been fully described.

What This Study Adds to the Field

We identified novel relationships between lung structural changes and systemic inflammation by simultaneously analyzing CT scans and blood RNA-sequencing gene expression using deep learning models. We identified two distinct Image-Expression Axes (IEAs) that characterize different inflammatory processes associated with emphysema and airway predominant COPD.

This article has an online data supplement, which is accessible from this issue’s table of content online atwww.atsjournals.org.
WITHDRAWN: A gene expression-based diagnostic classifier for identification of severe COVID-19 and multisystem inflammatory syndrome in children (MIS-C)
Authors: Sotomayor-Gonzalez Alicia , Loy Conor J. , Nguyen Jenny , Servellita Venice , Bhattacharya Sanchita , Lenz Joan , Williams Meagan , Suslovic Will , Cheng Alexandre P. , Bliss Andrew , Saldhi Prachi , Streithorst Jessica , Huh Hee Jae , Foresythe Abiodun , Oseguera Miriam , de la Cruz Katrina , Brazer Noah , Wood Nathan , Hsieh Charlotte , Bahar Burak , Gliwa Amelia , Bhakta Kushmita , Perez Maria A. , Anderson Evan J. , Chahroudi Ann , Delaney Meghan , Butte Atul J. , DeBiasi Roberta , Rostad Christina A. , De Vlaminck Iwijn , Chiu Charles
Published: September 2022

Withdrawal Statement

The authors have withdrawn their manuscript owing to data from patients who had not been consented being inadvertently used in the preprint. This has been corrected in the version of the study published in Cell Reports Medicine. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Quartet RNA reference materials and ratio-based reference datasets for reliable transcriptomic profiling
Authors: Yu Ying , Hou Wanwan , Wang Haiyan , Dong Lianhua , Liu Yaqing , Sun Shanyue , Yang Jingcheng , Cao Zehui , Zhang Peipei , Zi Yi , Li Zhihui , Liu Ruimei , Gao Jian , Chen Qingwang , Zhang Naixin , Li Jingjing , Ren Luyao , Jiang He , Shang Jun , Zhu Sibo , Wang Xiaolin , Qing Tao , Bao Ding , Li Bingying , Li Bin , Suo Chen , Pi Yan ,   The Quartet Project Team, Wang Xia , Dai Fangping , Scherer Andreas , Mattila Pirkko , Han Jingxiong , Zhang Lijun , Jiang Hui , Thierry-Mieg Danielle , Thierry-Mieg Jean , Xiao Wenming , Hong Huixiao , Tong Weida , Wang Jing , Li Jinming , Fang Xiang , Jin Li , Shi Leming , Xu Joshua , Qian Feng , Zhang Rui , Zheng Yuanting
Published: September 2022

As an indispensable tool for transcriptome-wide analysis of differential gene expression, RNA sequencing (RNAseq) has demonstrated great potential in clinical applications. However, the lack of multi-group RNA reference materials of biological relevance and the corresponding reference datasets for assessing the reliability of RNAseq hampers its wide clinical applications wherein the underlying biological differences among study groups are often small. As part of the Quartet Project for quality control and data integration of multiomic profiling, we established four RNA reference materials derived from immortalized B-lymphoblastoid cell lines from four members of a monozygotic twin family. Additionally, we constructed ratio-based transcriptome-wide reference datasets using multi-batch RNAseq datasets, providing “ground truth” for benchmarking. Moreover, Quartet-sample-based quality metrics were developed for assessing reliability of RNAseq technology in terms of intra-batch proficiency and cross-batch reproducibility. The small intrinsic biological differences among the Quartet samples enable sensitive assessment of performance of transcriptomic measurements. The Quartet RNA reference materials combined with the reference datasets can be served as unique resources for assessing data quality and improving reliability of transcriptomic profiling.
Clinical, socio-demographic, and parental correlates of early autism traits in a community cohort
Authors: Gale-Grant Oliver , Chew Andrew , Falconer Shona , França Lucas G.S , Fenn-Moltu Sunniva , Hadaya Laila , Harper Nicholas , Ciarrusta Judit , Charman Tony , Murphy Declan , Arichi Tomoki , McAlonan Grainne , Nosarti Chiara , Edwards A David , Batalle Dafnis
Published: September 2022

Background

Autism traits emerge between the ages of 1 and 2. It is not known if experiences which increase the likelihood of childhood autism are related to early trait emergence, or if other exposures are more important. Identifying factors linked to toddler autism traits in the general population may improve our understanding of the mechanisms underlying atypical neurodevelopment.

Methods

Clinical, socio-demographic, and parental information was collected at birth from 536 toddlers in London, UK (gestational age at birth, sex, maternal body mass index, age, parental education level, parental first language, parental history of neurodevelopmental disorders) and at 18 months (parent cohabiting status, two measures of social deprivation, three measures of maternal parenting style, and a measure of maternal postnatal depression). General neurodevelopment was assessed with the Bayley Scales of Infant and Toddler Development, 3rdEdition (BSID-III), and autism traits were assessed using the Quantitative Checklist for Autism in Toddlers (Q-CHAT). Multivariable models were used to identify associations between variables and Q-CHAT. A model including BSID-III was used to identify factors associated with Q-CHAT independent of general neurodevelopment. Models were also evaluated addressing variable collinearity with principal component analysis (PCA).

Results

A multivariable model explained 20% of Q-CHAT variance, with four individually significant variables (two measures of parenting style and two measures of socio-economic deprivation). After adding general neurodevelopment into the model 36% of Q-CHAT variance was explained, with three individually significant variables (two measures of parenting style and one measure of language development). After addressing variable collinearity with PCA, parenting style and social deprivation were positively correlated with Q-CHAT score via a single principal component, independently of general neurodevelopment. Neither sex nor family history of autism were associated with Q-CHAT score.

Limitations

The Q-CHAT is parent rated and is therefore a subjective opinion rather than a clinical assessment. We measured Q-CHAT at a single timepoint, and to date no participant has been followed up in later childhood, so we are focused purely on emerging traits rather than clinical autism diagnoses.

Conclusions

Autism traits are common at age 18 months, and greater emergence is specifically related to exposure to early life adversity.
Investigating the ability of astrocytes to drive neural network synchrony
Authors: Handy Gregory , Borisyuk Alla
Published: September 2022

Recent experimental works have implicated astrocytes as a significant cell type underlying several neuronal processes in the mammalian brain, from encoding sensory information to neurological disorders. Despite this progress, it is still unclear how astrocytes are communicating with and driving their neuronal neighbors. While previous computational modeling works have helped propose mechanisms responsible for driving these interactions, they have primarily focused on interactions at the synaptic level, with microscale models of calcium dynamics and neurotransmitter diffusion. Since it is computationally infeasible to include the intricate microscale details in a network-scale model, little computational work has been done to understand how astrocytes may be influencing spiking patterns and synchronization of large networks. We overcome this issue by first developing an “effective” astrocyte that can be easily implemented to already established network frameworks. We do this by showing that the astrocyte proximity to a synapse makes synaptic transmission faster, weaker, and less reliable. Thus, our “effective” astrocytes can be incorporated by considering heterogeneous synaptic time constants, which are parametrized only by the degree of astrocytic proximity at that synapse. We then apply our framework to large networks of exponential integrate-and-fire neurons with various spatial structures. Depending on key parameters, such as the number of synapses ensheathed and the strength of this ensheathment, we show that astrocytes can push the network to a synchronous state and exhibit spatially correlated patterns.

Author summary

In many areas of the brain, glial cells called astrocytes wrap their processes around synapses – the points of contact between neurons. The number of wrapped synapses and the tightness of wrapping varies between brain areas and changes during some diseases, such as epilepsy. We investigate the effect that this synaptic ensheathment has on communication between neurons and the resulting collective dynamics of the neuronal network. We present a general, computationally-efficient way to include astrocytes in neuronal networks using an “effective astrocyte” representation derived from detailed microscopic scale models. The resulting hybrid networks allow us to emulate and observe the effect of ensheathment conditions corresponding to different brain areas and disease states. In particular, we find that it makes the networks more likely to switch into a highly correlated regime, contrary to predictions from the traditional neurons-only view. These results open a new perspective on neural network dynamics, where our understanding of conditions for generating correlated brain activity (e.g., rhythms associated with various brain functions, epileptic seizures) needs to be reevaluated.
Engineering Alignment has Mixed Effects on hiPSC-CM Maturation
Authors: Kalkunte Nikhith G. , Delabmbre Talia E , Sohn Sogu , Pickett Madison , Parekh Sapun , Zoldan Janet
Published: September 2022

The potential of human induced pluripotent stem cell differentiated cardiomyocytes (hiPSC-CMs) is greatly limited by their functional immaturity. Strong relationships exist between CM structure and function, leading many in the field to seek ways to mature hiPSC-CMs by culturing on biomimetic substrates, specifically those that promote alignment. However, these in vitro models have so far failed to replicate the alignment that occurs during cardiac differentiation. We show that engineered alignment, incorporated before and during cardiac differentiation, affects hiPSC-CM electrochemical coupling and mitochondrial morphology. We successfully engineer alignment in differentiating hiPSCs as early as Day 4. We uniquely apply optical redox imaging to monitor the metabolic changes occurring during cardiac differentiation. We couple this modality with cardiac-specific markers, which allows us to assess cardiac metabolism in heterogeneous cell populations. The engineered alignment drives hiPSC-CM differentiation towards the ventricular compact CM subtype and improves electrochemical coupling in the short term. Moreover, we observe glycolysis to oxidative phosphorylation switch throughout differentiation and CM development. On the subcellular scale, we note changes in mitochondrial morphology in the long term. Our results demonstrate that cellular alignment accelerates hiPSC-CM maturity and emphasizes the interrelation of structure and function in cardiac development. We anticipate that combining engineered alignment with additional maturation strategies will result in improved development of mature CMs from hiPSC and strongly improve cardiac tissue engineering.

Impact Statement

This work demonstrates the mixed effect of engineered structure in inducing matured function of human induced pluripotent stem cell -derived cardiomyocytes. Isolating the impacts of hiPSC-CM alignment on functionality is a necessary step in optimizing the culture conditions to develop cardiac cell therapies. Furthermore, our work has broader implications concerning how we understand the impact of mechanical microenvironments on stem cell differentiation and development.
Experience-dependent flexibility in a molecularly diverse central-to-peripheral auditory feedback system
Authors: Frank Michelle M. , Sitko Austen A. , Suthakar Kirupa , Torres Cadenas Lester , Hunt Mackenzie , Yuk Mary Caroline , Weisz Catherine J.C. , Goodrich Lisa V.
Published: September 2022

Brainstem olivocochlear neurons (OCNs) modulate the earliest stages of auditory processing through feedback projections to the cochlea and have been shown to influence hearing and protect the ear from sound-induced damage through unclear mechanisms. Here, we used single-nucleus sequencing, anatomical reconstructions, and electrophysiology to characterize OCNs during postnatal development and after sound exposure. We identified markers for known OCN subtypes, medial (MOC) and lateral (LOC) OCNs, and show that they express distinct cohorts of physiologically relevant genes that change over development. In addition, we discovered a neuropeptide-enriched LOC subtype that produces Neuropeptide Y along with other neurotransmitters. Throughout the cochlea, both LOC subtypes extend arborizations over wide frequency domains. Moreover, LOC neuropeptide expression is strongly upregulated days after acoustic trauma, potentially providing a sustained protective signal to the cochlea. OCNs are therefore poised to have diffuse, dynamic effects on early auditory processing over timescales ranging from milliseconds to days.
Substrate-binding Glycine Residues are Major Determinants for Hydrolase and Ligase Activity of Plant Legumains
Authors: Hemu Xinya , Chan Ning-Yu , Liew Heng Tai , Hu Side , Zhang Xiaohong , Serra Aida , Lescar Julien , Liu Chuan-Fa , Tam James P
Published: September 2022

Peptide asparaginyl ligases (PALs) are Asn/Asp(Asx)-specific ligases that are useful for precision modifications of proteins and live-cell surfaces. However, PALs share high structural similarity to the far more common asparaginyl endopeptidases (AEPs), also known as legumains that hydrolyze peptide bonds after Asx, thus making it challenging to identify PALs in a sea of AEPs. Previously we identified sequences flanking the catalytic site as ligase activity determinants (LADs) for legumains. Here we show that two conserved substrate-binding Gly residues are critical, but negative determinants for ligase activity, based on a combined bioinformatics analysis of 1,500 plant legumains, mutagenesis and functional study of 16 novel legumains, plus identification of seven new PALs. We also show that PALs are rare and AEPs are much more common, accounting for about 1% and 88%, respectively. Our results suggest that specific glycine residues are molecular determinants to identify PALs and AEPs as two different legumain subfamilies.
Splicing modulators impair DNA damage response and induce killing of cohesin-mutant MDS/AML
Authors: Wheeler Emily C , Martin Benjamin J E , Doyle William C , Gorelov Rebecca A , Donahue Melanie , Jann Johann C , Abdel-Wahab Omar , Taylor Justin , Seiler Michael , Buonamici Silvia , Belizaire Roger , Adelman Karen , Tothova Zuzana
Published: September 2022

Splicing modulation is a promising treatment strategy pursued to date only in splicing-factor mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in cancer, including myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML), where they are associated with poor outcomes. Here, we show that cohesin mutations are biomarkers of sensitivity to drugs targeting the splicing-factor SF3B1 (H3B-8800 and E-7107). We identify drug-induced alterations in splicing and corresponding reduced gene expression of a large number of DNA repair genes, including BRCA1 and BRCA2, as the mechanism underlying this sensitivity in cell line models, primary patient samples and patient-derived xenograft (PDX) models of AML. We find that DNA damage repair genes are particularly sensitive to exon skipping induced by SF3B1 modulators given their long length and large number of exons per transcript. Furthermore, we demonstrate that treatment of cohesin-mutant cells with SF3B1 modulators not only results in impaired DNA damage response and accumulation of DNA damage, but it significantly sensitizes cells to subsequent killing by PARP inhibitors and chemotherapy, and leads to improved overall survival of PDX models of cohesin-mutant AML in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS and AML, and we propose this as a broader strategy for therapeutic targeting of other DNA damage-repair deficient cancers.

One Sentence Summary

We identify an unexpected effect of SF3B1 splicing inhibitors on regulation of DNA damage repair genes and show efficacy of combination treatment in cohesin-mutant MDS and AML.
Programming super DNA-enzyme molecules for on-demand enzyme activity modulation
Authors: Zhao Haipei , Xiu Xuehao , Li Mingqiang , Gou Mingyang , Tao Leyang , Zuo Xiaolei , Fan Chunhai , Tian Zhongqun , Song Ping
Published: September 2022

Dynamic interactions of enzymes, including programmable configuration and cycling of enzymes, play important roles in the regulation of cellular metabolism. Here, we construct a super DNA-enzymes molecule (SDEM) that comprises at least two cascade enzymes and linked DNA strands to control and detect metabolism. We find that the programmable SDEM which comprises glucose oxidase (GOx) and horseradish peroxidase (HRP) has a 50-fold lower detection of limit and a 1.6-fold higher reaction rate than free enzymes. SDEM can be assembled and disassembled using a hairpin structure and a displacement DNA strand to complete multiple cycles. An entropically driven catalytic assembly (catassembly) enables different SDEMs to switch from SDEM with GOx and HRP cascades to SDEM with sarcosine oxidase (SOX) and HRP cascades by over six orders of magnitude less time than no catassembly to detect different metabolisms (glucose and sarcosine) on demand.
In vitro synergistic action of TAT-RasGAP317-326 peptide with antibiotics against Gram-negative pathogens
Authors: Vizzarro Grazia , Jacquier Nicolas
Published: September 2022

Objectives

Multidrug-resistant (MDR) bacteria are a continuously increasing threat for medicine, causing infections recalcitrant to antibiotics. Antimicrobial peptides (AMPs) were identified as alternatives to antibiotics, being naturally occurring short peptides and part of the innate immune system of a vast majority of organisms. However, the clinical application of AMPs is limited by suboptimal pharmacokinetic properties and relatively high toxicity. Combinatorial treatments using AMPs and classical antibiotics may decrease the concentrations of AMPs required for bacterial eradication, thus lowering the side effects of these peptides.

Methods

Here, we investigate the in vitro efficiency of combinations of the recently described antimicrobial peptide TAT-RasGAP317-326 with a panel of commonly used antimicrobial agents against three Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii using checkerboard and time-kill assays.

Results

We identified synergistic combinations towards all three bacteria and demonstrated that these combinations had an increased bactericidal effect compared to individual drugs. Moreover, combinations were also effective against clinical isolates of A. baumannii. Finally, combination of TAT-RasGAP317-326 and meropenem had a promising antibiofilm effect towards A. baumannii.

Conclusion

Taken together, our results indicate that combinations of TAT-RasGAP317-326 with commonly-used antimicrobial agents may lead to the development of new treatment protocols against infections caused by MDR bacteria.
The population-level impact of Enterococcus faecalis genetics on intestinal colonisation and extraintestinal infection
Authors: Chaguza Chrispin , Pöntinen Anna K. , Top Janetta , Arredondo-Alonso Sergio , Freitas Ana R. , Novais Carla , Torres Carmen , Bentley Stephen D. , Peixe Luisa , Coque Teresa M. , Willems Rob J.L. , Corander Jukka
Published: September 2022

Enterococcus faecalis is a commensal pathogenic bacterium commonly found in the human gastrointestinal tract and a cause of opportunistic infections typically associated with multidrug resistance. The E. faecalis genetic changes associated with pathogenicity and extraintestinal infection, particularly through gut-to-bloodstream translocation, are poorly understood. Here, we investigate the E. faecalis genetic signatures associated with intestinal colonisation and extraintestinal infection and infection of hospitalised and non-hospitalised individuals using heritability estimation and a genome-wide association study (GWAS). We analysed 750 whole-genome sequences of faecal and bloodstream E. faecalis isolates from hospitalised patients and non-hospitalised individuals, respectively, predominantly in Europe. We found that E. faecalis infection of individuals depending on their hospitalisation status and extraintestinal infection are heritable traits and that ∼24% and ∼34% of their variation is explained by the considered genetic effects, respectively. Further, a GWAS using linear mixed models did not pinpoint any clear enrichment of individual genetic changes in isolates from different isolation sites and individuals with varying hospitalisation statuses, suggesting that these traits are highly polygenic. Altogether, our findings indicate that E. faecalis infection and extraintestinal infection are influenced by variation in genetic, host, and environmental factors, and ultimately the opportunistic pathogenic lifestyle of this versatile host generalist bacterium.
pCMLM: Genome Wide Association Study of Body Size Traits in Multiple Regions of Yak Based on the Provided Compressed Mixed Linear Model
Authors: Liu Xinrui , Chai Zhixin , Peng Wei , Kangzhu Yixi , Zhong Jincheng , Wang Jiabo
Published: September 2022

Objective

Yak is a unique large animal species living in the Qinghai-Tibet Plateau and the surrounding Hengduan Mountains, and has evolved several regional variety resources due to the special geographical and ecological environment in which it lives. Therefore, it is of great importance to investigate the genetic composition of body size traits among breeds in multiple regions for yak breeding and production.

Method

A genome-wide association analysis was performed on 94 yak individuals (a total of 31 variety resources) for five body size traits (body height, body weight, body length, chest circumference, and circumference of cannon bone). The individuals were clustered following known population habitat. The kinship of grouping individuals was used in the CMLM. This provided compressed mixed linear model was named pCMLM method.

Result

Total of 3,584,464 high-quality SNP markers were obtained on 30 chromosomes. Principal component analysis using the whole SNPs do not accurately classify all populations into multiple subpopulations, a result that is not the same as the population habitat. Six SNP loci were identified in the pCMLM-based GWAS with statistically significant correlation with body height, and four candidate genes (FXYD6, SOHLH2, ADGRB2, and OSBPL6), which in the vicinity of the variant loci, were screened and annotated. Two of these genes, ADGRB2 and OSBPL6, are involved in biological regulatory processes such as body height regulation, adipocyte proliferation and differentiation.

Conclusion

Based on the previous population information, the pCMLM can provide more sufficient associated results when the conventional CMLM can not catch optimum clustering groups. The fundamental information for quantitative trait gene localization or candidate gene cloning in the mechanism of yak body size trait formation.
Aminoglycoside tolerance inVibrio choleraeengages translational reprogramming associated with queuosine tRNA modification
Authors: Fruchard Louna , Babosan Anamaria , Carvalho Andre , Lang Manon , Li Blaise , Duchateau Magalie , Giai-Gianetto Quentin , Matondo Mariette , Bonhomme Frédéric , Hatin Isabelle , Arbes Hugo , Fabret Céline , Corler Enora , Sanchez Guillaume , Marchand Virginie , Motorin Yuri , Namy Olivier , de Crécy-Lagard Valérie , Mazel Didier , Baharoglu Zeynep
Published: September 2022

Tgt is the enzyme modifying the guanine (G) in tRNAs with GUN anticodon to queuosine (Q).tgtis required for optimal growth ofVibrio choleraein the presence of sub-lethal aminoglycoside concentrations. We further explored here the role of the Q34 in the efficiency of codon decoding upon tobramycin exposure. We characterized its impact on the overall bacterial proteome, and elucidated the molecular mechanisms underlying the effects of Q34 modification in antibiotic translational stress response. Using molecular reporters, we showed that Q34 impacts the efficiency of decoding at tyrosine TAT and TAC codons. Proteomics analyses revealed that the anti-SoxR factor RsxA is better translated in the absence oftgt. RsxA displays a codon bias towards tyrosine TAT and overabundance of RsxA leads to decreased expression of genes belonging to SoxR oxidative stress regulon. We also identified conditions that regulatetgtexpression. We propose that regulation of Q34 modification in response to environmental cues leads to translational reprogramming of transcripts bearing a biased tyrosine codon usage.In silicoanalysis further identified candidate genes which could be subject to such translational regulation, among which DNA repair factors. Such transcripts, fitting the definition of modification tunable transcripts, are central in the bacterial response to antibiotics.