bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploiting mechanisms for hierarchical branching structure of lung airway
Authors: Takigawa-Imamura Hisako , Fumoto Katsumi , Takesue Hiroaki , Miura Takashi
Published: March 2023

The lung airways exhibit distinct features with long, wide proximal branches and short, thin distal branches, crucial for optimal respiratory function. In this study, we investigated the mechanism behind this hierarchical structure through experiments and modeling, focusing on the regulation of branch length and width during the pseudoglandular stage. To evaluate the response of mouse lung epithelium to fibroblast growth factor 10 (FGF10), we monitored the activity of extracellular signal-regulated kinase (ERK). ERK activity exhibited an increase dependent on the curvature of the epithelial tissue, which gradually decreased with the progression of development. We then constructed a computational model that incorporates curvature-dependent growth to predict its impact on branch formation. It was demonstrated that branch length is determined by the curvature dependence of growth. Next, in exploring branch width regulation, we considered the effect of apical contraction, a mechanism we had previously proposed to be regulated by Wnt signaling. Analysis of a mathematical model representing apical constriction showed that branch width is determined by cell shape. Finally, we constructed an integrated computational model that includes curvature-dependent growth and cell shape controls, confirming their coordination in regulating branch formation. This study proposed that changes in the autonomous property of the epithelium may be responsible for the progressive branch morphology.
In vitro screening of non-antibiotic alternative growth promoter combinations in broilers
Authors: Li Zunyan , Zhang Beibei , Zhu Weimin , Lin Yingting , Jiang Linlin , Zhu Fenghua , Guo Yixuan
Published: March 2023

Available research on non-antibiotic alternative growth promoter (NAGPs) mainly focuses on the effect of a single preparation on the substitution effect of antibiotics. However, different NAGP might work together in harmony. Studies related to NAGP combinations are lacking. This study aimed to screen six non-antibiotic alternative growth promoter combinations (NAGPCs) in vitro so as to find a better alternative method to ensure feed efficiency and the broiler health. Pepsin and 42-d broiler ileal fluid were used for the in vitro digestion test, and the optimal addition levels of NAGPs and NAGPCs were selected based on dry matter (DM) and organic matter (OM) digestibility, microbiota of digestive fluid, and antioxidant capacity of digestive fluid. Results showed the optimum addition amount of Mannose oligosaccharide (MOS), fruit oligosaccharide (FOS), mannanase (MAN),Bacillus subtilis(BS), sodium butyrate (SB), guanidinoacetic acid (CA), xylanase (XYL), glucose oxidase (GO), and phytase (PT) were 0.2%, 0.9%, 0.03%, 0.05%, 0.08%, 0.002%, 0.008%, and 0.004%. The six best combinations were 0.2%MOS + 0.03%MAN + 0.15%SB, 0.2%MOS + 0.03%MAN + 0.05%BS, 0.2%MOS + 0.9%FOS + 0.15%SB, 0.2%MOS + 0.9%FOS + 0.05%BS, 0.2%MOS + 0.9%FOS + 0.03%MAN, and 0.2%MOS + 0.05%BS + 0.004%PT. In conclusion, NAGPCs improved the apparent digestibility of ileal DM and OM, intestinal flora and antioxidant capacity. Comparatively, under this condition, using NAGPC has more beneficial effects than using non-antibiotic alternative growth promoter.
The Potential of Low Press and Hypoxia Environment in Assisting Pan-cancer Treatment
Authors: Hu Xiaoxi , Chen Xinrui , Sun Mengzhen , Wang Xilu , Hu Zixin , Zhang Shixuan
Published: March 2023

Objective

A low incidence and mortality rate of cancer has been observed in high-altitude regions, suggesting a potential positive effect of low press and hypoxia (LPH) environment on cancer. Based on this finding, our study aimed to construct a pan-cancer prognosis risk model using a series of ADME genes intervened by low oxygen, to explore the impact of LPH environment on the overall survival (OS) of various kinds of cancers, and to provide new ideas and approaches for cancer prevention and treatment.

Datasets and Measures

The study used multiple sources of data to construct the pan-cancer prognosis risk model, including gene expression and survival data of 8,628 samples from the cancer genome atlas, and three gene expression omnibus databases were employed to validate the prediction efficiency of the prognostic model. The AltitudeOmics dataset was specifically used to validate the significant changes in model gene expression in LPH. To further identify the biomarkers and refine the model, various analytical approaches were employed such as single-gene prognostic analysis, weighted gene co-expression network analysis, and stepwise cox regression. And LINCS L1000, AutoDockTools, and STITCH were utilized to explore effective interacting drugs for model genes.

Main Outcomes and Conclusions

The study identified eight ADME genes with significant changes in the LPH environment to describe the prognostic features of pan-cancer. Lower risk scores calculated by the model were associated with better prognosis in 25 types of tumors, with a p-value of less than 0.05. The LPH environment was found to reduce the overall expression value of model genes, which could decrease the death risk of tumor prognosis. Additionally, it is found that the low-risk group had a higher degree of T cell infiltration based on immune infiltration analysis. Finally, drug exploration led to the identification of three potential model-regulating drugs. Overall, the study provided a new approach to construct a pan-cancer survival prognosis model based on ADME genes from the perspective of LPH and offered new ideas for future tumor prognosis research.
Used paper tissues for pathogen identification in acute respiratory infection
Authors: Rector Annabel , Bloemen Mandy , Van Ranst Marc , Wollants Elke
Published: March 2023

We investigated the potential of used paper tissues as a non-invasive sampling method for the diagnosis of acute respiratory infections. The method allowed the identification and typing of respiratory pathogens in symptomatic individuals, as well as in collective samples taken at a community level. The collection of used paper tissues could therefore be useful in epidemiological surveillance for SARS-CoV-2 and other respiratory pathogens such as influenzavirus, respiratory syncytial virus, entero/rhinoviruses andStreptococcus pneumoniae.
The potential contribution of vaccination uptake to occupational differences in risk of SARS-CoV-2: Analysis of the ONS COVID-19 Infection Survey
Authors: Wilkinson Jack , Demou Evangelia , Cherrie Mark , Edge Rhiannon , Gittins Matthew , Katikireddi S Vittal , Kromydas Theocharis , Mueller William , Pearce Neil , van Tongeren Martie , Rhodes Sarah
Published: March 2023

Objectives

To assess variation in vaccination uptake across occupational groups as a potential explanation for variation in risk of SARS-CoV-2 infection.

Design

We analysed data from the UK Office of National Statistics COVID-19 Infection Survey linked to vaccination data from the National Immunisation Management System in England from December 1st2020 to 11thMay 2022. We analysed vaccination uptake and SARS-CoV-2 infection risk by occupational group and assessed whether adjustment for vaccination reduced the variation in risk between occupational groups.

Setting

Results

Estimated rates of triple-vaccination were high across all occupational groups (80% or above), but were lowest for food processing (80%), personal care (82%), hospitality (83%), manual occupations (84%), and retail (85%). High rates were observed for individuals working in health (95% for office-based, 92% for those in patient-facing roles) and education (91%) and office-based workers not included in other categories (90%). The impact of adjusting for vaccination when estimating relative risks of infection was generally modest (ratio of hazard ratios reduced from 1.38 to 1.32), but was consistent with the hypothesis that low vaccination rates contribute to elevated risk in some groups. Conversely, estimated relative risk for some occupational groups, such as people working in education, remained high despite high vaccine coverage.

Conclusions

Variation in vaccination coverage might account for a modest proportion of occupational differences in infection risk. Vaccination rates were uniformly very high in this cohort, which may suggest that the participants are not representative of the general population. Accordingly, these results should be considered tentative pending the accumulation of additional evidence.
A beta-Poisson model for infectious disease transmission
Authors: Hilton Joe , Hall Ian
Published: March 2023

Outbreaks of emerging and zoonotic infections represent a substantial threat to human health and well-being. These outbreaks tend to be characterised by highly stochastic transmission dynamics with intense variation in transmission potential between cases. The negative binomial distribution is commonly used as a model for transmission in the early stages of an epidemic as it has a natural interpretation as the convolution of a Poisson contact process and a gamma-distributed infectivity. In this study we expand upon the negative binomial model by introducing a beta-Poisson mixture model in which infectious individuals make contacts at the points of a Poisson process and then transmit infection along these contacts with a beta-distributed probability. We show that the negative binomial distribution is a limit case of this model, as is the zero-inflated Poisson distribution obtained by combining a Poisson-distributed contact process with an additional failure probability. We assess the beta-Poisson models applicability by fitting it to secondary case distributions (the distribution of the number of subsequent cases generated by a single case) estimated from outbreaks covering a range of pathogens and geographical settings. We find that while the beta-Poisson mixture can achieve a closer to fit to data than the negative binomial distribution, it is consistently outperformed by the negative binomial in terms of Akaike Information Criterion, making it a suboptimal choice on parsimonious grounds. The beta-Poisson performs similarly to the negative binomial model in its ability to capture features of the secondary case distribution such as overdispersion, prevalence of superspreaders, and the probability of a case generating zero subsequent cases. Despite this possible shortcoming, the beta-Poisson distribution may still be of interest in the context of intervention modelling since its structure allows for the simulation of measures which change contact structures while leaving individual-level infectivity unchanged, and vice-versa.
Comparing the clinical trial characteristics of industry–funded trials and non– industry–funded trials
Authors: Hughes Emily , Van Bakel Tamara , Raudanskis Ashley , Ray Prachi , Hodzic-Santor Benazir , Purohit Ushma , Sacks Chana A. , Fralick Michael
Published: March 2023

Importance: In randomized controlled trials (RCTs), small sample size and lack of blinding can cause biased and spurious results. Whether and how study characteristics differ based on a trial's funder is an important area to study. Objective: To compare study characteristics of RCTs funded by industry with study characteristics of RCTs not funded by industry. Design, Setting and Participants: We systematically reviewed all RCTs published between 2015 and 2019 in the New England Journal of Medicine (NEJM), Lancet, and Journal of the American Medical Association (JAMA). Our primary data sources were ClinicalTrials.gov and MEDLINE. Data extraction included manual review and use of natural language processing. Main Outcomes and Measures: We compared the rate of blinding, use of placebo, and sample size. We used natural language processing to analyze the sentiment of the study's conclusion as reported in the abstract. As proxies for knowledge dissemination, we calculated the AltMetric scores and number of times the article was cited (citation count). Results: We identified 1533 RCTs published by NEJM, Lancet, and JAMA between 2015 and 2019. Of these RCTs, 697 were funded by industry. Trials funded by industry were more likely to be blinded (n=378, 54% vs n=318, 38%), more likely to include a placebo (n=317, 45% vs n=196, 23%), more likely to post their results on ClinicalTrials.gov (78%, 443 of 570 vs 41%, 207 of 501) compared to trials that were not industry funded. Industry–funded RCTs had a smaller sample size than non–industry–funded RCTs (median=557 [IQR: 230, 1369] vs 648 [IQR: 301, 1916], P<0.01). Trials funded by industry had more citations than non–industry–funded trials (285 vs 145, p < 0.01), while per–manuscript Almetric scores were similar between both groups (229 vs 226, p=0.2). Conclusions and Relevance: These data highlight important variability in key metrics of trial quality and call attention to specific areas of improvement, especially for non–industry–funded trials.
Conserving genetic diversity during climate change: Niche marginality and discrepant monitoring capacity in Europe
Authors: Pearman Peter B. , Broennimann Olivier , Albayrak Tamer , Alves Paulo Célio , Bertola Laura D. , Biedrzycka Aleksandra , Buzan Elena , Cubric-Curik Vlatka , Fedorca Ancuta , Godoy José A. , Hvilsom Christina , Klinga Peter , Konopiński Maciej K. , Kopatz Alexander , Laikre Linda , Lopez Fernandez Margarida , Mergeay Joachim , Neophytou Charalambos , Pálsson Snæbjörn , Paz-Vinas Ivan , Posledovich Diana , Rolečková Barbora , Ruņģis Dainis , Segelbacher Gernot , Kavčič Sonnenschein Katja , Thurfjell Henrik , Träger Sabrina , Vernesi Cristiano , Vilà Carles , Westergren Marjana , Zachos Frank E. , Guisan Antoine , Bruford Michael
Published: March 2023

Genetic monitoring of populations currently attracts interest in the context of the Convention on Biological Diversity but needs long-term planning and investments. Genetic diversity has been largely neglected in biodiversity monitoring, and when addressed is treated separately, detached from other conservation issues, such as habitat alteration due to climate change. Genetic monitoring supports the conservation and management of fisheries, game, and threatened populations. It also can contribute to the assessment of predicted and realized impacts of climate change, and their management. We report the first accounting of genetic monitoring efforts among countries in Europe (their ‘genetic monitoring capacity’, GMC) to determine where GMC suggests the combination of national infrastructure, political support and resources for continued and expanded monitoring. Overlaying GMC with areas where species ranges approach current and future climate niche limits (i.e., niche marginality) helps identify whether GMC coincides with anticipated climate change effects on biodiversity. Our analysis suggests that country area extent, financial resources, and conservation policy influence GMC, high values of which inconsistently match joint species patterns of climate niche marginality. Populations at niche margins likely hold genetic diversity that is important to adaptation to changing climate, and our results illuminate the need in Europe for expanded genetic monitoring across the climate gradients occupied by species, a need arguably greatest in southeastern European countries.
VRK3 depletion induces cell cycle arrest and metabolic reprogramming of Pontine Diffuse Midline Glioma (DMG)-K27 altered cells
Authors: Menez Virginie , Kergrohen Thomas , Shasha Tal , Silva-Evangelista Claudia , Ledret Ludivine , Auffret Lucie , Subecz Chloé , Lancien Manon , Ajlil Yassine , Beccaria Kévin , Blauwblomme Thomas , Oberlin Estelle , Grill Jacques , Castel David , Debily Marie-Anne
Published: March 2023

We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMG-K27M cell fitness. Gene expression studies afterVRK3knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG followingVRK3knock-down. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations,e.g.with the mitochondrial ClpP protease activator ONC201.
Beyond the reference: gene expression variation and transcriptional response to RNAi inC. elegans
Authors: Bell Avery Davis , Chou Han Ting , Paaby Annalise B.
Published: March 2023

A universal feature of living systems is that natural variation in genotype underpins variation in phenotype. Yet, research in model organisms is often constrained to a single genetic background, the reference strain. Further, genomic studies that do evaluate wild strains typically rely on the reference strain genome for read alignment, leading to the possibility of biased inferences based on incomplete or inaccurate mapping; the extent of reference bias can be difficult to quantify. As an intermediary between genome and organismal traits, gene expression is well positioned to describe natural variability across genotypes generally and in the context of environmental responses, which can represent complex adaptive phenotypes.C. eleganssits at the forefront of investigation into small-RNA gene regulatory mechanisms, or RNA interference (RNAi), and wild strains exhibit natural variation in RNAi competency following environmental triggers. Here, we examine how genetic differences among five wild strains affect theC. eleganstranscriptome in general and after inducing RNAi responses to two germline target genes. Approximately 34% of genes were differentially expressed across strains; 411 genes were not expressed at all in at least one strain despite robust expression in others, including 49 genes not expressed in reference strain N2. Despite the presence of hyper-diverse hotspots throughout theC. elegansgenome, reference mapping bias was of limited concern: over 92% of variably expressed genes were robust to mapping issues. Overall, the transcriptional response to RNAi was strongly strain-specific and highly specific to the target gene, and the laboratory strain N2 was not representative of the other strains. Moreover, the transcriptional response to RNAi was not correlated with RNAi phenotypic penetrance; the two germline RNAi incompetent strains exhibited substantial differential gene expression following RNAi treatment, indicating an RNAi response despite failure to reduce expression of the target gene. We conclude that gene expression, both generally and in response to RNAi, differs acrossC. elegansstrains such that choice of strain may meaningfully influence scientific conclusions. To provide a public, easily accessible resource for querying gene expression variation in this dataset, we introduce an interactive website athttps://wildworm.biosci.gatech.edu/rnai/.
Unravelling the mystery of endemic versus translocated populations of the endangered Australian lungfish (Neoceratodus forsteri)
Authors: Biello Roberto , Ghirotto Silvia , Schmidt Daniel J. , Fuselli Silvia , Roberts David T. , Espinoza Tom , Hughes Jane M. , Bertorelle Giorgio
Published: March 2023

The Australian lungfish is a primitive and endangered representative of the subclass Dipnoi. The distribution of this species is limited to south-east Queensland, with some populations considered endemic and others possibly descending from translocations in the late nineteenth century shortly after European discovery. Attempts to resolve the historical distribution for this species have met with conflicting results based on descriptive genetic studies. Understanding if all populations are endemic or some are the result of, or influenced by, translocation events, has implications for conservation management. In this work, we analysed the genetic variation at three types of markers (mtDNA genomes, 11 STRs, and 5,196 nuclear SNPs) using the Approximate Bayesian Computation algorithm to compare several demographic models. We postulated different contributions of Mary River and Burnett River gene pools into the Brisbane River and North Pine River populations, related to documented translocation events. We ran the analysis for each marker separately, and we also estimated the posterior probabilities of the models combining the markers. Nuclear SNPs have the highest power to correctly identify the true model amongst the simulated datasets (where the model was known), but different markers typically provided similar answers. The most supported demographic model able to explain the real dataset implies that an endemic gene pool is present in the Brisbane and North Pine Rivers where past translocations are documented. These results will inform ongoing conservation efforts for this endangered and iconic species and warrant careful consideration of future genetic management of the Australian lungfish populations.
Continuous Multiplexed Phage Genome Editing Using Recombitrons
Authors: Fishman Chloe B. , Crawford Kate D. , Bhattarai-Kline Santi , Zhang Karen , González-Delgado Alejandro , Shipman Seth L.
Published: March 2023

Bacteriophages, which naturally shape bacterial communities, can be co-opted as a biological technology to help eliminate pathogenic bacteria from our bodies and food supply1. Phage genome editing is a critical tool to engineer more effective phage technologies. However, editing phage genomes has traditionally been a low efficiency process that requires laborious screening, counter selection, orin vitroconstruction of modified genomes2. These requirements impose limitations on the type and throughput of phage modifications, which in turn limit our knowledge and potential for innovation. Here, we present a scalable approach for engineering phage genomes using recombitrons: modified bacterial retrons3that generate recombineering donor DNA paired with single stranded binding and annealing proteins to integrate those donors into phage genomes. This system can efficiently create genome modifications in multiple phages without the need for counterselection. Moreover, the process is continuous, with edits accumulating in the phage genome the longer the phage is cultured with the host, and multiplexable, with different editing hosts contributing distinct mutations along the genome of a phage in a mixed culture. In lambda phage, as an example, recombitrons yield single-base substitutions at up to 99% efficiency and up to 5 distinct mutations installed on a single phage genome, all without counterselection and only a few hours of hands-on time.
Stretch-injury promotes activation of microglia with enhanced phagocytic and synaptic stripping activities
Authors: Procès Anthony , Alpizar Yeranddy A. , Halliez Sophie , Brône Bert , Saudou Frédéric , Ris Laurence , Gabriele Sylvain
Published: March 2023

Microglial cells must act as the first line of defense of the central nervous system, but they can be exposed to various mechanical signals that may trigger their activation. While the impact of chemical signaling on brain cells has been studied in detail, our current understanding of the mechanical signaling in microglia is still limited. To address this challenge, we exposed microglial cells to a single mechanical stretch and compared their behavior to chemical activation by lipopolysaccharide treatment. Here we show that stretching microglial cells results in their activation, demonstrating a strong mechanosensitivity. Stretched microglial cells exhibited higher Iba1 protein levels, a denser actin cytoskeleton and migrated more persistently. In contrary to LPS-treated cells, stretched microglia maintain a robust secretory profile of chemokines and cytokines, except for TNF-α, highlighting the relevance of this model. Interestingly, a single stretch injury results in more compacted chromatin and DNA damage, suggesting possible long-term genomic instabilities in stretched microglia. Using neuronal networks in compartmentalized microfluidic chambers, we found that stretched microglial cells exhibit enhanced phagocytic and synaptic stripping activities. Altogether, our results propose that the immune potential of microglial cells can be unlocked by stretching events to maintain brain tissue homeostasis after mechanical injury.
Replication fork plasticity upon replication stress requires rapid nuclear actin polymerization
Authors: Palumbieri Maria Dilia , Merigliano Chiara , Acosta Daniel González , von Känel Thomas , Welter Bettina , Stoy Henriette , Krietsch Jana , Ulferts Svenja , Sanchi Andrea , Grosse Robert , Chiolo Irene , Lopes Massimo
Published: March 2023

Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and fixed cells, we visualized nuclear actin filaments in unperturbed S phase, rapidly extending in number and thickness upon genotoxic treatments, and taking frequent contact with replication factories. Chemically or genetically impairing nuclear actin polymerization shortly before these treatments prevents active fork slowing and abolishes fork reversal. Defective fork plasticity is linked to reduced recruitment of RAD51 and SMARCAL1 to nascent DNA. Conversely, PRIMPOL gains access to replicating chromatin, promoting unrestrained and discontinuous DNA synthesis, which is associated with increased chromosomal instability and decreased cellular resistance to replication stress. Hence, nuclear F-actin orchestrates replication fork plasticity and is a key molecular determinant in the rapid cellular response to genotoxic treatments.
Parasite hybridization promotes spreading of endosymbiotic viruses
Authors: Heeren Senne , Maes Ilse , Sanders Mandy , Lye Lon-Fye , Arevalo Jorge , Llanos-Cuentas Alejandro , Garcia Lineth , Lemey Philippe , Beverley Stephen M , Cotton James A , Dujardin Jean-Claude , Van den Broeck Frederik
Published: March 2023

Viruses are the most abundant biological entities on Earth and play a significant role in the evolution of many organisms and ecosystems. In pathogenic protozoa, the presence of endosymbiotic viruses has been linked to an increased risk of treatment failure and severe clinical outcome. Here, we studied the molecular epidemiology of the zoonotic disease cutaneous leishmaniasis in Peru and Bolivia through a joint evolutionary analysis ofLeishmania braziliensisparasites and their endosymbioticLeishmaniaRNA virus. We show that parasite populations circulate in isolated pockets of suitable habitat and are associated with single viral lineages that appear in low prevalence. In contrast, groups of hybrid parasites were geographically and ecologically dispersed, and commonly infected from a pool of genetically diverse viruses. Our results suggest that parasite hybridization, likely due to increased human migration and ecological perturbations, increased the frequency of endosymbiotic interactions known to play a key role in disease severity.
Glioblastoma induces the recruitment and differentiation of hybrid neutrophils from skull bone marrow
Authors: Lad By Meeki , Beniwal Angad S. , Jain Saket , Shukla Poojan , Jung Jangham , Shah Sumedh S. , Yagnik Garima , Babikir Husam , Nguyen Alan T. , Gill Sabraj , Young Jacob S. , Lui Austin , Salha Diana , Diaz Aaron , Aghi Manish K.
Published: March 2023

Tumor-associated neutrophil (TAN) effects on glioblastoma biology remain under-characterized. We show here that ‘hybrid’ neutrophils with dendritic features – including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate MHCII-dependent T cell activation – accumulate intratumorally and suppress tumor growthin vivo. Trajectory analysis of patient TAN scRNA-seq identifies this phenotype as a polarization state which is distinct from canonical cytotoxic TANs and differentiates intratumorally from immature precursors absent in circulation. Rather, these hybrid-inducible immature neutrophils – which we identified in patient and murine glioblastomas – arise from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a potent contributor of antitumoral myeloid APCs, including hybrid TANs and dendritic cells, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow – such as intracalvarial AMD3100 whose survival prolonging-effect in GBM we demonstrate – present therapeutic potential.
Interplay between mechanochemical patterning and glassy dynamics in cellular monolayers
Authors: Boocock Daniel , Hirashima Tsuyoshi , Hannezo Edouard
Published: March 2023

Living tissues are characterized by an intrinsically mechano-chemical interplay of active physical forces and complex biochemical signalling pathways. Either feature alone can give rise to complex emergent phenomena, for example mechanically driven glassy dynamics and rigidity transitions, or chemically driven reaction-diffusion instabilities. An important question is how to quantitatively assess the contribution of these different cues to the large-scale dynamics of biological materials. We address this in MDCK monolayers, considering both mechanochemical feedbacks between ERK signalling activity and cellular density as well as a mechanically active tissue rheology via a self-propelled vertex model. We show that the relative strength of active migration forces to mechanochemical couplings controls a transition from uniform active glass to periodic spatiotemporal waves. We parameterize the model from published experimental datasets on MDCK monolayers, and use it to make new predictions on the correlation functions of cellular dynamics and the dynamics of topological defects associated with the oscillatory phase of cells. Interestingly, MDCK monolayers are best described by an intermediary parameter region in which both mechanochemical couplings and noisy active propulsion have a strong influence on the dynamics. Finally, we study how tissue rheology and ERK waves feedback on one another, and uncover a mechanism via which tissue fluidity can be controlled by mechano-chemical waves both at the local and global levels.
BEATRICE: Bayesian Fine-mapping from Summary Data using Deep Variational Inference
Authors: Ghosal Sayan , Schatz Michael C. , Venkataraman Archana
Published: March 2023

We introduce a novel framework BEATRICE to identify putative causal variants from GWAS statistics. Identifying causal variants is challenging due to their sparsity and high correlation in the nearby regions. To account for these challenges, we rely on a hierarchical Bayesian model that imposes a binary concrete prior on the set of causal variants. We derive a variational algorithm for this fine-mapping problem by minimizing the KL divergence between an approximate density and the posterior probability distribution of the causal configurations. Correspondingly, we use a deep neural network as an inference machine to estimate the parameters of our proposal distribution. Our stochastic optimization procedure allows us to simultaneously sample from the space of causal configurations. We use these samples to compute the posterior inclusion probabilities and determine credible sets for each causal variant. We conduct a detailed simulation study to quantify the performance of our framework against two state-of-the-art baseline methods across different numbers of causal variants and different noise paradigms, as defined by the relative genetic contributions of causal and non-causal variants. We demonstrate that BEATRICE achieves uniformly better coverage with comparable power and set sizes, and that the performance gain increases with the number of causal variants. We also show the efficacy BEATRICE in finding causal variants from the GWAS study of Alzheimer’s disease. In comparison to the baselines, only BEATRICE can successfully find the APOEϵ2 allele, a commonly associated variant of Alzheimer’s. Thus, we show that BEATRICE is a valuable tool to identify causal variants from eQTL and GWAS summary statistics across complex diseases and traits.
Apigenin exerts anti-cancer effects in colon cancer possibly by regulating Heat shock protein 90 alpha family class A member 1 (HSP90AA1)
Authors: Sain Arindam , Khamrai Dipshikha , Kandasamy Thirukumaran , Naskar Debdut
Published: March 2023

Apigenin, a natural flavonoid, has shown early promise in colon cancer (CC); thus, exploring potential mechanisms of apigenin in CC is obligatory. In this study, shared targets of apigenin and CC were identified through different online tools and subjected to functional enrichment analyses like Gene Ontology and KEGG. Further, the protein-protein interaction network of the shared targets was developed (via STRING); hub/core targets were identified (MCODE application). The top targets of apigenin in CC were identified by molecular docking; further investigated for differential gene and protein expression in CC and their influence on CC patient survival (using TCGA data). Based on the docking score of the 13 hub genes, the top 3 targets (HSP90AA1, MMP9, PTGS2) were selected, and their expression was significantly elevated and related to poor overall survival in CC (exceptPTGS2). Molecular dynamics simulation further validated protein-ligand interactions and selected HSP90AA1 as the best target of apigenin in CC. Finally, apigenin was found to be involved in the cytotoxicity of CC cells (COLO-205) by reducingHSP90AA1expression. The results of this study identified HSP90AA1 as one of the prime targets of apigenin in CC, and apigenin might act on HSP90AA1 to exert its anti-cancer mechanism.
Hierarchical Clustering and Omics Analysis Revealed Massive Molecular Shifts in a Tree under Combined Hypoxia and Salinity
Authors: Cisse El-Hadji Malick , Jiang Bai-Hui , Yin Li-Yan , Miao Ling-Feng , Zhou Jing-Jing , Mekontso Francine Ngaffo , Li Da-Dong , Xiang Li-Shan , Yang Fan
Published: March 2023

Field and Greenhouse studies that attempted to describe the molecular responses of trees under waterlogging (WL) combined with salinity (ST) are quasi-inexistent. To dissect plant-specific molecular responses and patterns under SWL, we integrated transcriptional and metabolic analyses involving common differentially expressed genes (DEGs) and metabolites (DMs) patterns inDalbergia odoriferaleaflets. SWL-treated seedlings exhibited an impressively high number of DEGs and DMs compared to ST or WL. Although the main common DEGs and DMs showed a neutral pattern, gene ontology enrichment following the classification in different functional categories of SWL-transcripts displayed a predominant synergistic pattern mode. Hierarchical and silhouette analysis regrouped different morpho-physiological clusters following the treatment, SWL was mainly grouped with both single stress. SWL induced a massive shutdown of the photosynthesis apparatus throughLHCBs- andPSA-related genes. Starch and plastoglobuli synthesis appeared to be drastically affected by SWL, while ABA content confirmed by ABA synthesis related-genes (ABF,ABA1andNCED) variations showed a less-needed role.NXN(Nucleoredoxin) genes are the main factors that sustain the antioxidant system under SWL. Here we provide the first molecular responses, characterization and patterns of a tree under SWL that would significantly shed light on our understanding of the molecular mechanisms underlying combined stress.
Spatial and temporal variation in abundance of introduced African fig fly (Zaprionus indianus) (Diptera: Drosophilidae) in the eastern United States
Authors: Rakes Logan M. , Delamont Megan , Cole Christine , Yates Jillian A. , Blevins Lynsey Jo , Hassan Fatima Naureen , Bergland Alan O. , Erickson Priscilla A.
Published: March 2023

The African fig fly,Zaprionus indianus(Gupta), has spread globally from its native range in tropical Africa, becoming an invasive crop pest in select areas such as Brazil.Z. indianuswas first reported in the United States in 2005 and has since been documented as far north as Canada. As a tropical species,Z. indianusis expected to have low cold tolerance, likely limiting its ability to persist at northern latitudes. In North America, the geographic regions whereZ. indianuscan thrive and seasonal fluctuations in its abundance are not well understood. The purpose of this study was to characterize the temporal and spatial variation inZ. indianusabundance to better understand its invasion of the eastern United States. We sampled drosophilid communities over the growing season at two orchards in Virginia from 2020-2022 and several locations along the East Coast during the fall of 2022. Virginia abundance curves showed similar seasonal dynamics across years with individuals first detected around July and becoming absent around December. Massachusetts was the northernmost population and noZ. indianuswere detected in Maine. Variation inZ. indianusrelative abundance was high between nearby orchards and across different fruits within orchards but was not correlated with latitude. Fitness of wild-caught females decreased later in the season and at higher latitudes. The patterns ofZ. indianusabundance shown here demonstrate an apparent susceptibility to cold and highlight a need for systematic sampling to accurately characterize the range and spread ofZ. indianus.
Morphological Attributes ofGlycine max(Soybean)
Authors: Bashir Gazala
Published: March 2023

Heavy metal like lead and chromium present in environment in large quantities cause a severe environmental concern. Significant risks to the environment and agriculture are posed by heavy metal contamination of the air, water, and soil as a result of increased urbanisation and industrialization. Heavy metal pollution in soils can harm nearby ecosystems, groundwater, agricultural productivity, and human health because of its persistence and high toxicity. Heavy metals are accumulated in the tissues of plants growing in metal-contaminated soil, which can have a negative impact on the morphology of the plant. The present study was carried out to determine the effect of different concentrations (50ml, 100ml, 150ml and 200ml) of chromium and lead on morphological attributes of three varieties (JS:335, JS:80-21, JS:75-46) of soybean(Glycine max). The result of the present study showed that the exposure ofGlycine maxto Pb and Cr resulted in a decrease in total length, number of nodes and number of leaves of a plant. The shape of leaves in case of treated plants was also changed from ovoid to heart and oval shapes, at higher concentration of heavy metals. Among the three different varieties (JS:335, JS:80-21, JS:75-46) ofGlycine. max(soybean)JS:335showed maximum reduction and theJS:80-21showed least reduction in the growth of a plant. Lead treatment proved more toxic than chromium treatment for all the three different varieties (JS:335, JS:80-21, JS:75-46) ofGlycine max.
Learning the functional landscape of microbial communities
Authors: Skwara Abigail , Gowda Karna , Yousef Mahmoud , Diaz-Colunga Juan , Raman Arjun S. , Sanchez Alvaro , Tikhonov Mikhail , Kuehn Seppe
Published: March 2023

Microbial consortia exhibit complex functional properties in contexts ranging from soils to bioreactors to human hosts. Understanding how community composition determines emergent function is a major goal of microbial ecology. Here we address this challenge using the concept of community-function landscapes – analogs to fitness landscapes – that capture how changes in community composition alter collective function. Using datasets that represent a broad set of community functions, from production/degradation of specific compounds to biomass generation, we show that statistically-inferred landscapes quantitatively predict community functions from knowledge of strain presence or absence. Crucially, community-function landscapes allow prediction without explicit knowledge of abundance dynamics or interactions between species, and can be accurately trained using measurements from a small subset of all possible community compositions. The success of our approach arises from the fact that empirical community-function landscapes are typically not rugged, meaning that they largely lack high-order epistatic contributions that would be difficult to fit with limited data. Finally, we show this observation is generic across many ecological models, suggesting community-function landscapes can be applied broadly across many contexts. Our results open the door to the rational design of consortia without detailed knowledge of abundance dynamics or interactions.
A lipopeptidomimetic of transcriptional activation domains selectively disrupts Med25 PPIs
Authors: Pattelli Olivia N. , Valdivia Estefanía Martínez , Beyersdorf Matthew S. , Regan Clint S. , Rivas Mónica , Merajver Sofia D. , Cierpicki Tomasz , Mapp Anna K.
Published: March 2023

Short amphipathic peptides are capable of binding to transcriptional coactivators, often targeting the same binding surfaces as native transcriptional activation domains. However, they do so with modest affinity and generally poor selectivity, limiting their utility as synthetic modulators. Here we show that incorporation of a medium-chain, branched fatty acid to the N-terminus of one such heptameric lipopeptidomimetic (34913-8) increases the affinity for the coactivator Med25 >10-fold (Ki>>100 μM to 10 μM). Importantly, the selectivity of 34913-8 for Med25 compared to other coactivators is excellent. 34913-8 engages Med25 through interaction with the H2 face of itsActivatorInteractionDomain and in doing so stabilizes full-length protein in the cellular proteome. Further, genes regulated by Med25-activator PPIs are inhibited in a cell model of triple-negative breast cancer. Thus, 34913-8 is a useful tool for studying Med25 and the Mediator complex biology and the results indicate that lipopeptidomimetics may be a robust source of inhibitors for activator-coactivator complexes.
Modification of DNA by a viral enzyme and charged tRNA
Authors: Silva Rebekah M. B. , Slyvka Anton , Lee Yan-Jiun , Guan Chudi , Lund Sean R. , Raleigh Elisabeth A. , Skowronek Krzysztof , Bochtler Matthias , Weigele Peter R.
Published: March 2023

Bacteriophage enzymes synthesize varied and complex DNA hypermodifications. The enzyme encoded by the phage Mu genemomis necessary for post-replicative carbamoylmethyl addition to the exocyclic amine of deoxyadenosine in DNA during the lytic phase of the viral life-cycle. The molecular details of this modification reaction, including the molecular origins of the modification itself, have long eluded understanding. Here, we demonstrate that Mom co-opts the translational machinery of the host by harvesting activated glycine from charged tRNAGlyto hypermodify adenine. Based on this insight, we report the firstin vitroreconstitution of the Mu hypermodification from purified components. Using isotope labeling, we demonstrate that the carbamoyl nitrogen of the Mom modification is derived from theN6 of adenine, indicating an on-base rearrangement of theN6 aminoacylation product, possibly via a cyclic intermediate. Informed by the X-ray crystal structure of Mom, we have probed the location of the active site, identified a novel insertion, and established substrate specificities of the Mom enzyme.
Allosterically coupled conformational dynamics in solution prepare the sterol transfer protein StarD4 to release its cargo upon interaction with target membranes
Authors: Xie Hengyi , Weinstein Harel
Published: March 2023

Complex mechanisms regulate the cellular distribution of cholesterol, a critical component of eukaryote membranes involved in regulation of membrane protein functions directly and through the physiochemical properties of membranes. StarD4, a member of the steroidogenic acute regulator-related lipid-transfer (StART) domain (StARD)-containing protein family, is a highly efficient sterol-specific transfer protein involved in cholesterol homeostasis. Its mechanism of cargo loading and release remains unknown despite recent insights into the key role of phosphatidylinositol phosphates in modulating its interactions with target membranes. We have used large-scale atomistic Molecular dynamics (MD) simulations to study how the dynamics of cholesterol bound to the StarD4 protein can affect interaction with target membranes, and cargo delivery. We identify the two major cholesterol (CHL) binding modes in the hydrophobic pocket of StarD4, one near S136&S147 (the Ser-mode), and another closer to the putative release gate located near W171, R92&Y117 (the Trp-mode). We show that conformational changes of StarD4 associated directly with the transition between these binding modes facilitate the opening of the gate. To understand the dynamics of this connection we apply a machine-learning algorithm for the detection of rare events in MD trajectories (RED), which reveals the structural motifs involved in the opening of a front gate and a back corridor in the StarD4 structure occurring together with the spontaneous transition of CHL from the Ser-mode of binding to the Trp-mode. Further analysis of MD trajectory data with the information-theory based NbIT method reveals the allosteric network connecting the CHL binding site to the functionally important structural components of the gate and corridor. Mutations of residues in the allosteric network are shown to affect the performance of the allosteric connection. These findings outline an allosteric mechanism which prepares the CHL-bound StarD4 to release and deliver the cargo when it is bound to the target membrane.