bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic analysis of cultivated infant microbiomes identifiesBifidobacterium2’-fucosyllactose utilization can be facilitated by co-existing species
Authors: Lou Yue Clare , Rubin Benjamin E. , Schoelmerich Marie C. , DiMarco Kaden , Borges Adair L. , Rovinsky Rachel , Song Leo , Doudna Jennifer A. , Banfield Jillian F. 
Published: March 2023

AbstractHuman milk oligosaccharides (HMOs) ensure proper infant gut microbiome establishment. Isolate studies have revealed the genetic basis for HMO metabolism, but they exclude the possibility of HMO assimilation via synergistic interactions involving multiple organisms. Here, we investigated microbiome responses to 2’-fucosyllactose (2’FL), a prevalent HMO and infant formula additive, by establishing individualized microbiomes using fecal samples from three different infants as the inocula.Bifidobacterium breve, a prominent member of infant microbiomes, typically cannot metabolize 2’FL. Using metagenomic data, we predicted that extracellular fucosidases encoded by co-existing members such asRuminococcus gnavusinitiate 2’FL breakdown, thus critical forB. breve’sgrowth. Using both targeted co-cultures and by supplementation ofR. gnavusinto one microbiome, we show thatR. gnavuscan promote extensive growth ofB. brevethrough the release of lactose from 2’FL. Overall, microbiome cultivation combined with genome-resolved metagenomics demonstrated that HMO utilization can vary with an individual’s microbiome.
Phage administration with repeated intravenous doses leads to faster phage clearance in mammalian hosts
Authors: Tan Xin , Chen Kai , Jiang Zhihuan , Liu Ziqiang , Wang Siyun , Ying Yong , Zhang Jieqiong , Yuan Shengjian , Huang Zhipeng , Gao Ruyue , Zhao Min , Weng Aoting , Yang Yongqing , Luo Huilong , Zhang Daizhou , Ma Yingfei 
Published: March 2023

AbstractObjectivesPhage therapy has shown a great promise for the treatment of multidrug-resistant bacterial infections. However, the lack of a thorough and organized understanding of phage-body interactions has limited its clinical application.MethodsHere, we administered different purified phages (Salmonellaphage SE_SZW1,Acinetobacterphage AB_SZ6, andPseudomonasphage PA_LZ7) intravenously to healthy animals (rats and monkeys) to evaluate the phage-induced host responses and phage pharmacokinetics (PK) with different intravenous (IV) doses in healthy animals. The plasma and the organs were sampled after different IV doses to determine the phage biodistribution, the phage-induced cytokines, and antibodies. The potential side effects of phages on animals were assessed.ResultsA non-compartment model revealed that the plasma phage titer gradually decreased over time following a single dose. Repeated doses caused that the plasma phage titer at 5 minutes dropped 2-3 Log10compared to the first dose regardless of phage types in rats. Host innate immune responses were activated including the upregulated expression (>10-fold) of TNF-αand splenic enlargement following repeated doses. Phage-specific neutralization antibodies in animals receiving phages were detected. Similar results were obtained from monkeys.ConclusionsThe mammalian bodies were well-tolerant to the administered phages. The animal responses to the phages and the phage biodistribution profiles could have a significant impact on the efficacy of phage therapy.
Mammalian cells internalize bacteriophages and utilize them as a food source to enhance cellular growth and survival
Authors: Bichet Marion C. , Adderley Jack , Avellaneda Laura , Gearing Linden J. , Deffrasnes Celine , David Cassandra , Pepin Genevieve , Gantier Michael P. , Lin Ruby CY , Patwa Ruzeen , Moseley Gregory W. , Doerig Christian , Barr Jeremy J. 
Published: March 2023

ABSTRACTThere is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate diverse and unexplored symbioses. Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here we applied highly purified phage T4, free from bacterial by-products and endotoxins to mammalian cells and analyzed the cellular responses using luciferase reporter and antibody microarray assays. Phage preparations were appliedin vitroto either A549 lung epithelial cells, MDCK-I kidney cells, or primary mouse bone marrow derived macrophages with the phage-free supernatant serving as a comparative control. Highly purified T4 phages were rapidly internalized by mammalian cells and accumulated within macropinosomes but did not activate the inflammatory DNA response TLR9 or cGAS-STING pathways. Following eight hours of incubation with T4 phage, whole cell lysates were analyzed via antibody microarray that detected expression and phosphorylation levels of human signaling proteins. T4 phage internalization led to the activation of AKT-dependent pathways, resulting in an increase in cell metabolism, survival, and actin reorganization, the last being critical for macropinocytosis and potentially regulating a positive feedback loop to drive further phage internalization. T4 phages additionally down-regulated CDK1 and its downstream effectors, leading to an inhibition of cell cycle progression and an increase in cellular growth through a prolonged G1 phase. These interactions demonstrate that highly purified T4 phages do not activate DNA-mediated inflammatory pathways but do trigger protein phosphorylation cascades that promote cellular growth and survival. We conclude that mammalian cells are internalizing bacteriophages as a food source to promote cellular growth and metabolism.
Investigating the marginal and herd effects of COVID-19 vaccination for reducing case fatality rate: Evidence from the United States
Authors: Li Tenglong , Wang Zilong , He Shuyue , Chen Ying 
Published: March 2023

AbstractVaccination campaigns have been rolled out in most countries to increase the vaccination coverage and protect against case mortality during the ongoing pandemic. To evaluate the effectiveness of COVID-19 vaccination, it is vital to disentangle the herd effect from the marginal effect and parameterize them separately in a model. To demonstrate this, we study the relationship between the COVID-19 vaccination coverage and case fatality rate (CFR) based on a U.S. vaccination coverage at county level, with daily records from March 11th, 2021 to Jan 26th, 2022 for 3109 U.S. counties. Using segmented regression, we discovered three breakpoints of the vaccination coverage, at which the herd effects could potentially exist. Controlling for county heterogeneity, we found the size of the marginal effect was not constant but actually enlarged as the vaccination coverage increased, and only the herd effect at the first breakpoint was statistically significant, which implied indirect benefit of vaccination may exist at the early stage of a vaccination campaign. Our results have demonstrated that public health researchers should carefully differentiate and quantify the herd and marginal effects in analyzing vaccination data, to better inform vaccination campaign strategies as well as evaluate vaccination effectiveness.
Phosphorylation controls spatial and temporal activities of motor-PRC1 complexes to complete mitosis
Authors: Gluszek-Kustusz Agata , Craske Benjamin , Legal Thibault , McHugh Toni , Welburn Julie P.I. 
Published: March 2023

ABSTRACTDuring mitosis, spindle architecture alters as chromosomes segregate to daughter cells. The microtubule crosslinker Protein Required for Cytokinesis 1 (PRC1) is essential for spindle stability, chromosome segregation and completion of cytokinesis, but how it recruits motors to the central spindle to coordinate the segregation of chromosomes is unknown. Here, we combine structural and cell biology approaches to show that the human CENP-E motor, which is essential for chromosome capture and alignment by microtubules, binds to PRC1 through a conserved hydrophobic motif. This binding mechanism is also used by Kinesin-4 Kif4A:PRC1. Usingin vitroreconstitution, we demonstrate that CENP-E slides antiparallel PRC1-crosslinked microtubules. We find that the regulation of CENP-E -PRC1 interaction is spatially and temporally coupled with relocalization to overlapping microtubules in anaphase. Finally, we demonstrate that the PRC1:microtubule motor interaction is essential in anaphase to control chromosome partitioning, retain central spindle integrity and ensure cytokinesis. Taken together our findings reveal the molecular basis for the cell cycle regulation of motor-PRC1 complexes to couple chromosome segregation and cytokinesis.
Superposition of target structures enables design of bi-stable RNA molecules with deep learning
Authors: Blum Christopher F. , Kolkhof Petra , Kollmann Markus 
Published: March 2023

AbstractThe ability to design RNA molecules with specific structures and functions could facilitate research and developments in biotechnology, biology and pharmacy. Here we present a flexible RNA design framework based on deep learning that locally optimizes sequences by gradient-guided search methods. We demonstrate its effectiveness by designing bi-stable RNA molecules by superimposing conformer target structures.
Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells
Authors: Perea Valerie , Baron Kelsey R. , Dolina Vivian , Aviles Giovanni , Rosarda Jessica D. , Guo Xiaoyan , Kampmann Martin , Wiseman R. Luke 
Published: March 2023

SUMMARYThe integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.
Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway
Authors: Zhang Junbing , Simpson Claire M. , Berner Jacqueline , Chong Harrison B. , Fang Jiafeng , Sahin Zehra Ordulu , Weiss-Sadan Tom , Possemato Anthony P. , Harry Stefan , Takahashi Mariko , Yang Tzu-yi , Richter Marianne , Patel Himani , Smith Abby E. , Carlin Alexander D. , Hubertus de Groot Adriaan F. , Wolf Konstantin , Shi Lei , Wei Ting-Yu , Dürr Benedikt R. , Chen Nicholas J. , Vornbäumen Tristan , Wichmann Nina O. , Pooladanda Venkatesh , Matoba Yuske , Kumar Shaan , Kim Eugene , Bouberhan Sara , Olivia Esther , Rueda Bo , Bardeesy Nabeel , Liau Brian , Lawrence Michael , Stokes Matt P. , Beausoleil Sean A. , Bar-Peled Liron 
Published: March 2023

AbstractMultiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it’s unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H2O2sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H2O2accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.
Intragenic DNA inversions expand bacterial coding capacity
Authors: Chanin Rachael B. , West Patrick T. , Park Ryan M. , Wirbel Jakob , Green Gabriella Z. M. , Miklos Arjun M. , Gill Matthew O. , Hickey Angela S. , Brooks Erin F. , Bhatt Ami S. 
Published: March 2023

AbstractBacterial populations that originate from a single bacterium are not strictly clonal. Often, they contain subgroups with distinct phenotypes. Bacteria can generate heterogeneity through phase variation: a preprogrammed, reversible mechanism that alters gene expression levels across a population. One well studied type of phase variation involves enzyme-mediated inversion of specific intergenic regions of genomic DNA. Frequently, these DNA inversions flip the orientation of promoters, turning ON or OFF adjacent coding regions within otherwise isogenic populations. Through this mechanism, inversion can affect fitness, survival, or group dynamics. Here, we develop and apply bioinformatic approaches to discover thousands of previously undescribed phase-variable regions in prokaryotes using long-read datasets. We identify ‘intragenic invertons’, a surprising new class of invertible elements found entirely within genes, in bacteria and archaea. To date, inversions within single genes have not been described. Intragenic invertons allow a gene to encode two or more versions of a protein by flipping a DNA sequence within the coding region, thereby increasing coding capacity without increasing genome size. We experimentally characterize specific intragenic invertons in the gut commensalBacteroides thetaiotaomicron, presenting a ‘roadmap’ for investigating this new gene-diversifying phenomenon.One-Sentence SummaryIntragenic DNA inversions, identified using long-read sequencing datasets, are found in many phyla across the prokaryotic tree of life.
Nitric oxide regulates metabolism in murine stress erythroid progenitors to promote recovery during inflammatory anemia
Authors: Ruan Baiye , Chen Yuanting , Trimidal Sara , Koo Imhoi , Qian Fenghua , Cai Jingwei , Mcguigan John , Hall Molly A. , Patterson Andrew D. , Prabhu K. Sandeep , Paulson Robert F. 
Published: March 2023

AbstractInflammation skews bone marrow hematopoiesis increasing the production of myeloid effector cells at the expense of steady-state erythropoiesis. A compensatory stress erythropoiesis response is induced to maintain homeostasis until inflammation is resolved. In contrast to steady-state erythroid progenitors, stress erythroid progenitors (SEPs) utilize signals induced by inflammatory stimuli. However, the mechanistic basis for this is not clear. Here we reveal a nitric oxide (NO)-dependent regulatory network underlying two stages of stress erythropoiesis, namely proliferation, and the transition to differentiation. In the proliferative stage, immature SEPs and cells in the niche increased expression of inducible nitric oxide synthase (Nos2oriNOS) to generate NO. Increased NO rewires SEP metabolism to increase anabolic pathways, which drive the biosynthesis of nucleotides, amino acids and other intermediates needed for cell division. This NO-dependent metabolism promotes cell proliferation while also inhibiting erythroid differentiation leading to the amplification of a large population of non-committed progenitors. The transition of these progenitors to differentiation is mediated by the activation of nuclear factor erythroid 2-related factor 2 (Nfe2l2 or Nrf2). Nrf2 acts as an anti-inflammatory regulator that decreases NO production, which removes the NO-dependent erythroid inhibition and allows for differentiation. These data provide a paradigm for how alterations in metabolism allow inflammatory signals to amplify immature progenitors prior to differentiation.Key pointsNitric-oxide (NO) dependent signaling favors an anabolic metabolism that promotes proliferation and inhibits differentiation.Activation of Nfe2l2 (Nrf2) decreases NO production allowing erythroid differentiation.
Developmental Characterization of Neuronal Migration Anomalies and Axon Proliferation in mTOR pathway-associated Malformations of Cortical Development
Authors: Hoffman Paige , Svalina Matthew N. , Flores Chiara , Brzezinski Christine , Kushner J. Keenan , Staple Brandon , Franco Santos , Alexander Allyson L. 
Published: March 2023

ABSTRACTDrug-resistant epilepsy (DRE) is a prevalent problem in children that can lead to abnormal development and various psychiatric comorbidities. Malformations of cortical development (MCD) include focal cortical dysplasia, tuberous sclerosis complex and hemimegalencephaly, which are the most common pathologies among children who undergo surgical resection for treatment of DRE. These disorders share many histopathological features, including dyslamination of the cerebral cortex and enlarged neuronal somata. Recently, genetic mutations in the mammalian target of rapamycin (mTOR) signaling cascade have been shown to underpin most MCDs. Rodent models, including the RhebCAmodel, recapitulate histologic and physiologic aspects of human DRE. However, there have been few studies characterizing the developmental time point of the histological changes seen in MCDs. In this study, we usein uteroelectroporation to upregulate the Rheb protein (directly upstream of mTOR) in a focal area of the neocortex. We demonstrate that mTOR dysregulation leads to focal dyslamination and increased neuronal size that is histologically similar to MCD, which correlates to spontaneous recurrent seizures. We used immunohistochemistry to investigate neuronal lamination at several time points during development between E18 and P21 and show early differences in lamination that persisted through development. Furthermore, the increased axonal length associated with mTOR upregulation occurs early in development. Our study provides a time frame for the initial development of abnormal neuronal migration and cellular growth that occurs in MCDs, and our data supports that these anatomical changes may contribute to the formation of epileptic networks.
Volumetric analysis of the terminal ductal lobular unit architecture and cell phenotypes in the human breast
Authors: Paavolainen Oona , Peurla Markus , Koskinen Leena M. , Pohjankukka Jonna , Saberi Kamyab , Tammelin Ella , Sulander Suvi-Riitta , Valkonen Masi , Mourao Larissa , Boström Pia , Brück Nina , Ruusuvuori Pekka , Scheele Colinda LGJ , Hartiala Pauliina , Peuhu Emilia 
Published: March 2023

AbstractThe major lactiferous ducts of the human breast branch out and ultimately end at terminal ductal lobular units (TDLUs). These glandular structures are the source of milk upon lactation, and also the most common origin of breast cancer. Despite their functional and clinical importance, the three dimensional (3D) architecture of TDLUs has remained undetermined, largely due to their absence in rodent animal models. By utilizing recent technological advances in optical tissue clearing, 3D reconstruction histology and microscopy, we imaged the 3D structure of healthy human breast tissue to determine whether general branching patterns or cell type specific niches exist in the TDLU. Our data demonstrate that highly branched TDLUs, also exhibiting elevated proliferation, are uncommon in the breast tissue regardless of donor age, parity or hormonal contraception. Overall, TDLUs have a consistent shape and their branch parameters are largely comparable between different TDLUs and individuals irrespective of donor age or parity. Simulation of TDLU branching morphogenesis in 3D by mathematical modelling suggests that evolutionarily conserved mechanisms regulate mammary gland branching in humans and mice, despite their anatomical differences. The data also demonstrate a new level of organization within the TDLU structure identifying a main subtree that dominates in bifurcation events and exhibits a more duct-like keratin expression pattern. In all, our data provide the first structural insights into 3D human breast anatomy and branching, and exemplify the power of volumetric imaging in deeper understanding of human breast biology.Graphical Abstract
ipsecr: An R package for awkward spatial capture–recapture data
Authors: Efford Murray G. 
Published: March 2023

AbstractSome capture–recapture models for population estimation cannot easily be fitted by the usual methods (maximum likelihood and Markov‐chain Monte Carlo). For example, there is no straightforward probability model for the capture of animals in traps that hold a maximum of one individual (‘single‐catch traps’), yet such data are commonly collected. It is usual to ignore the limit on individuals per trap and analyse with a competing‐risk ‘multi‐catch’ model that gives unbiased estimates of average density. However, that approach breaks down for models with varying density.Simulation and inverse prediction was suggested by Efford (2004) for estimating population density with data from single‐catch traps, but the method has been little used, in part because the existing software allows only a narrow range of models. I describe a new R package that refines the method and extends it to include models with varying density, trap interference and other sources of non‐independence among detection histories.The method depends on (i) a function of the data that generates a proxy for each parameter of interest and (ii) functions to simulate new datasets given values of the parameters. By simulating many datasets, it is possible to infer the relationship between proxies and parameters and, by inverting that relationship, to estimate the parameters from the observed data.The method is applied to data from a trapping study of brushtail possumsTrichosurus vulpeculain New Zealand. A feature of these data is the high frequency of non‐capture events that disabled traps (interference). Allowing for a time‐varying interference process in a model fitted by simulation and inverse prediction increased the steepness of inferred year‐on‐year population decline. Drawbacks and possible extensions of the method are discussed.
Generating continuous maps of genetic diversity using moving windows
Authors: Bishop Anusha P. , Chambers E. Anne , Wang Ian J. 
Published: March 2023

Abstract

Genetic diversity plays a key role in maintaining population viability by preventing inbreeding depression and providing the building blocks for adaptation. Understanding how genetic diversity varies across space is, therefore, of key interest in conservation and population genetics.

Here, we introduce wingen, an r package for calculating continuous maps of genetic diversity, including nucleotide diversity, allelic richness, and heterozygosity, from standard genotypic and spatial data using a spatial moving window approach. We provide functions to account for variation in sample size across space using rarefaction, to create kriging‐interpolated maps of genetic diversity, and to mask any areas that are outside the area of interest.

Tests with simulated and empirical datasets demonstrate that wingen can successfully capture variation in genetic diversity across landscapes from both reduced‐representation and whole genome sequencing datasets. For reduced‐representation datasets, wingen's functions can be run easily on a standard laptop computer, and we provide options for parallelization to increase the efficiency of running larger whole genome datasets.

wingen provides novel and computationally tractable tools for creating informative maps of genetic diversity with applications for conservation prioritization as well as population and landscape genetic analyses.