bluuebunny/crossref_metadata_2025 huggingface dataset:
Historical biogeography supports Point Conception as the site of turnover between temperate East Pacific ichthyofaunas
Authors: Miller Elizabeth Christina
Published: May 2023

The northern and southern marine faunas of the temperate Northeastern Pacific meet within California as part of one of the few eastern boundary upwelling ecosystems of the world. Traditionally, it is believed that Point Conception is the precise site of turnover between these two faunas due to sharp changes in oceanographic conditions. However, evidence from intraspecific phylogeography and species range terminals do not support this view, finding stronger biogeographic breaks elsewhere along the coast. Here I develop a new application of historical biogeographic approaches to uncover sites of transition between faunas without needing ana priorihypothesis of where these occur. I used this approach to determine whether the point of transition between northern and southern temperate faunas occurs at Point Conception or elsewhere within California. I also take advantage of expert-vetted latitudinal range data of California fish species from the 1970s and the 2020s to assess how biogeography could change with the backdrop of climate change. The site of turnover was found to occur near Point Conception, in concordance with the traditional view. I suggest that recent species- and population-level processes such as dispersal and speciation could be expected to give signals of different events from historical biogeography, possibly explaining the discrepancy across studies. Species richness of California has increased since the 1970s, mostly due to new species from Baja California. Range shifts under warming conditions will have the consequence of increasing the disparity between northern and southern faunas of California, creating a more divergent biogeography.
Facile determination of the Poisson’s ratio and Young’s modulus of polyacrylamide gels and polydimethylsiloxane
Authors: Smith Ariell M. , Inocencio Dominique Gabriele , Pardi Brandon M. , Gopinath Arvind , Eguiluz Roberto Andresen
Published: May 2023

Polyacrylamide hydrogels (PAH) and polydimethylsiloxane (PDMS) are two soft materials often used in cell mechanics and mechanobiology, in manufacturing lab-on-a chip applications, among others. This is partly due to the ability to tune their elasticity with ease, in addition to various chemical modifications. For affine polymeric networks, two (of three) elastic constants – the Young’s modulus (E), the shear modulus (G), and the Poisson’s ratio (ν) – describe the purely elastic response to external forces. However, the literature addressing the experimental determination of ν for PAH (also sometimes referred to as PAA gels in the literature) and PDMS is surprisingly limited when compared to the literature reporting values ofEandG. Here, we present a facile method to obtain the Poison’s ratio and Young’s modulus for PAH and PDMS based on static tensile tests, and cross-correlate these values with those obtained via a second independent method, shear rheology. We show that: i) the Poisson’s ratio may vary significantly from the value for incompressible materials (ν = 0.5), and ii) find a high degree of agreement between shear rheology and macroscopic static tension tests for PAH but not PDMS.

Abstract Figure
MIM-CyCIF: Masked Imaging Modeling for Enhancing Cyclic Immunofluorescence (CyCIF) with Panel Reduction and Imputation
Authors: Sims Zachary , Mills Gordon B. , Chang Young Hwan
Published: May 2023

CyCIF quantifies multiple biomarkers, but panel capacity is compromised by technical challenges including tissue loss. We propose a computational panel reduction, inferring surrogate CyCIF data from a subset of biomarkers. Our model reconstructs the information content from 25 markers using only 9 markers, learning co-expression and morphological patterns. We demonstrate strong correlations in predictions and generalizability across breast and colorectal cancer tissue microarrays, illustrating broader applicability to diverse tissue types.
Mendelian Randomization analyses identify causal associations of human gut microbiome composition on intelligence
Authors: Yao Shi , Han Ji-Zhou , Wang Xin , Wang Jia-Hao , Qian Long , Wu Hao , Guo Jing , Dong Shan-Shan , Guo Yan , Yang Tie-Lin
Published: May 2023

Background

Growing evidence indicates that dynamic changes in the gut microbiome can affect intelligence; however, whether the relationships are causal is unknown.

Methods

We conducted a bidirectional two-sample Mendelian randomization (MR) analysis using the summary statistics from the largest GWAS meta-analysis of gut microbiota composition (n = 18,340) and intelligence (n = 269,867). Inverse-variance weighted method was used to conduct the MR analyses complemented by a range of sensitivity analyses to validate the robustness of the results. We further applied a two-step MR analysis to evaluate whether the effect of identified taxa on intelligence was mediated by regulating the brain volume.

Results

MR evidence suggested a risk effect of the genusOxalobacteron intelligence (β = –0.032; 95% confidence interval, –0.049 to –0.015;P= 1.88 ×10-4) and a protective effect of the genusFusicatenibacteron intelligence (β = 0.051; 95% confidence interval, 0.023 to 0.079;P= 3.03× 10-4). In the other direction, we did not find causal evidence of intelligence on gut microbiome composition. The mediation analysis showed that the effect of genusFusicatenibacteron intelligence was partly mediated by regulating the brain volume, with a mediated proportion of 26.7% (95% confidence interval, 4.9% to 48.5%).

Conclusions

Our findings may help reshape our understanding of the microbiota-gut-brain axis and development of novel intervention approaches for preventing cognitive impairment.
Polygenic Risk for Depression and Anterior and Posterior Hippocampal Volume in Children and Adolescents
Authors: Hurtado Hailee , Hansen Melissa , Strack Jordan , Vainik Uku , Decker Alexandra L. , Khundrakpam Budhachandra , Duncan Katherine , Finn Amy S. , Mabbott Donald J. , Merz Emily C.
Published: May 2023

Background

Depression has frequently been associated with smaller hippocampal volume. The hippocampus varies in function along its anterior-posterior axis, with the anterior hippocampus more strongly associated with stress and emotion processing. The goals of this study were to examine the associations among parental history of anxiety/depression, polygenic risk scores for depression (PGS-DEP), and anterior and posterior hippocampal volumes in children and adolescents. To examine specificity to PGS-DEP, we examined associations of educational attainment polygenic scores (PGS-EA) with anterior and posterior hippocampal volume.

Methods

Participants were 350 3– to 21-year-olds (46% female). PGS-DEP and PGS-EA were computed based on recent, large-scale genome-wide association studies. High-resolution, T1-weighted magnetic resonance imaging (MRI) data were acquired, and a semi-automated approach was used to segment the hippocampus into anterior and posterior subregions.

Results

Children and adolescents with higher PGS-DEP were more likely to have a parent with a history of anxiety/depression. Higher PGS-DEP was significantly associated with smaller anterior but not posterior hippocampal volume. PGS-EA were not associated with anterior or posterior hippocampal volumes.

Limitations

Participants in these analyses were all of European ancestry.

Conclusions

Polygenic risk for depression may lead to smaller anterior but not posterior hippocampal volume in children and adolescents, and there may be specificity of these effects to PGS-DEP rather than PGS-EA. These findings may inform the earlier identification of those in need of support and in the future could inform the design of more effective, personalized treatment strategies.
A network-based model ofAspergillus fumigatuselucidates regulators of development and defensive natural products of an opportunistic pathogen
Authors: Carriel Cristobal Carrera , Pyne Saptarshi , Halberg-Spencer Spencer A. , Park Sung Chul , Seo Hye-won , Schmidt Aidan , Calise Dante G. , Ané Jean-Michel , Keller Nancy P. , Roy Sushmita
Published: May 2023

Aspergillus fumigatusis a notorious pathogenic fungus responsible for various harmful, sometimes lethal, diseases known as aspergilloses. Understanding the gene regulatory networks that specify the expression programs underlying this fungus’ diverse phenotypes can shed mechanistic insight into its growth, development, and determinants of pathogenicity. We used eighteen RNA-seq datasets (seventeen publicly available and one previously unpublished) ofAspergillus fumigatusto construct a comprehensive gene regulatory network resource. Our resource, named GRAsp (GeneRegulation ofAspergillus fumigatus), was able to recapitulate known regulatory pathways such as response to hypoxia, iron and zinc homeostasis, and secondary metabolite synthesis. Further, GRAsp was experimentally validated in two cases: one in which GRAsp accurately identified an uncharacterized transcription factor negatively regulating the production of the virulence factor gliotoxin and another where GRAsp revealed the bZip protein, AtfA, as required for fungal responses to microbial signals known as lipo-chitooligosaccharides. Our work showcases the strength of using network-based approaches to generate new hypotheses about regulatory relationships inAspergillus fumigatus. We also unveil an online, user-friendly version of GRAsp available to theAspergillusresearch community.
Zfp36l1establishes the high affinity CD8 T cell response by directly linking TCR affinity to cytokine sensing
Authors: Petkau Georg , Mitchell Twm J. , Evans Marian Jones , Matheson Louise , Salerno Fiamma , Turner Martin
Published: May 2023

How individual T cells compete for and respond to IL2 at the molecular level, and, as a consequence, how this shapes population dynamics and the selection of high affinity clones is still poorly understood. Here we describe how the RNA binding protein ZFP36L1, acts as a sensor of TCR affinity to promote clonal expansion of high affinity CD8 T cells. As part of an incoherent feed forward loop ZFP36L1 has a non-redundant role in suppressing negative regulators of cytokine signalling and mediating a selection mechanism based on competition for IL2. We suggest that ZFP36L1 acts as a sensor of antigen affinity and establishes dominance of high affinity T cells by installing a hierarchical response to IL2.
The renal capsule, a vibrant and adaptive cell environment of the kidney in homeostasis and aging
Authors: Korin Ben , Avraham Shimrit , Moncada Reuben , Ho Terence , Tleugabulova Mayra Cruz , Menon Hari , Darmanis Spyros , Liang Yuxin , Modrusan Zora , Chalouni Cecile , Victoria Charles , Rangell Linda , Havnar Charles , Ewart Will , Jones Charles , Jiang Jian , Dunlap Debra , Dohse Monika , McKay Andrew , Webster Joshua D , Durinck Steffen , Shaw Andrey S
Published: May 2023

The kidney is a complex organ that governs many physiological parameters. It is roughly divided into three parts, the renal pelvis, medulla, and cortex. Covering the cortex is the renal capsule, a serosal tissue that provides protection and forms a barrier for the kidney. Serosal tissues of many organs have been recently shown to play a vital role in homeostasis and disease. Analyses of the cells that reside in these tissues have identified distinct cell types with unique phenotypes. Here, we characterized this niche and found that it is mainly comprised of fibroblasts and macrophages, but also includes other diverse cell types. Characterizing renal capsule-associated macrophages, we found that they consist of a distinct subset (i.e., TLF+macrophages) that is nearly absent in the kidney parenchyma. Injury, disease, and other changes that involve the kidney, affected the cell composition of the renal capsule, indicating its dynamic response to changes within the organ parenchyma. Lastly, we studied age-related changes in the renal capsule and found that aging affected the cell composition and inflammatory phenotype of macrophages, increased CD8 T cells and other lymphocyte counts, and promoted a senescence-associated phenotype in fibroblasts. Taken together, our data illustrate the complexity and heterogeneity of the renal capsule and its underlying changes during aging and disease, improving our understanding of the kidney serosa that may be valuable for novel renal therapies.
Diazo-carboxyl click chemistry enables rapid and sensitive quantification of carboxylic acid metabolites
Authors: Li Cong , Cheng Kunlun , Zhao Qijin , Jin Li , Wang Xuelian , Liufu Tongling , Zhao Xutong , Li Xiaochuan , Wang Xiao , Lyu Jia , Huang Dong , Li Pingping , Chen Xiao-Wei , Wang Zhaoxia , Hu Xinli , Quan Li , Chen Zhixing
Published: May 2023

Carboxylic acids are central metabolites in bioenergetics, signal transduction and post-translation protein regulation. Unlike its genomic and transcriptomic counterparts, the quest for metabolomic profiling in trace amounts of biomedical samples is prohibitively challenging largely due to the lack of sensitive and robust quantification schemes for carboxylic acids. Based on diazo-carboxyl click chemistry, here we demonstrate DQmB-HA method as a rapid derivatization strategy for the sensitive analysis of hydrophilic, low-molecular-weight carboxylic acids. To the investigated metabolites, DQmB-HA derivatization method renders 5 to 2,000-fold higher response on mass spectrometry along with improved chromatographic separation on commercial UHPLC-MS machines. Using this method, we present the near-single-cell analysis of carboxylic acid metabolites in mouse egg cells before and after fertilization. Malate, fumarate and β-hydroxybutyrate were found to decrease in mouse zygotes. We also showcase the kinetic profiling of TCA-cycle intermediates inside adherent cells cultured in one well of 96-well plates during drug treatment. FCCP and AZD3965 were shown to have overlapped but different effects on the isotope labeling of carboxylic acids. Finally, we apply DQmB-HA method to plasma or serum samples (down to 5 μL) from mice and humans collected on pathological and physiological conditions. The measured changes of succinate, β-hydroxybutyrate, and lactate in blood corroborate previous literatures in ischemia-reperfusion injury mouse model, acute fasting-refeeding mouse model, and human individuals diagnosed with mitochondrial dysfunction diseases, respectively. Overall, DQmB-HA method offers a sensitive, rapid and user-friendly quantification scheme for carboxylic acid metabolites, paving the road toward the ultimate goals of single-cell metabolomic analysis and bedside monitoring of biofluid samples.
A Superior “Thumb” Drive: Optimizing DNA Stability for DNA Data Storage
Authors: Liu Jiun-You
Published: May 2023

DNA digital data storage is an emerging technology with the potential to keep up with increasing demands in space, energy, and materials used for information storage. To make DNA storage systems more practical and cost-effective, it is crucial to determine how the physical and chemical properties of DNA affect its performance. Thus far, scientists have experimented with various DNA storage mediums and encoding techniques to maintain DNA stability. In this study, we first review existing strategies for maintaining DNA stability under various environmental constraints, organized according to the application of the storage system (Archival Storage, Working Storage, and Dynamic Storage). Then, we report on our own quantitative evaluation of the tradeoffs between storage density and DNA stability to identify the optimal system configurations for distinct storage scenarios.
Early warning signals are hampered by a lack of critical transitions in empirical lake data
Authors: O’Brien Duncan A. , Deb Smita , Gal Gideon , Thackeray Stephen J. , Dutta Partha S. , Matsuzaki Shin-ichiro S. , May Linda , Clements Christopher F.
Published: May 2023

Quantifying the potential for abrupt non-linear changes in ecological communities is a key managerial goal, leading to a significant body of research aimed at identifying indicators of approaching regime shifts. Most of this work has built on the theory of bifurcations, with the assumption that critical transitions are a common feature of complex ecological systems. This has led to the development of a suite of often inaccurate early warning signals (EWSs), with more recent techniques seeking to overcome their limitations by analysing multivariate time series or applying machine learning. However, it remains unclear whether regime shifts and/or critical transitions are common occurrences in natural systems, and – if they are present – whether classic and second-generation EWS methods predict rapid community change. Here, using multitrophic data on nine lakes from around the world, we both identify the type of transition a lake is exhibiting, and the reliability of classic and second generation EWSs methods to predict whole ecosystem change. We find few instances of critical transitions in our lake dataset, with different trophic levels often expressing different forms of abrupt change. The ability to predict this change is highly technique dependant, with multivariate EWSs generally classifying correctly, classical rolling window univariate EWSs performing not better than chance, and recently developed machine learning techniques performing poorly. Our results suggest that predictive ecology should start to move away from the concept of critical transitions and develop methods suitable for predicting change in the absence of the strict bounds of bifurcation theory.
Centromere Innovations Within a Mouse Species
Authors: Gambogi Craig W. , Pandey Nootan , Dawicki-McKenna Jennine M. , Arora Uma P. , Liskovykh Mikhail A. , Ma Jun , Lamelza Piero , Larionov Vladimir , Lampson Michael A. , Logsdon Glennis A. , Dumont Beth L. , Black Ben E.
Published: May 2023

Mammalian centromeres direct faithful genetic inheritance and are typically characterized by regions of highly repetitive and rapidly evolving DNA. We focused on a mouse species,Mus pahari,that we found has evolved to house centromere-specifying CENP-A nucleosomes at the nexus of a satellite repeat that we identified and term π-satellite (π-sat), a small number of recruitment sites for CENP-B, and short stretches of perfect telomere repeats. OneM. paharichromosome, however, houses a radically divergent centromere harboring ∼6 Mbp of a homogenized π-sat-related repeat, π-satB, that contains >20,000 functional CENP-B boxes. There, CENP-B abundance drives accumulation of microtubule-binding components of the kinetochore, as well as a microtubule-destabilizing kinesin of the inner centromere. The balance of pro and anti-microtubule-binding by the new centromere permits it to segregate during cell division with high fidelity alongside the older ones whose sequence creates a markedly different molecular composition.

Teaser

Chromatin and kinetochore alterations arise in response to evolutionarily rapid changes to underlying repetitive centromere DNA.
Gene-by-environment interactions influence the fitness cost of gene copy-number variation in yeast
Authors: Robinson DeElegant , Vanacloig-Pedros Elena , Cai Ruoyi , Place Michael , Hose James , Gasch Audrey P
Published: May 2023

Variation in gene copy number can alter gene expression and influence downstream phenotypes; thus copy-number variation (CNV) provides a route for rapid evolution if the benefits outweigh the cost. We recently showed that genetic background significantly influences how yeast cells respond to gene over-expression (OE), revealing that the fitness costs of CNV can vary substantially with genetic background in a common-garden environment. But the interplay between CNV tolerance and environment remains unexplored on a genomic scale. Here we measured the tolerance to gene OE in four genetically distinctSaccharomyces cerevisiaestrains grown under sodium chloride (NaCl) stress. OE genes that are commonly deleterious during NaCl stress recapitulated those commonly deleterious under standard conditions. However, NaCl stress uncovered novel differences in strain responses to gene OE. West African strain NCYC3290 and North American oak isolate YPS128 are more sensitive to NaCl stress than vineyard BC187 and laboratory strain BY4743. Consistently, NCYC3290 and YPS128 showed the greatest sensitivities to gene OE. Although most genes were deleterious, hundreds were beneficial when overexpressed – remarkably, most of these effects were strain specific. Few beneficial genes were shared between the NaCl-sensitive isolates, implicating mechanistic differences behind their NaCl sensitivity. Transcriptomic analysis suggested underlying vulnerabilities and tolerances across strains, and pointed to natural CNV of a sodium export pump that likely contributes to strain-specific responses to OE of other genes. Our results reveal extensive strain-by-environment interaction in the response to gene CNV, raising important implications for the accessibility of CNV-dependent evolutionary routes under times of stress.
Go west: population genomics reveals unexpected population fluctuations and little gene flow in Western Hemisphere populations of the predatory lady beetle,Hippodamia convergens
Authors: Sethuraman Arun , Nunziata Schyler O. , Jones Angela , Obrycki John , Weisrock David W.
Published: May 2023

The convergent lady beetle,Hippodamia convergens, is used extensively in augmentative biological control of aphids, thrips, and whiteflies across its native range in North America, and was introduced into South America in the 1950s. OverwinteringH. convergenspopulations from its native western range in the United States are commercially collected and released across its current range in the eastern U.S., with little knowledge of the effectiveness of augmentative biological control usingH. convergens. Here we use a novel ddRADseq-based SNP/haplotype discovery approach to estimate its range-wide population diversity, differentiation, and recent evolutionary history. Our results indicate (1) significant population differentiation among eastern U.S., western U.S., and South American populations ofH. convergens, with (2) little to no detectable recent admixture between them, despite repeated population augmentation, and (3) continued recent population size expansion across its range. These results contradict previous findings using microsatellite markers. In light of these new findings, the implications for the effectiveness of augmentative biological control usingH. convergensare discussed. Additionally, because quantifying the non-target effects of augmentative biological control is a difficult problem in migratory beetles, our results could serve as a foundation cornerstone in improving and predicting the efficacy of future releases ofH. convergensacross its range.
Default Values And Read-Across Proposal For Dermal Absorption Based On Human Skin In Vitro Studies Dataset With Pesticides
Authors: Sarti D. , Wagner J. , Palma F. , Kalvan H. , Giachini M. , Lautenschalaeger D. , Lupianhez V. , Pires J. , Sales M. , Faria P. , Bertomeu L. , Le Bras M.
Published: May 2023

The skin is the main route of exposure to plant protection products for operators, workers, residents, and bystanders. Assessing dermal absorption is key for evaluating pesticide exposure risks. However, conductingin vitrodermal absorption studies using human skin is resource-intensive. Therefore, establishing realistic regulatory default values is essential for non-dietary risk assessment and ensuring safety. This project analysed 468in vitrodermal absorption studies with human skin compiled by ProHuma. Combined with a prior database by Aggarwal et al. (2015), the dataset comprised 759 GLP-compliant studies covering 25 formulation types and 248 active substances at various concentrations. The assessment confirmed earlier findings that dermal absorption shows no correlation with molecular weight or log Pow and does not increase linearly with dilution. Based on the comprehensive ProHuma/ECPA dataset, dermal absorption default values are proposed: 2% for solid concentrates, 5% for liquid concentrates, 30% for solid dilutions, and 34% for liquid dilutions. These values, derived conservatively using the 95th percentile, better represent formulations and agricultural use cases, reducing the need for unnecessary studies. The project also suggests read-across between different formulation types. By proposing more realistic default values and read-across approaches, it streamlines decision-making and supports safety in agriculture.
Hyperactivity in mice induced by opioid agonists with partial intrinsic efficacy and biased agonism; alone and in combination with morphine
Authors: Acevedo-Canabal Agnes , Grim Travis W. , Schmid Cullen L. , McFague Nina , Stahl Edward L. , Kennedy Nicole M. , Bannister Thomas D. , Bohn Laura M.
Published: May 2023

Opioid analgesics like morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Here we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using35S-GTPγS binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists, SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay.
Dynamically stiffening biomaterials reveal age- and sex-specific differences in pulmonary arterial adventitial fibroblast activation
Authors: Mueller Mikala C. , Du Yanmei , Walker Lori A. , Magin Chelsea M.
Published: May 2023

Respiratory diseases like pulmonary arterial hypertension (PAH) frequently exhibit sexual dimorphism. Female PAH patients are more susceptible to the disease but have increased survival rates. This phenomenon is known as the estrogen paradox, and the underlying mechanisms are not fully understood. During PAH progressionin vivo, human pulmonary arterial adventitial fibroblasts (hPAAFs) differentiate into an activated phenotype. These cells produce excess, aberrant extracellular matrix proteins that stiffen the surrounding pulmonary arterial tissues. Here, we employed dynamic poly(ethylene glycol)-alpha methacrylate (PEGαMA)-based biomaterials to study how the age and sex of human serum influenced hPAAF activation in response to microenvironmental stiffeningin vitro. Results showed female and male cells responded differently to increases in microenvironmental stiffness and serum composition. Male hPAAFs were less activated than female cells on soft hydrogels and more responsive to increases in microenvironmental stiffness regardless of serum composition. Female hPAAF activation followed this pattern only when cultured in younger (age < 50) female serum or when older (age ≥ 50) female serum was supplemented with estradiol. Otherwise, female hPAAF activation was relatively high on both soft and stiffened hydrogels, with little difference in activation between the two conditions. Collectively, these results suggest that it may be possible to model the estrogen paradox observed in PAHin vitroand that it is critical for researchers to report cell sex and serum source when conductingin vitroexperimentation.
IMMUNE RESPONSE TO SARS CoV2 INFECTION BY TLR3, TLR4 AND TLR7 GENE EXPRESSION
Authors: Marignac Veronica L. Martinez , Oertlin Gloria S. , Favant Jose Luis , Fleischman Erika , Salinas Mercedes , Marchetti Gaston , Gassali Zaida , Richard Silvina M.
Published: May 2023

Toll-like receptors (TLRs) may be involved both in the initial failure of viral clearance and in the subsequent development of severe clinical manifestations of COVID-19, essentially ARDS (acute respiratory distress syndrome) with fatal respiratory failure. We present the gene expression of TLR 3, 4, and 7 in nasopharyngeal total RNA samples from 150 individuals positive for SARS Cov2 (DET) by molecular techniques of isothermal amplification (Neokit SA) and 152 SARS Cov2 non detectable (ND) ambulatory and hospitalized patients with a non-defined respiratory disease, and we compared with the symptomatology developed by all those patients. We analyzed 4 cohorts: 1-SARS Cov2 genome detected patients with severe to high symptomatology (n=107); 2-SARS Cov2 genome detected patients low to mild symptomatology (n=43); 3-SARS Cov2 genome non detected patients with severe to high symptomatology (n=109); and 4-SARS Cov2 genome non detected patients low to mild symptomatology (n=41).

Our results not only contradict few previous study, it also corrects for sample size bias, showing no significant differences of expression for TLR3, TLR4 and TLR7 between SARS Cov2 DET and ND total cohort of patients (Non Paired T –Test p Value>0.1). When compared severity of symptoms -presence of symptoms from the COVID-19 12 WHO diagnosis symptoms- and gene expression, here we found significant positive correlation between severe symptomatology, and the number of symptoms and death for TLR4 and TLR7 for both DET and ND COVID-19 patients. When the cohort was construct with low/middle and severe symptoms, the Correlation Coefficient showed that expression of TLR4 and TLR7 was significantly amplified in those ND patients with severe symptomatology (p Value= 0.00311) as well as for TLR3 in ND low to mild symptoms cohort of patients. We also showed and discussed the results obtained of these genes expression and the sex and age of patients. In summary, our data suggest that although our innate immune system with TLRs contributes to the elimination of viruses, it can also be associated with harm to the host due to persistent inflammation and tissue destruction. We confirmed that principally TLR4 and TLR7 could be involved not only in the pathogenesis of COVID□19 but also in other respiratory diseases with same symptomatology. We agree with previous studies that treatments focus on TLR4 and TLR7 expression in inflammatory respiratory diseases could be a start point against severe symptoms development.
Factors associated with within-individual variability of lung function for people with cystic fibrosis: a longitudinal registry study
Authors: Palma Marco , Keogh Ruth H , Carr Siobhán B , Szczesniak Rhonda , Taylor-Robinson David , Wood Angela M , Muniz-Terrera Graciela , Barrett Jessica K
Published: May 2023

Lung function is a key outcome used in the evaluation of disease progression in cystic fibrosis. The variability of individual lung function measurements over time (within-individual variability) has been shown to predict subsequent lung function changes. Nevertheless, the association between within-individual lung function variability and demographic and genetic covariates is not quantified. We performed a longitudinal analysis of data from a cohort of 7099 adults with cystic fibrosis (between 18 and 49 years old) from the UK cystic fibrosis registry, containing annual review data between 1996 and 2020. A mixed-effects location-scale model is used to quantify mean FEV1(forced expiratory volume in 1 second) trajectories and FEV1within-individual variability as a function of sex, age at annual review, age at diagnosis, genotype and birth cohort. Mean FEV1decreased with age and lung function variability showed an approximately quadratic trend by age. Males showed higher FEV1mean and variability than females across the whole age range. Individuals who died during follow-up showed on average higher lung function variability than those who survived. This work opens new avenues for further research to understand the role of within-individual lung function variability in disease progression and prediction of key outcomes such as mortality.
Conserving a threatened North American walnut: a chromosome-scale reference genome for butternut (Juglans cinerea)
Authors: Guzman-Torres Cristopher R. , Trybulec Emily , LeVasseur Hannah , Akella Harshita , Amee Maurice , Strickland Emily , Pauloski Nicole , Williams Martin , Romero-Severson Jeanne , Hoban Sean , Woeste Keith , Pike Carolyn C. , Fetter Karl C. , Webster Cynthia N. , Neitzey Michelle L. , O’Neill Rachel J. , Wegrzyn Jill L.
Published: May 2023

With the advent of affordable and more accurate third generation sequencing technologies and the associated bioinformatic tools, it is now possible to sequence, assemble, and annotate more species of conservation concern than ever before.Juglans cinerea, commonly known as butternut or white walnut, is a member of the walnut family, native to the Eastern United States and Southeastern Canada. The species is currently listed as Endangered on the IUCN Red List due to decline from an invasive fungus known asOphiognomonia clavigignenti-juglandacearum(Oc-j) that causes butternut canker. Oc-j creates visible sores on the trunks of the tree which essentially starves and slowly kills the tree. Natural resistance to this pathogen is rare. Conserving butternut is of utmost priority due to its critical ecosystem role and cultural significance. As part of an integrated undergraduate and graduate student training program in biodiversity and conservation genomics, the first reference genome forJuglans cinereais described here. This chromosome-scale 539 Mb assembly was generated from over 100X coverage of Oxford Nanopore long reads and scaffolded with theJuglans mandshuricagenome. Scaffolding with a closely related species oriented and ordered the sequences in a manner more representative of the structure of the genome without altering the sequence. Comparisons with sequenced Juglandaceae revealed high levels of synteny and further supportedJ. cinerea’srecent phylogenetic placement. Comparative assessment of gene family evolution revealed a significant number of contracting families, including several associated with biotic stress response.
Neuro-Regenerative Behavior of Adipose-Derived Stem Cells in Aligned Collagen I Hydrogels
Authors: Lewis Mackenzie , David Gabriel , Jacobs Danielle , Woessner Alan E. , Kuczwara Patrick , Kim Jin-Woo , Quinn Kyle P. , Song Younghye
Published: May 2023

Peripheral nerve injuries persist as a major clinical issue facing the US population and can be caused by stretch, laceration, or crush injuries. Small nerve gaps are simple to treat, and the nerve stumps can be reattached with sutures. In longer nerve gaps, traditional treatment options consist of autografts, hollow nerve guidance conduits, and, more recently, manufactured fibrous scaffolds. These manufactured scaffolds often incorporate stem cells, growth factors, and/or extracellular matrix (ECM) proteins to better mimic the native environment but can have issues with homogenous cell distribution or uniformly oriented neurite outgrowth in scaffolds without fibrous alignment. Here, we utilize a custom device to fabricate collagen I hydrogels with aligned fibers and encapsulated adipose-derived mesenchymal stem cells (ASCs) for potential use as a peripheral nerve repair graft. Analysis of these scaffolds in vitro revealed heightened therapeutic secretome from ASCs, ECM deposition, and dorsal root ganglia (DRG) neurite outgrowth along the axis of fiber alignment. Our platform serves as an in vitro testbed platform to assess neuro-regenerative potential of ASCs in aligned collagen fiber scaffolds and may provide guidance on next-generation nerve repair scaffold design.
Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging
Authors: Paine Patrick Treat , Rechsteiner Cheyenne , Morandini Francesco , Desdin Mico Gabriela , Mrabti Calida , Parras Alberto , Haghani Amin , Brooke Robert , Horvath Steve , Seluanov Andrei , Gorbunova Vera , Ocampo Alejandro
Published: May 2023

Unlike aged somatic cells, which exhibit a decline in molecular fidelity and eventually reach a state of replicative senescence, pluripotent stem cells can indefinitely replenish themselves while retaining full homeostatic capacity. The conferment of beneficial-pluripotency related traits via in vivo partial cellular reprogramming (IVPR) significantly extends lifespan and restores aging phenotypes in mouse models. Although the phases of cellular reprogramming are well characterized, details of the rejuvenation processes are poorly defined. To understand whether epigenetic reprogramming can ameliorate DNA damage, we created reprogrammable accelerated aging mouse model with an ERCC1 mutation. Importantly, using enhanced partial reprogramming by combining small molecules with the Yamanaka factors, we observed potent reversion of DNA damage, significant upregulation of multiple DNA damage repair processes, and restoration of the epigenetic clock. In addition, we present evidence that pharmacological inhibition of ALK5 and ALK2 receptors in TGFb pathway is able to phenocopy some benefits including epigenetic clock restoration suggesting a role in the mechanism of rejuvenation by partial reprogramming.
Intermediate basal cell population in prostate homeostasis and cancer initiation
Authors: Guo Wangxin , Zhang Xiaoyu , Li Lin , Shao Pengfei , Zhang Hongjiong , Liu Kuo , Liang Chao , Wang Shuoming , Peng Yunyi , Ju Yi , Yu Chen , Chen Luonan , Zhou Bin , Gao Dong
Published: May 2023

Many glandular epithelia are mainly composed of basal cells and luminal cells, including the prostate gland. Adult prostate basal and luminal cells are independently self-sustained by unipotent stem cells that can reactivate multipotency under prostate inflammation and carcinogenesis contexts. However, the defined basal stem cell populations responsible for prostate regeneration and their cell fates in prostate homeostasis, inflammation and carcinogenesis remain unclear. Using a genetic proliferation tracer (ProTracer) system, we found that basal cells exhibited extensive cell loss and proliferation during androgen-mediated prostate regression and regeneration, respectively. A rare intermediate basal cell population that expresses luminal cell markers (Nkx3.1andPbsn) (termed Basal-B) and a large basal cell population (termed Basal-A) were identified in mouse prostates by single-cell RNA sequencing. Basal-B cells exhibited a greater capacity for organoid formation and luminal cell differentiationin vitro. Genetic lineage tracing using dual recombinases showed that prostate homeostasis and regeneration are not driven by specific basal cell types. Fate-mapping results showed that Basal-B cells had a greater tendency to generate luminal cells under bacteria-induced prostate inflammation. Deletion ofPtenin basal cells resulted in Basal-A-to-Basal-B-to-luminal transition and prostatic intraepithelial neoplasia. Moreover, the human Basal-B-cell population was significantly increased in human benign prostate hyperplasia and prostatic intraepithelial neoplasia samples compared with normal prostate samples. This study identifies intermediate Basal-B cells as a potential stem cell population and provides genetic evidence of prostate basal cell lineage plasticity under physiological and pathological contexts.
Clearing the way to the external world: do ants make optimal decisions when removing obstacles from their subterranean galleries?
Authors: Devers Louis E. , Cléradin Clémentine , Bescond-Michel Zoé , Latil Gérard , Fourcassié Vincent
Published: May 2023

Transport tasks are simple tasks whose cost can be easily measured and that are thus well suited to test optimality hypotheses. Here we focus on a particular type of transport that occur when ants are clearing obstacles from their subterranean galleries. In the laboratory we studied how they extract an object from a gallery of various inclinations. We expected that if ants behave optimally, they should remove the object by the gallery extremity requiring the lower energetic effort. At the colony-level, we found that the obstacle was more often extracted by the lower end of the tube, even if this required a higher amount of mechanical work. At the individual level however, ants showed mechanically optimal pulling behaviours in 75% of cases. Our results suggest that individual ants take into account both the inclination of the gallery and the position of the obstacle in it to decide in which direction they pull. In addition, they seem to base their decision to release the obstacle on the relative effort they perceive while pulling. Using a simple simulation model, we argue that the suboptimal extraction bias observed at the colony-level can be explained by the sequential nature of the extraction task.
Transcription-directed membrane association organizes the chloroplast nucleoid structure
Authors: Palomar V. Miguel , Fujii Sho , Rothi M. Hafiz , Jaksich Sarah , Coke Adriana N. , Wang Joyful , Wierzbicki Andrzej T.
Published: May 2023

DNA is organized into chromatin-like structures, which support the maintenance and regulation of genomes. A unique and poorly understood form of DNA packaging exists in chloroplasts, which are endosymbiotic organelles responsible for photosynthesis. Chloroplast genomes, together with associated proteins, form membraneless structures known as nucleoids. The internal arrangement of the nucleoid, molecular mechanisms of DNA packaging, and connections between nucleoid structure and gene expression remain mostly unknown. We show thatArabidopsis thalianachloroplast nucleoids have a unique organization driven by DNA binding to the thylakoid membranes. DNA associated with the membranes has high protein occupancy, reduced DNA accessibility, and is highly transcribed. In contrast, genes with low levels of transcription are further away from the membranes, have lower protein occupancy, and higher DNA accessibility. Disruption of transcription at specific genes in sigma factor mutants causes a corresponding reduction in membrane association, indicating that RNA polymerase activity causes DNA tethering to the membranes. We propose that transcription organizes the chloroplast nucleoid into a transcriptionally active membrane-associated core and a less active periphery.
Selenoprotein synthesis is not induced by hepatotoxic drugs
Authors: Shetty Sumangala P. , He Dongming , Copeland Paul R.
Published: May 2023

Background and Aims

Many of the proteins that contain the amino acid selenocysteine are required for optimal defense against cellular stress. As such, one might expect selenoprotein synthesis to persist or be induced upon cellular insult. Because selenocysteine is incorporated by a complex post-transcriptional mechanism, monitoring the transcription of selenoprotein genes is not adequate to understand the regulation of selenoprotein synthesis. We aimed to determine whether selenoprotein synthesis is regulated by the induction of hepatotoxic stress.

Methods

We used hepatotropic clinically relevant drugs to evaluate the regulation of selenoprotein synthesis in human hepatocarcinoma cells.

Results

We found that two drugs, benzbromarone and sorafenib, caused significant inhibition of selenoprotein synthesis. However, the loss of selenoprotein expression was not specific as total protein synthesis was similarly down-regulated only by benzbromarone and sorafenib.

Conclusions

These results allow us to conclude that these hepatotoxins do not induce or preserve selenoprotein synthesis as a protective mechanism.

Highlights

The treatment of liver cells with hepatotoxic and hepatotropic compounds does not result in increased synthesis of selenoproteins.

Compounds that induced the canonical oxidative stress response that features NRF2 activation eliminated selenoprotein synthesis.

The downregulation of selenoproteins was accompanied by general inhibition of protein synthesis.
Single cell assessment of human stem cell derived mesolimbic models and their responses to substances of abuse
Authors: Rudibaugh Thomas P. , Tam Ryan W. , Estridge R. Chris , Keung Albert J.
Published: May 2023

The mesolimbic pathway connects ventral tegmental area dopaminergic neurons and striatal medium spiny neurons, playing a critical role in reward and stress behaviors. Exposure to substances of abuse during development and adulthood has been linked to adverse outcomes and molecular changes. The rise of human cell repositories and whole genome sequences enables human functional genomics ‘in a dish’, offering insights into human-specific responses to substances of abuse. Characterizations ofin vitromodels are necessary to ensure appropriate experimental designs and accurate interpretation of results. This study provides a comprehensive characterization of these models and their responses to substances of abuse, introducing new culture conditions for generating medium spiny neurons and dopaminergic neurons from human pluripotent stem cells. Single cell analysis reveals cell type-specific transcriptomic responses to dopamine, cocaine, and morphine, including compound and cell type-specific transcriptomic signatures related to neuroinflammation and alterations in signaling pathways. These findings offer a resource for future genomics studies leveraging human stem cell-derived models.

Teaser

Generation and characterization of a novel mesolimbic pathway model and its response to acute dopamine, morphine, and cocaine.
Using multiscale molecular modeling to analyze possible NS2b-NS3 protease inhibitors from medicinal plants endemic to the Philippines
Authors: Cordero Allen Mathew F. , Gonzales Arthur A.
Published: May 2023

Philippine folkloric medicinal plants likeEuphorbia hirta(locally known as tawa-tawa),Carica papaya(papaya),Psidium guajava(guava), andMomordica charantia(bittermelon) have been used as a treatment for dengue. However, limited studies have been conducted regarding the extensive effects of these plants, especially their anti-dengue activity. This study evaluated 2,944 ligands from phytochemicals found in various medicinal plants as potential dengue inhibitors that could be developed into cost-effective and efficient therapeutic agents. SwissADME and Chembioserver online servers were used to conduct tests on absorption, distribution, metabolism, excretion, and toxicity (ADMET) for all ligands, resulting in 1,265 compounds being pharmacologically viable. By targeting the NS2b-NS3 protease of the dengue virus, specifically its catalytic triad of Asp 75, Ser 135, and His 51 residues, we can inhibit the replication of the virus. Molecular docking results showed ten ligands with comparable docking scores to the reference compounds. Attachment to the binding site is strengthened by electrostatic, polar, and hydrophobic interactions and the formation of hydrogen bonds.

Furthermore, we also evaluated their stability using molecular dynamics simulations on GROMACS 2021.3. Molecular dynamics simulations of up to 100 ns of chemical time suggest eight of the ten candidate ligands are stable while binding to the active site. Free energy calculations using molecular mechanics Poisson-Boltzmann surface area also proved that six of the eight stable ligands exceeded the binding energies of the reference compounds. Results showed that veramiline fromVeratrum mengtzeanum(pimacao), etiolin fromLilion martagon(Turk’s cap lily), hydroxyverazine fromEclipta prostrata(false daisy), chlorogenin fromYucca gloriosa(palm lily), cyclobranol fromEuphorbia hirta(tawa-tawa), and ecliptalbine fromEclipta albamaintained their structural stability throughout the simulations. They also displayed good oral bioavailability and potential drug-like characteristics. These six compounds warrant furtherin vitroandin vivoinvestigation as potential dengue therapies.