bluuebunny/crossref_metadata_2025 huggingface dataset:
PRODUCTION OF XYLANASE BY Aspergillus niger GIO AND Bacillus megaterium THROUGH SOLID-STATE FERMENTATION
Authors: Fasiku Samuel Adedayo , Bello Mobolaji Akeem , Odeniyi Olubusola Ayoola
Published: March 2023

Xylanase breaks xylan down to xylose which is used in industries such as pulp and paper, food, and feed, among others. The utilization of wastes for xylanase production is economical, hence, this work aimed at producing xylanase through solid-state fermentation and characterizing the enzyme. Xylanase-producing strains of Bacillus megaterium and Aspergillus niger GIO were inoculated separately in a 5 and 10 days solid fermentation study on maize straw, rice straw, sawdust, corn cob, sugarcane bagasse, conifer liters, alkaline-pretreated maize straw (APM), and combined-alkaline and biological-pretreated maize straw, respectively. The best substrate was selected for xylanase production. The crude enzyme was extracted from the fermentation medium and xylanase activity was characterized using parameters such as temperature, cations, pH, and surfactants. Among different substrates, the highest xylanase activity of 3.18 U/mL was recorded when Aspergillus niger GIO was grown on APM. The xylanase produced by Aspergillus niger GIO and Bacillus megaterium had their highest activities (3.67 U/mL, 3.36 U/mL) at 40 °C after 30 and 45 minutes of incubation, respectively. Optimum xylanase activities (4.58 and 3.58 U/mL) of Aspergillus niger GIO and Bacillus megaterium, respectively were observed at pH 5.0 and 6.2. All cations used enhanced xylanase activities except magnesium ion. Sodium dodecyl sulfate supported the highest xylanase activity of 6.13 and 6.90 U/mL for Aspergillus niger GIO and Bacillus megaterium, respectively. High yields of xylanase were obtained from Aspergillus niger GIO and Bacillusmegaterium cultivated on alkaline pretreated maize straw.  The xylanase activities were affected by pH, temperature, surfactants, and cations.
IRES-independent, eIF2A/eIF2D-dependent translation of the enterovirus genome
Authors: Kim Hyejeong , Aponte-Diaz David , Sotoudegan Mohamad S. , Arnold Jamie J. , Cameron Craig E.
Published: March 2023

RNA recombination in positive-strand RNA viruses is a molecular-genetic process, which permits the greatest evolution of the genome and may be essential to stabilizing the genome from the deleterious consequences of accumulated mutations. Enteroviruses represent a useful system to elucidate the details of this process. On the biochemical level, it is known that RNA recombination is catalyzed by the viral RNA-dependent RNA polymerase using a template-switching mechanism. For this mechanism to function in cells, the recombining genomes must be located in the same subcellular compartment. How a viral genome is trafficked to the site of genome replication and recombination, which is membrane associated and isolated from the cytoplasm, is not known. We hypothesized that genome translation was essential for co-localization of genomes for recombination. We show that complete inactivation of internal ribosome entry site (IRES)-mediated translation of a donor enteroviral genome enhanced recombination instead of impairing it. Recombination did not occur by a non-replicative mechanism. Rather, sufficient translation of the non-structural region of the genome occurred to support subsequent steps required for recombination. The non-canonical translation initiation factors, eIF2A and eIF2D, were required for IRES-independent translation. Our results support an eIF2A/eIF2D-dependent mechanism under conditions in which the eIF2-dependent mechanism is inactive. Detection of an IRES-independent mechanism for translation of the enterovirus genome provides an explanation for a variety of debated observations, including non-replicative recombination and persistence of enteroviral RNA lacking an IRES. The existence of an eIF2A/eIF2D-dependent mechanism in enteroviruses predicts the existence of similar mechanisms in other viruses.
Can a Simple Phenomenological Model Explain the Mechanics of Eccentric Contractions?
Authors: Yeo Sang Hoon , Herzog Walter
Published: March 2023

Notwithstanding decades of research, predictions from the existing muscle models on eccentric contraction remain elusive. This study aimed to test the possibility that a relatively simple phenomenological muscle model, based on an adapted Hill-type muscle model with some novel assumptions, can capture the mechanics of eccentric contractions. The result of the simulations, although preliminary, support the potential of the proposed model in predicting the mechanics of eccentric contraction.
Validation of the Brazilian version of the Processes of Change Questionnaire in Weight Management in adults with overweight and obesity in Brazil
Authors: de Carvalho Quênia , Ziani Paola Rampelotto , Montezano Bruno Braga , Goularte Jeferson Ferraz , Rosa Adriane R
Published: March 2023

Introduction

This study aimed to analyze the psychometric properties of the Brazilian version of the Processes of Change Questionnaire in Weight Management (P-Weight) questionnaire.

Methods

A total of 656 adults participated in the study, including people in weight loss treatment and people from the general community. All participants responded to the Process of Change Questionnaire (P-Weight), the Stages of Change Questionnaire (S-Weight), and the Eating Attitudes Test (EAT-26), which assesses risk of eating disorder used as a measure of external validity. Socio-demographic variables were also investigated.

Results

The 33-item P-weight questionnaire showed satisfactory psychometric properties with high internal consistency (Cronbach’s alpha=0.959). Exploratory and confirmatory factor analyses revealed a 4-factor model similar to the original Spanish version of P-Weight with a slightly rearrangement of the items (KMO=0.92, df (528, n=328) =8,401.015; p<0.0001). We found significant associations between processes and stages of change (p<0.001) and a moderate correlation between the four subscales of P-weight and EAT-26 (p<0.001). Finally, the mean score of P-Weight were higher in clinical sample compared to the general community, suggesting the sensitivity to discriminate cases and controls (p<0.001).

Conclusion

This study showed the validity and reliability of the Brazilian version of the P-Weight scale. Therefore, the P-Weight is readily available to help professionals to employ precision interventions to weight loss considering the patient’s motivational stage in combination with their individual use of the cognitive processes of change.
Wolbachiainfection at least partially rescues the fertility and ovary defects of several newDrosophila melanogaster bag of marblesprotein-coding mutants
Authors: Wenzel Miwa , Aquadro Charles F.
Published: March 2023

TheD. melanogasterprotein coding genebag of marbles(bam) plays a key role in early male and female reproduction by forming complexes with partner proteins to promote differentiation in gametogenesis. Like another germline gene,Sex lethal,bamgenetically interacts with the endosymbiontWolbachia, asWolbachiarescues the reduced fertility of abamhypomorphic mutant. Here, we explored the specificity of thebam-Wolbachiainteraction by generating 22 newbammutants, with ten mutants displaying fertility defects. Nine of these mutants trend towards rescue by thewMelWolbachiavariant, with eight statistically significant at the fertility and/or cytological level. In some cases, fertility was increased a striking 20-fold. There is no specificity between the rescue and the known binding regions ofbam, suggestingwMel does not interact with one singularbampartner to rescue the reproductive phenotype. We further tested ifwMel interacts withbamin a non-specific way, by increasingbamtranscript levels or acting upstream in germline stem cells. A fertility assessment of abamRNAi knockdown mutant reveals thatwMel rescue is specific to functionally mutantbamalleles and we find no obvious evidence ofwMel interaction with germline stem cells inbammutants.

Author Summary

Reproduction in theDrosophila melanogasterfruit fly is dependent on thebag of marbles(bam) gene, which acts early in the process of generating eggs and sperm. Mutations to this gene negatively impact the fertility of the fly, causing it to be sterile or have fewer progeny. Interestingly, we find that the bacteriaWolbachia, which resides within reproductive cells across a wide range of insects, partially restores the fertility and ovary phenotype of severalbammutants of which the resultant Bam protein is altered from wildtype. The protein function of Bam is further suggested to be important by the lack of rescue for a fly that has a fertility defect due to low expression of a non-mutatedbamgene. Previous work makes similar conclusions aboutWolbachiawith another reproductive gene,Sex lethal(Sxl), highlighting the potential for rescue of fertility mutants to occur in a similar way across different genes. An understanding of the ways in whichWolbachiacan affect host reproduction provides us with context with which to frameWolbachia’s impact on host genes, such asbamandSxl,and consider the evolutionary implications ofWolbachia’s infection inD. melanogasterfruit flies.
MetaLLM: Residue-wise Metal ion Prediction Using Deep Transformer Model
Authors: Shishir Fairuz Shadmani , Sarker Bishnu , Rahman Farzana , Shomaji Sumaiya
Published: March 2023

Proteins bind to metals such as copper, zinc, magnesium, etc., serving various purposes such as importing, exporting, or transporting metal in other parts of the cell as ligands and maintaining stable protein structure to function properly. A metal binding site indicates the single amino acid position where a protein binds a metal ion. Manually identifying metal binding sites is expensive, laborious, and time-consuming. A tiny fraction of the millions of proteins in UniProtKB – the most comprehensive protein database – are annotated with metal binding sites, leaving many millions of proteins waiting for metal binding site annotation. Developing a computational pipeline is thus essential to keep pace with the growing number of proteins. A significant shortcoming of the existing computational methods is the consideration of the long-term dependency of the residues. Other weaknesses include low accuracy, absence of positional information, hand-engineered features, and a pre-determined set of residues and metal ions. In this paper, we propose MetaLLM, a metal binding site prediction technique, by leveraging the recent progress in self-supervised attention-based (e.g. Transformer) large language models (LLMs) and a considerable amount of protein sequences publicly available. LLMs are capable of modelling long residual dependency in a sequence. The proposed MetaLLM uses a transformer pre-trained on an extensive database of protein sequences and later fine-tuned on metal-binding proteins for multi-label metal ions prediction. A 10-fold cross-validation shows more than 90% precision for the most prevalent metal ions.
Aging impairs cold-induced beige adipogenesis and adipocyte metabolic reprogramming
Authors: Holman Corey D. , Sakers Alexander P. , Calhoun Ryan P. , Cheng Lan , Fein Ethan C. , Jacobs Christopher , Tsai Linus , Rosen Evan D. , Seale Patrick
Published: March 2023

The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process. We found that aging increases the expression ofCd9and other fibro-inflammatory genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes. Fibroblastic ASPC populations from young and aged mice were equally competent for beige differentiationin vitro, suggesting that environmental factors suppress adipogenesisin vivo. Examination of adipocytes by single nucleus RNA-sequencing identified compositional and transcriptional differences in adipocyte populations with age and cold exposure. Notably, cold exposure induced an adipocyte population expressing high levels ofde novolipogenesis (DNL) genes, and this response was severely blunted in aged animals. We further identified natriuretic peptide clearance receptorNpr3, a beige fat repressor, as a marker gene for a subset of white adipocytes and an aging-upregulated gene in adipocytes. In summary, this study indicates that aging blocks beige adipogenesis and dysregulates adipocyte responses to cold exposure and provides a unique resource for identifying cold and aging-regulated pathways in adipose tissue.
Deletion of smooth muscle O-GlcNAc transferase prevents development of atherosclerosis in western diet-fed hyperglycemic ApoE-/-mice in vivo
Authors: Khanal Saugat , Bhavnani Neha , Mathias Amy , Lallo Jason , Gupta Shreya , Ohanyan Vahagn , Ferrell Jessica , Raman Priya
Published: March 2023

Accumulating evidence highlights protein O-GlcNAcylation as a putative pathogenic contributor of diabetic vascular complications. We previously reported that elevated protein O-GlcNAcylation correlates with increased atherosclerotic lesion formation and VSMC proliferation in response to hyperglycemia. However, the role of O-GlcNAc transferase (OGT), regulator of O-GlcNAc signaling, in evolution of diabetic atherosclerosis remains elusive. The goal of this study was to determine whether smooth muscle OGT (smOGT) plays a direct role in hyperglycemia-induced atherosclerotic lesion formation and SMC de-differentiation. Using tamoxifen-inducibleMyh11-CreERT2and OGTfl/flmice, we generated smOGTWTand smOGTKOmice, with and without ApoE-null backgrounds. Following STZ-induced hyperglycemia, smOGTWTand smOGTKOmice were kept on standard laboratory diet for study duration. In a parallel study, smOGTWTApoE-/-and smOGTKOApoE-/-were kept on Western diet beginning 8-wks-age. Animals harvested at 14-16-wks-age were used for plasma and tissue collection. Loss of smOGT augmented SM contractile marker expression in aortic vessels of STZ-induced hyperglycemic smOGTKOmice. Consistently, smOGT deletion attenuated atherosclerotic lesion lipid burden (Oil red O), plaque area (H&E), leukocyte (CD45) and smooth muscle cell (ACTA2) abundance in Western diet-induced hyperglycemic smOGTKOApoE-/-mice. This was accompanied with increased SM contractile markers, and reduced inflammatory and proliferative marker expression. Further, smOGT deletion attenuated YY1 and SRF expression (transcriptional regulators of SM contractile genes) in hyperglycemic smOGTKOApoE-/-and smOGTKOmice. These data uncover an atheroprotective outcome of smOGT loss-of-function and suggest a direct regulatory role of OGT-mediated O-GlcNAcylation in VSMC de-differentiation in hyperglycemia.
Cellular heterogeneity of the developing worker honey bee (Apis mellifera) pupa: a single cell transcriptomics analysis
Authors: Patir Anirudh , Raper Anna , Fleming Robert , Henderson Beth EP , Murphy Lee , Henderson Neil C , Clark Emily , Freeman Tom C , Barnett Mark W
Published: March 2023

It is estimated that animals pollinate 87.5% of flowering plants worldwide and that managed honey bees (Apis mellifera) account for 30-50% of this ecosystem service to agriculture. In addition to their important role as pollinators, honey bees are well-established insect models for studying learning and memory, behaviour, caste differentiation, epigenetic mechanisms, olfactory biology, sex determination and eusociality. Despite their importance to agriculture, knowledge of honey bee biology lags behind many other livestock species. In this study we have used scRNA-Seq to map cell types to different developmental stages of the worker honey bee (prepupa at day 11 and pupa at day 15), and sought to determine their gene signatures and thereby provide potential functional annotations for as yet poorly characterized genes. To identify cell type populations we examined the cell-to-cell network based on the similarity of the single-cells’ transcriptomic profiles. Grouping similar cells together we identified 63 different cell clusters of which 15 clusters were identifiable at both stages. To determine genes associated with specific cell populations or with a particular biological process involved in honey bee development, we used gene co-expression analysis. We combined this analysis with literature mining, the honey bee protein atlas and Gene Ontology analysis to determine cell cluster identity. Of the cell clusters identified, 9 were related to the nervous system, 7 to the fat body, 14 to the cuticle, 5 to muscle, 4 to compound eye, 2 to midgut, 2 to hemocytes and 1 to malpighian tubule/pericardial nephrocyte. To our knowledge, this is the first whole single cell atlas of honey bees at any stage of development and demonstrates the potential for further work to investigate their biology of at the cellular level.
Dual role of striatal astrocytes in behavioral flexibility and metabolism in the context of obesity
Authors: Montalban Enrica , Chao Daniela Herrera Moro , Ansoult Anthony , Pham Cuong , Contini Andrea , Castel Julien , Hassouna Rim , Hardonk Marene , Petitbon Anna , Foppen Ewout , Gangarossa Giuseppe , Trifilieff Pierre , Li Dongdong , Luquet Serge , Martin Claire
Published: March 2023

Brain circuits involved in metabolic control and reward-associated behaviors are potent drivers of feeding behavior and are both dramatically altered in obesity, a multifactorial disease resulting from genetic and environmental factors. In both mice and human, exposure to calorie-dense food has been associated with increased astrocyte reactivity and pro-inflammatory response in the brain. Although our understanding of how astrocytes regulate brain circuits has recently flourish, whether and how striatal astrocytes contribute in regulating food-related behaviors and whole-body metabolism is still unknown. In this study, we show that exposure to enriched food leads to profound changes in neuronal activity and synchrony. Chemogenetic manipulation of astrocytes activity in the dorsal striatum was sufficient to restore the cognitive defect in flexible behaviors induced by obesity, while manipulation of astrocyte in the nucleus accumbens led to acute change in whole-body substrate utilization and energy expenditure. Altogether, this work reveals a yet unappreciated role for striatal astrocyte as a direct operator of reward-driven behavior and metabolic control.
Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice
Authors: Ding Yufang , Yanagi Karin , Yang Fang , Callaway Evelyn , Cheng Clint , Hensel Martha E , Menon Rani , Alaniz Robert C. , Lee Kyongbum , Jayaraman Arul
Published: March 2023

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and TNF-a and fatty acid induced inflammatory responses in an aryl-hydrocarbon receptor (AhR) dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic TG, liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A’s beneficial effects likely reflect the metabolite’s direct actions on the liver. Administration of I3A partially reversed WD induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β- oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to NASH.
Intermediate antiparallel fibrils in Aβ40 Dutch mutant aggregation: nanoscale insights from AFM-IR
Authors: Banerjee Siddhartha , Naik Tanmayee , Ghosh Ayanjeet
Published: March 2023

Cerebral Amyloid Angiopathy (CAA), which involves amyloid deposition in blood vessels leading to fatal cerebral hemorrhage and recurring strokes, is present in the majority Alzheimer’s disease cases. Familial mutations in the amyloid β peptide is correlated to higher risks of CAA, and are mostly comprised of mutations at residues 22 and 23. While the structure of the wild type Aβ peptide has been investigated in great detail, less is known about the structure of mutants involved in CAA and evolutions thereof. This is particularly true for mutations at residue 22, for which detailed molecular structures, as typically determined from Nuclear Magnetic Resonance (NMR) spectroscopy or electron microscopy, do not exist. In this report, we have used nanoscale infrared (IR) spectroscopy augmented with Atomic Force Microscopy (AFM-IR) to investigate structural evolution of the Aβ Dutch mutant (E22Q) at the single aggregate level. We show that that in the oligomeric stage, the structural ensemble is distinctly bimodal, with the two subtypes differing with respect to population of parallel β-sheets. Fibrils on the other hand are structurally homogeneous, with early-stage fibrils distinctly anti parallel in character, which develop parallel β-sheets upon maturation. Furthermore, the antiparallel structure is found to be a persistent feature across different stages of aggregation.
Seed functional ecology in Brazilian rock outcrop vegetation: an integrative synthesis
Authors: Ordóñez-Parra Carlos A. , Medeiros Natália F. , Dayrell Roberta L.C. , Le Stradic Soizig , Negreiros Daniel , Cornelissen Tatiana , Silveira Fernando A. O.
Published: March 2023

Background and Aims

Rock outcrop vegetation is distributed worldwide and hosts a diverse and unique flora that evolved under harsh environmental conditions. Unfortunately, seed ecology in such ecosystems has received little attention, especially regarding seed traits, germination responses to abiotic factors and the potential role of phylogenetic relatedness on such features Here, we provide the first quantitative and phylogenetically-informed synthesis of the seed functional ecology of Brazilian rock outcrop vegetation, with a particular focus on quartzitic and ironstonecampo rupestre.

Methods

Using a database of functional trait data, we calculated the phylogenetic signal of seven seed traits for 371 taxa and tested whether they varied among growth forms, geographic distribution, and microhabitats. We also conducted meta-analyses that included 4,252 germination records for 102 taxa to assess the effects of light, temperature, and fire-related cues on the germination ofcampo rupestrespecies and explored how the aforementioned ecological groups and seed traits modulate germination responses.

Key Results

All traits and germination responses showed a moderate-to-strong phylogenetic signal.Campo rupestrespecies responded positively to light and had maximum germination between 20-25 °C. The effect of temperatures beyond this range was moderated by growth form, species geographic distribution, and microhabitat. Seeds exposed to heat shocks above 80 °C lost viability, but smoke accelerated germination. We found a moderating effect of seed mass for in responses to light and heat shocks, with larger, dormant seeds tolerating heat better but less sensitive to light. Species from xeric habitats evolved phenological strategies to synchronise germination during periods of increased soil water availability.

Conclusions

Phylogenetic relatedness plays a major role in shaping seed ecology of Brazilian rock outcrop vegetation. Nevertheless, seed traits and germination responses varied significantly between growth forms, species geographic distribution and microhabitats, providing support to the regeneration niche hypothesis and the role of functional traits in shaping germination in these ecosystems.
Inference of single cell profiles from histology stains with the Single-Cell omics from Histology Analysis Framework (SCHAF)
Authors: Comiter Charles , Vaishnav Eeshit Dhaval , Ciampricotti Metamia , Li Bo , Yang Yiming , Rodig Scott J. , Turner Madison , Pfaff Kathleen L. , Jané-Valbuena Judit , Slyper Michal , Waldman Julia , Vigneau Sebastian , Wu Jingyi , Blosser Timothy R. , Segerstolpe Åsa , Abravanel Daniel , Wagle Nikil , Zhuang Xiaowei , Rudin Charles M. , Klughammer Johanna , Rozenblatt-Rosen Orit , Kobayash-Kirschvink Koseki J. , Shu Jian , Regev Aviv
Published: March 2023

Tissue biology involves an intricate balance between cell-intrinsic processes and interactions between cells organized in specific spatial patterns, which can be respectively captured by single-cell profiling methods, such as single-cell RNA-seq (scRNA-seq), and histology imaging data, such as Hematoxylin-and-Eosin (H&E) stains. While single-cell profiles provide rich molecular information, they can be challenging to collect routinely and do not have spatial resolution. Conversely, histological H&E assays have been a cornerstone of tissue pathology for decades, but do not directly report on molecular details, although the observed structure they capture arises from molecules and cells. Here, we leverage adversarial machine learning to develop SCHAF (Single-Cell omics from Histology Analysis Framework), to generate a tissue sample’s spatially-resolved single-cell omics dataset from its H&E histology image. We demonstrate SCHAF on two types of human tumors—from lung and metastatic breast cancer—training with matched samples analyzed by both sc/snRNA-seq and by H&E staining. SCHAF generated appropriate single-cell profiles from histology images in test data, related them spatially, and compared well to ground-truth scRNA-Seq, expert pathologist annotations, or direct MERFISH measurements. SCHAF opens the way to next-generation H&E2.0 analyses and an integrated understanding of cell and tissue biology in health and disease.
Interpretation of Predictions in Drug-Gut Bacteria Interactions Using Machine Learning
Authors: Joshi Himanshu , Prakash Meher K
Published: March 2023

Gut bacteria play a crucial role in host’s metabolism. Both antibiotic and non-antibiotic drugs affect the gut bacteria ecosystem, which negatively affects the host’s health. Also, gut bacteria metabolize drugs, making them ineffective to the target. The structure-activity relationship studies of drugs have the scope to make them more effective, efficient, and specific to the target. Previous machine learning studies use the available data to predict the activity of drugs and gut bacteria on each other, but these models lack interpretability. Herein, we study the drug-gut bacteria interaction using interpretable machine learning models. In this study, we identify the most important physicochemical features of the drug, which decide the drug-gut bacteria interactions with each other. One of the key findings of this work is that the higher-positive charged drug molecules can inhibit the growth of gut bacteria more. In contrast, the higher-negative charged drug molecules have higher possibility to get metabolized by gut bacteria.
Global effects of identity and aging on the human sperm methylome
Authors: de Sena Brandine Guilherme , Aston Kenneth I , Jenkins Timothy G , Smith Andrew D
Published: March 2023

As the average age of fatherhood increases worldwide, so too does the need for understanding effects of aging in male germline cells. Molecular change, including epigenomic alterations, may impact off-spring. Age-associated change to DNA cytosine methylation in the cytosine-guanine (CpG) context is a hallmark of aging tissues, including sperm. Prior studies have led to accurate models that predict a man’s age based on specific methylation features in the DNA of sperm, but the relationship between aging and global DNA methylation in sperm remains opaque. Further clarification requires a more complete survey of the methylome with assessment of variability within and between individuals.

We collected sperm methylome data in a longitudinal study of ten healthy fertile men. We used whole-genome bisulfite sequencing of samples collected 10 to 18 years apart from each donor. We found that, overall, variability between donors far exceeds age-associated variation. After controlling for donor identity, we see significant age-dependent genome-wide change to the methylome. Notably, trends of change with age depend on genomic location or annotation, with contrasting signatures that correlate with gene density and proximity to centromeres and promoter regions. These molecular signatures reflect a stable process that begins in early adulthood, progressing steadily through most of the lifespan, and warrants consideration in any future study of the aging sperm epigenome.
RExPRT: a machine learning tool to predict pathogenicity of tandem repeat loci
Authors: Fazal Sarah , Danzi Matt C. , Xu Isaac , Kobren Shilpa Nadimpalli , Sunyaev Shamil , Reuter Chloe , Marwaha Shruti , Wheeler Matthew , Dolzhenko Egor , Lucas Francesca , Wuchty Stefan , Tekin Mustafa , Züchner Stephan , Aguiar-Pulido Vanessa
Published: March 2023

Tandem repeats (TRs) are polymorphic sequences of DNA that are composed of repeating units of motifs, whose lengths can vary depending on the type of TR. Expansions of TRs are responsible for approximately 50 monogenic diseases, compared to over 4,300 disease causing genes disrupted by single nucleotide variants and small indels. It appears thus reasonable to expect the discovery of additional pathogenic repeat expansions, which has the potential of significantly narrowing the current diagnostic gap in many diseases. Recently, short and long-read whole genome sequencing with the use of advanced bioinformatics tools, have identified a growing number of TR expansions in the human population. The majority of these loci are expanded in <1% of genomes. Categorizing and prioritizing such TR loci is a growing challenge to human genomic studies. We present a first-in-class machine learning tool, RExPRT (Repeat EXpansion Pathogenicity pRediction Tool), which is designed to distinguish pathogenic from benign TR expansions. Leave-one-out cross validation results demonstrated that an ensemble approach comprised of support vector machines (SVM) and extreme gradient boosted decision tree (XGB) classify TRs with a precision of 92% and a recall of 90%. Further validation of RExPRT on unseen test data demonstrate a similar precision of 86%, and a recall of 60%. RExPRT’s high precision in particular, will be of significant value to large-scale discovery studies, which require the prioritization of promising candidate loci for time-consuming and costly functional follow-up studies. Application of RExPRT to ~800,000 TRs in the reference genome identified ~30,000 TRs that would be likely pathogenic upon expansion. Thus, RExPRT establishes a foundation for the application of machine learning approaches to categorize the pathogenicity of tandem repeat loci.
A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway
Authors:   The Proteostasis Consortium,   Overall coordination, Elsasser Suzanne , Elia Lisa P. , Morimoto Richard I. , Powers Evan T. ,   Harvard Medical School group, Elsasser Suzanne , Finley Daniel ,   University of California, San Francisco and Gladstone Institutes group I, Costa Beatrice , Budron Maher , Tokuno Zachary , Wang Shijie , Iyer Rajshri G. , Barth Bianca , Mockler Eric , Elia Lisa P. , Finkbeiner Steve ,   University of California, San Francisco group II, Gestwicki Jason E. ,   Northwestern University group, Richardson Reese A. K. , Stoeger Thomas , Morimoto Richard I. ,   The Scripps Research Institute group, Tan Ee Phie , Xiao Qiang , Cole Christian M. , Massey Lynée A. , Garza Dan , Powers Evan T. , Kelly Jeffery W. ,   Stanford University group, Rainbolt T. Kelly , Chou Ching-Chieh , Masto Vincent B. , Frydman Judith ,   New York University group, Nixon Ralph A.
Published: March 2023

The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, approximately 2,700 components that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental entity in biology that is essential for cellular health and has direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, which hinders its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. We provided in a previous manuscript a list of chaperones and folding enzymes as well as the components that make up the machineries for protein synthesis, protein trafficking into and out of organelles, and organelle-specific degradation pathways. Here, we provide a curated list of 838 unique high-confidence components of the autophagy-lysosome pathway, one of the two major protein degradation systems in human cells.
The ER membrane protein complex governs lysosomal turnover of a mitochondrial tail-anchored protein, BNIP3, to restrict mitophagy
Authors: Delgado Jose M , Shepard Logan Wallace , Lamson Sarah W , Liu Samantha L , Shoemaker Christopher J
Published: March 2023

Lysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, violate this assumption. Rather, BNIP3 and NIX are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all of its lysosome-mediated degradation, even upon mitophagy induction. To identify how BNIP3, a tail-anchored protein in the outer mitochondrial membrane, is delivered to lysosomes, we performed a genome-wide CRISPR screen for factors influencing BNIP3 flux. By this approach, we revealed both known modifiers of BNIP3 stability as well as a pronounced reliance on endolysosomal components, including the ER membrane protein complex (EMC). Importantly, the endolysosomal system regulates BNIP3 alongside, but independent of, the ubiquitin-proteosome system (UPS). Perturbation of either mechanism is sufficient to modulate BNIP3-associated mitophagy and affect underlying cellular physiology. In short, while BNIP3 can be cleared by parallel and partially compensatory quality control pathways, non-autophagic lysosomal degradation of BNIP3 is a strong post-translational modifier of BNIP3 function. More broadly, these data reveal an unanticipated connection between mitophagy and TA protein quality control, wherein the endolysosomal system provides a critical axis for regulating cellular metabolism. Moreover, these findings extend recent models for tail-anchored protein quality control and install endosomal trafficking and lysosomal degradation in the canon of pathways that ensure tight regulation of endogenous TA protein localization.
Time-dependent neural arbitration between cue associative and episodic fear memories
Authors: Cortese Aurelio , Ohata Ryu , Alemany Maria , Kitagawa Norimichi , Imamizu Hiroshi , Koizumi Ai
Published: March 2023

After traumatic events, simple cue-threat associative memories strengthen while episodic memories become fragmented. However, how the brain prioritizes cue associations over episodic coding of traumatic events remains unclear. Here, we developed a new episodic threat conditioning paradigm in which participants concurrently form two memory representations: cue associations and episodic cue sequence. We discovered that these two distinct memories compete for physiological fear expression, reorganizing overnight from an overgeneralized cue-based to a precise sequence-based expression. With multivariate fMRI, we track inter-area communication of the memory representations and demonstrate that a shift from hippocampal-dominant to prefrontal-dominant control of the fear regulatory circuit governs this memory maturation. Critically, this overnight reorganization is altered in individuals with heightened trait anxiety. Together, these findings suggest the brain prioritizes generalizable associative memories under recent traumatic stress, but resorts to selective episodic memories 24 hrs later. Time-dependent memory competition provides a unifying account for memory dysfunctions in posttraumatic stress disorders.
Duckweed evolution: from land back to water
Authors: Fang Yang , Tian Xueping , Jin Yanling , Du Anping , Ding Yanqiang , Liao Zhihua , He Kaize , Zhao Yonggui , Guo Ling , Xiao Yao , Xu Yaliang , Chen Shuang , Che Yuqing , Tan Li , Wang Songhu , Li Jiatang , Yi Zhuolin , Chen Lanchai , Zhao Leyi , Zhang Fangyuan , Li Guoyou , Li Jinmeng , Xiong Qinli , Zhang Yongmei , Zhang Qing , Cao Xuan Hieu , Zhao Hai
Published: March 2023

Terrestialization is supposedly an important evolutionary process plant experience. However, directions of land back to water acquired little attention. Here we integrate multiproxy evidence to elucidate the evolution of duckweed. Three genera of duckweed show chronologically gradient degeneration in roots structure and stomatal function and decrease in lignocellulose content, accompanied by gradual contraction in relevant gene numbers and/or decline in transcription. The gene numbers in the main phytohormonal pathway are also gradually decreased. The co-action of auxin and rhizoid development gene causes a gradual decrease in adventitious roots. The significant expansion of the flavonoid pathway is also related to the adaptation of duckweed to floating growth. This study reconstructs the evolution history of duckweeds from land back to water, reverse to that of early land plants.

With terrestrialization being the popularly acknowledged plant evolutionary process, little is known about the evolution of higher plant from land back to water. Here we integrate multiproxy evidence to elucidate the gradual reverse evolution of duckweed. Three genera of duckweed show chronologically gradient degeneration in the structure of roots, the function of stomata, and decrease in lignocellulose content, accompanied by gradient contraction in relevant gene numbers and/or decline in transcript expression. The gene numbers in the main phytohormonal pathway are also gradually decreased. The co-action of auxin and rhizoid development gene causes a gradual decrease in adventitious roots. The significant expansion of the flavonoid pathway is also highly related to the adaptation of duckweed to floating growth. Our study combined with the fossil evidence reconstruct the evolution history of duckweeds from land back to water, reverse to that of early land plants. This study reconstructed the process of how a land plant returns to water, a reverse evolutionary approach which is different from what we studied in textbook about plant terrestrialization. This finding could be helpful for us to deeply and widely understand the adaptation of plant to the environment, and to expand and deepen the knowledge of evolution theory.
Is adaptive foraging adaptive? A resource-consumer eco-evolutionary model
Authors: Ledru Leo , Garnier Jimmy , Guillot Océane , Faou Erwan , Noûs Camille , Ibanez Sébastien
Published: March 2023

Phenotypic plasticity has important ecological and evolutionary consequences. In particular, behavioural phenotypic plasticity such as adaptive foraging (AF) by consumers, may enhance community stability. Yet little is known about the ecological conditions that favor the evolution of AF, and how the evolutionary dynamics of AF may modulate its effects on community stability. In order to address these questions, we constructed an eco-evolutionary model in which resource and consumer niche traits underwent evolutionary diversification. Consumers could either forage randomly, only as a function of resources abundance, or adaptatively, as a function of resource abundance, suitability and consumption by competitors. AF evolved when the niche breadth of consumers with respect to resource use was large enough and when the ecological conditions allowed substantial functional diversification. In turn, AF promoted further diversification of the niche traits in both guilds. This suggests that phenotypic plasticity can influence the evolutionary dynamics at the community-level. Faced with a sudden environmental change, AF promoted community stability directly and also indirectly through its effects on functional diversity. However, other disturbances such as persistent environmental change and increases in mortality, caused the evolutionary regression of the AF behaviour, due to its costs. The causal relationships between AF, community stability and diversity are therefore intricate, and their outcome depends on the nature of the environmental disturbance, in contrast to simpler models claiming a direct positive relationship between AF and stability.
Modeling the role of immune cell conversion in the tumor-immune microenviroment
Authors: Moffett Alexander S. , Deng Youyuan , Levine Herbert
Published: March 2023

Tumors develop in a complex physical, biochemical, and cellular milieu, referred to as the tumor microenvironment. Of special interest is the set of immune cells that reciprocally interact with the tumor, the tumor-immune microenvironment (TIME). The diversity of cell types and cell-cell interactions in the TIME has led researchers to apply concepts from ecology to describe the dynamics. However, while tumor cells are known to induce immune cells to switch from anti-tumor to pro-tumor phenotypes, this type of ecological interaction has been largely overlooked. To address this gap in cancer modeling, we develop a minimal, ecological model of the TIME with immune cell conversion, to highlight this important interaction and explore its consequences. A key finding is that immune conversion increases the range of parameters supporting a co-existence phase in which the immune system and the tumor reach a stalemate. Our results suggest that further investigation of the consequences of immune cell conversion, using detailed, data-driven models, will be critical for greater understanding of TIME dynamics.
Estimation of Interaction and Growth Parameters to Develop a Computational Model for Gut Bacteria
Authors: Joshi Himanshu , Prakash Meher K.
Published: March 2023

The relevance of gut bacterial balance to human health can not be overemphasized. The gut bacterial balance delicately relies on several factors inherent to the person as well as to the environment. As the volume of evidences for the gut bacterial influence on health and the clinical data on the variance of the bacterial population across cohorts continue to grow exponentially, it is important to develop a theoretical model for gut bacteria. In this work, we suggest a new computational method for estimating the interaction parameters from the cross-sectional data of bacterial abundances in a cohort, without requiring a longitudinal followup. We introduce a nutrient type based bacterial growth model and use the Monte Carlo approach to estimate the matrix of interaction parameters for the 14 major bacterial species. These parameters were used in a comprehensive first-level computational model we developed for the large intestine to understand the patterns of re-establishing balance with different nutrient types.
Lepidopteran Synteny Units (LSUs) reveal deep conservation of macrosynteny in butterflies and moths
Authors: Traut Walther , Sahara Ken , ffrench-Constant Richard H.
Published: March 2023

Advances in DNA sequencing technologies have, for the first time, provided us with enough whole chromosome-level genomes to understand in detail how chromosome number and composition change over time. Here, we use the genomes of butterflies and moths to look at the levels and age of macrosynteny in the Lepidoptera and Trichoptera. We used comparative BUSCO analsysis to define reproducible units of macrosynteny which we term ‘Lepidopteran Synteny Units’ or LSUs. The 31 chromosomes of the model butterflyMelitaea cinxiaserved as a reference point. The results show that chromosome-wide macrosynteny extends from the most basal branches of the Lepidopteran phylogeny to the most distal. This synteny also extends to the order Trichoptera, a sister group of the Lepidoptera. Thus, chromosome-wide macrosynteny has been conserved for a period of >200 My in this group of insects. We found no major interchromosomal translocations, reciprocal or non-reciprocal, in the genomes studied. Intrachromosomal rearrangements, in contrast, were abundant. Beyond its use in defining LSUs, this type of homology-based analysis will be useful in determining the relationships between chromosomal elements in different animals and plants. Further, by more precisely defining the breakpoints of chromosomal rearrangements we can begin to look at their potential roles in chromosomal evolution.

Statement

The authors declare no conflicting interests

Contributions

Conceptualisation: W.T., R.H.f.; data analysis: W.T.; writing & editing: W.T., K.S., R.H.f All authors read and approved the final manuscript.
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Long-Term Risk of Immune-Related diseases
Authors: Israel Ariel , Schäffer Alejandro A , Berkovitch Matitiahu , Ozeri David J. , Merzon Eugene , Green Ilan , Golan-Cohen Avivit , Ruppin Eytan , Vinker Shlomo , Magen Eli
Published: March 2023

BACKGROUND

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzymatic disorder, particularly prevalent in Africa, Asia and the Middle East. In the US, about 14% of black men are affected. Individuals with G6PD deficiency are often asymptomatic but may develop hemolysis following an infection or upon consumption of specific medications. Despite some evidence that G6PD deficiency affects the immune system, the long- term health risks associated with G6PD deficiency had not been studied in a large population.

METHODS

In this retrospective cohort study, health records from G6PD deficient individuals were compared to matched controls in a national healthcare provider in Israel (Leumit Health Services). Rates of infectious diseases, allergic conditions and autoimmune disorders were compared between groups.

RESULTS

The cohort included 7,473 G6PD deficient subjects (68.7% men) matched with 29,892 control subjects (4:1 ratio) of the same age, gender, socioeconomic status and ethnic group, followed during 14.3±6.2 years.

Significantly increased rates for autoimmune disorders, infectious diseases and allergic conditions were observed throughout this period. Notable increases were observed for rheumatoid arthritis (OR 2.41, p<0.001), systemic lupus erythematosus (OR 4.56, p<0.001), scleroderma (OR 6.87, p<0.001), pernicious anemia (OR=18.70, P<0.001), fibromyalgia (OR 1.98, p<0.001), Graves’ disease (OR 1.46, P=0.001), and Hashimoto’s thyroiditis (OR 1.26, P=0.001). These findings were corroborated with elevated rates of positive autoimmune serology and higher rates of treatment with medications commonly used to treat autoimmune conditions in the G6PD deficient group.

CONCLUSION

G6PD deficient individuals suffer from higher rates of autoimmune disorders, infectious diseases, and allergic conditions.