bluuebunny/crossref_metadata_2025 huggingface dataset:
NAD+activates renal metabolism and protects from chronic kidney disease in a model of Alport syndrome
Authors: Jones Bryce A. , Gisch Debora L. , Myakala Komuraiah , Sadiq Amber , Cheng Ying-Hua , Taranenko Elizaveta , Panov Julia , Korolowicz Kyle , Melo Ferreira Ricardo , Yang Xiaoping , Santo Briana A. , Allen Katherine C. , Yoshida Teruhiko , Wang Xiaoxin X. , Rosenberg Avi Z. , Jain Sanjay , Eadon Michael T. , Levi Moshe
Published: March 2024

Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+levels are decreased in CKD, and NAD+supplementation is protective. However, both the mechanism of how NAD+supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+precursor, stimulates renal peroxisome proliferator-activated receptor alpha signaling and restores FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing shows that renal metabolic pathways are impaired in Alport mice and activated by NR in both sexes. These transcriptional changes are confirmed by orthogonal imaging techniques and biochemical assays. Single nuclei RNA-sequencing and spatial transcriptomics, both the first of their kind from Alport mice, show that NAD+supplementation restores FAO in proximal tubule cells. Finally, we also report, for the first time, sex differences at the transcriptional level in this Alport model. In summary, we identify a nephroprotective mechanism of NAD+supplementation in CKD, and we demonstrate that the proximal tubule cells substantially contribute to this benefit.
Exploring Genomic Large Language Models: Bridging the Gap between Natural Language and Gene Sequences
Authors: Liu Huaqing , Zhou Shuxian , Chen Peiyi , Liu Jiahui , Huo Ku-Geng , Han Lanqing
Published: March 2024

Motivation

With the rapid development of genomic sequencing technologies and accumulation of sequencing data, there is an increasing demand for analysis tools that are more user-friendly for non-programmer users. In support of this initiative, we developed an all-in-one tool called GenomicLLM that can understand simple grammar in the question input and perform different types of analyses and tasks accordingly.

Reaults

We trained the GenomicLLM model using three large open-access datasets, namely GenomicLLM_GRCh38, Genome Understanding Evaluation and GenomicBenchmarks, and developed a hybrid tokenization approach to allow better comprehension from mixed corpora that include sequence and non-sequence inputs. GenomicLLM can carry out a wider range of tasks. In the classification tasks that are also available in the state-of-the-art DNABERT-2 and HyenaDNA, GenomicLLM has comparable performance. Moreover, GenomicLLM can also carry out other regression and generation tasks that are not accomplishable by these tools. In summary, we demonstrated here a successful large language model with a mixture of gene sequences and natural language corpus that enables a wider range of applications.

Availability and implementation

Codes and data can be accessed athttps://github.com/Huatsing-Lau/GenomicLLMandhttps://zenodo.org/records/10695802
Separation of telomere protection from length regulation by two different point mutations at amino acid 492 of RTEL1
Authors: Smoom Riham , May Catherine Lee , Lichtental Dan , Skordalakes Emmanuel , Kaestner Klaus H. , Tzfati Yehuda
Published: March 2024

RTEL1 is an essential DNA helicase that plays multiple roles in genome stability and telomere length regulation. A variant of RTEL1 with a lysine at position 492 is associated with short telomeres inMus spretus, while a conserved methionine at this position is found inM. musculus, which has ultra-long telomeres. In humans, a missense mutation at this position (Rtel1M492I) causes a fatal telomere biology disease termed Hoyeraal-Hreidarsson syndrome (HHS). Introducing theRtel1M492Kmutation intoM. musculusshortened the telomeres of the resulting strain, termed ‘Telomouse’, to the length of human telomeres. Here, we report on a mouse strain carrying theRtel1M492Imutation, termed ‘HHS mouse’. The HHS mouse telomeres are not as short as those of Telomice but nevertheless they display higher levels of telomeric DNA damage, fragility and recombination, associated with anaphase bridges and micronuclei. These observations indicate that the two mutations separate critical functions of RTEL1: M492K mainly reduces the telomere length setpoint, while M492I predominantly disrupts telomere protection. The two mouse models enable dissecting the mechanistic roles of RTEL1 and the different contributions of short telomeres and DNA damage to telomere biology diseases, genomic instability, cancer, and aging.
Device Design and Diagnostic Imaging of Radiopaque 3D Printed Tissue Engineering Scaffolds
Authors: Delemeester Mitchell , Pawelec Kendell M. , Hix Jeremy M.L. , Siegenthaler James R. , Lissy Micah , Douek Philippe , Houmeau Angèle , Si-Mohamed Salim , Shapiro Erik M.
Published: March 2024

3D printed biomaterial implants are revolutionizing personalized medicine for tissue repair, especially in orthopedics. In this study, a radiopaque Bi2O3doped polycaprolactone (PCL) composite is developed and implemented to enable the use of diagnostic X-ray technologies, especially photon counting X-ray computed tomography (PCCT), for comprehensive in vivo device monitoring. PCL filament with homogeneous Bi2O3nanoparticle (NP) dispersion (0.8 to 11.7 wt%) are first fabricated. Tissue engineered scaffolds (TES) are then 3D printed with the composite filament, optimizing printing parameters for small feature size and severely overhung geometries. These composite TES are characterized via micro-computed tomography (µCT), tensile testing, and a cytocompatibility study, with Bi2O3mass fractions as low as 2 wt% providing excellent radiographic distinguishability, improved tensile properties, and equivalent cytocompatibility of neat PCL. The excellent radiographic distinguishability is validated in situ by imaging 4 and 7 wt% TES in a mouse model with µCT, showing excellent agreement with in vitro measurements. Subsequently, CT image-derived swine menisci are 3D printed with composite filament and re-implanted in their corresponding swine legsex vivo. Re-imaging the swine legs via clinical CT allows facile identification of device location and alignment. Finally, the emergent technology of PCCT unambiguously distinguishes implanted menisci in situ.
Azadirachta indica:derived, red-emitting, carbon nanoparticles for cellular bioimaging and potential therapeutics
Authors: Gandhi Stuti , Jain Sweny , Bhatia Dhiraj , Yadav Pankaj
Published: March 2024

Red-emitting carbon nanoparticles (CNPs) were synthesized by the refluxed green synthesis method using ethanolic extract of neem leaves (Azadirachta indica). These nanoparticles were called as nQDs (neem quantum dots). The nQDs exhibited excellent photoluminescence properties with a maximum emission at 672nm, and the average size of nQDs was around 47nm. In thein-vitrostudy, Retinal Pigment epithelial (RPE1) cells and SUM159A cells showed enhanced cellular uptake. In RPE1 cells, the cellular uptake was higher than in SUM159A cells. In the biocompatibility assay, SUM159A cell viability declined with the increasing nQDs concentration. The results show that red-emissive CNPs can be synthesized fromAzadirachta indica(neem) leaves using a simple method with a possible application in bioimaging and therapeutics.

Abstract Figure
Oolonghomobisflavans fromCamellia sinensisdisaggregate tau fibrils across Alzheimer’s disease models
Authors: Duangjan Chatrawee , Chang Xinmin , Seidler Paul M. , Curran Sean P.
Published: March 2024

Alzheimer’s disease (AD) is a common debilitating neurodegenerative disease with limited treatment options. Amyloid-β (Aβ) and tau fibrils are well-established hallmarks of AD, which can induce oxidative stress, neuronal cell death, and are linked to disease pathology. Here, we describe the effects of Oolonghomobisflavan A (OFA) and Oolonghomobisflavan B (OFB) on tau fibril disaggregation and prionogenic seeding. Transcriptomic analysis of OF-treated animals reveals the induction of a proteostasis-enhancing and health-promoting signature. OFA treatment reduced the burden of Tau protein aggregation in aC. elegansmodel expressing pathogenic human tau (“hTau-expressing”) and promoted Tau disaggregation and inhibited seeding in assays usingex vivobrain-derived paired helical filament tau protein fibrils from Alzheimer’s disease brain donors. Correspondingly, treatment with OF improved multiple fitness and aging-related health parameters in the hTau-expressingC. elegansmodel, including reproductive output, muscle function, and importantly, reversed the shortened lifespan stemming from pathogenic Tau expression. Collectively, this study provides new evidence supporting the neuroprotective effects of OFs and reveal a new therapeutic strategy for targeting AD and other neurodegenerative diseases characterized by tauopathy.
A temporal sequence of heterochronic gene activities promotes stage-specific developmental events inC. elegans
Authors: Ivanova Maria , Moss Eric G.
Published: March 2024

The heterochronic genes of the nematodeCaenorhabditis eleganscontrol the succession of postembryonic developmental events. The four core heterochronic geneslin-14, lin-28, hbl-1,andlin-41act in a sequence to specify cell fates specific to each of the four larval stages. It was previously shown thatlin-14has two activities separated in time that promote L1 and L2 developmental events, respectively. Using the auxin-inducible degron system, we find thatlin-28andhbl-1each have two activities that control L2 and L3 events which are also separated in time. Relative to events they control, bothlin-28andhbl-1appear to act just prior to or concurrently with events of the L2. Relative to each other,lin-28andhbl-1appear to act simultaneously. By contrast, thelin-14activity controlling L2 events precedes those oflin-28andhbl-1controlling the same events, suggestinglin-14’s regulation oflin-28is responsible for the delay. Likewise, the activities oflin-28andhbl-1controlling L3 fates act well in advance of those fates, suggesting a similar regulatory gap.lin-41acts early in the L3 to affect fates of the L4, although it was not possible to determine whether it too has two temporally separated activities. We also uncovered a feedback phenomenon that prevents the reactivation of heterochronic gene activity late in development after it has been down-regulated. This study places the heterochronic gene activities into a timeline of postembryonic development relative to one another and to the developmental events whose timing they control.
Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension
Authors: Harvey Lloyd D , Alotaibi Mona , Kim Hee-Jung Janice , Tai Yi-Yin , Tang Ying , Sun Wei , El Khoury Wadih , Woodcock Chen-Shan C , Aaraj Yassmin Al , St. Croix Claudette M , Stolz Donna B , Lee Jiyoung , Cheng Mary Hongying , Schwantes-An Tae-Hwi , Desai Ankit A , Pauciulo Michael W , Nichols William C , Webb Amy , Lafyatis Robert , Nouraie Mehdi , Wu Haodi , McDonald Jeffrey G , Chauvet Caroline , Cheng Susan , Bahar Ivet , Bertero Thomas , Benza Raymond L , Jain Mohit , Chan Stephen Y
Published: March 2024

Vascular inflammation critically regulates endothelial cell (EC) pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulation of lysosomal activity and cholesterol metabolism have known inflammatory roles in disease, but their relevance to PAH is unclear. In human pulmonary arterial ECs and in PAH, we found that inflammatory cytokine induction of the nuclear receptor coactivator 7 (NCOA7) both preserved lysosomal acidification and served as a homeostatic brake to constrain EC immunoactivation. Conversely, NCOA7 deficiency promoted lysosomal dysfunction and proinflammatory oxysterol/bile acid generation that, in turn, contributed to EC pathophenotypes. In vivo, mice deficient for Ncoa7 or exposed to the inflammatory bile acid 7α-hydroxy-3-oxo-4-cholestenoic acid (7HOCA) displayed worsened PAH. Emphasizing this mechanism in human PAH, an unbiased, metabolome-wide association study (N=2,756) identified a plasma signature of the same NCOA7-dependent oxysterols/bile acids associated with PAH mortality (P<1.1x10-6). Supporting a genetic predisposition to NCOA7 deficiency, in genome-edited, stem cell-derived ECs, the common variant intronic SNP rs11154337 in NCOA7 regulated NCOA7 expression, lysosomal activity, oxysterol/bile acid production, and EC immunoactivation. Correspondingly, SNP rs11154337 was associated with PAH severity via six-minute walk distance and mortality in discovery (N=93, P=0.0250; HR=0.44, 95% CI [0.21-0.90]) and validation (N=630, P=2x10-4; HR=0.49, 95% CI [0.34-0.71]) cohorts. Finally, utilizing computational modeling of small molecule binding to NCOA7, we predicted and synthesized a novel activator of NCOA7 that prevented EC immunoactivation and reversed indices of rodent PAH. In summary, we have established a genetic and metabolic paradigm and a novel therapeutic agent that links lysosomal biology as well as oxysterol and bile acid processes to EC inflammation and PAH pathobiology. This paradigm carries broad implications for diagnostic and therapeutic development in PAH and in other conditions dependent upon acquired and innate immune regulation of vascular disease.
PfCAP-H is essential for assembly of condensin I complex and karyokinesis during asexual proliferation ofPlasmodium falciparum
Authors: Gurung Pratima , McGee James P. , Dvorin Jeffrey D.
Published: March 2024

Condensin I is a pentameric complex that regulates the mitotic chromosome assembly in eukaryotes. The kleisin subunit CAP-H of the condensin I complex acts as a linchpin to maintain the structural integrity and loading of this complex on mitotic chromosomes. This complex is present in all eukaryotes and has recently been identified inPlasmodium spp. However, how this complex is assembled and whether the kleisin subunit is critical for this complex in these parasites is yet to be explored. To examine the role of PfCAP-H during cell division within erythrocytes, we generated an inducible PfCAP-H knockout parasite. We find that PfCAP-H is dynamically expressed during mitosis with the peak expression at the metaphase plate. PfCAP-H interacts with PfCAP-G and is a non-SMC member of the condensin I complex. Notably, the absence of PfCAP-H does not alter the expression of PfCAP-G but affects its localization at the mitotic chromosomes. While mitotic spindle assembly is intact in PfCAP-H deficient parasites, duplicated centrosomes remain clustered over the mass of unsegmented nuclei with failed karyokinesis. This failure leads to the formation of an abnormal nuclear mass, while cytokinesis occurs normally. Altogether, our data suggest that PfCAP-H plays a crucial role in maintaining the structural integrity of the condensin I complex on the mitotic chromosomes and is essential for the asexual development of malarial parasites.

Importance

Mitosis is a fundamental process forPlasmodiumparasites, which plays a vital role in their survival within two distinct hosts - human andAnophelesmosquitoes. Despite its great significance, our comprehension of mitosis and its regulation remains limited. In eukaryotes, mitosis is regulated by one of the pivotal complexes known as condensin complexes. The condensin complexes are responsible for chromosome condensation, ensuring the faithful distribution of genetic material to daughter cells. While condensin complexes have recently been identified inPlasmodium spp, our understanding of how this complex is assembled and their precise functions during the blood stage development ofPlasmodium falciparumremains largely unexplored. In this study, we investigate the role of a central protein, PfCAP-H, during the blood stage development ofP. falciparum. Our findings reveal that PfCAP-H is essential and plays a pivotal role in upholding the structure of condensin I and facilitating karyokinesis.
Prenatal Exposure to Environmentally Relevant Low Dosage Dibutyl Phthalate Reduces Placental Efficiency in CD-1 Mice
Authors: Pontifex Tasha , Yang Xinran , Tracy Ayna , Burns Kimberlie , Craig Zelieann , Zhou Chi
Published: March 2024

Introduction

Dibutyl phthalate (DBP), a phthalate congener, is widely utilized in consumer products and medication coatings. Women of reproductive age have a significant burden of DBP exposure through consumer products, occupational exposure, and medication. Prenatal DBP exposure is associated with adverse pregnancy/fetal outcomes and cardiovascular diseases in the offspring. However, the role of fetal sex and the general mechanisms underlying DBP exposure-associated adverse pregnancy outcomes are unclear. Wehypothesizethat prenatal DBP exposure at an environmentally relevant low dosage adversely affects fetal-placental development and function during pregnancy in a fetal sex-specific manner.

Methods

Adult female CD-1 mice (8-10wks) were orally treated with vehicle (control) or with environmentally relevant low DBP dosages at 0.1 μg/kg/day (refer as DBP0.1) daily from 30 days before pregnancy through gestational day (GD) 18.5. Dam body mass composition was measured non-invasively using the echo-magnetic resonance imaging system. Lipid disposition in fetal labyrinth and maternal decidual area of placentas was examined using Oil Red O staining.

Results

DBP0.1 exposure did not significantly affect the body weight and adiposity of non-pregnant adult female mice nor the maternal weight gain pattern and adiposity during pregnancy in adult female mice. DBP0.1 exposure does not affect fetal weight but significantly increased the placental weight at GD18.5 (indicative of decreased placental efficiency) in a fetal sex-specific manner. We further observed that DBP0.1 significantly decreased lipid disposition in fetal labyrinth of female, but not male placentas, while it did not affect lipid disposition in maternal decidual.

Conclusions

Prenatal exposure to environmentally relevant low-dosage DBP adversely impacts the fetal-placental efficiency and lipid disposition in a fetal sex-specific manner.
Rare and Common Variants Associated with Alcohol Consumption Identify a Conserved Molecular Network
Authors: Leger Brittany S. , Meredith John J. , Ideker Trey , Sanchez-Roige Sandra , Palmer Abraham A.
Published: March 2024

Genome-wide association studies (GWAS) have identified hundreds of common variants associated with alcohol consumption. In contrast, rare variants have only begun to be studied for their role in alcohol consumption. No studies have examined whether common and rare variants implicate the same genes and molecular networks. To address this knowledge gap, we used publicly available alcohol consumption GWAS summary statistics (GSCAN, N=666,978) and whole exome sequencing data (Genebass, N=393,099) to identify a set of common and rare variants for alcohol consumption. Gene-based analysis of each dataset have implicated 294 (common variants) and 35 (rare variants) genes, including ethanol metabolizing genesADH1BandADH1C, which were identified by both analyses, andANKRD12, GIGYF1, KIF21B, andSTK31, which were identified only by rare variant analysis, but have been associated with related psychiatric traits. We then used a network colocalization procedure to propagate the common and rare gene sets onto a shared molecular network, revealing significant overlap. The shared network identified gene families that function in alcohol metabolism, includingADH, ALDH, CYP, andUGT. 74 of the genes in the network were previously implicated in comorbid psychiatric or substance use disorders, but had not previously been identified for alcohol-related behaviors, includingEXOC2, EPM2A, CACNB3, andCACNG4. Differential gene expression analysis showed enrichment in the liver and several brain regions supporting the role of network genes in alcohol consumption. Thus, genes implicated by common and rare variants identify shared functions relevant to alcohol consumption, which also underlie psychiatric traits and substance use disorders that are comorbid with alcohol use.
Resistance Gene Association and Inference Network (ReGAIN): A Bioinformatics Pipeline for Assessing Probabilistic Co-Occurrence Between Resistance Genes in Bacterial Pathogens
Authors: Bring Horvath Elijah R. , Stein Mathew G. , Mulvey Matthew A. , Hernandez Edgar J. , Winter Jaclyn M.
Published: March 2024

The rampant rise of multidrug resistant (MDR) bacterial pathogens poses a severe health threat, necessitating innovative tools to unravel the complex genetic underpinnings of antimicrobial resistance. Despite significant strides in developing genomic tools for detecting resistance genes, a gap remains in analyzing organism-specific patterns of resistance gene co-occurrence. Addressing this deficiency, we developed the Resistance Gene Association and Inference Network (ReGAIN), a novel web-based and command line genomic platform that uses Bayesian network structure learning to identify and map resistance gene networks in bacterial pathogens. ReGAIN not only detects resistance genes using well- established methods, but also elucidates their complex interplay, critical for understanding MDR phenotypes. Focusing on ESKAPE pathogens, ReGAIN yielded a queryable database for investigating resistance gene co-occurrence, enriching resistome analyses, and providing new insights into the dynamics of antimicrobial resistance. Furthermore, the versatility of ReGAIN extends beyond antibiotic resistance genes to include assessment of co-occurrence patterns among heavy metal resistance and virulence determinants, providing a comprehensive overview of key gene relationships impacting both disease progression and treatment outcomes.

Graphical Abstract
Glomerular Elasticity and Gene Expression Patterns Define Two Phases of Alport Nephropathy
Authors: Yoon Joonho , Liu Zhenan , Alaba Mathew , Bruggeman Leslie A. , Janmey Paul A. , Arana Carlos A. , Ayenuyo Oluwatoyosi , Medeiros Isabela , Eddy Sean , Kretzler Matthias , Henderson Joel M. , Nair Viji , Naik Abhijit S. , Chang Audrey N. , Miller R. Tyler
Published: March 2024

Objectives

To understand the early stages if Alport nephropathy, we characterize the structural, functional, and biophysical properties of glomerular capillaries and podocytes inCol4α3-/-mice, analyze kidney cortex transcriptional profiles at three time points, and investigate the effects of the ER stress mitigation by TUDCA on these parameters. We use human FSGS associated genes to identify molecular pathways rescued by TUDCA.

Findings

We define a disease progression timeline inCol4α3-/-mice. Podocyte injury is evident by 3 months, with glomeruli reaching maximum deformability at 4 months, associated with 40% podocytes loss, followed by progressive capillary stiffening, increasing proteinuria, reduced renal function, inflammatory infiltrates, and fibrosis from months 4 to 7. RNA sequencing at 2, 4, and 7 months reveals increased cytokine and chemokine signaling, matrix and cell injury, and activation of the TNF pathway genes by 7 months, similar to NEPTUNE FSGS cohorts. These features are suppressed by TUDCA.

Conclusions

We define two phases ofCol4α3-/-nephropathy. The first is characterized by podocytopathy, increased glomerular capillary deformability and accelerated podocyte loss, and the second by increased capillary wall stiffening and renal inflammatory and profibrotic pathway activation. Disease suppression by TUDCA treatment identifies potential therapeutic targets for treating Alport and related nephropathies.
A Qualitative Descriptive Study Exploring Caregivers' Information Needs and Experience Caring for a Child with Chronic Heart Failure
Authors: Cunningham Chentel , Conway Jennifer , Zahoui Ziad , Haykowsky Mark J , Scott Shannon D.
Published: March 2024

Background: Chronic phenotypes of pediatric heart failure pose life-long burdensome symptoms for the healthcare system and families. Treatment involves complex medical therapies with few surgical options until more advanced, refractory stages. Caregivers must become proficient in providing care to these vulnerable children in the home environment, which imposes a high amount of stress. Despite caregiver demands, little is known about caregiver information needs and experiences caring for a child with chronic heart failure. Therefore, a qualitative approach employing semi-structured interviews aimed to fill this knowledge gap. Methods: A qualitative descriptive methodology guided our study. Participants were recruited from a tertiary cardiac centre in Edmonton, Alberta, Canada. Data collection and analysis occurred concurrently. Semi-structured interviews were conducted until data redundancy was achieved. Inductive content analysis was used to uncover categories. Results: Eleven interviews identified five main categories. Three categories related to information needs: 1) sources of information, 2) profound stress steepens the learning curve, and 3) acknowledging that learning heart failure takes time. Two categories related to experience: 4) the emotional rollercoaster, feelings of emotional distress, and 5) the hard reality of caring for a child with heart failure: always on the clock. Conclusions: To our knowledge, this is the first North American situated qualitative study to provide key insights about caregivers? information needs and experiences caring for a child with chronic heart failure. This knowledge provides insight to enhance and optimize clinical care and outcomes in this population and will inform the design of an arts-based information tool targeting caregivers.
Digesting the data: Proper validation in ancient metagenomic studies is essential
Authors: Pach Aleksandra Laura , Lanigan Liam T , Niemann Jonas , Pedersen Mikkel Winther , Schroeder Hannes
Published: March 2024

In a recent publication in this journal, Reynoso-García et al. [1] used shotgun sequencing to analyze human coprolites (paleofeces) from two pre-Columbian contexts in Puerto Rico to reconstruct the diet of the island’s Indigenous population before the arrival of Europeans. Based on the results, the team claim to have identified various edible New World plant species, including maize (Zea mays), sweet potato (Ipomoea batatas), chili pepper (Capsicum annuum), peanut (Arachis spp.), papaya (Carica papaya), and tomato (Solanum lycopersicum), as well as other cultivars such as cotton (Gossypium barbadense) and tobacco (Nicotiana sylvestris) [1]. Reynoso-García et al. [1] also claim to have identified edible fungi, includingUstilago spp., which according to the authors, further supports their findings and points to the consumption ofhuitlacocheor corn smut, a known delicacy in Mexico today that is believed to have originated in Aztec times [2].

Shotgun DNA sequencing of archaeological samples, such as dental calculus or coprolites, provides a powerful tool to reconstruct ancient microbial communities and to study the evolution of the human microbiome [e.g. 3,4–6]. In some instances, shotgun sequencing results can also provide insights into the diet and subsistence strategies of past communities [e.g. 7,8]. However, identifying DNA from dietary sources in complex shotgun metagenomic datasets is far from straightforward. As has been discussed previously [9,10], and as we demonstrate below, one of the main challenges is the risk of false positives. Any potential dietary signals should, therefore, be carefully assessed. Unfortunately, we feel that Reynoso-García et al.’s study [1] falls short in that regard and we conclude that while it is entirely possible (and even likely, based on other evidence [e.g. 11,12]) that the Indigenous inhabitants of Puerto Rico subsisted on a diet that included some, or even all of the edible plant taxa the team identified, the DNA results they present do not, in and of themselves, support that claim.
Nosemosis negatively affects honeybee survival: experimental and meta-analytic evidence
Authors: Ostap-Chec M. , Cait J. , Scott R. W. , Arct A. , Moroń D. , Rapacz M. , Miler K.
Published: March 2024

Nosemosis, caused by microsporidian parasites of the genusNosema, is considered a significant health concern for insect pollinators, including the economically important honeybee (Apis mellifera). Despite its acknowledged importance, the impact of this disease on honeybee survivorship remains unclear. Here, a standard laboratory cage trial was used to compare mortality rates between healthy andNosema-infected honeybees. Additionally, a systematic review and meta-analysis of existing literature were conducted to explore how nosemosis contributes to increased mortality in honeybees tested under standard conditions. The review and meta-analysis included 50 studies that reported relevant experiments involving healthy andNosema-infected individuals. Studies lacking survivorship curves or information on potential moderators, such as spore inoculation dose, age of inoculated bees, or factors that may impact energy expenditure, were excluded. Both the experimental results and meta-analysis revealed a consistent, robust effect of infection, indicating a threefold increase in mortality among the infected group of honeybee workers (hazard ratio for infected individuals = 3.16 [1.97, 5.07] and 2.99 [2.36, 3.79] in the experiment and meta-analysis, respectively). However, the meta-analysis also indicated high heterogeneity in the effect magnitude, which was not explained by our moderators. Furthermore, there was a serious risk of bias within studies and potential publication bias across studies. The findings underscore knowledge gaps in the literature. It is stressed that laboratory cage trials should be viewed as an initial step in evaluating the impact ofNosemaon mortality and that complementary field and apiary studies are essential for identifying effective treatments to preserve honeybee populations.
Inferring fungal growth rates from optical density data
Authors: Hameed Tara , Motsi Natasha , Bignell Elaine , Tanaka Reiko J.
Published: March 2024

Quantifying fungal growth underpins our ability to effectively treat severe fungal infections. Current methods quantify fungal growth rates from time-course morphology-specific data, such as hyphal length data. However, automated large-scale collection of such data lies beyond the scope of most clinical microbiology laboratories. In this paper, we propose a mathematical model of fungal growth to estimate morphology-specific growth rates from easy-to-collect, but indirect, optical density (OD600) data ofAspergillus fumigatusgrowth (filamentous fungus). Our method accounts for OD600being an indirect measure by explicitly including the relationship between the indirect OD600measurements and the calibrating true fungal growth in the model. Therefore, the method does not requirede novogeneration of calibration data. Our model outperformed reference models at fitting to and predicting OD600growth curves and overcame observed discrepancies between morphology-specific rates inferred from OD600versus directly measured data in reference models that did not include calibration.

Author summary

Quantifying fungal growth is essential for antifungal drug discovery and monitoring antifungal resistance. As fungal growth is complex, with fungal morphology (shape) dynamically changing over time, previous studies have quantified fungal growth by estimating growth rates during specific fungal morphologies (morphology-specific growth rates) or by mathematically modelling fungal growth. However, collecting time-series data that captures the morphological information required for mathematical model fitting or estimating morphology-specific growth rates is prohibitively time consuming for large-scale drug testing in most microbiology laboratories. Alternatively, fungal growth can be quickly, although indirectly, quantified by measuring the optical density (OD) of a broth culture. However, changes in OD are not always reflective of true changes in fungal growth because OD is an indirect measure. This paper proposes a method to model fungal growth and estimate a morphology-specific growth rate from indirect OD600measurements of the major mould pathogen,Aspergillus fumigatus. We explicitly model the relationship between measured indirect OD600data and true fungal growth (calibration). The presented work serves as the much-needed foundation for estimating and comparing morphology-specific fungal growth rates in varying antifungal drug concentrations using only OD600data.
Improved prediction of site-rates from structure with averaging across homologs
Authors: Norn Christoffer , Oliveira Fábio , André Ingemar
Published: March 2024

Variation in mutation rates at sites in proteins can largely be understood by the constraint that proteins must fold into stable structures. Models that calculate site-specific rates based on protein structure and a thermodynamic stability model have shown a significant but modest ability to predict empirical site-specific rates calculated from sequence. Models that use detailed atomistic models of protein energetics do not outperform simpler approaches using packing density. We demonstrate that a fundamental reason for this is that empirical site-specific rates are the result of the average effect of many different microenvironments in a phylogeny. By analyzing the results of evolutionary dynamics simulations, we show how averaging site-specific rates across many extant protein structures can lead to correct recovery of site-rate prediction. This result is also demonstrated in natural protein sequences and experimental structures. Using predicted structures, we demonstrate that atomistic models can improve upon contact density metrics in predicting site-specific rates from a structure. The results give fundamental insights into the factors governing the distribution of site-specific rates in protein families.
The Importance of Regulatory Network Structure for Complex Trait Heritability and Evolution
Authors: Stone Katherine , Platig John , Quackenbush John , Fagny Maud
Published: March 2024

Complex traits are determined by many loci—mostly regulatory elements—that, through combinatorial interactions, can affect multiple traits. Such high levels of epistasis and pleiotropy have been proposed in the omnigenic model and may explain why such a large part of complex trait heritability is usually missed by genome-wide association studies while raising questions about the possibility for such traits to evolve in response to environmental constraints. To explore the molecular bases of complex traits and understand how they can adapt, we systematically analyzed the distribution of SNP heritability for ten traits across 29 tissue-specific Expression Quantitative Trait Locus (eQTL) networks. We find that heritability is clustered in a small number of tissue-specific, functionally relevant SNP-gene modules and that the greatest heritability occurs in local “hubs” that are both the cornerstone of the network’s modules and tissue-specific regulatory elements. The network structure could thus both amplify the genotype-phenotype connection and buffer the deleterious effect of the genetic variations on other traits. We confirm that this structure has allowed complex traits to evolve in response to environmental constraints, with the local “hubs” being the preferential targets of past and ongoing directional selection. Together, these results provide a conceptual framework for understanding complex trait architecture and evolution.
Beta-hydroxybutyrate promotes basal insulin secretion while decreasing glucagon secretion in mouse and human islets
Authors: Banerjee Risha , Zhu Ying , Brownrigg George P. , Moravcova Renata , Rogalski Jason C. , Foster Leonard J. , Johnson James D. , Kolic Jelena
Published: March 2024

Dietary carbohydrates raise blood glucose and limiting carbohydrate intake improves glycemia in patients with type 2 diabetes. Low carbohydrate intake (< 25 g) allows the body to utilize fat as its primary fuel. As a consequence of increased fatty acid oxidation, the liver produces ketones to serve as an alternative energy source. β-Hydroxybutyrate (βHB) is the most abundant ketone. While βHB has a wide range of functions outside of the pancreas, its direct effects on islet cell function remain understudied. We examined human islet secretory response to acute racemic βHB treatment and observed increased insulin secretion at low glucose concentrations (3 mM glucose). Because βHB is a chiral molecule, existing as both R and S forms, we further studied insulin and glucagon secretion following acute treatment with individual βHB enantiomers in human and C57BL6/J mouse islets. We found that acute treatment with R-βHB increased insulin secretion and decreased glucagon secretion at physiological glucose concentrations in both human and mouse islets. Proteomic analysis of human islets treated with R-βHB over 72 h showed altered abundance of proteins that may promote islet cell health and survival. Collectively, our data show that physiological concentrations of βHB influence hormone secretion and signaling within pancreatic islets.
Dynamic role of monocytes and meningeal macrophages in bacterial meningoencephalitis
Authors: Gres Vitka , Lohrmann Florens , Fuchs Vidmante , Bosch Lance Fredrick Pahutan , Lösslein Anne , Neuber Jana , Moghadam Zohreh Mansoori , Martins Tiago , Baasch Sebastian , Henschel Julia , Freudenhammer Mirjam , Prinz Marco , Kierdorf Katrin , Kolter Julia , Erny Daniel , Henneke Philipp
Published: March 2024

1.

Macrophages in the dura mater are substantial contributors to the immune defense of the brain, however, their site-specific origin and function in bacterial infections of the central nervous system are incompletely understood.

In a natural model of streptococcal meningoencephalitis, where bacteria systemically spread via the bloodstream to the brain, we found streptococci to be largely restricted in the meninges. Further sporadic spread of bacteria to the underlying brain parenchyma caused a region-restricted microglia activation. Invasion of monocytes, but not granulocytes into brain and leptomeninges correlated to the disease severity. Inflammation in the dura was accompanied by activation and loss of dural macrophages, and by the rapid engraftment of highly activated monocytes. In addition, monocyte progenitors in the skull marrow underwent drastic changes and acquired a more immature phenotype likely due to infection-induced emergency myelopoiesis. Notably, while dural monocytes were derived from adjacent skull marrow in a CCR2-independent fashion, the high demand for dural monocytes in streptococcal meningoencephalitis required intact CCR2 signalling and involved the long bone marrow, indicating heterogeneity in monocyte recruitment. Furthermore, meningoencephalitis increased monocyte progeny from monocyte-dendritic cell progenitors compared to the homeostatic, granulocyte-monocyte progenitor-dominated origin. Accordingly, monocytes in the dura, recruited from distinct reservoirs depending on disease-inherent needs, are intertwined with the disease course and may thus offer opportunities for therapeutic interventions.
doubletrouble:an R/Bioconductor package for the identification, classification, and analysis of gene and genome duplications
Authors: Almeida-Silva Fabricio , Van de Peer Yves
Published: March 2024

Gene and genome duplications are major evolutionary forces that shape the diversity and complexity of life. However, different duplication modes have distinct impacts on gene function, expression, and regulation. Existing tools for identifying and classifying duplicated genes are either outdated or not user-friendly. Here, we presentdoubletrouble, an R/Bioconductor package that provides a comprehensive and robust framework for analyzing duplicated genes from genomic data.doubletroublecan detect and classify gene pairs as derived from six duplication modes (segmental, tandem, proximal, retrotransposon-derived, DNA transposon-derived, and dispersed duplications), calculate substitution rates, detect signatures of putative whole-genome duplication events, and visualize results as publication-ready figures. We applieddoubletroubleto classify the duplicated gene repertoire in 822 eukaryotic genomes, which we made available through a user-friendly web interface (available athttps://almeidasilvaf.github.io/doubletroubledb).doubletroubleis freely accessible from Bioconductor (https://bioconductor.org/packages/doubletrouble), and it provides a valuable resource to study the evolutionary consequences of gene and genome duplications.
racoon_clip – a complete pipeline for single-nucleotide analyses of iCLIP and eCLIP data
Authors: Klostermann Melina , Zarnack Kathi
Published: March 2024

Here, we introduceracoon_clip, a sustainable and fully automated pipeline for the complete processing of iCLIP and eCLIP data to extract RNA binding signal at single-nucleotide resolution.racoon_clipis easy to install and execute, with multiple pre-settings and fully customizable parameters, and outputs a conclusive summary report with visualizations and statistics for all analysis steps.

Availability and Implementation

racoon_clipis implemented as a snakemake-powered command line tool (snakemake version ≥ 7.22, Python version ≥ 3.9). The latest release can be downloaded from GitHub (https://github.com/ZarnackGroup/racoon_clip/tree/main) and installed via pip. A detailed documentation, including installation, usage and customization, can be found athttps://racoon-clip.readthedocs.io/en/latest/.

The example datasets can be downloaded from the Short Read Archive (SRA; iCLIP: SRR5646576, SRR5646577, SRR5646578) or the ENCODE Project (eCLIP: ENCSR202BFN).

Contact

Kathi Zarnack,kathi.zarnack@bmls.de

Issue Section

Genome analysis
A Silicon Diode based Optoelectronic Interface for Bidirectional Neural Modulation
Authors: Fu Xin , Hu Zhengwei , Li Wenjun , Ma Liang , Chen Junyu , Liu Muyang , Liu Jie , Hu Shuhan , Wang Huachun , Huang Yunxiang , Tang Guo , Zhang Bozhen , Cai Xue , Wang Yuqi , Li Lizhu , Ma Jian , Shi Song-Hai , Yin Lan , Zhang Hao , Li Xiaojian , Sheng Xing
Published: March 2024

The development of advanced neural modulation techniques is crucial to neuroscience research and neuroengineering applications. Recently, optical-based, non-genetic modulation approaches have been actively investigated to remotely interrogate the nervous system with high precision. Here, we show that a thin-film, silicon (Si)-based diode device is capable to bidirectionally regulate in vitro and in vivo neural activities upon adjusted illumination. When exposed to high-power and short-pulsed light, the Si diode generates photothermal effects, evoking neuron depolarization and enhancing intracellular calcium dynamics. Conversely, low-power and long-pulsed light on the Si diode hyperpolarizes neurons and reduces calcium activities. Furthermore, the Si diode film mounted on the brain of living mice can activate or suppress cortical activities under varied irradiation conditions. The presented material and device strategies reveal an innovated optoelectronic interface for precise neural modulations.

Teaser

A thin-film, silicon (Si)-based diode device is capable to bidirectionally regulate in vitro and in vivo neural activities.
Chitosan induces salicylic acid local and systemically in banana plants and reduces colonization by the pathogenFusarium oxysporumf. sp. cubense TR4
Authors: Lopez-Moya Federico , Zorrilla-Fontanesi Jassmin , Lozano-Soria Ana , de Larrinoa Ganado Naia Fernandez , Moreno González Celia Mei , Hernández Arnau , Torres Ariadna , Gonzalez-Silvera Daniel , Gunsé Benet , Lopez Jimenez Jose Angel , Lopez-Llorca Luis V.
Published: March 2024

Banana (Musaspp.) is essential for food security. For its clonality is highly susceptible to pests and diseases. The wilt fungusFusarium oxysporumf. sp.cubenseTropical Race 4 (FocTR4) threatens banana production worldwide. We notice that chitosan protects banana from biotic stress. Chitosan, a plant defence elicitor with antimicrobial activity, triggers salicylic acid (SA) and methyl salicylate biosynthesis and induces systemic acquired resistance (SAR) genes, mainly flavin-dependent monooxygenase 1 (FMO1), in banana. Chitosan promotes root exudation of SA and emission of methyl salicylate (MeSA). Banana germplasm,Petit Naine,Gros Michel,Enzirabahima,Yangambi Km5andFoconahbanana differ in their response to chitosan. Chitosan induces, in Foc resistantYangambi Km5, ca. 7-fold FMO1. Preventive chitosan treatments together with the endophytic biocontrol fungusPochonia chlamydosporiastrain 123 reduce (ca. 4-fold) colonization of banana roots by FocTR4. Therefore, chitosan and beneficial endophytes can help to manage sustainably FocTR4 in banana.
Khdc3 Regulates Metabolism Across Generations in a DNA-Independent Manner
Authors: Senaldi Liana , Hassan Nora , Cullen Sean , Balaji Uthra , Trigg Natalie , Gu Jinghua , Finkelstein Hailey , Phillips Kathryn , Conine Colin , Smith-Raska Matthew
Published: March 2024

Genetic variants can alter the profile of heritable molecules such as small RNAs in sperm and oocytes, and in this manner ancestral genetic variants can have a significant effect on offspring phenotypes even if they are not themselves inherited. Here we show that wild type female mice descended from ancestors with a mutation in the mammalian germ cell geneKhdc3have hepatic metabolic defects that persist over multiple generations. We find that genetically wild type females descended fromKhdc3mutants have transcriptional dysregulation of critical hepatic metabolic genes, which persist over multiple generations and pass through both female and male lineages. This was associated with dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with mutational ancestry. The oocytes ofKhdc3-null females, as well as their wild type descendants, had dysregulation of multiple small RNAs, suggesting that these epigenetic changes in the gametes transmit the phenotype between generations. Our results demonstrate that ancestral mutation inKhdc3can produce transgenerational inherited phenotypes, potentially indefinitely.
Multiple triggers converge to preferential effector coupling in the CB2R through a complex allosteric communication network
Authors: Morales-Pastor Adrian , Miljus Tamara , Stepniewski Tomasz Maciej , Ledesma Vicente , Heydenreich Franziska , Flock Tilman , Plouffe Bianca , Le Gouill Christian , Duchaine Jean , Guba Wolfgang , Rufer Arne , Grether Uwe , Bouvier Michel , Veprintsev Dmitry , Selent Jana
Published: March 2024

G protein-coupled receptors are important therapeutic drug targets for a wide range of diseases. Their ability to preferentially engage specific signaling pathways over others can be exploited to design drugs that target only disease-associated pathways leading to an improved safety profile. However, the underlying molecular mechanisms for preferential pathway engagement are complex and remain largely elusive. To elucidate the multifaceted actions at the receptor level that lead to preferential coupling, we employ a combination of techniques. Our approach integrates systematic mutagenesis of the CB2R and comprehensive profiling of Gαi2 and β-arrestin1 engagements with computer simulations to track mutant-induced impacts on receptor dynamics. Most importantly, our research discloses multiple triggers on a complex allosteric communication network (ACN) that converge to preferential CB2R coupling by modulating evolutionary conserved motifs (e.g., CWxP, NPxxY, sodium binding site). Potent triggers for a preferential Gαi2 response exhibit high levels of connectivity and are located in proximity to connections with high information transmission. Our insights highlight the complexity of GPCR signaling and can guide the rational design of drug candidates tailored to evoke specific functional responses that can enhance the precision and efficacy of therapeutic interventions.