bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of aac3IIc, aac(6)Ib and armA genes encoding aminoglycoside resistance in Klebsiella pneumoniae in Burkina Faso.
Authors: DJAGBARE Pamane , NADEMBEGA Christelle , ANDOGNABA Ursule Wendkèta , OBIRI-YEBOAH Dorcas , SIMPORE Jacques
Published: July 2023

BackgroundKlebsiella pneumoniae is the second most frequently isolated bacterium in medical bacteriology laboratory after Escherichia coli. It can be responsible for many infections including urinary tract infections and pneumonia. The treatment of these infections is often prolonged because of the resistance of this bacterium to antibiotics. The production of aminoglycoside-modifying enzymes and the production of RNA methylases confer resistance to aminoglycosides. In Burkina Faso, studies on bacterial resistance to aminoglycosides, an antibiotic regularly prescribed and consumed by patients, are limited, hence the purpose of this study was to determine the prevalence of aminoglycoside resistance genes in K. pneumoniae isolated from urine and pus samples.Methods and FindingsA total of 150 Klebsiella strains from pus and urine cultures were collected from October 2018 to June 2019 in two hospitals in Ouagadougou and were included in this study. After plating on Muller Hinton (MH) medium to obtain pure colonies, antibiotic susceptibility testing was performed with aminoglycosides, β-lactams, fluoroquinolones and sulfonamides. PCR testing for the phoE gene allowed genotypic identification of Klebsiella pneumoniae. PCRs were then performed on strains with at least one aminoglycoside resistance for identification of the aac(6')-Ib, aac(3)-IIc, and armA resistance genes.Antibiotic susceptibility testing showed that 38.67% (58/150) of the strains were resistant to Tobramycin, 28.67% (43/150) to Gentamicin, 10.00% (15/150) to Netilmicin, 8.67% (13/150) to Kanamycin, 4.67% (7/150) to Amikacin and 0.67% (1/150) to Neomycin. Of the 63 strains (42.66%) with at least one aminoglycoside resistance, the resistance genes, aac(3)-IIc and aac(6')-Ib were detected in 49 strains (77.77%) and 39 strains (61.90%), respectively; and 34 strains (53.97%) had both genes. Among the 16S rRNA genes, the armA gene was present in 19.04% of the strains (12/63).ConclusionAminoglycoside resistance in K. pneumoniae strains in this study is primarily due to aac(3)-IIc and aac(6')-Ib acetyltransferases. Although armA RNA methylases genes are less frequent, increased surveillance is necessary due to the high level of aminoglycoside resistance conferred by this gene.
Allocoprobacillus halotolerans gen. nov., sp. nov and Coprobacter tertius sp. nov., isolated from human gut microbiota
Authors: Teng Nancy M. Y. , Kiu Raymond , Evans Rhiannon , Baker David J. , Zenner Christian , Robinson Stephen D. , Hall Lindsay J.
Published: July 2023

Two novel bacterial isolates were cultured from faecal samples of patients attending the Breast Care clinic at the Norwich and Norfolk University Hospital. Strain LH1062T was isolated from a 58-year-old female diagnosed with invasive adenocarcinoma with ductal carcinoma in situ. Strain LH1063T was isolated from a healthy 51-year-old female. Isolate LH1062T was predicted to be a potential novel genus most closely related to

Coprobacillus

, whilst LH1063T was predicted to be a novel species belonging to

Coprobacter

. Both strains were characterized by polyphasic approaches including 16S rRNA gene analysis, core-genome analysis, average nucleotide identity (ANI) comparisons and phenotypic analysis. Initial screening of the 16S rRNA gene of LH1062T returned a nucleotide identity of 93.4 % to

Longibaculum muris

. For LH1063T, nucleotide identity was a 92.6 % to

Coprobacter secundus

. Further investigations showed that LH1062T had a genome size of 2.9 Mb and G+C content of 31.3 mol %. LH1063T had a genome size of 3.3Mb and G+C content of 39.2 mol %. Digital DNA-DNA hybridization (dDDH) and ANI values of LH1062T with its closest relative,

Coprobacillus cateniformis

JCM 10604T, were 20.9 and 79.54 %, respectively. For LH1063T, the dDDH and ANI values with its closest relative,

Coprobacter secundus

177T, were 19.3 and 77.81 %, respectively. Phenotypic testing confirmed that LH1062T could not be matched to a known validly published isolate in any database; thereby indicating a novel genus for which the name Allocoprobacillus gen. nov. is now proposed with LH1062T (=DSM 114537T=NCTC 14686T) being the type strain of the proposed novel species Allocoprobacillus halotolerans sp. nov. Strain LH1063T (=DSM 114538T=NCTC 14698T) fits within the genus

Coprobacter

and, it being the third species within this genus, the name Coprobacter tertius sp. nov. is proposed.
Evidence of a role for CutRS and actinorhodin in the secretion stress response in Streptomyces coelicolor M145
Authors: McLean Thomas C. , Beaton Ainsley D. M. , Martins Carlo , Saalbach Gerhard , Chandra Govind , Wilkinson Barrie , Hutchings Matthew I.
Published: July 2023

CutRS was the first two-component system to be identified in

Streptomyces

species and is highly conserved in this genus. It was reported >25 years ago that deletion of cutRS increases the production of the antibiotic actinorhodin in

Streptomyces coelicolor

. However, despite this early work, the function of CutRS has remained enigmatic until now. Here we show that deletion of cutRS upregulates the production of the actinorhodin biosynthetic enzymes up to 300-fold, explaining the increase in actinorhodin production. However, while ChIP-seq identified 85 CutR binding sites in

S. coelicolor

none of these are in the actinorhodin biosynthetic gene cluster, meaning the effect is indirect. The directly regulated CutR targets identified in this study are implicated in extracellular protein folding, including two of the four highly conserved HtrA-family foldases: HtrA3 and HtrB, and a putative VKOR enzyme, which is predicted to recycle DsbA following its catalysis of disulphide bond formation in secreted proteins. Thus, we tentatively propose a role for CutRS in sensing and responding to protein misfolding outside the cell. Since actinorhodin can oxidise cysteine residues and induce disulphide bond formation in proteins, its over production in the ∆cutRS mutant may be a response to protein misfolding on the extracellular face of the membrane.
Hypoxic Microenvironment Promotes PTBP1 Lactonization and IGF2BP2 Read Defects Mediate the Development of Preeclampsia
Authors: Qu Hongmei , Li Xiaoyan , Li Qian , Yang Xiaoming , Feng Yan , Yu Li , Qu Liping , Mu Linsong , Zou Yanfen , Chu Yongli
Published: July 2023

Objective

As an idiopathic hypertensive disorder of pregnancy, pre-eclampsia (PE) remains a major cause of maternal and neonatal morbidity and mortality, with no effective strategy for causal treatment.

Methods

This study was performed by downloading the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) based on the GSE173193 dataset, including single-cell sequencing data from placental samples of two PE patients and two normal controls. Placental cell subpopulations and their transcriptional heterogeneity were compared between PE and healthy pregnancies, and the mechanisms of PE cell dynamics in the hypoxic microenvironment were confirmed by in vitro experiments.

Results

In this study, we constructed a large-scale single-cell transcriptome ecological landscape of 26,416 cells from healthy pregnant and PE patients placenta and further identified a PE-specific CSNK2B-positive subpopulation of chorionic villous trophoblast (EVT) cells. Specifically, this study revealed that the EVT subpopulation PTBP1 was inactivated by lactonization in the hypoxic microenvironment, resulting in low expression of the N6-methyladenosine (m6A) reading protein IGF2BP2. On the basis of this, low expression of IGF2BP2 inhibits mitochondrial autophagy, causes the accumulation of damaged mitochondria, exacerbates lactic acid accumulation while inducing EVT apoptosis on the one hand. In particular, hypoxia may initially promote oxidative stress through the production of mitochondrial reactive oxygen species. on the other hand, it inhibits EVT adherent spot signaling, decreases EVT invasive ability, leads to impaired placental spiral vessel recast, and promotes PE disease process. In addition, there are interactions between abnormal metabolic signaling of PE-specific EVT subpopulations and microenvironmental immune cells, which activate metabolic inflammation.

Conclusion

The present study not only provides a new cell biological and genetic basis for elucidating the pathogenesis of PE, but also contributes to the design of an allopathic treatment strategy for PE.
Exploring Genetic Associations of Three Types of Risk Factors with Ischemic Stroke: An Integrated Bioinformatics Study
Authors: Liu Yi , Wang Weili , Cui Xin , Xie Yanming
Published: July 2023

Background

Ischemic stroke (IS) is a primary cause of disability and mortality globally. More and more reports suggest a strong association between blood pressure, blood glucose, and blood lipids and their metabolic products with IS.

Methods

We extracted the genetic tools of blood pressure, blood glucose, and blood lipids and their metabolites as instrumental variables, which were then paired with GWAS data on IS and a Mendelian randomization (MR) analysis was performed to assess the effect of these exposures on the disease. Following the positive results, colocalization analysis was performed to identify shared genes associated with exposures and IS. We then performed differential expression analysis using the GEO dataset to identify the differentially expressed associated genes (DEAGs) from associated shared genes. Additional analyzes were performed on these DEAGs to obtain their importance scores using four machine learning models. A nomogram was created using genes with high importance scores to predict the level of risk assessment between DEAGs and IS.

Results

There is a positive correlation between blood pressure, blood glucose and the risk of IS onset, while blood lipids and their metabolic products are positively or negatively correlated with the risk. There are 64 shared genes of blood pressure, blood lipids and their metabolic products with IS. Thirteen DEAGs were obtained, and among which FURIN, MAN2A2, HDDC3, ALDH2, and TOMM40 were identified as feature genes for creating the nomogram which can quantitatively predict the risk of IS onset with the expression of these feature genes. By cluster analysis, we found that DEAGs expression underlying immune inflammation, angiogenesis and development, lipid metabolism, etc.

Conclusion

This study suggests a significant association between blood pressure, blood glucose, and blood lipids and their metabolic products with IS, and predicts that these exposures mainly regulate the occurrence, development, and prognosis of IS through mechanisms such as DNA repair, DNA methylation, mitochondrial repair, apoptosis, autophagy, etc.
xTrimoPGLM: Unified 100B-Scale Pre-trained Transformer for Deciphering the Language of Protein
Authors: Chen Bo , Cheng Xingyi , Li Pan , Geng Yangli-ao , Gong Jing , Li Shen , Bei Zhilei , Tan Xu , Wang Boyan , Zeng Xin , Liu Chiming , Zeng Aohan , Dong Yuxiao , Tang Jie , Song Le
Published: July 2023

Protein language models have shown remarkable success in learning biological information from protein sequences. However, most existing models are limited by either autoencoding or autoregressive pre-training objectives, which makes them struggle to handle protein understanding and generation tasks concurrently. We propose a unified protein language model, xTrimoPGLM, to address these two types of tasks simultaneously through an innovative pre-training framework. Our key technical contribution is an exploration of the compatibility and the potential for joint optimization of the two types of objectives, which has led to a strategy for training xTrimoPGLM at an unprecedented scale of 100 billion parameters and 1 trillion training tokens. Our extensive experiments reveal that 1) xTrimoPGLM significantly outperforms other advanced baselines in 18 protein understanding benchmarks across four categories. The model also facilitates an atomic-resolution view of protein structures, leading to an advanced 3D structural prediction model that surpasses existing language model-based tools. 2) xTrimoPGLM not only can generate de novo protein sequences following the principles of natural ones, but also can perform programmable generation after supervised fine-tuning (SFT) on curated sequences. These results highlight the substantial capability and versatility of xTrimoPGLM in understanding and generating protein sequences, contributing to the evolving landscape of foundation models in protein science. Trained weight for the xTrimoPGLM model, and downstream datasets are available athttps://huggingface.co/proteinglm.
Learning Complete Protein Representation by Deep Coupling of Sequence and Structure
Authors: Hu Bozhen , Tan Cheng , Xia Jun , Zheng Jiangbin , Huang Yufei , Wu Lirong , Liu Yue , Xu Yongjie , Li Stan Z.
Published: July 2023

Learning effective representations is crucial for understanding proteins and their biological functions. Recent advancements in language models and graph neural networks have enabled protein models to leverage primary or tertiary structure information to learn representations. However, the lack of practical methods to deeply co-model the relationships between protein sequences and structures has led to suboptimal embeddings. In this work, we propose CoupleNet, a network that couples protein sequence and structure to obtain informative protein representations. CoupleNet incorporates multiple levels of features in proteins, including the residue identities and positions for sequences, as well as geometric representations for tertiary structures. We construct two types of graphs to model the extracted sequential features and structural geometries, achieving completeness on these graphs, respectively, and perform convolution on nodes and edges simultaneously to obtain superior embeddings. Experimental results on a range of tasks, such as protein fold classification and function prediction, demonstrate that our proposed model outperforms the state-of-the-art methods by large margins.
Outcome devaluation by sensory-specific satiety alters Pavlovian-conditioned behavior in male and female rats
Authors: Sood Ankit , Richard Jocelyn M.
Published: July 2023

Goal-directed behavior relies on accurate mental representations of the value of expected outcomes. Disruptions to this process are a central feature of several neuropsychiatric disorders, including addiction. Goal-directed behavior is most frequently studied using instrumental paradigms paired with outcome devaluation, but cue-evoked behaviors in Pavlovian settings can also be goal-directed and therefore sensitive to changes in outcome value. Emerging literature suggests that male and female rats may differ in the degree to which their Pavlovian-conditioned responses are goal-directed, but interpretation of these findings is complicated by the tendency of female and male rats to engage in distinct types of Pavlovian responses when trained with localizable cues. Here, we used outcome devaluation via sensory-specific satiety to assess the behavioral responses in male and female Long Evans rats trained to respond to an auditory CS (conditioned stimulus) in a Pavlovian-conditioning paradigm. We found that satiety-induced devaluation led to a decrease in behavioral responding to the reward-predictive CS, with males showing an effect on both port entry latency and probability and females showing an effect only on port entry probability. Overall, our results suggest that outcome devaluation affects Pavlovian-conditioned responses in both male and female rats, but that females may be less sensitive to outcome devaluation.
KISS1 is a potential immunological and prognostic biomarker for cancer metastasis in pan-cancer and affects breast cancer in a different way
Authors: Jiang Hao , Xiao Jianru , Zhang Hao , Li Bo , Xu Wei , Li Zhenxi
Published: July 2023

Metastasis to other organs accounts for the majority of death in cancer patients. Metastatic capacity enables tumor cells resist to chemotherapy. KISS1 had been found to suppress metastasis in cancers like melanoma, but improve the metastatic phenotype of breast cancers, which means its role in tumor metastasis is tissue context-dependent. This character suggests the KISS1 might have promising potential to interpret tumor metastasis in a pan-cancer perspective. Here, we analyzed the potential functions of KISS1 in pan-cancer, especially in breast cancer, by the datasets of TCGA and GTEx. KISS1 exhibited a different expression status between mRNA level and protein level in pan-cancers, with a significant association between KISS1 expression and prognosis of cancer patients. Besides, the correlation between KISS1 expression and immune cell infiltration, immunosuppressive cells, immune checkpoint genes, TMB, MSI, tumor purity and HRD indicates the potential role in regulating immunotherapy. Thereafter, we further clarified the role of KISS1 in promoting metastasis in breast cancer. Furthermore, we found that the post-translational modification may explains the KISS1 protein stability in breast cancers. In summary, our first pan-cancer study offers new insights and relatively comprehensive understandings of the oncogenic roles of KISS1 across various cancers.
Mitonuclear sex determination? Empirical evidence from bivalves
Authors: Smith Chase H. , Mejia-Trujillo Raquel , Breton Sophie , Pinto Brendan J. , Kirkpatrick Mark , Havird Justin C.
Published: July 2023

Genetic elements encoded in nuclear DNA determine the sex of an individual in many animals. In bivalves, however, mitochondrial DNA (mtDNA) has been hypothesized to contribute to sex determination in lineages that possess doubly uniparental inheritance (DUI). In these cases, females transmit a female mtDNA (F mtDNA) to all offspring, while male mtDNA (M mtDNA) is transmitted only from fathers to sons. Because M mtDNA is inherited in the same way as Y chromosomes, it has been hypothesized that mtDNA may be responsible for sex determination. However, the role of mitochondrial and nuclear genes in sex determination has yet to be validated in DUI bivalves. In this study, we used DNA, RNA, and mitochondrial short non-coding RNA (sncRNA) sequencing to explore the role of mitochondrial and nuclear elements in the sexual development pathway of the freshwater musselPotamilus streckersoni(Bivalvia: Unionida). We found that the M mtDNA shed a sncRNA partially within a male-specific mitochondrial gene that targeted pathways hypothesized to be involved in female development and mitophagy. RNA-seq confirmed the gene target was significantly upregulated in females, supporting a direct role of mitochondrial sncRNAs in gene silencing. These findings support the hypothesis that M mtDNA inhibits female development. Genome-wide patterns of genetic differentiation and heterozygosity did not support a nuclear sex determining region, although we cannot reject that nuclear factors are involved with sex determination. Our results provide further evidence that mitochondrial loci contribute to diverse, non-respiratory functions and provide a first glimpse into an unorthodox sex determining system.
Exploring multi-omics latent embedding spaces for characterizing tumor heterogeneity and tumoral fitness effects
Authors: Wang Fengao , Liu Junwei , Gao Feng , Li Yixue
Published: July 2023

The ecological and evolutionary perspectives of tumorigenesis can be characterized as a process of microevolution in tumor cells that altered the tumor microenvironment and further induced tumor cell proliferation, metastasis, and the death of tumor patients. Here, we introduced XgeneVAE, an interpretable unsupervised deep learning framework that quantified the semantic changes in multi-omics embedding space for characterizing the microevolution processes and fitness effects of heterogeneous tumor samples. We then validated that the scales of the latent embedding variances can reflect the differences in the overall survival of tumor patients, as well as their applications in uncovering the driving genomic alternations in different cancer types. These results confirmed that the XgeneVAE model can better represent the heterogeneity in distinct cancer types and as an interpretable model for understanding the fitness effects in tumorigenesis and their association with clinical outcomes.
MulticomponentAyurvedaformulationLodhrasavamameliorates steatosis and lipotoxicity in HepG2 cell model of NAFLD
Authors: Kouser Sania , Banvi Pranav Girish , Garawadmath Soumya , Kumar Subrahmanya , Vishnuprasad Chethala N
Published: July 2023

Background

Non-alcoholic fatty liver disease (NAFLD) is a complex, multifactorial and multi-system disorder. It is one of the major contributors of liver disease worldwide. Among the many factors involved in the pathogenesis of NAFLD, free fatty acids (FFAs) such as palmitic acid induced lipotoxicity promotes steatosis, oxidative stress and insulin resistance that activate apoptotic cascades leading to tissue damage and inflammation. Since NAFLD is a multifactorial metabolic disorder, conventional target-based drug therapies have limited success. Therefore, the use of multicomponent ayurveda herbal formulations could be a promising alternative due to their multitargeted mechanisms of action. The present study investigates the effects and underlying mechanism of actions of an ayurveda formulation,Lodhrasavam(TDU-LS-1), in the in-vitro model of NAFLD.

Methods

Lipotoxicity was induced in HepG2 cells by treating the cells with 1mM palmitic acid for 24 hrs followed by drug (TDU-LS-1) treatment for another 24 hrs. The effect of TDU-LS-1 on lipotoxicity was evaluated by MTT assay. The effect of TDU-LS-1 on steatosis was studied by estimating intracellular triglycerides, lipid droplets formation and expression of genes involved in lipid metabolism. Further, to examine the antioxidant activity, DPPH scavenging assay was performed.

Results/discussion

TDU-LS-1 was found to increase the antioxidant activity in a concentration dependent manner with an IC50 of 16.45 μg GAE/ml. Palmitic acid induced lipotoxicity in HepG2 cells was reduced by lower concentrations of TDU-LS-1. Also, the results from triglyceride (TAG) assay, Oil-Red-O staining and BODIPY 493/503 confocal imaging suggest that TDU-LS-1 reduces the palmitate induced triglyceride deposition and lipid droplet accumulation in HepG2 cells. Further, the qRT-PCR analysis of TDU-LS-1 at a concentration of 32 μg/GAE revealed that it modulates the expression of SREBP, FASN, SCD1, ACOX, and PPARγ that are relevant in hepatic lipid metabolism. Our results suggest that TDU-LS-1 can reducede novolipogenesis, peroxisomal lipid peroxidation as well as lipotoxicity in thein vitropalmitate-induced NAFLD model in HePG2 cells.
The fate of sulfamethoxazole and trimethoprim in a micro-aerated anaerobic membrane bioreactor: implications for antibiotic resistance spreading
Authors: Piaggio Antonella L. , Mittapalli Srilekha , Calderón-Franco David , Weissbrodt David G. , van Lier Jules B. , de Kreuk Merle K. , Lindeboom Ralph E.F.
Published: July 2023

Interest in reusing treated wastewater drives efforts to eliminate antibiotics from water sources to prevent antibiotic resistance. Micro-aerated anaerobic membrane bioreactors (MA-AnMBR) promote wastewater reuse with high organic matter conversion to biogas, under a small footprint. However, the fates of antibiotics, antibiotic-resistant bacteria (ARB), and their antibiotic-resistance genes (ARGs) are not known in these systems. We studied the effects, conversions, and resistance induction, following the addition of 150 μg·L-1of two antibiotics, sulfamethoxazole (SMX) and trimethoprim (TMP), in a laboratory-scale MA-AnMBR. TMP and SMX were removed at 97 and 86%, indicating that micro-aeration did not hamper the removal of the antibiotics. These antibiotics only affected the pH and biogas composition of the process, with a significant change in pH from 7.8 to 7.5, and a decrease in biogas CH4content from 84 to 78%. TMP was rapidly adsorbed onto the sludge and subsequently degraded during the long retention of the solids of 27 days. SMX adsorption was minimal, but the applied hydraulic retention time of 2.6 days was sufficiently long to biodegrade SMX. The levels of three ARGs (sul1andsul2for SMX,dfrA1) and one mobile genetic element biomarker (intI1) were analysed by qPCR, in combination with ARB tracked by plating. Additions of the antibiotics increased the relative abundances of all ARGs andintI1in the MA-AnMBR sludge, with thesul2gene folding 15 times after 310 days of operation. The MA-AnMBR was able to reduce the concentration of ARB in the permeate by 3 log.

Highlights

Additions of SMX and TMP had a negligible effect on the MA-AnMBR performance.

The laboratory-scale MA-AnMBR removed 86% of SMX and 97% of TMP.

A 3 log removal of ARB was achieved between sludge and UF permeate.

Relative abundances of ARGs were similar in sludge and permeate.

TMP and SMX resistance is better assessed by the heterotrophic plate count of ARB.
The night-time sleep and autonomic activity of male and female professional road cyclists competing in the Tour de France and Tour de France Femmes
Authors: Sargent Charli , Jasinski Summer , Capodilupo Emily R. , Powers Jeremy , Miller Dean J. , Roach Gregory D.
Published: July 2023

Objective

The objective of this study was to examine the capacity of male and female professional cyclists to recover between daily race stages while competing in the 109thedition of the Tour de France (2022) and the 1stedition of the Tour de France Femmes (2022), respectively.

Methods

The 17 participating cyclists were 8 males from a single team (aged 28.0 ± 2.5 years [mean ± 95% confidence interval]) and 9 females from two separate teams (aged 26.7 ± 3.1 years). Cyclists wore a fitness tracker (WHOOP 4.0) to capture recovery metrics primarily related to night-time sleep and autonomic activity. Data were collected for the entirety of the events and for 7 days of baseline before the events. The primary analyses tested for a main effect of ‘stage type’ – i.e., rest, flat, hilly, mountain or time trial for males and flat, hilly or mountain for females – on the various recovery metrics.

Results

During baseline, total sleep time at night was 7.2 ± 0.3 h for male cyclists and 7.7 ± 0.3 h for female cyclists, sleep efficiency (i.e., total sleep time as a percentage of time in bed) was 87.0 ± 4.4 % for males and 88.8 ± 2.6 % for females, resting heart rate was 41.8 ± 4.5 beats·min-1for males and 45.8 ± 4.9 beats·min-1for females, and heart rate variability during sleep was 108.7 ± 17.0 ms for males and 119.8 ± 26.4 ms for females. During their respective events, total sleep time at night was 7.2 ± 0.1 h for males and 7.5 ± 0.3 h for females, sleep efficiency was 86.4 ± 1.2 % for males and 89.6 ± 1.2 % for females, resting heart rate was 44.5 ± 1.2 beats·min-1for males and 50.2 ± 2.0 beats·min-1for females, and heart rate variability during sleep was 99.1 ± 4.2 ms for males and 114.3 ± 11.2 ms for females. For male cyclists, there was a main effect of ‘stage type’ on recovery, such that heart rate variability during sleep was lowest after mountain stages. For female cyclists, there was also a main effect of ‘stage type’ on recovery, such that the percentage of light sleep in a sleep period (i.e., lower-quality sleep) was highest after mountain stages.

Conclusions

Some aspects of recovery were compromised in cyclists after the most demanding days of racing, i.e., mountain stages. Overall however, the cyclists obtained a reasonable amount of good-quality sleep while competing in these highly demanding endurance events. This study demonstrates that it is now feasible to assess recovery metrics in professional athletes during multiple-day endurance events using validated fitness trackers.
Strengthening Community Roots: Anchoring Newcomers in Wellness and Sustainability (SCORE!): A protocol for the co-design and evaluation of a healthy active living program among a newcomer community in Canada
Authors: Wahi Gita , Kandasamy Sujane , Bangdiwala Shrikant , Baumann Andrea , Arsenio Mary Crea- , Desai Dipika , Georgiades Kathy , Jackson-Best Fatimah , Kwan Matthew , Montague Patricia , Newbold Bruce , Sherifali Diana , Sim Amanda , de Souza Russell J. , Anand Sonia S.
Published: July 2023

BACKGROUND

The burden of childhood obesity and cardiometabolic risk factors affecting newcomer Canadians living in lower socioeconomic circumstances is a concerning public health issue. This paper describes Strengthening Community Roots: Anchoring Newcomers in Wellness and Sustainability (SCORE!), an academic-community research partnership to co-design interventions that nurture and optimize healthy activity living (HAL) among a community of children and families new to Canada in Hamilton, Ontario, Canada.

METHODS/DESIGN

Our overarching program is informed by a socio-ecological model, and will co-create HAL interventions for children and families new to Canada rooted in outdoor, nature-based physical activity. We will proceed in three phases: Phase 1) synthesis of existing evidence regarding nature based HAL interventions among children and families; Phase 2) program development through four data collection activities including: i) community engagement activities to build trustful relationships and understand barriers and facilitators, including establishing a community advisory and action board, qualitative studies including a photovoice study, and co-design workshops to develop programs; ii) characterizing the demographics of the community through a household survey; iii) characterizing the built environment and HAL programs/services available in the community by developing an accessible real-time systems map; and iv) reviewing municipal policies relevant to HAL and sustainability; leading to Phase 3) implementation and evaluation of the feasibility of co-designed HAL programs.

CONCLUSION

The etiology of childhood obesity and related chronic diseases is complex and multifactorial, as are intervention strategies. The SCORE! program of research brings together partners including community members, service providers, academic researchers, and organizational leaders to build a multi-component intervention that promotes the health and wellness of newcomer children and families.
Mon1a and FCHO2 are required for maintenance of Golgi architecture
Authors: Bagley Dustin C. , Morham Scott G. , Kaplan Jerry , Ward Diane M.
Published: July 2023

Mon1a has been shown to function in the endolysosomal pathway functioning in the Mon1-Ccz1 complex and it also acts in the secretory pathway where it interacts with dynein and affects ER to Golgi traffic. Here we show that Mon1a is also required for maintenance of the Golgi apparatus. We identified the F-BAR protein FCHO2 as a Mon1a-interacting protein by both yeast two-hybrid analysis and co-immunoprecipitation. siRNA-dependent reductions in Mon1a or FCHO2 resulted in Golgi fragmentation. Membrane trafficking through the secretory apparatus in FCHO2-depleted cells was unaltered, however, reduction of FCHO2 affected the uniform distribution of Golgi enzymes necessary for carbohydrate modification. Fluorescence recovery after photobleaching analysis showed that the Golgi ministacks in Mon1a- or FCHO2-silenced cells did not exchange resident membrane proteins. The effect of FCHO2 silencing on Golgi structure was partially cell cycle-dependent and required mitosis-dependent Golgi fragmentation, whereas the effect of Mon1a-silencing on Golgi disruption was not cell cycle-dependent. mCherry-FCHO2 transiently colocalized on Golgi structures independent of Mon1a. These findings suggest that Mon1a has functions throughout the secretory pathway including interacting with dynein at the ER-Golgi interface in vesicle formation and then interacting with FCHO2 at the Golgi to generate lateral links between ministacks, thus creating Golgi ribbons.
Coupled Environmental and Demographic Fluctuations Shape the Evolution of Cooperative Antimicrobial Resistance
Authors: Hernández-Navarro Lluís , Asker Matthew , Rucklidge Alastair M. , Mobilia Mauro
Published: July 2023

There is a pressing need to better understand how microbial populations respond to antimicrobial drugs, and to find mechanisms to possibly eradicate antimicrobial-resistant cells. The inactivation of antimicrobials by resistant microbes can often be viewed as a cooperative behavior leading to the coexistence of resistant and sensitive cells in large populations and static environments. This picture is however greatly altered by the fluctuations arising in volatile environments, in which microbial communities commonly evolve. Here, we study the eco-evolutionary dynamics of a population consisting of an antimicrobial resistant strain and microbes sensitive to antimicrobial drugs in a time-fluctuating environment, modeled by a carrying capacity randomly switching between states of abundance and scarcity. We assume that antimicrobial resistance is a shared public good when the number of resistant cells exceeds a certain threshold. Eco-evolutionary dynamics is thus characterized by demographic noise (birth and death events) coupled to environmental fluctuations which can cause population bottlenecks. By combining analytical and computational means, we determine the environmental conditions for the long-lived coexistence and fixation of both strains, and characterize afluctuation-drivenantimicrobial resistance eradication mechanism, where resistant microbes experience bottlenecks leading to extinction. We also discuss the possible applications of our findings to laboratory-controlled experiments.
A stress sensor IRE1α is required for bacterial exotoxin-induced inflammasome activation in tissue-resident macrophages
Authors: Sasaki Izumi , Fukuda-Ohta Yuri , Nakai Chihiro , Wakaki-Nishiyama Naoko , Okamoto Chizuyo , Orimo Takashi , Okuzaki Daisuke , Morita Shuhei , Kaji Shiori , Furuta Yuki , Hemmi Hiroaki , Kato Takashi , Yamamoto Asumi , Tanaka Takashi , Hoshino Katsuaki , Fukuda Shinji , Miyake Kensuke , Kuroda Etsushi , Ishii Ken J. , Iwawaki Takao , Furukawa Koichi , Kaisho Tsuneyasu
Published: July 2023

Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1β (IL-1β), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarified the roles of IRE1α, an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1β production from RPMs. In RPMs, CTB is incorporated into ER and induced ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1α-deficient RPMs showed a significant impairment of CT- or CTB-induced IL-1β production, indicating that IRE1α was required for CT- or CTB-induced IL-1β production from RPMs. This study first demonstrates the critical roles of IRE1α in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages.

One sentence summary

IRE1α is required for NLRP3 and pyrin-mediated IL-1β production
Breaking Down Cell-Free DNA Fragmentation: A Markov Model Approach
Authors: Tsui Terence H.L. , Xie Phil F. , Chulián Salvador , Pérez-García Víctor M.
Published: July 2023

Cell-free DNA (cfDNA) is released into the bloodstream from cells in various physiological and pathological conditions. The use of cfDNA as a non-invasive biomarker has attracted attention, but the dynamics of cfDNA fragmentation in the bloodstream are not well understood and have not been previously studied computationally.

To address this issue, we present a Markovian model called FRIME (Fragmentation, Immigration, and Exit) that captures three leading mechanisms governing cfDNA fragmentation in the bloodstream. The FRIME model enables the simulation of cfDNA fragment profiles by sampling from the stationary distribution of FRIME processes. By varying the parameters of our model, we generate fragment profiles similar to those observed in liquid biopsies and provide insight into the underlying biological mechanisms driving the fragmentation dynamics.

To validate our model, we compare simulated FRIME profiles with mitochondrial and genomic cfDNA fragment profiles. Our simulation results are consistent with experimental and clinical observations and highlight potential physicochemical differences between mitochondrial and genomic cfDNA.

The FRIME simulation framework provides an initial step towards an improved computational understanding of DNA fragmentation dynamics in the bloodstream and may aid in the analysis of liquid biopsy data.

Author summary

Cell-free DNA (cfDNA) released into the bloodstream from cells in different conditions is the basis for liquid biopsies, thus being non-invasive biomarkers of potential interest. However, the dynamics of cfDNA fragmentation in the bloodstream remain poorly understood and are yet to be studied computationally. To address this issue, we developed a Markovian model which captures the three leading mechanisms governing cfDNA fragmentation in the bloodstream: FRagmentation, IMmigration, and Exit (FRIME). The FRIME model enables the simulation of cfDNA fragment profiles by sampling from the stationary distribution of FRIME processes. Simulation results are compared with mitochondrial and genomic cfDNA fragment profiles, which show consistency with experimental and clinical observations. The FRIME simulation framework is a significant step towards understanding DNA fragmentation dynamics in the bloodstream, uncovering potential physicochemical differences between mitochondrial and genomic cfDNA, and aiding the analysis of liquid biopsy data.
Induction of plant disease resistance by mixed oligosaccharide elicitors prepared from plant cell wall and crustacean shells
Authors: Pring Sreynich , Kato Hiroaki , Imano Sayaka , Camagna Maurizio , Tanaka Aiko , Kimoto Hisashi , Chen Pengru , Shrotri Abhijit , Kobayashi Hirokazu , Fukuoka Atsushi , Saito Makoto , Suzuki Takamasa , Terauchi Ryohei , Sato Ikuo , Chiba Sotaro , Takemoto Daigo
Published: July 2023

Basal plant immune responses are activated by the recognition of the conserved pathogen-associated molecular patterns (PAMPs), or breakdown molecules released from plants after damage by pathogen infection, so-called danger-associated molecular patterns (DAMPs). While chitin-oligosaccharide (CHOS), a primary component of the fungal cell wall, is most known as PAMP, plant cell wall-derived oligosaccharides, cello-oligosaccharides (COS) from cellulose and xylo-oligosaccharide (XOS) from hemicellulose, are representative DAMPs, which activate signaling steps similar to PAMP-induced immunity to elicit defenses and provide protection against pathogens. In this study, elicitor activities of COS prepared from cotton linters, XOS prepared from corn cobs as well as chitin-oligosaccharide (CHOS) from crustacean shells were comparatively investigated. In Arabidopsis, treatment of COS, XOS or CHOS triggered typical defense responses such as reactive oxygen species (ROS) production, activation of MAP kinases phosphorylation, callose depositions, and activation of the promoter for defense-related transcription factorWRKY33. When COS, XOS and CHOS were used at concentrations with similar activity in inducing ROS production and callose depositions, CHOS was particularly highly potent in activating the MAPK kinases andWRKY33promoters. Among the COS and XOS with different degrees of polymerization (DP), cellotriose (DP3) and xylotetraose (DP4) showed the highest activity for the activation ofWRKY33promoter. Simultaneous treatment of COS, XOS and CHOS leads to a strong transcriptional change for defense-related genes, and gene ontology (GO) enrichment analysis of RNAseq data revealed that a mixture of three oligosaccharide (oligo-mix) effectively activate the plants disease resistance. In practice, treatment of the oligo-mix enhanced the resistance of tomato to powdery mildew, but plant growth was not inhibited but rather tended to be promoted, providing evidence that mixed oligosaccharides have beneficial effects on improving disease resistance in plants, making them a promising class of compounds for practical application.
DICTrank: The largest reference list of 1318 human drugs ranked by risk of drug-induced cardiotoxicity using FDA labeling
Authors: Qu Yanyan , Li Ting , Liu Zhichao , Li Dongying , Tong Weida
Published: July 2023

Drug-induced cardiotoxicity (DICT) is one of the leading causes of drug attrition in clinical trials or withdrawal from the market. Many studies have been conducted to detect DICT in the early stage of drug development and clinical diagnosis, but the success is limited, as evident by the high attrition rate at all clinical phases due to DICT. Most of these efforts, if not all, have focused on specific adverse events and/or mechanisms associated with DICT, such as QT prolongation and hERG-related cardiotoxicity. However, given the broad spectrum of cardiotoxicity, it is necessary to develop a reference drug list with a systematic annotation of DICT potential across a large number of drugs and drug classes. Such a list is essential for developing effective DICT diagnostic biomarkers and early prediction strategies using new approach methods (NAMs), including artificial intelligence (AI). By utilizing labeling documents for FDA (U.S. Food and Drug Administration)-approved drugs, we developed a drug classification scheme to prioritize drugs based on their DICT potential. This resulted in DICTrank, which is the largest dataset of drugs annotated with ranked DICT risk in humans. DICTrank categorizes drugs into four categories of DICT concerns by integrating DICT severity and labeling content. The dataset consists of 1318 drugs, classified as follows: Most-DICT-Concern (341), Less-DICT-Concern (528), No-DICT-Concern (343), and Ambiguous-DICT-Concern (106; lacking sufficient information in the labeling document to determine cardiotoxicity potential). DICTrank covers a wide range of drug therapeutic categories. Using this extensive DICT dataset, we discovered that several therapeutic categories were significantly enriched with drugs of Most-DICT-Concern as well as the association of daily dose with drug class. These categories include antineoplastic agents, sex hormones and modulators of the genital system, anti-inflammatory and antirheumatic products, beta-blocking agents, and cardiac therapy. DICTrank represents the largest drug list for DICT to date, and it could contribute to the development of NAMs and AI models for the early identification of DICT risk during drug development and beyond.
The PHB Granule Biogenesis Pathway inCaulobacter
Authors: de Koning Edward A. , Panjalingam Mayura , Tran Jessica , Eckhart Michael R. , Dahlberg Peter D. , Shapiro Lucy
Published: July 2023

PHB granules are bacterial organelles that store excess carbohydrates in the form of water-insoluble polyhydroxybutyrate (PHB). The PHB polymerase, phasin (a small amphipathic protein), and active PHB synthesis are essential for the formation of mature PHB granules inCaulobacter crescentus. Granule formation was found to be initiated by the condensation of self-associating PHB polymerase-GFP into foci, closely followed by the recruitment and condensation of phasin-mCherry. Following the active synthesis of PHB and granule maturation, the polymerase dissociates from mature granules and the PHB depolymerase is recruited to the granule. The polymerase directly binds phasinin vitrothrough its intrinsically disordered N-terminal domain. Thus, granule biogenesis is initiated and controlled by the action of a PHB polymerase and an associated helper protein, phasin, that together synthesize the hydrophobic granule content while forming the granule’s protein boundary.

Importance

Like eukaryotes, bacteria organize their cytoplasm in subcellular compartments. These bacterial compartments can be membrane-bound (e.g. magnetosomes), or membraneless with protein-encased shells (e.g. carboxysomes). Here we investigate howCaulobacterforms membrane-less compartments that store the water-insoluble carbohydrate polymer polyhydroxybutyrate (PHB). A PHB polymerase is essential for granule biogenesis and we observed a direct interaction with the granule associated protein phasin through the disordered N-terminus of the polymerase. We found that PHB granules form by sequential recruitment of key proteins, beginning with the polymerase, and that the granule composition changes as these organelles mature.
Myosin XV is a negative regulator of signaling filopodia during long-range lateral inhibition
Authors: Clements Rhiannon , Smith Tyler , Cowart Luke , Zhumi Jennifer , Sherrod Alan , Cahill Aidan , Hunter Ginger L
Published: July 2023

The self-organization of cells during development is essential for the formation of healthy tissues, and requires the coordination of cell activities at local scales. Cytonemes, or signaling filopodia, are dynamic actin-based cellular protrusions that allow cells to engage in contact mediated signaling at a distance. While signaling filopodia have been shown to support several signaling paradigms during development, less is understood about how these protrusions are regulated. We investigated the role of the plus-end directed, unconventional MyTH4-FERM myosins in regulating signaling filopodia during sensory bristle patterning on the dorsal thorax of the fruit fly Drosophila melanogaster. We found that Myosin XV is required for regulating signaling filopodia dynamics and, as a consequence, lateral inhibition more broadly throughout the patterning epithelium. We found that Myosin XV is required for limiting the length and number of signaling filopodia generated by bristle precursor cells. Cells with additional and longer signaling filopodia due to loss of Myosin XV are not signaling competent, due to altered levels of Delta ligand and Notch receptor along their lengths. We conclude that Myosin XV acts to negatively regulate signaling filopodia, as well as promote the ability of signaling filopodia to engage in long-range Notch signaling. Since Myosin XV is present across several vertebrate and invertebrate systems, this may have significance for other long-range signaling mechanisms.
A machine learning approach for quantifying age-related histological changes in the mouse kidney
Authors: Sheehan Susan , Mawe Seamus , Chen Mandy , Klug Jenna , Ladiges Warren , Korstanje Ron , Mahoney J. Matthew
Published: July 2023

The ability to quantify aging-related changes in histological samples is important, as it allows for evaluation of interventions intended to effect health span. We used a machine learning architecture that can be trained to detect and quantify these changes in the mouse kidney. Using additional held out data, we show validation of our model, correlation with scores given by pathologists using the Geropathology Research Network aging grading scheme, and its application in providing reproducible and quantifiable age scores for histological samples. Aging quantification also provides the insights into possible changes in image appearance that are independent of specific geropathology-specified lesions. Furthermore, we provide trained classifiers for H&E-stained slides, as well as tutorials on how to use these and how to create additional classifiers for other histological stains and tissues using our architecture.This architecture and combined resources allow for the high throughput quantification of mouse aging studies in general and specifically applicable to kidney tissues.