bluuebunny/crossref_metadata_2025 huggingface dataset:
INFLAMMATORY MARKERS AND BODY MASS INDEX AMOUNG HISPANIC CHILDREN
Authors: Lang Henry , Loudermilk Elaine N. , Clark W. Andrew , Marrs Jo-Ann , Joyner T. Andrew , Wang Liang , Gerber Kathryn S. , Alamian Arsham
Published: July 2023

Background and Objectives

Body mass index (BMI) is inversely proportional with adiponectin levels among adults, while insulin, C-reactive protein (CRP), interleukin 6 (IL-6), resistin, and tumor necrosis factor-alpha (TNF-α) have been linked with elevated BMI. The role and relation of these biomarkers with BMI among Hispanic pediatric populations are less known. Thus, the objective of this cross-sectional study was to examine the association of inflammatory markers with the odds of overweight/obesity while controlling for several sociodemographic factors among a Hispanic youth population of Northeast Tennessee.

Methods

Height, weight, demographic information, and blood samples were collected from 107 Hispanic children aged 2 to 10 years recruited at a large community health center in 2015-2016 in Northeast Tennessee. Data for this research were accessed and analyzed in 2022. Multivariable logistic regression was conducted to assess the relations between adiponectin, insulin, resistin, CRP, TNF-α, and IL-6, and overweight/obesity vs. having a healthy (normal) weight.

Results

Adiponectin levels were significantly lower among overweight/obese Hispanic children (p = 0.0048) compared to healthy weight children. The odds of overweight/obesity decreased by 4% for every one-unit increase in serum adiponectin. Insulin levels were significantly higher among overweight/obese Hispanic children (p = 0.0048) compared to healthy weight children (p=0.0008). The odds of overweight/obesity increased by 7% for every one-unit increase in serum insulin. Resistin, IL-6, TNF-α, and CRP were not significantly associated with overweight/obesity in this population.

Conclusion

Adiponectin behaves similarly in Hispanic youth as it does in other pediatric populations, possibly making it a valuable marker when examining metabolic health status in this population.
The RNA binding proteins ZFP36L1 and ZFP36L2 are dysregulated in airway epithelium in human and a murine model of asthma
Authors: Rynne Jennifer , Ortiz-Zapater Elena , Bagley Dustin C. , Doherty George , Kanabar Varsha , Jackson David , Parsons Maddy , Rosenblatt Jody , Adcock Ian , Martinez-Nunez Rocio T
Published: July 2023

Asthma is the most common chronic inflammatory disease of the airways. The airway epithelium is a key driver of the disease, and numerous studies have established genome-wide differences in mRNA expression between health and asthma. However, the underlying molecular mechanisms for such differences remain poorly understood. We investigated the expression and possible role of the tristetraprolin (TTP) family of RNA binding proteins (RBPs), which are poorly understood in asthma. The human TTP family is comprised ofZFP36,ZFP36L1andZFP36L2,and has essential roles in immune regulation by determining the stability and translation of myriad mRNAs encoding for inflammatory mediators. We foundZFP36L1andZFP36L2mRNA levels significantly downregulated in the airway epithelium of patients with very severe asthma in different cohorts (5 healthy vs 8 severe asthma; 36 moderate asthma vs 37 severe asthma on inhaled steroids vs 26 severe asthma on oral corticoids). Integrating several datasets allowed us to infer that mRNAs potentially targeted by these RBPs are increased in severe asthma.Zfp36l1was downregulated in the lung of a mouse model of asthma, and immunostaining ofex vivolung slices with a dual antibody demonstrated that Zfp36l1/l2 nuclear localization is increased in the airway epithelium of an acute asthma mouse model. Immunostaining of human bronchial biopsies showed that airway epithelial cell staining of ZFP36L1 was decreased in severe asthma as compared with mild, while ZFP36L2 was upregulated. We propose that the dysregulation of ZFP36L1/L2 levels as well as their subcellular mislocalization contributes to changes in mRNA expression and cytoplasmic fate in asthma.
A Parkinson’s disease genetic risk score associates with blood DNAm on chromosome 17
Authors: Casazza William , Schaffner Samantha L. , Artaud Fanny , Domenighetti Cloé , Baglietto Laura , Schulze-Hentrich Julia M. , Lesage Suzanne , Brice Alexis , Corvol Jean-Christophe , Mostafavi Sara , Kobor Michael S. , Elbaz Alexis , Dennis Jessica K. ,   DIG-PD Study Group
Published: July 2023

Although Parkinson’s disease (PD) coincides with altered immune functioning, there are few reproducible associations between blood DNA methylation (DNAm) and PD case-control status. Integrative analyses of genotype and blood DNAm can address this gap and can help us characterize the biological function of PD genetic risk loci. First, we tested for associations between a PD genetic risk score (GRS) and DNAm. Our GRS included 36 independent genome-wide significant variants from the largest GWAS of PD to date. Our discovery sample was TERRE, consisting of French agricultural workers (71 PD cases and 147 controls). The GRS associated with DNAm at 85 CpG sites, with 19 associations replicated in an independent sample (DIG-PD). The majority of CpG sites (73) are within a 1.5 Mb window on chromosome 17, and 36 CpG sites annotate toMAPTandKANSL1, neighboring genes that affect neurodegeneration. All associations were invariant to non-genetic factors, including exposure to commercial-grade pesticides, and omitting chromosome 17 variants from the GRS had little effect on association. Second, we compared our findings to the relationship between individual PD risk loci and blood DNAm using blood mQTL from a large independent meta-analysis (GoDMC). We found 79 CpG sites that colocalized with PD loci, and via summary Mendelian randomization analysis, we show 25/79 CpG sites where DNAm causally affects PD risk. The nine largest causal effects are within chromosome 17, including an effect withinMAPT. Thus, all integrative analyses prioritized DNAm on chromosome 17, drawing from multiple independent data sets, meriting further study of this region.
Urinary Cortisol and Cardiovascular Events in Women vs. Men: The Multi-Ethnic Study of Atherosclerosis
Authors: Flynn Spencer , Srikanthan Preethi , Ravellette Keeley , Inoue Kosuke , Watson Karol , Horwich Tamara
Published: July 2023

Background

Research suggests that women experience greater cardiovascular ischemic effects from stress than men. Visceral adiposity is an endocrine tissue that differs by sex and interacts with stress hormones. We hypothesized that urinary cortisol would be associated with increased cardiovascular events and change in coronary artery calcium score (CAC) in women, and these relationships would vary by central obesity.

Methods

In the Multi-Ethnic Study of Atherosclerosis Stress Ancillary study, cortisol was quantified by 12-hour overnight urine collection. Central obesity was estimated by waist-hip ratio (WHR). Multivariable Cox models estimated the relationship between cortisol and cardiovascular events and assessed for moderation by WHR. The relationship between cortisol and change in CAC Agatston score was assessed by Tobit regression models.

Results

918 patients were analyzed with median follow up of 11 years. There was no association between urinary cortisol and cardiovascular events in the cohort. However, in individuals with below median WHR, higher urinary cortisol levels (upper tertile) were associated with higher cardiovascular event rates in the full cohort, women, and men, but not in groups with above median WHR. There was significant moderation by WHR in women, but not men, whereby the association between elevated cortisol and increased cardiovascular events diminished as WHR increased. Urinary cortisol was associated with increased change in CAC in women (P=0.003) but not men, without moderation by WHR.

Conclusions

Our study highlights associations between cortisol and subclinical atherosclerosis in women, and moderation of the relationship between cortisol and cardiovascular events by central obesity in both genders.
Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling
Authors: Chang Nydia P. , DaPrano Evan M. , Evans Wesley R. , Nissenbaum Marialaina , McCourt Micheal , Alzate Diego , Lindman Marissa , Chou Tsui-Wen , Atkins Colm , Kusnecov Alexander W. , Huda Rafiq , Daniels Brian P.
Published: July 2023

Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. RIPK3 signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the MPTP model of Parkinson’s disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of DAMP signaling. Using human cell culture systems, we show that factors released from dying neurons signal through RAGE to induce RIPK3-dependent astrocyte activation. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3.
Characterization of a novel temperate phage facilitatingin vitrodispersal of multicellular bacteria
Authors: Jaffal Hoda , Kortebi Mounia , Misson Pauline , Tavares Paulo , Ouldali Malika , Leh Hervé , Lautru Sylvie , Lioy Virginia S. , Lecointe François , Bury-Moné Stéphanie
Published: July 2023

Streptomycesare renowned for their prolific production of specialized metabolites with applications in medicine and agriculture. These multicellular bacteria present a sophisticated developmental cycle, and play a key role in soil ecology. Little is known aboutStreptomyces-phage interactions and the impact of phages onStreptomycesphysiology. In this study, we investigated the conditions governing the expression and production of ‘Samy’, a prophage found inStreptomyces ambofaciensATCC 23877. This siphoprophage is produced simultaneously with the activation of other mobile genetic elements. We show that Samy production increases bacterial dispersal underin vitrostress conditions. Altogether, we unveiled a new property of a bacteriophage infection that it is closely linked to the multicellular community life ofStreptomycesbacteria.

Graphical summary

IMPORTANCE

Streptomycesare multicellular bacteria producing valuable metabolites, including antibiotics, with applications in medicine and agriculture. In this study, we characterized a novel temperate phage, named Samy, and its impact on bacteria physiology. Remarkably, the presence and production of Samy increases bacterial dispersal underin vitrostress conditions. This constitutes an emerging property associated with bacteriophage infection that might enhance the spread of the species. Our study reveals a new aspect of bacteriophage infection in the context of multicellular aggregate dynamics.
Long-lived coherences for magnetic interactions in proteins
Authors: Teleanu Florin , Ciumeica Andrei , Ianc Octavian , Lupulescu Adonis , Sadet Aude , Vasos Paul R.
Published: July 2023

Living systems rely on molecular building blocks of low symmetry such as amino-acids and nucleotides, which generally yield short-lived magnetic transitions in response to electromagnetic radiation. This is the first demonstration that in proteins of relatively large size local magnetic symmetry can be induced to enable the detection of interactions based on long-lived coherent transitions of nuclear spins. Long-lived coherences (LLC’s) are superpositions of quantum states with singlet and triplet spin-permutation symmetries that feature significantly longer relaxation time constants compared to those of standard nuclear spin coherences. We report in this study that glycine residues in Lysozyme, a 14.3 kDa protein, feature Gly-Hα2,3LLC’s with relaxation time constants twice as long as the classical counterparts. Using a new excitation method for LLC’s in glycines 4, 49, 54, 67, 117, and 126, Lysozyme Gly-Hαdipolar interactions with neighboring hydrogen spins were mapped in a high magnetic field – at 950 MHz1H Larmor frequency. As predicted by theory, the positions of nearby atoms in the protein structure on one side or the other of Gly molecular symmetry planes reflecting protons Hα2,3determines the signs of LLC magnetic interaction signals. LLC-based transfers therefore yield stereospecific signals from glycine residues to1H neighboring atoms. The symmetry-encoded sign of the detected signals provides angle constraints, in addition to the distance information. LLC probes based on naturally-abundant1H spins can be useful for in-cell spectroscopy, circumventing the introduction of heterogenous spin labels for following protein-ligand or protein-protein interactions in the natural environment.

This is the first demonstration that magnetisation transfer through space from long-lived coherences can be obtained in proteins. Applications of LLC’s were believed to be limited to systems featuring fast rotational motion in solution, mainly small molecules. This new LLC-based method yields stereospecific distance constraints and has the potential to extend the protein-size domain for the study of intra- and intermolecular interactions.
Kitacrispants for systematic image-based genetic screens of complex traits in zebrafish larvae
Authors: Mazzaferro Eugenia , Metzendorf Christoph , Zhang Hanqing , Mujica Endrina , Höijer Ida , Alavioon Ghazal , Campos Costa Joao , Cook Naomi L. , Gry Vienberg Sara , Djordjevic Djordje , Larsson Anders , Ameur Adam , Emmanouilidou Anastasia , Allalou Amin , den Hoed Marcel
Published: July 2023

With thousands of loci identified by genome-wide association studies for complex traits, there is a need forin vivomodel systems that can reliably and quickly infer the role of large numbers of candidate genes. CRISPR/Cas9-based functional screens in F0zebrafish represent such a system. However, negative controls used so far – including scrambled guide RNAs (gRNAs), inactivated Cas9, and sham injections – do not elicit the same cellular and organismal responses as mutagenesis by CRISPR/Cas9, and may fuel biased conclusions. Here, we show that targetingkitafacilitates efficient optical pre-screening for successful mutagenesis, higher quality imaging data, and efficient classification of cases and controls. We identified and tested two gRNAs that targetkitawith similarly high mutagenic efficiency and effects on pigmentation, and are free from off-target effects or major effects on cardiometabolic traits. We propose several approaches that will result in valid, unbiased conclusions.
Regulation of mitochondrial calcium uniporter expression and calcium signalling by lncRNATug1in cardiomyocytes
Authors: Trewin Adam J. , Weeks Kate L. , Wadley Glenn. D. , Lamon Séverine
Published: July 2023

Cardiomyocyte calcium homeostasis is a tightly regulated process. The mitochondrial calcium uniporter (MCU) complex can buffer elevated cytosolic Ca2+levels and consists of pore-forming proteins including MCU, and various regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca2+and activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long non-coding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNATug1increased the expression ofMcuand associated genes. To further explore this, we performed antisense LNA knockdown ofTug1(Tug1KD) in H9c2 rat cardiomyocytes.Tug1KD increased MCU protein expression, yet pyruvate dehydrogenase dephosphorylation, which is indicative of mitochondrial Ca2+uptake was not enhanced. However, RNA-seq revealed thatTug1KD increasedMcualong with differential expression of >1000 genes including many related to Ca2+regulation pathways in the heart. To understand the effect of this on Ca2+signalling, we measured phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to driveMcugene expression. In response a Ca2+stimulus, the increase in CaMKII and CREB phosphorylation was attenuated byTug1KD. Inhibition of CaMKII, but not CREB, partially prevented theTug1KD- mediated increase inMcu. Together, these data suggest thatTug1modulates MCU expression via a mechanism involving CaMKII and regulates cardiomyocyte Ca2+signalling which could have important implications for cardiac function.
Metabolomic rearrangement controls the intrinsic microbial response to temperature changes
Authors: Knapp Benjamin D. , Willis Lisa , Gonzalez Carlos , Vashistha Harsh , Touma Joanna Jammal , Tikhonov Mikhail , Ram Jeffrey , Salman Hanna , Elias Josh E. , Huang Kerwyn Casey
Published: July 2023

Temperature is one of the key determinants of microbial behavior and survival, whose impact is typically studied under heat- or cold-shock conditions that elicit specific regulation to combat lethal stress. At intermediate temperatures, cellular growth rate varies according to the Arrhenius law of thermodynamics without stress responses, a behavior whose origins have not yet been elucidated. Using single-cell microscopy during temperature perturbations, we show that bacteria exhibit a highly conserved, gradual response to temperature upshifts with a time scale of ∼1.5 doublings at the higher temperature, regardless of initial/final temperature or nutrient source. We find that this behavior is coupled to a temperature memory, which we rule out as being neither transcriptional, translational, nor membrane dependent. Instead, we demonstrate that an autocatalytic enzyme network incorporating temperature-sensitive Michaelis-Menten kinetics recapitulates all temperature-shift dynamics through metabolome rearrangement, which encodes a temperature memory and successfully predicts alterations in the upshift response observed under simple-sugar, low-nutrient conditions, and in fungi. This model also provides a mechanistic framework for both Arrhenius-dependent growth and the classical Monod Equation through temperature-dependent metabolite flux.
Multiplex, quantitative, high-resolution imaging of protein:protein complexes via hybridization chain reaction
Authors: Schulte Samuel J. , Shin Boyoung , Rothenberg Ellen V. , Pierce Niles A.
Published: July 2023

Signal amplification based on the mechanism of hybridization chain reaction (HCR) facilitates spatial exploration of gene regulatory networks by enabling multiplex, quantitative, high-resolution imaging of RNA and protein targets. Here, we extend these capabilities to the imaging of protein:protein complexes, using proximity-dependent cooperative probes to conditionally generate a single amplified signal if and only if two target proteins are colocalized within the sample. HCR probes and amplifiers combine to provide automatic background suppression throughout the protocol, ensuring that even if reagents bind nonspecifically in the sample, they will not generate amplified background. We demonstrate protein:protein imaging with high signal-to-background in human cells, mouse proT cells, and highly autofluorescent formalin-fixed paraffin-embedded (FFPE) human breast tissue sections. Further, we demonstrate multiplex imaging of 3 different protein:protein complexes simultaneously and validate that HCR enables accurate and precise relative quantitation of protein:protein complexes with subcellular resolution in an anatomical context. Moreover, we establish a unified framework for simultaneous multiplex, quantitative, high-resolution imaging of RNA, protein, and protein:protein targets, with 1-step, isothermal, enzyme-free HCR signal amplification performed for all target classes simultaneously.

Abstract Figure
Recombinant Ranpirnase enhances the expression of co-transfected mRNA by modulating cellular metabolic activity
Authors: Wu Xiujin , Chen Liang , Lei Yingxue , Peng Xu , Zhang Yaoyi , Yang Guang , Yin Hailin , Xu Kai
Published: July 2023

As the world’s first approved prophylactic mRNA vaccine, the development of the Covid-19 mRNA vaccine marks a milestone in mRNA therapeutics. However, achieving efficient transgene expression in therapeutic applications such as protein replacement and cancer therapeutical vaccines remains challenging. This study explores the use of recombinant Ranpirnase, a small ribonuclease, as a novel expression-enhancing tool for mRNA-based therapeutics. In Balb/c mice, co-expression of Ranpirnase significantly increased transgene expression levels by 3-to 6-fold and prolonged expression duration by more than 85%, regardless of mRNA nucleoside modification status. Recombinant Ranpirnase induces a cytostatic state in host cells, stabilizing mRNA and protein transcripts, thereby enhancing transgene expression. Importantly, co-expression of Ranpirnase recombinants did not cause detectable cytotoxicity or alter the tissue distribution of transgene expression, ensuring safety and tolerability at higher translation levels. The compact size of the recombinant Ranpirnase gene allows for seamless fusion with the target gene or co-transfection with existing delivery technologies. Altogether, recombinant Ranpirnase shows promise as an expression-enhancing element in mRNA-based therapeutics, including veterinary applications.
Evaluating AI-Assistance for Pathologists in Diagnosing and Grading Laryngeal Lesions
Authors: Bellahsen-Harrar Yaëlle , Lubrano Mélanie , Lépine Charles , Beaufrère Aurélie , Bocciarelli Claire , Brunet Anaïs , Decroix Elise , El-Sissy Franck Neil , Fabiani Bettina , Morini Aurélien , Tilmant Cyprien , Walter Thomas , Badoual Cécile
Published: July 2023

Importance

Diagnosis of head and neck squamous dysplasias and carcinomas is challenging, with a moderate inter-rater agreement. Nowadays, new artificial intelligence (AI) models are developed to automatically detect and grade lesions, but their contribution to the performance of pathologists hasn’t been assessed.

Objective

To evaluate the contribution of our AI tool in assisting pathologists in diagnosing squamous dysplasia and carcinoma in the head and neck region.

Design, Setting, and Participants

We evaluated the effectiveness of our previously described AI model, which combines an automatic classification of laryngeal and pharyngeal squamous lesions with a confidence score, on a panel of eight pathologists coming from different backgrounds and with different levels of experience on a subset of 115 slides.

Main Outcomes and Measures

The main outcome was the inter-rater agreement, measured by the weighted linear kappa. Other outcomes on diagnostic efficiency were assessed using pairedttests.

Results

AI-Assistance significantly improved the inter-rater agreement (linear kappa 0.73, 95%CI [0.711-0.748] with assistance versus 0.675, 95%CI [0.579-0.765] without assistance, p < 0.001). The agreement was even better on high confidence predictions (mean linear kappa 0.809, 95%CI [0.784-0.834] for assisted review, versus 0.731, 95%CI [0.681-0.781] non-assisted, p = 0.018). These improvements were particularly strong for non-specialized and younger pathologists. Hence, the AI-Assistance enabled the panel to perform on par with the expert panel described in the literature.

Conclusions and Relevance

Our AI-Assistance is of great value for helping pathologists in the difficult task of diagnosing squamous dysplasias and carcinomas, improving for the first time the inter-rater agreement. It demonstrates the possibility of a truly Augmented Pathology in complex tasks such as the classification of head and neck squamous lesions.
The rare DRB1*04-DQ8 haplotype is the main discriminative HLA class II genetic driver of Early-Onset Type 1 Diabetes in the Portuguese population
Authors: Caramalho Iris , Matoso Paula , Ligeiro Dário , Paixão Tiago , Sobral Daniel , Fitas Ana Laura , Limbert Catarina , Demengeot Jocelyne , Penha-Gonçalves Carlos
Published: July 2023

Background

Early-onset Type 1 diabetes (EOT1D) is considered a disease subtype with distinctive immunological and clinical features. While both Human Leukocyte Antigen (HLA) and non-HLA variants contribute to age at T1D diagnosis, detailed analyses of EOT1D-specific genetic determinants are still lacking. This study scrutinized the involvement of the HLA class II locus in EOT1D genetic control.

Methods

We conducted genetic association and regularized logistic regression analyses to evaluate genotypic, haplotypic and allelic variants inDRB1,DQA1andDQB1genes in children with EOT1D (diagnosed at ≤5 years of age; n=97), individuals with later-onset disease (LaOT1D; diagnosed 8-30 years of age; n=96) and nondiabetic control subjects (n=169), in the Portuguese population.

Findings

Analysis of EOT1D and LaOT1D unrelated patients in comparison with controls, revealed the rare DRB1*04:08-DQ8 haplotype is specifically associated with EOT1D (corrected p-value=1.4×10-5) and represents the major discriminative HLA class II genetic factor. Allelic association further indicated the DRB1*04:08 allele is a distinctive EOT1D susceptibility factor (corrected p-value=7.0×10-7). Conversely, the classical T1D risk allele DRB1*04:05 was absent in EOT1D children while was associated with LaOT1D (corrected p-value=1.4×10-2).

Interpretation

This study uncovered that EOT1D holds a distinctive spectrum of HLA class II susceptibilityloci, which includes risk factors overlapping with LaOT1D and discriminative genetic configurations. These findings warrant replication studies in larger multicentric settings and may impact target screening strategies and follow-up of young children with high T1D genetic risk.

Funding

European Foundation for the Study of Diabetes, Maratona da Saúde and Fundação para a Ciência e a Tecnologia.
Seasonal malaria chemoprevention and the spread ofPlasmodium falciparumquintuple mutant parasites resistant to sulfadoxine-pyrimethamine: a modelling study
Authors: Masserey Thiery , Lee Tamsin , Kelly Sherrie L , Hastings Ian M , Penny Melissa A
Published: July 2023

Background

Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) prevents millions of clinical malaria cases in children under five in Africa’s Sahel region. However, parasites partially resistant to SP (with “quintuple” mutations) potentially threaten SMC protective effectiveness. We evaluated its spread and clinical consequences.

Methods

An individual-based malaria transmission model with explicit parasite dynamics and drug pharmacological models, was used to identify and quantify the influence of factors driving quintuple mutant spread and predict the time needed for the mutant to spread from 1% to 50% of inoculations for several SMC deployment strategies. We estimated the impact of this spread on SMC effectiveness against clinical malaria.

Findings

Higher transmission intensity, SMC coverage, and expanded age range of chemoprevention promoted mutant spread. SMC implementation in a high transmission setting (40% parasite prevalence in children aged 2-10 years) with four monthly cycles to children aged three months to five years (with 95% initial coverage declining each cycle), the mutant requires 53·1 years (95% CI 50·5–56·0) to spread from 1% to 50% of inoculations. This time increased in lower transmission settings and reduced by half when SMC was extended to children under ten, or reduced by 10-13 years when an additional monthly cycle of SMC was deployed. For the same setting, the effective reduction in clinical cases in children receiving SMC was 79·0% (95% CI 77·8–80·8) and 60·4% (95% CI 58·6–62·3) during the months of SMC implementation when the mutant was absent or fixed in the population, respectively.

Interpretation

SMC with SP+AQ leads to a relatively slow spread of SP-resistant quintuple mutants and remains effective at preventing clinical malaria despite the mutant spread. SMC with SP+AQ should be considered in seasonal settings where this mutant is already prevalent.

Funding

Swiss National Science Foundation and Marie Curie Individual Fellowship.
Antibiotics of the future are prone to resistance in Gram-negative pathogens
Authors: Daruka Lejla , Czikkely Márton Simon , Szili Petra , Farkas Zoltán , Balogh Dávid , Grézal Gábor , Maharramov Elvin , Vu Thu-Hien , Sipos Levente , Juhász Szilvia , Dunai Anett , Daraba Andreea , Számel Mónika , Sári Tóbiás , Stirling Tamás , Vásárhelyi Bálint Márk , Ari Eszter , Christodoulou Chryso , Manczinger Máté , Enyedi Márton Zsolt , Jaksa Gábor , Kovács Károly , van Houte Stineke , Pursey Elizabeth , Pintér Lajos , Haracska Lajos , Kintses Bálint , Papp Balázs , Pál Csaba
Published: July 2023

Despite the ongoing development of new antibiotics, the future evolution of bacterial resistance may render them ineffective. We demonstrate that antibiotic candidates currently under development are as prone to resistance evolution in Gram-negative pathogens as clinically employed antibiotics. Resistance generally stems from both genomic mutations and the transfer of antibiotic resistance genes from microbiomes associated with humans, both factors carrying equal significance. The molecular mechanisms of resistance overlap with those found in commonly used antibiotics. Therefore, these mechanisms are already present in natural populations of pathogens, indicating that resistance can rapidly emerge through selection of pre-existing bacterial variants. However, certain combinations of antibiotics and bacterial strains are less prone to developing resistance, emphasizing the potential of narrow-spectrum antibacterial therapies that could remain effective. Our comprehensive framework allows for predicting future health risks associated with bacterial resistance to new antibiotics.
The Arf-GAP Age2 localizes to the late-Golgi via a conserved amphipathic helix
Authors: Manzer Kaitlyn M. , Fromme J. Christopher
Published: July 2023

Arf GTPases are central regulators of the Golgi complex, which serves as the nexus of membrane trafficking pathways in eukaryotic cells. Arf proteins recruit dozens of effectors to modify membranes, sort cargos, and create and tether transport vesicles, and are therefore essential for orchestrating Golgi trafficking. The regulation of Arf activity is controlled by the action of Arf-GEFs, which activate via nucleotide exchange, and Arf-GAPs, which inactivate via nucleotide hydrolysis. The localization dynamics of Arf GTPases and their Arf-GAPs during Golgi maturation have not been reported. Here we use the budding yeast model to examine the temporal localization of the Golgi Arf-GAPs. We also determine the mechanisms used by the Arf-GAP Age2 to localize to the Golgi. We find that the catalytic activity of Age2 and a conserved sequence in the unstructured C-terminal domain of Age2 are both required for Golgi localization. This sequence is predicted to form an amphipathic helix and mediates direct binding of Age2 to membranesin vitro. We also report the development of a probe for sensing active Arf1 in living cells and use this probe to characterize the temporal dynamics of Arf1 during Golgi maturation.
Endocytic vesicles act as vehicles for glucose uptake in response to growth factor stimulation
Authors: Tsutsumi Ryouhei , Ueberheide Beatrix , Liang Feng-Xia , Neel Benjamin G. , Sakai Ryuichi , Saito Yoshiro
Published: July 2023

Glycolysis is a fundamental cellular process, yet its regulatory mechanisms remain incompletely understood. Here, we show that a subset of glucose transporter 1 (GLUT1/SLC2A1) co-endocytoses with platelet-derived growth factor (PDGF) receptor (PDGFR) upon PDGF-stimulation. Furthermore, multiple glycolytic enzymes localize to these endocytosed PDGFR/GLUT1-containing vesicles adjacent to mitochondria. Contrary to current models, which emphasize the importance of glucose transporters on the cell surface, we find that PDGF-stimulated glucose uptake depends on receptor/transporter endocytosis. Our results suggest that growth factors generate glucose-loaded endocytic vesicles that deliver glucose to the glycolytic machinery in proximity to mitochondria, and argue for a new layer of regulation for glycolytic control governed by cellular membrane dynamics.
The epidemiological investigation of hyperlipidemia in the northern Henan Province
Authors: Lu Xing , Lin Ziyang , Yang Junzheng
Published: July 2023

Background/purpose

Hyperlipidemia is a kind of diseases with the characteristic of high level of blood lipids, it could directly result in several serious diseases including atherosclerosis and coronary heart disease to threat to human health. Therefore, to understand the epidemiological status and risk factors of hyperlipidemia is important for the prevention, diagnosis, and treatment of hyperlipidemia.

Methods

The clinical data in Xinxiang Central Hospital from 2019-2021 were collected, and those data were classified and analyzed according to the basic information of investigation subjects and risk factors.

Results

A total of 670 investigation subjects were collected in this investigation including 521 males and 149 females, accounting for 77.76% and 22.24% in the total investigation population, respectively; age range of investigation subjects was 20-97 year old; there were 390 people with a history of smoking and 346 people were never smoking, accounting for 58.21% and 51.64% in the total investigation population, respectively; in this investigation, the proportion of peasant farmers was the highest (353/670, 52.69%), followed by retire population (164/670, 24.48%); in terms of education level, the proportion of people graduating from middle school was the highest (338/670, 50.45%), followed by those graduating from primary school (249/670, 37.16%); the statistical results found that the incident of hyperlipidemia were correlated to gender (P<0.01), ethnicity (P<0.01), age (P<0.05), marital status (P<0.05), education level (P<0.001), hypertension (P<0.05) and diabetes mellitus (P<0.001), had no relation to occupation (P>0.05), cerebral hemorrhage, angina pectoris, ischemic stroke, gastrointestinal ulcers, coronary heart disease, chronic renal insufficiency, myocardial infarction, heart failure, peripheral artery disease, chronic obstructive pulmonary disease (P>0.05).

Conclusion

The epidemiological status of hyperlipidemia in northern Henan Province had the specificity, the incident of hyperlipidemia was correlated to gender, ethnicity, age, marital status, education level, hypertension, and diabetes mellitus, those results may provide basis for the prevention and treatment for hyperlipidemia in northern Henan Province.
Federated analysis of the contribution of recessive coding variants to 29,745 developmental disorder patients from diverse populations
Authors: Chundru V. Kartik , Zhang Zhancheng , Walter Klaudia , Lindsay Sarah , Danecek Petr , Eberhardt Ruth Y. , Gardner Eugene J. , Malawsky Daniel S. , Wigdor Emilie M. , Torene Rebecca , Retterer Kyle , Wright Caroline F. , McWalter Kirsty , Sheridan Eamonn , Firth Helen V. , Hurles Matthew E. , Samocha Kaitlin E. , Ustach Vincent D. , Martin Hilary C.
Published: July 2023

Autosomal recessive (AR) coding variants are a well-known cause of rare disorders. We quantified the contribution of these variants to developmental disorders (DDs) in the largest and most ancestrally diverse sample to date, comprising 29,745 trios from the Deciphering Developmental Disorders (DDD) study and the genetic diagnostics company GeneDx, of whom 20.4% have genetically-inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide AR coding variants ranged from ∼2% to ∼18% across genetically-inferred ancestry groups, and was significantly correlated with the average autozygosity (r=0.99, p=5x10-6). Established AR DD-associated (ARDD) genes explained 90% of the total AR coding burden, and this was not significantly different between probands with genetically-inferred European versus non-European ancestries. Approximately half the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. We estimated that ∼1% of undiagnosed patients in both cohorts were attributable to damaging biallelic genotypes involving missense variants in established ARDD genes, highlighting the challenge in interpreting these. By testing for gene-specific enrichment of damaging biallelic genotypes, we identified two novel ARDD genes passing Bonferroni correction,KBTBD2(p=1x10-7) andCRELD1(p=9x10-8). Several other novel or recently-reported candidate genes were identified at a more lenient 5% false-discovery rate, includingZDHHC16andHECTD4. This study expands our understanding of the genetic architecture of DDs across diverse genetically-inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may allow us to diagnose more patients than discovering the remaining genes.
SCN9A gene therapy: Novel mechanism to inhibit cellular senescence in astrocytesin vitro
Authors: Shah Divyash , Leonardi Donna , Waldron Alyssa
Published: July 2023

Cellular aging, also known as senescence, is a form of proliferation arrest that occurs in cells with age. In individuals, this process occurs due to telomere degradation and consequent dysfunction. In the nervous system, senescence of astrocytes, the most common neuronal support cells, has been associated with inflammation and forms of neurodegeneration associated with various disease pathologies. Thus, studying senescence may be a unique approach to understanding brain and aging and consequential diseases as well. Studies have shown that transcription downregulation of SCN9A led to reversal of senescence in epithelial cells. So, this study explores the role of SCN9A in astrocytes.

In silicopatient gene analysis reveals multiple significant pathways associated with neuronal aging including ion channel regulation. Subsequent analysis shows the downregulation of SCN9A is associated with genes in the neuronal senescence pathway.In vitrostudies showed that astrocytes with knockdowned SCN9A did not undergo senescence as significantly as regular astrocytes. Furthermore, protein analysis presented a novel role for SCN9A in the astrocyte senescence pathway and an association with preventing DNA leakage. This study suggests SCN9A plays a large role in neurodegeneration and it should be studied in reversing senescence and even treatment plans for brain aging.
Downregulation of a cell polarity protein potentiates Chikungunya Virus infection in host cells
Authors: Kumar Ramesh , Tatiya Pushkar , Dey Debajit , Ratra Yashika , Mian Syed Yusuf , Chaudhary Shikha , Suhag Kirti , Basak Soumen , Banerjee Manidipa
Published: July 2023

Downregulation of the host cell pro-apoptotic pathways confers a selective advantage to viral pathogens, and many viruses interfere with such regulatory mechanisms in order to enhance their propagation in infected cells. The Scribble cell polarity complex, which is composed of multiple adapter proteins including human Scribble, Dlg and MAGI, controls a variety of host cell functionalities including apoptosis, morphology, polarity, signaling and migration. In the recent years, components from several viral pathogens, including oncogenic viruses, have been found to associate with and modulate the activities of this complex, particularly that of the proapoptotic protein Scribble. Here, we establish a critical role for the downregulation of Scribble expression for the potentiation of Chikungunya Virus (CHIKV) infection. CHIKV is a well-known mosquito-borne alphavirus, which has caused outbreaks in more than 100 countries and constitutes a global health hazard. While the majority of the CHIKV proteome is well characterized, the role of a small structural protein 6K, and its transframe variant, TF, which is generated from the 6K sequence by ribosomal slippage and frameshifting, is not established as yet. We show that TF triggers the punctation, ubiquitination and degradation of Scribble during CHIKV infection, and that the downregulation of Scribble during CHIKV infection. We show that the association of TF with the PDZ domains of Scribble is mediated through a PDZ-domain binding motif at the C-terminus of TF. Thus, our work establishes a role for the downregulation of Scribble in alphavirus infections for the first time, while allocating a novel role in host modulation to the mysterious 6K/TF component of alphaviruses.
Evolution of cullin E3 ubiquitin ligases and function in trypanosomes
Authors: del Pino Ricardo Canavate , Zoltner Martin , Yamada Kayo , Butterfield Erin R. , Field Mark C.
Published: July 2023

Post-translational modifications (PTMs) modulate protein function, with ubiquitylation a pre-eminent example with major roles in protein turnover. Ubiquitylation utilises a ligase enzyme cascade for conjugation of ubiquitin to client proteins and cullin-RING ligases are amongst the most complex known. We reconstructed evolution of cullin-RING E3 ubiquitin ligases across eukaryotes and experimentally characterised two cullin complexes in trypanosomatids, a taxon highly divergent from animals and fungi. We find considerable diversity within cullins and, in particular, trypanosomatids share only a minority of cullins with other lineages. Furthermore, we identify expansions in cullin client adaptor protein families, novel client adaptors and demonstrate client specificity. Finally we show that ornithine decarboxylase (TbODC), an important target of the drug trypanosome eflornithine, is a substrate for TbCul-A and overturn earlier models for eflornithine specificity. These studies highlight lineage-specific roles for cullin E3s and their contributions towards eukaryotic complexity.
Characterization of Pik1 function in fission yeast reveals its conserved role in lipid synthesis and not cytokinesis
Authors: Willet Alaina H. , Turner Lesley A. , Park Joshua S. , Ren Liping , Snider Chloe E. , Gould Kathleen L.
Published: July 2023

Phosphatidylinositol (PI)-4-phosphate (PI4P) is a lipid found at the plasma membrane (PM) and Golgi in cells from yeast to humans. PI4P is generated from PI by PI4-kinases and can be converted to PI-4,5-bisphosphate [PI(4,5)P2].Schizosaccharomyces pombehave 2 essential PI4-kinases: Stt4 and Pik1. Stt4 localizes to the PM and its loss from the PM results in a decrease of PM PI4P and PI(4,5)P2. As a result, cells divide non-medially due to disrupted cytokinetic ring-PM anchoring. However, the localization and function ofS. pombePik1 has not been thoroughly examined. Here, we found that Pik1 localizes exclusively to the trans-Golgi and is required for Golgi PI4P production. We determined that Ncs1 regulates Pik1, but unlike in other organisms, it is not required for Pik1 Golgi localization. When Pik1 function was disrupted, PM PI4P but not PI(4,5)P2levels were reduced, a major difference with Stt4. We conclude that Stt4 is the chief enzyme responsible for producing the PI4P that generates PI(4,5)P2. Also, that cells with disrupted Pik1 do not divide asymmetrically highlights the specific importance of PM PI(4,5)P2for cytokinetic ring-PM anchoring.

Summary statement

Fission yeast Pik1 localizes exclusively to the trans-Golgi independently of Ncs1, where it contributes to PI4P but not PI(4,5)P2synthesis. Pik1 does not affect cytokinesis.
Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins
Authors: Avolio Rosario , Agliarulo Ilenia , Criscuolo Daniela , Sarnataro Daniela , Auriemma Margherita , De Lella Sabrina , Pennacchio Sara , Calice Giovanni , Ng Martin Y. , Giorgi Carlotta , Pinton Paolo , Cooperman Barry S. , Landriscina Matteo , Esposito Franca , Matassa Danilo Swann
Published: July 2023

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein, we identify the molecular mechanisms involved, showing that TRAP1 (1) binds both mitochondrial and cytosolic ribosomes, as well as translation elongation factors; (2) slows down translation elongation rate; and (3) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.
Activation of prefrontal cortex and striatal regions in rats after shifting between rules in a T-maze
Authors: Oberto Virginie , Gao Hongying , Biondi Ana , Sara Susan J. , Wiener Sidney I.
Published: July 2023

Prefrontal cortical and striatal areas have been identified by inactivation or lesion studies to be required for behavioral flexibility, including selecting and processing of different types of information. In order to identify these networks activated selectively during the acquisition of new reward contingency rules, rats were trained to discriminate orientations of bars presented in pseudorandom sequence on two video monitors positioned behind the goal sites on a T-maze with return arms. A second group already trained in the visual discrimination task learned to alternate left and right goal arm visits in the same maze while ignoring the visual cues still being presented. In each experimental group, once the rats reached criterion performance, the brains were prepared after a 90-min delay for later processing for c-fos immunohistochemistry. While both groups extinguished a prior strategy and acquired a new rule, they differed by the identity of the strategies and previous learning experience. Among the 28 forebrain areas examined, there were significant increases in the relative density of c-fos immunoreactive cell bodies after learning the second rule in the prefrontal cortex cingulate, the prelimbic and infralimbic areas, the dorsomedial striatum and the core of the nucleus accumbens, the ventral subiculum, and the central nucleus of the amygdala. These largely correspond to structures previously identified in inactivation studies, and their neurons fire synchronously during learning and strategy shifts. The data suggest that this dynamic network may underlie reward-based selection for action—a type of cognitive flexibility.
Delone lattice studies in C
3, the space of three complex variables
Authors: Andrews Lawrence C. , Bernstein Herbert J.
Published: July 2023

The Delone (Selling) scalars, which are used in unit-cell reduction and in lattice-type determination, are studied in C
3, the space of three complex variables. The three complex coordinate planes are composed of the six Delone scalars. The transformations at boundaries of the Selling-reduced orthant are described as matrices of operators. A graphical representation as the projections onto the three coordinates is described. Note, in his later publications, Boris Delaunay used the Russian version of his surname, Delone.