bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical integration of tactile inputs distributed across timescales
Authors: Wan Wenyu , Ridderinkhof K. Richard , Ghosh Arko
Published: July 2024

Sensory experiences in the real world cut across timescales from milliseconds to seconds. Emerging evidence suggests that somatosensory processing is sensitive to the temporal structure of the stimuli in the sub-second scale, yet only a few select ranges within this scale have been studied. To process real-world information, the integration of tactile inputs must occur over a much broader temporal range. To address temporal integration across timescales, we recorded scalp EEG signals from somatosensory cortex in response to a train of tactile pulses presented to the fingertips with varying inter-stimulus intervals (ISI) spanning 100 to 10,000 ms. To capture a rich variety of influences of the temporal structure on the cortical signals, we used a multi-dimensional event-related potential where the stimulations are separated according to the next interval structure. We tracked cortical tactile processing through its early (<75 ms), intermediate (75 to 150 ms) and late stages (150 to 300 ms). We find that the early and late stages of cortical activity were similarly dominated by the preceding ISI; EEG signals were suppressed with ISIs < 500 ms and enhanced with longer ISIs, with this effect persisting even when ISIs were approximately 8 seconds. The intermediate stage of cortical activity was sensitive to both the previous and the penultimate ISIs. Our findings suggest that the specific somatosensory cortical networks integrate temporal structure across timescales to enable complex sensory experiences.
Transformer Graph Variational Autoencoder for Generative Molecular Design
Authors: Nguyen Trieu , Karolak Aleksandra
Published: July 2024

In the field of drug discovery, the generation of new molecules with desirable properties remains a critical challenge. Traditional methods often rely on SMILES (Simplified Molecular Input Line Entry System) representations for molecular input data, which can limit the diversity and novelty of generated molecules. To address this, we present the Transformer Graph Variational Autoencoder (TGVAE), an innovative AI model that employs molecular graphs as input data, thus captures the complex structural relationships within molecules more effectively than string models. To enhance molecular generation capabilities, TGVAE combines a Transformer, Graph Neural Network (GNN), and Variational Autoencoder (VAE). Additionally, we address common issues like over-smoothing in training GNNs and posterior collapse in VAE to ensure robust training and improve the generation of chemically valid and diverse molecular structures. Our results demonstrate that TGVAE outperforms existing approaches, generating a larger collection of diverse molecules and discovering structures that were previously unexplored. This advancement not only brings more possibilities for drug discovery but also sets a new level for the use of AI in molecular generation.
Control of cholesterol-induced adipocyte inflammation by the Nfe2l1-Atf3 pathway
Authors: Jethwa Carolin , Hoffmann Anne , Kotschi Stefan , Caesar Janina , Kern Matthias , Worthmann Anna , Schlein Christian , Khani Sajjad , Arús Bernardo A. , Bruns Oliver T. , Ghosh Adhideb , Wolfrum Christian , Döring Yvonne , Herzig Stephan , Weber Christian , Blüher Matthias , Widenmaier Scott B. , Hotamışlıgil Gökhan S. , Bartelt Alexander
Published: July 2024

While adipocytes are critical pillars of energy metabolism, their dysfunction is linked to adipose tissue (AT) inflammation, insulin resistance, and ectopic lipotoxicity in cardiometabolic diseases. However, the mechanisms causing adipocyte inflammation and insulin resistance remain unclear. Here, we show that excess cholesterol induces adipocyte dysfunction, which is suppressed by the transcription factor Nfe2l1 (nuclear factor erythroid derived-2, like-1). Nfe2l1 is required to sustain proteasome function in adipocytes and proteotoxic stress induces adipocyte inflammation via the activation of Atf3. In humans, the Nfe2l1-proteasome pathway is inversely correlated to body mass index (BMI) in an adipose-depot specific manner. In mice, loss of adipocyte Nfe2l1 caused AT inflammation with a pronounced infiltration of macrophages and T cells. Mice lacking adipocyte Nfe2l1 displayed severe adipocyte dysfunction during diet-induced obesity (DIO), characterized by lower adipokine levels, steatosis, glucose intolerance and insulin resistance.Nfe2l1ΔATmice on an Apoe-deficient (Apoe−/−) background fed a cholesterol-rich Western Diet (WD), developed a lipoatrophy-like syndrome, dyslipidemia, and enhanced atherosclerosis. Our results reveal an important role for proteasome-mediated proteostasis in adipocytes and indicate that Nfe2l1 is linked to metabolic health in humans and preclinical mouse models. Promoting proteostasis in adipocytes may thus alleviate inflammation in obesity, potentially averting adverse cardiometabolic outcomes.

Graphical abstract
Integratingin silicopredictions with an engineered tissue assay identifies Perlecan as an age-perturbed re-quiescence cue for muscle stem cells
Authors: Jacques Erik , Garcia Pauline , Mercier Orane , Hu Yechen , Degletagne Cyril , Ravent Jade , Fall Sidy , Almeida Maira P. , Wheeler Aaron R. , Angers Stephane , Gilbert Penney M. , Le Grand Fabien
Published: July 2024

Skeletal muscle regeneration is mediated by resident muscle stem cells that produce progeny to repair or recreate muscle. Critical to this function is the ability to transition between states of proliferation and quiescence. This balancing act is disrupted with age, leading to eroded regenerative capacity. Notwistanding, mechanisms by which the regenerating niche directs MuSCs return to the dormant state are largely unknown. Since single-cell RNAseq methods exclude the analysis of multinucleated cells, we generated single-nuclei RNAseq datasets of regenerating muscle to capture the full breadth of myogenic progression. With this, we uncovered new transition states between differentiating myocytes and syncytial multinucleated cells. Using cell communication inference tools, we highlighted receptor-ligand interactions between MuSCs and fusing nuclei. We leveraged a bespoke biomimetic 3D niche that induces MuSC quiescence, to filter the predicted interactions using a Cas9-based functional genomics approach. We found the proteoglycan Perlecan (Hspg2) promotes MuSC re-quiescence.Hspg2silencingin vivo, during muscle regeneration, induced an aging-like phenotype and perturbed MuSC re-quiescence. Notably, the temporal profile and overall levels of Perlecan were altered with age. Exogenous supplementation with Endorepellin (truncated Perlecan) rescued MuSC decline following aged muscle regeneration, offering a new therapeutic target. Thus, couplingin silicopredictions with a 3Din vitroassay followed byin vivoinvestigations revealed a previously inaccessible window of biology; that spatiotemporal coordination of MuSC re-quiescence is directed by fusing myonuclei.
Parallel selection in domesticated Atlantic salmon from divergent founders including parallel selection on WGD-derived homeologous regions
Authors: Buso Pauline , Diblasi Célian , Manousi Domniki , Kwak Jun Soung , de Leon Arturo Vera Ponce , Stenløkk Kristina , Barson Nicola , Saitou Marie
Published: July 2024

Aquaculture has a considerably shorter history compared to the domestication of plants and animals. Among aquatic species, those that have undergone whole genome duplication events (WGD) seem particularly successful. This suggests that genetic redundancy from WGD is important for domestication, possibly similar to plant domestication. Atlantic salmon (Salmo salar), which has experienced a lineage-specific WGD, has undergone rapid domestication through intensive breeding since the 1960s.

Here, we examined the genomic responses to the domestication of Atlantic salmon, including the impacts of WGD, by comparing the whole genome sequence data of aquaculture and wild populations from two lineages: the Eastern and Western Atlantic (Western Norway and North America). Our analysis revealed shared selective sweeps on identical SNPs in major histocompatibility complex (MHC) genes across distinct aquaculture populations compared to their wild counterparts. This SNP level parallelism suggests that a combination of long-term balancing selection and recent human-induced selection has significantly shaped the evolutionary trajectory of MHC genes. In addition, we observed selective sweeps on gene pairs in the homeologous regions originating from WGD, highlighting WGD’s role in maintaining genomic variation and potentially reducing pleiotropy through sub-functionalization.

This unique type of “parallel” selection contributes to adapting to the intensive artificial conditions of aquaculture. These findings provide valuable insights into the genetic mechanisms of domestication and adaptive responses in Atlantic salmon, suggesting that the salmonid whole genome duplication has underpinned their successful rapid domestication. Our research emphasizes the importance of maintaining genetic diversity to support sustainable aquaculture practices.
T6SS-mediated competition byStenotrophomonas rhizophilashapes seed-borne bacterial communities and seed-to-seedling transmission dynamics
Authors: Garin Tiffany , Brault Agathe , Marais Coralie , Briand Martial , Préveaux Anne , Simonin Marie , Barret Matthieu , Sarniguet Alain
Published: July 2024

Seeds harbor diverse microbial communities important for plant growth and health. During germination, seed exudation triggers intense microbial competition, shaping the communities transmitted to seedlings. This study explores the role of the bacterial type VI secretion system (T6SS)-mediated interference competition in seed microbiota transmission to seedlings. Distribution of T6SS within 180 genome sequences of seed-borne bacterial strains enabled the construction of SynCom with different levels of phylogenetic diversity and T6SS richness. These SynComs were inoculated withStenotrophomonas rhizophilaCFBP13503, a bacterial strain which possesses a T6SS activein vitroandin planta. SynComs compositions were comparedin vitrowith CFBP13503 wild-type strain or its isogenic T6SS-deficient mutant. Additionally, the effects of T6SS on the whole bacterial community dynamics during seed-to-seedling transmission were examined following seed-inoculation. The T6SS ofS. rhizophilaCFBP13503 targeted a large number of bacteria belonging to 5 different families The phylogenetic proximity and metabolic overlap of preys with CFBP13503 partly explains the sensitivity phenotype observed. The T6SS of CFBP13503 modulates the abundance of a few specific bacterial taxa during seed-to-seedling transmission depending on seed microbial initial inoculation and plant stage. Depending on the sensitivity of the co-inoculated competitors, the T6SS can provide a competitive advantage to CFBP13503, resulting in an increase in population size.

Importance

The high prevalence of T6SS in seed-borne bacteria supports the importance of T6SS-mediated competition for seed microbiota assembly.In vitro,S. rhizophilaCFBP13503 T6SS exerts a strong impact on bacterial community dynamics. The susceptibility to T6SS increases with the phylogenetic and metabolic proximity of bacteria to CFBP13503, suggesting an influence of interspecies trophic patterns in T6SS-mediated competitions.In plantaand in soil, CFBP13503 T6SS influences specific bacterial taxa, leading to shifts in bacterial interactions and distinct community dynamics. T6SS-mediated competition plays a pivotal role in shaping seed bacterial communities and the dynamics of seed-to-seedling transitions.
Preclinical Pediatric Molecular Analysis for Therapy Choice (MATCH)
Authors: Blankenship Kaley , Chang Ti-Cheng , Fan Yiping , Gordon Brittney , Wright William C. , Kieffer Matthew , Karlstrom Asa , Jeon Jongrye , Patel Anand G. , Dapper Jason , Caufield William V. , Freeman Burgess B. , Federico Sara , Clay Michael R. , Wu Gang , Zhou Xin , Hoffmann Lauren , Geeleher Paul , Dyer Michael A. , McEvoy Justina , Stewart Elizabeth
Published: July 2024

Pediatric solid tumors arise from diverse tissues during development and exhibit a wide range of molecular, cellular and genetic features. This diversity, combined with the low incidence of pediatric cancer makes it increasingly difficult to personalize therapy for individual patients based on the unique features of their tumors. Therefore, well-credentialed preclinical models that capture the diversity and heterogeneity of pediatric solid tumors are essential for identifying molecular targeted therapeutics for precision medicine. Here, we report 281 orthotopic patient derived xenografts (O-PDXs) from 224 patients representing 24 different types of pediatric solid tumors. We have performed genomic characterization of the O-PDXs and compared them to their corresponding patient tumors. To demonstrate the feasibility and utility of using such a diverse collection of O-PDXs in preclinical studies, we performed a preclinical pediatric precision medicine trial based on the NCI-COG Pediatric MATCH trial enrollment criteria. We also tested molecular targeted therapy for a novel oncogenic fusion recently reported in pediatric melanoma and precision drug delivery using nano-liposomal irinotecan. Our studies demonstrate the value of large, well-credentialed preclinical models for future precision medicine in pediatric oncology using single agents, drug combinations and novel drug formulations.

Translational Relevance

This study demonstrates the value of utilizing fully characterized preclinical models of pediatric solid tumors to evaluate the response to precision medicine approaches. Our results demonstrate the importance of performing comprehensive preclinical testing using multiple orthotopic patient derived xenografts to validate and prioritize vulnerabilities identified through genomic or integrated analyses which can be translated into clinical trials. Importantly, this study identified combinations using nano-liposomal irinotecan in a precision drug delivery approach that may benefit pediatric solid tumor patients. In addition, all models and their associated data are made freely available to the scientific community through the Childhood Solid Tumor Network.
Impaired fatty acid import or catabolism in macrophages restricts intracellular growth ofMycobacterium tuberculosis
Authors: Simwela Nelson V. , Jaecklein Eleni , Sassetti Christopher M. , Russell David G.
Published: July 2024

Abstract

Mycobacterium tuberculosis(Mtb) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellularMtbutilize host derived lipids to maintain infection, the role of macrophage lipid processing on the bacteria’s ability to access the intracellular lipid pool remains undefined. We utilized a CRISPR-Cas9 genetic approach to assess the impact of sequential steps in fatty acid metabolism on the growth of intracellularMtb. Our analyzes demonstrate that macrophages which cannot either import, store or catabolize fatty acids restrictMtbgrowth by both common and divergent anti-microbial mechanisms, including increased glycolysis, increased oxidative stress, production of pro-inflammatory cytokines, enhanced autophagy and nutrient limitation. We also show that impaired macrophage lipid droplet biogenesis is restrictive toMtbreplication, but increased induction of the same fails to rescueMtbgrowth. Our work expands our understanding of how host fatty acid homeostasis impactsMtbgrowth in the macrophage.
Cleavage region organizes the structural architecture of the B2 SINE ribozyme
Authors: Singhal Ankush , Mrozowich Tyler , Chaudhury Susmit Narayan , Rivera Carlos , Badmalia Maulik , Lee Jeannie T. , Patel Trushar R. , Sanbonmatsu Karissa Y.
Published: July 2024

The SINE-encoded B2 retrotransposon is an RNA Polymerase III transcript that gets upregulated during various cellular stress responses. The B2 noncoding RNA can directly inhibit RNA Polymerase II, leading to a significant downregulation of transcripts during stress. Our recent findings have shown that B2 is a self-cleaving epigenetic ribozyme and that cleavage can be induced by interactions with epigenetic factors, co-regulating its function across distinct chromatin-binding target loci. Here, by integrating RNA chemical probing, small angle X-ray scattering, and 3D motif modeling, we determine structural ensemble-to-function relations for the B2 SINE ribozyme RNA. Perturbations of the RNA suggest that the B2 SINE ribozyme has a well-defined secondary structure and dynamic tertiary structure that both critically depend on the presence of the active site of cleavage. In an RNA engineering approach, we examine the effect of point mutations, deletions of the main cleavage site and deletions of the cleavage domain on the structural ensemble of the RNA. By combining this with functional data, we obtain relations of structural ensembles to various functional states. This perturbative approach serves as a template to unravel the relation of structural ensembles to functional states for other ncRNA and mRNA systems.
Red harvester ants (Pogonomyrmex barbatus) do not distinguish between sorghum head mold symptomatic and asymptomatic seeds
Authors: Elliott-Vidaurri Lilly V. , Penn Hannah J. , Choudhury Robin A.
Published: July 2024

Red harvester ants,Pogonomyrmex barbatus(Smith) (Hymenoptera: Formicidae), common in the Lower Rio Grande Valley of Texas, are known to gather seeds from areas around their nests and store the seeds inside their nests for later consumption. As these ants often nest in and near agricultural fields, some of these seeds may be from crops and may also be infected with fungal plant pathogens. These pathogens can degrade seed coats and may cause the seeds to rot within the ant nests, decreasing storage time and potentially spreading the pathogen to other stored seeds. We studied how head mold, a common sorghum disease, changed ant preferences for sorghum seeds. Using seed depots, we evaluated foraging preferences for sorghum seeds with and without head mold and then monitored how many seeds of each type were collected by the colonies after 1, 2, 4, and 24 hours. We found that red harvester ants did not have any significant preference for infected or uninfected seeds, taking both equally over time. Given this non-preference, ants were assumed to be storing infected seeds next to uninfected seeds within their colonies. However, the risk that stored pathogen-infected seeds poses as a source of future seed infection to seeds within the nest and plants in the surrounding field needs to be further examined.
Cryptosporidiumoocysts andGiardiacysts at two South African wastewater treatment plants
Authors: Gonose Thandubuhle , Du Preez Hein , Venter Stephanus N , Grundlingh Monique
Published: July 2024

CryptosporidiumandGiardiaare one of the most prominent parasitic protozoans found in wastewater treated by wastewater treatment plants (WWTPs). They cause Cryptosporidiosis and Giardiasis respectively, which can be fatal in immuno-compromised individuals. Thus, their removal by WWTPs is essential. This study aimed at investigating the prevalence ofCrytposporiumandGiardiathrough treatment processes at two South African wastewater treatment plants and assessing the efficiency of the WWTPs in removing them. A total of 162 samples (54 raw influents, 36 primary treated effluents, 36 secondary treated effluents and 36 final treated effluents) were collected from two South African WWTPs over a period of one year. Results obtained from the study show thatCryptosporidiumwas detected in 98% (159/162) of the samples collected, whilst Giardia was detected in 99% (160/162) of the samples collected from both wastewater treatment plants. BothCrytposporiumandGiardiawere detected in 100% (n=54) of raw influent samples. The same result was obtained in primary treated effluent, where bothCryptosporidiumandGiardiawas detected in 100% (n=36) of the samples collected. In secondary treated effluent, 36 samples were collected andCryptosporidiumwas detected in 94% of the samples, whereasGiardiawas detected in 100% of the samples. In the final treated effluent samples, bothCryptosporidiumandGiardiawhere detected 97% (n=36) of the samples collected. Detection ofCryptosporidiumandGiardiain most of the wastewater treatment stages indicated these parasites are prevalent in the two WWTPs. Although the two WWTPs showed high removal of the two parasites in wastewater, their presence in the final treated effluent indicated the inefficiency of treatment processes in their removal. This highlights the potential of these WWTPs in contaminating receiving water sources.

IMPORTANCE OF THE STUDY

This study will specifically evaluate the removal of Cryptosporidium oocysts and Giardia cysts by two South African WWTPs and will estimate their ability of removing them. The study will also attempt to give insight into the potential and extend of treated effluent in polluting surface water resources with respect to Cryptosporidium and Giardia. Identification of the potential sources of the pollution is one of the significant parts in resolving this problem. Hence the finding of the study are very important in an endeavour to eliminate pollution of water source.
ASO-mediated knockdown of GPNMB in mutant-GRNandGrn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses
Authors: Wallings Rebecca L. , Gillett Drew A. , Staley Hannah A. , Mahn Savanna , Mark Julian , Neighbarger Noelle , Kordasiewicz Holly , Hirst Warren D. , Tansey Malú Gámez
Published: July 2024

Background

Increases in GPNMB are detectable in FTD-GRNcerebrospinal fluid (CSF) and post-mortem brain, and brains of agedGrn-deficient mice. Although no upregulation of GPNMB is observed in the brains of youngGrn-deficient mice, peripheral immune cells of these mice do exhibit this increase in GPNMB. Importantly, the functional significance of GPNMB upregulation in progranulin-deficient states is currently unknown. Given that GPNMB has been discussed as a potential therapeutic target inGRN-mediated neurodegeneration, it is vital for the field to determine what the normal function of GPNMB is in the immune system, and whether targeting GPNMB will elicit beneficial or deleterious effects.

Methods

The effects of GPNMB knock-down via antisense oligonucleotide (ASO) were assessed in peripheral blood mononuclear cells (PBMCs) from 25 neurologically healthy controls (NHCs) and age- and sex-matched FTD-GRNpatients, as well as peritoneal macrophages (pMacs) from progranulin-deficient (Grn-/-) and B6 mice. Lysosomal function, antigen presentation and MHC-II processing and recycling were assessed, as well as cytokine release and transcription.

Results

We demonstrate here that ASO-mediated knockdown of GPNMB increases lysosomal burden and cytokine secretion in FTD-GRN carrier and neurologically healthy controls (NHCs) monocytes. ASO-mediated knockdown of GPNMB inGrn-deficient macrophages decreased lysosomal pan-cathepsin activity and protein degradation. In addition, ASO-mediated knockdown of GPNMB increased MHC-II surface expression, which was driven by decreased MHC-II uptake and recycling, in macrophages fromGrn-deficient females. Finally, ASO-mediated knockdown of GPNMB dysregulated IFNγ-stimulated cytokine transcription and secretion by mouse macrophages due to the absence of regulatory actions of the GPNMB extracellular fragment (ECF).

Conclusions

Our data herein reveals that GPNMB has a regulatory effect on multiple immune effector functions, including capping inflammation and immune responses in myeloid cells via secretion of its ECF. Therefore, in progranulin-deficient states, the drastic upregulation in GPNMB transcript and protein may represent a compensatory mechanism to preserve lysosomal function in myeloid cells. These novel findings indicate that targeted depletion in FTD-GRNwould not be a rational therapeutic strategy because it is likely to dysregulate important immune cell effector functions.
Murine aortic valve cell heterogeneity at birth
Authors: Bluemn Theresa , Kessler Julie R. , Kim Andrew J , Drnevich Jenny , Lincoln Joy
Published: July 2024

Heart valve function requires a highly organized extracellular matrix (ECM) network that provides the necessary biomechanical properties needed to withstand pressure changes during each cardiac cycle. Lay down of the valve ECM begins during embryogenesis and continues throughout postnatal stages when it is remodeled into stratified layers and arranged according to blood flow. Alterations in this process can lead to dysfunction and if left untreated, heart failure. Despite this, the mechanisms that establish structure-function relationships of the valve, particularly during postnatal maturation, are poorly understood. To address this, single cell transcriptomics was performed on murine aortic valve structures at postnatal day one (PND1). Overall, 18 clusters of 7 diverse cell populations were identified, including a novel VEC subpopulation unique to PND1, and three previously unappreciated VIC subpopulations defined as “primitive”, “remodeling” and “bioactive”. Additional lineage tracing of the “primitive” VIC subpopulation in mice uncovered a temporal and spatial trajectory throughout postnatal maturation. In summary, this work highlights the heterogeneity of cell types within the aortic valve structure at birth that contribute to establishing and maintaining structure and function throughout life.
Effectiveness of Pasteurization for the Inactivation of H5N1 Influenza Virus in Raw Whole Milk
Authors: Alkie Tamiru , Nasheri Neda , Romero-Barrios Pablo , Catford Angela , Krishnan Jay , Pama Lemarie , Hooper-McGrevy Kathleen , Nfon Charles , Cutts Todd , Berhane Yohannes
Published: July 2024

Highly pathogenic avian influenza (HPAI) clade 2.3.4.4b H5Nx viruses continue to cause episodic incursions and have been detected in more than 12 taxonomic orders encompassing more than 80 avian species, land and marine mammals, including recent detections in dairy cattle. The HPAI H5N1 spillover to these important livestock species creates a new interface for human exposure and raises food safety concerns. Presence of H5N1 genetic material in one out of five retail pasteurized milk samples in the USA has prompted the evaluation of pasteurization processes for the inactivation of influenza viruses. Our study examined whether pasteurization could effectively inactivate HPAI H5N1 inoculated raw whole milk samples. We heated 1 mL of non-homogenized cow’s milk samples to attain an internal temperature of 63°C or 72°C and spiked with 6.3 log EID50of clade 2.3.4.4b H5N1 virus. Complete inactivation was achieved after incubation of the H5N1 spiked raw milk at 63°C for 30 minutes. In addition, complete viral inactivation was observed in seven out of eight replicates of raw milk samples treated at 72°C for 15 seconds. In one replicate, a 4.56 log reduction was achieved, which is about 1 log higher than the average viral quantities detected in bulk tanks in affected areas. Therefore, we conclude that pasteurization of milk is an effective strategy for mitigation of risk of human exposure to milk contaminated with H5N1 virus.
Staphylococcal superantigens promote bacterial persistence following postoperative surgical site infection
Authors: Dufresne Karine , Tuffs Stephen W. , Walton Nicholas R. , Kasper Katherine J. , Mohorovic Ivor , Hasan Farah , Bentall Tracey , Heinrichs David E. , Delport Johan , Mele Tina S. , McCormick John K.
Published: July 2024

Staphylococcus aureusis a predominant cause of postoperative surgical site infections and persistent bacteremia. Here we describe a patient that following a total knee arthroplasty subsequently experienced three episodes ofS. aureusbacteremia over a period of 4 months. The initial blood stream isolate (SAB-0429) was a clonal complex (CC) 5 and methicillin resistantS. aureus(MRSA), whereas two subsequent blood stream isolates (SAB-0485 and SAB-0495) were CC5 isolates but methicillin sensitiveS. aureus(MSSA). The two latter isolates harbored a plasmid encoding three superantigen genes not present in the primary MRSA isolate. SAB-0485 and SAB-0495 expressed the plasmid encoded staphylococcal enterotoxin R (SER) exotoxin and demonstrated increased superantigen activity compared with SAB-0429. Compared to SAB-0429, the latter isolates also demonstrated an increased bacterial burden in a mouse bacteremia model that was dependent on increased IFNγ production. Curing of the plasmid from SAB-0485 reduced this virulence phenotype. These findings suggest that the superantigen exotoxins may provide a selective advantage in chronic postsurgical infections.
Unhealthful plant-based diet associates with frailty risk predominantly in men with low income from the UK Biobank cohort
Authors: Schorr Kerstin , Rodriguez-Girondo Mar , van den Berg Niels , de Groot Lisette CPMG , Slagboom P. Eline , Beekman Marian
Published: July 2024

Objective

Plant-based diets (PBD) are generally promoted as beneficial for health. However, whether this is also the case at older ages, when energy deficits, muscle loss and frailty affect health, is unclear. Research has shown that among older adults, particularly in men, a healthful PBD is associated with a lower frailty risk. This relation was however, not studied in the context of socio-economic status (SES), a major factor influencing the risk of frailty. Therefore, we aim to assess whether plant-based diets associate with frailty risk at older ages and whether this association is moderated by sex and income in a large population-based dataset.

Methods

we investigated data from the UK Biobank (UKB) (n=73 180, mean age=55.48±7.87). We applied a plant-based diet index [range 17-85], differentiating between a healthful (hPDI) and unhealthful plant-based diet (uPDI). Frailty was assessed by the Fried frailty phenotype and categorized into 0-4 symptoms of frailty. Average household income was divided into three categories: low (<18.000 £), medium (18.000-52.000 £) and high (>52.000 £). We applied an ordinal logistic regression model with frailty as the categorical outcome and PDI as continuous predictor while adjusting for age, sex, ethnicity, education, BMI and UKB assessment center. Secondly, we included an interaction term (PDI*sex*income). To identify subgroups driving any interactions, we stratified by sex and subsequently by income group to determine the effect of PDI in subgroups while additionally adjusting for lifestyle factors.

Results

a 10-unit increase in hPDI, was associated with 3.4% lower odds for frailty (OR=0.966, 95%CI [0.946, 0.987]), whereas a 10-unit increase in uPDI was associated with 7.7% greater odds for frailty (OR=1.077, 95%CI [1.054, 1.101]). The association between uPDI and frailty was moderated by income and sex (uPDI*income*sex, p=0.002), whereas no such moderation was found for hPDI (p=0.602). Subsequent stratification reveals a significant effect of uPDI on frailty particularly among men with low income (OR=1.177, 95% CI [1.069, 1.298]), but not for women. This association in men largely persisted after adjustment for additional lifestyle factors (OR=1.119, 95%CI [0.995, 1.258]).

Conclusion

we observed that adherence to an unhealthful plant-based diet was associated with a higher risk for frailty. This relation was especially observed for men with lower incomes and not explained by other lifestyle factors. Therefore, this group may profit from refraining from an unhealthful plant-based diet.

Highlights

Healthful plant-based diet associated with lower frailty risk

Association of unhealthful plant-based diet and higher frailty risk is moderated by income and sex

Unhealthful plant-based diet is associated with frailty particularly in men with low income
Five-year changes in 24-hour sleep-wake activity and dementia risk in oldest old women
Authors: Milton Sasha , Cavaillès Clémence , Ancoli-Israel Sonia , Stone Katie L , Yaffe Kristine , Leng Yue
Published: July 2024

INTRODUCTION

Sleep disruptions are associated with cognitive aging in older adults. However, it is unclear whether longitudinal changes in 24-hour multidimensional sleep-wake activity are linked to cognitive impairment in the oldest old.

METHODS

We studied 733 cognitively unimpaired women (mean age=82.5±2.9 years) who completed two actigraphy assessments over five years. We performed hierarchical clustering on principal components in nine sleep, napping, and circadian rest-activity rhythm parameters to identify multidimensional sleep-wake change profiles and multinomial logistic regression to evaluate the associations between sleep-wake changes and risk of cognitive impairment at follow-up.

RESULTS

We identified three sleep-wake change profiles: Stable Sleep (43.8%), Declining Nighttime Sleep (34.9%), and Increasing Sleepiness (21.3%). After adjustment for demographics and comorbidities, women with Increasing Sleepiness had approximately doubled (odds ratio=2.21, p=0.018) risk of dementia compared to those with Stable Sleep.

DISCUSSION

Increasing sleepiness may be an independent marker or risk factor for dementia in oldest old women.
Strength and durability of indirect protection against SARS-CoV-2 infection through vaccine and infection-acquired immunity
Authors: Tan Sophia T. , Rodríguez-Barraquer Isabel , Kwan Ada T. , Blumberg Seth , Park Hailey J. , Hutchinson Justine , Leidner David , Lewnard Joseph A. , Sears David , Lo Nathan C.
Published: July 2024

Early investigation revealed that COVID-19 vaccines confer indirect protection to fully susceptible and unvaccinated persons, defined as a reduced risk of SARS-CoV-2 infection among social contacts of vaccinated individuals. However, indirect protection from infection-acquired immunity and its comparative strength and durability to vaccine-derived indirect protection in the current epidemiologic context of high levels of vaccination, prior infection, and novel variants are not well characterized. Here, we show that both infection-acquired and vaccine-derived immunity independently yield indirect protection to close social contacts with key differences in their strength and waning. Analyzing anonymized data from a system-wide SARS-CoV-2 surveillance program of 177,319 residents across 35 California state prisons from December 2021 to December 2022 in a case-control design, we find that vaccine-derived indirect protection against Omicron SARS-CoV-2 infection is strongest within three months post-vaccination [30% (95% confidence interval: 20-38%)] with subsequent modest protection, whereas infection-acquired immunity provides 38% (24-50%) indirect protection to roommates for 6 months after SARS-CoV-2 infection, with moderate indirect protection persisting for over one year. Variant-targeted vaccines (bivalent formulation including Omicron subvariants BA.4/BA.5) confer strong indirect protection for at least three months [40% (3-63%)]. These results have important implications for understanding the long-term transmission dynamics of SARS-CoV-2 and can guide vaccine policy and public health measures, especially in high-risk environments such as prisons.
An International, Cross-Sectional Survey of Cardiology Researchers and Clinicians: Perceptions of Complementary, Alternative, and Integrative Medicine
Authors: Ng Jeremy Y. , Masood Mehvish , Kathir Sivany , Cramer Holger
Published: July 2024

Background

Complementary, alternative, and integrative medicine (CAIM) has been increasing in popularity for patients with cardiovascular illnesses. However, little is known about perceptions of CAIM among cardiology researchers and clinicians. In response, this study aimed to assess the practices, perceptions, and attitudes towards CAIM among cardiology researchers and clinicians.

Methods

An anonymous, digital cross-sectional survey was administered to researchers and clinicians who have published articles in cardiology journals indexed in OVID MEDLINE. The survey was sent to 37,915 researchers and clinicians and included 5-point Likert scales, multiple-choice questions, and open-ended questions. Basic descriptive statistics were drawn from quantitative data, and a thematic content analysis was conducted to analyze open-ended responses.

Results

Among the 309 respondents, the majority (n=173, 55.99%) identified themselves as both researchers and clinicians in the field of cardiology. While 45.78% (n=114) of participants expressed agreement regarding the safety of CAIM therapies, 44.40% (n=111) disagreed on their efficacy. Most respondents believed in the value of conducting research on CAIM therapies (79.2%, n=198). Respondents perceived mind-body therapies (57.61%, n=159) and biologically based practices (47.46%, n=131) as the most promising interventions for the prevention and treatment of cardiovascular conditions. Biofield therapies were the least favoured for integration into mainstream medical practices (11.93%, n=29).

Conclusions

While cardiology researchers and clinicians perceive CAIM therapies to have potential, many are hesitant about integrating such interventions into the current medical system due to a perceived lack of scientific evidence and standardized products. Insights from this study may help establish educational resources for healthcare practitioners.

Clinical Perspective

What is New?

While complementary, alternative, and integrative medicine (CAIM) therapies are generally perceived by cardiology professionals as being safe and as having multiple potential benefits, there remains a strong need for additional research and training on CAIM interventions.

In this study, support for CAIM therapies varied by modality, with mind-body therapies and biologically based practices garnering the most favor and biofield therapies garnering the least.

What Are the Clinical Implications?

Given the rising demand for CAIM interventions and the significance of lifestyle factors for cardiac conditions, there is a critical need for cardiology professionals to access CAIM-based research and education to meet patients’ needs.
Impaired Experience-Dependent Theta Oscillation Synchronization and Inter-Areal Synaptic Connectivity in the Visual Cortex of Fmr1 KO Mice
Authors: Cheng Xi , Nareddula Sanghamitra , Gao Hao-Cheng , Chen Yueyi , Xiao Tiange , Nadew Yididiya Y. , Xu Fan , Edens Paige Alyssa , Quinn Christopher J. , Kimbrough Adam , Huang Fang , Chubykin Alexander A.
Published: July 2024

Fragile X syndrome (FX) is the most prevalent inheritable form of autism spectrum disorder (ASD), characterized by hypersensitivity, difficulty in habituating to new sensory stimuli, and intellectual disability. Individuals with FX often experience visual perception and learning deficits. Visual experience leads to the emergence of the familiarity-evoked theta band oscillations in the primary visual cortex (V1) and the lateromedial area (LM) of mice. These theta oscillations in V1 and LM are synchronized with each other, providing a mechanism of sensory multi-areal binding. However, how this multi-areal binding and the corresponding theta oscillations are altered in FX is not known. Using iDISCO whole brain clearing with light-sheet microscopy, we quantified immediate early gene Fos expression in V1 and LM, identifying deficits in experience-dependent neural activity in FX mice. We performed simultaneous in vivo recordings with silicon probes in V1 and LM of awake mice and channelrhodopsin-2-assisted circuit mapping (CRACM) in acute brain slices to examine the neural activity and strength of long-range synaptic connections between V1 and LM in both wildtype (WT) and Fmr1 knockout (KO) mice, the model of FX, before and after visual experience. Our findings reveal synchronized familiarity-evoked theta oscillations in V1 and LM, the increased strength of V1→LM functional and synaptic connections, which correlated with the corresponding changes of presynaptic short-term plasticity in WT mice. The LM oscillations were attenuated in FX mice and correlated with impaired functional and synaptic connectivity and short-term plasticity in the feedforward (FF) V1→LM and feedback (FB) LM→V1 pathways. Finally, using 4Pi single-molecule localization microscopy (SMLM) in thick brain tissue, we identified experience-dependent changes in the density and shape of dendritic spines in layer 5 pyramidal cells of WT mice, which correlated with the functional synaptic measurements. Interestingly, there was an increased dendritic spine density and length in naïve FX mice that failed to respond to experience. Our study provides the first comprehensive characterization of the role of visual experience in triggering inter-areal neural synchrony and shaping synaptic connectivity in WT and FX mice.
Designer DNA Strand Displacement Reaction toward Controlled Release of Cargos
Authors: Hu Chih-Hsiang , Veneziano Remi
Published: July 2024

Dynamic DNA nanotechnology systems are used to design DNA logic circuits, signal amplification mechanisms for biosensing, and smart release system that could potentially be used in several biomedical applications. The toehold-mediated strand displacement reaction (TMSDR) is one of the main methods for designing DNA-based biomolecular logic circuits. However, the reaction behaviour such as the displacement rate and the quantity of strand released are difficult to control and often requires chemically modified strands or addition of enzymes. This makes the TMSDR versatility and specificity limited, and not always adapted for biomedical applications. Therefore, further understanding the sequence design parameters enabling fine tuning of the TMSDR behaviour without the need for complex modification, would enable its broader application. In this study, using a DNA motif developed for multiplexed release, we examine how mismatched base(s) in the trigger strand is affecting the release rate and quantity released and found that both location and type of mismatched base(s) significantly impact the displacement parameters of the TMSDR. This allows for a finer control of the cargo release for the multiplexed release system that could be used for varying biomedical applications and help developing release system mimicking the natural distribution of biomolecules.
ATG9A and ARFIP2 cooperate to regulate PI4P levels for lysosomal repair
Authors: De Tito Stefano , Almacellas Eugenia , Yu Daniel Dai , Zhang Wenxin , Millard Emily , Hervás Javier H. , Pellegrino Enrica , Panagi Ioanna , Fodge Ditte , Thurston Theresa L.M , Gutierrez Maximiliano , Tooze Sharon A.
Published: July 2024

Lysosome damage activates multiple pathways to prevent lysosome-dependent cell death, including a repair mechanism involving ER-lysosome membrane contact sites, phosphatidylinositol 4-kinase- 2a (PI4K2A), phosphatidylinositol-4 phosphate (PI4P) and oxysterol-binding protein-related proteins (ORPs), lipid transfer proteins. PI4K2A localizes to trans-Golgi network and endosomes yet how it is delivered to damaged lysosomes remains unknown. During acute sterile damage, and damage caused by intracellular bacteria, we show that ATG9A-containing vesicles perform a critical role in delivering PI4K2A to damaged lysosomes. ADP ribosylation factor interacting protein 2 (ARFIP2), a component of ATG9A vesicles, binds and sequesters PI4P on lysosomes, balancing ORP- dependent lipid transfer and promoting retrieval of ATG9A vesicles through recruitment of the adaptor protein complex-3 (AP-3). Our results reveal a role for mobilized ATG9A vesicles and ARFIP2 in lysosome homeostasis after damage and bacterial infection.
Creating Coarse-Grained Systems with COBY: Towards Higher Accuracy in Membrane Complexity
Authors: Andreasen Mikkel Dahl , Souza Paulo C. T. , Schott Birgit , Zuzic Lorena
Published: July 2024

Current trends in molecular modelling are geared towards increasingly realistic representations of the modelled systems. This is reflected in larger, more complex systems, which are difficult to build and would ideally rely on a software that converts user-provided descriptors into system coordinates. This is not a trivial task, as the building algorithms use simplifications that can introduce inaccuracies in the system properties that do not correspond to the requested values. We created COBY, a coarse-grained system builder that can create a large variety of systems in a single command call using Martini molecule models. We improved the accuracy of the complex membrane and solvent building procedures, introduced a variety of arguments that can be used to build diverse systems, and implemented features intended for force field development. COBY can be used to build flat membranes of any degree of complexity, handle protein and solvent insertion, solute flooding, stacked membranes, membrane patches and pores, and includes advanced functionalities such as molecule import, lipid building from fragments, handling of multiple parameter libraries, and several choices of algorithms for interpreting user-provided system descriptors. COBY is an open-source software written in Python 3, and the code, documentation, and tutorials are hosted at github.com/MikkelDA/COBY.
Lack of Single Amino Acids Transcriptionally Remodels Sensory Systems to Enhance the Intake of Protein and Microbiota
Authors: Ezra-Nevo Gili , Henriques Sílvia F , Münch Daniel , Francisco Ana Patrícia , Baltazar Célia , Elias Ana Paula , Deplancke Bart , Ribeiro Carlos
Published: July 2024

Adequate intake of dietary essential amino acids (eAAs) is vital for protein synthesis and metabolism. Any single eAA deprivation is sufficient to increase protein intake inDrosophila melanogaster. How such nutritional “needs” are transformed into behavioral “wants” remains poorly understood. We derived transcriptomes from the heads of flies deprived of individual eAAs to identify mechanisms by which this is achieved. We found that, while specific eAA deprivations have unique effects on gene expression, a large set of changes are shared across deprivations. We show thatOr92aupregulation upon eAA deprivation increases the exploitation of yeast, the main protein source of flies. Furthermore,Ir76aupregulation was crucial for feeding onLactobacillus, a gut bacterium that ameliorates the fitness of eAA-deprived flies. Our work uncovers common and unique transcriptional changes induced by individual eAA deprivations in an animal and reveals novel mechanisms underlying the organism’s behavioral and physiological response to eAA challenges.