bluuebunny/crossref_metadata_2025 huggingface dataset:
Antimicrobial resistance profiles of Escherichia coli isolated from clinical and environmental samples: findings and implications
Authors: Kasanga Maisa , Shempela Doreen Mainza , Daka Victor , Mwikisa Mark J , Sikalima Jay , Chanda Duncan , Mudenda Steward
Published: April 2024

Background

The overuse and misuse of antimicrobials has worsened the problem of antimicrobial resistance (AMR) globally. This study investigated the AMR profiles of Escherichia coli isolated from clinical and environmental samples in Lusaka, Zambia.

Methods

This was a cross-sectional study conducted from February 2023 to June 2023 using 450 samples. VITEK® 2 Compact was used to identify E. coli and perform antimicrobial susceptibility testing. Data analysis was done using WHONET 2022 and SPSS version 25.0.

Results

Of the 450 samples, 66.7% (n = 300) were clinical samples, whereas 33.3% (n = 150) were environmental samples. Overall, 47.8% (n = 215) (37.8% clinical and 10% environmental) tested positive for E. coli. Of the 215 E. coli isolates, 66.5% were MDR and 42.8% were ESBL-producers. Most isolates were resistant to ampicillin (81.4%), sulfamethoxazole/trimethoprim (70.7%), ciprofloxacin (67.9%), levofloxacin (64.6%), ceftriaxone (62.3%) and cefuroxime (62%). Intriguingly, E. coli isolates were highly susceptible to amikacin (100%), imipenem (99.5%), nitrofurantoin (89.3%), ceftolozane/tazobactam (82%) and gentamicin (72.1%).

Conclusions

This study found a high resistance of E. coli to some antibiotics that are commonly used in humans. The isolation of MDR and ESBL-producing E. coli is a public health concern and requires urgent action. Therefore, there is a need to instigate and strengthen interventional strategies including antimicrobial stewardship programmes to combat AMR in Zambia.
Suspected North Carolina counterfeit pill-involved deaths, 2020–2022
Authors: Friederich Laura W , Cox Mary E , Hyson Brian E , Bishop-Freeman Sandra C
Published: April 2024

The NC Office of the Chief Medical Examiner regularly assumes jurisdiction over deaths that are suspicious, unusual or unattended by a medical professional. In recent years, the presence of counterfeit pills is occasionally suggested by investigatory notes and/or scene findings that document reported consumption of prescription drugs, or prescription drugs on scene, which are not reflected in the final autopsy findings after toxicological analysis of the decedent’s blood samples. Counterfeit pill consumption is a major public health hazard worthy of attention from the forensic toxicology community. Seventy-five cases from January 2020 to December 2022 serve as a convenience sample of cases where prescription pills including formulations of alprazolam, oxycodone and hydrocodone were specifically referenced during the death scene investigation as recently consumed, yet an unexpected substance was found during toxicological analysis rather than the expected pharmaceutical drug. Of note, novel benzodiazepines detected included flualprazolam, etizolam, clonazolam metabolite (8-aminoclonazolam), bromazolam, flubromazolam and desalkylflurazepam. Decedents’ ages ranged from 16 to 69, across 33 different NC counties. Case notes indicated that eight of the decedents obtained pills through direct personal relationships, six decedents obtained them from “the street” and one decedent likely purchased pills online. Pills were largely consumed orally or through insufflation. Seven case reports contained indication that decedents knew or suspected the counterfeit nature of their pills. This study describes the context and characteristics of 2020–2022 suspected counterfeit pill-involved deaths in NC to further the understanding of the forensic science community, law enforcement partners, public health stakeholders and those potentially at risk through the consumption of counterfeit pills.
Private Landowner Willingness to Manage Their Land for Carbon Sequestration in New York State
Authors: Stedman Richard Clark , Armstrong Andrea , Walsh Kathryn Bills , Connelly Nancy
Published: April 2024

Efforts to enhance carbon sequestration, including afforestation and reforestation, are critical strategies to meet the New York State (NYS) climate goals. In NYS, converting underutilized lands to mature forests can mitigate 4.9 million metric tons of CO2 annually, but 97% of suitable lands are privately owned. These mitigation figures do not consider landowner willingness to grow mature forest. Drawing on a survey of 979 NYS landowners, we explored interest in growing mature forest, potential barriers, and how they can be mitigated. Survey results indicate landowners seem reasonably interested (about one-third were “very interested”) in converting at least some of their land to mature forest for carbon sequestration. Respondents were most willing to convert land in young forest and shrubland and least willing to convert fallow fields, grassland, and agricultural land. Key barriers are related to inadequate labor and financial resources. Incentives focused on finances most increase willingness but only modestly so.

Study Implications: Land availability for carbon sequestration can only be realistically understood if we consider private landowner willingness to grow forests. We observed relatively strong enthusiasm for converting young forest and shrubland. Land conversion proponents could tailor management and communication strategies to owners of these land types. Conversion is tied to overcoming negative attitudes about the potential conflict between current management and managing for carbon sequestration and providing resources for conversion. Landowner willingness was less when the agricultural footprint was greater. With much farmland in NYS, the amount of land available for reforestation may be lower than what landcover-based estimates suggest.
SpatialSPM: statistical parametric mapping for the comparison of gene expression pattern images in multiple spatial transcriptomic datasets
Authors: Ohn Jungyoon , Seo Mi-Kyoung , Park Jeongbin , Lee Daeseung , Choi Hongyoon
Published: April 2024

Spatial transcriptomic (ST) techniques help us understand the gene expression levels in specific parts of tissues and organs, providing insights into their biological functions. Even though ST dataset provides information on the gene expression and its location for each sample, it is challenging to compare spatial gene expression patterns across tissue samples with different shapes and coordinates. Here, we propose a method, SpatialSPM, that reconstructs ST data into multi-dimensional image matrices to ensure comparability across different samples through spatial registration process. We demonstrated the applicability of this method by kidney and mouse olfactory bulb datasets as well as mouse brain ST datasets to investigate and directly compare gene expression in a specific anatomical region of interest, pixel by pixel, across various biological statuses. Beyond traditional analyses, SpatialSPM is capable of generating statistical parametric maps, including T-scores and Pearson correlation coefficients. This feature enables the identification of specific regions exhibiting differentially expressed genes across tissue samples, enhancing the depth and specificity of ST studies. Our approach provides an efficient way to analyze ST datasets and may offer detailed insights into various biological conditions.
Controlling genome topology with sequences that trigger post-replication gap formation during replisome passage: the E. coli RRS elements
Authors: Pham Phuong , Wood Elizabeth A , Dunbar Emma L , Cox Michael M , Goodman Myron F
Published: April 2024

We report that the Escherichia coli chromosome includes novel GC-rich genomic structural elements that trigger formation of post-replication gaps upon replisome passage. The two nearly perfect 222 bp repeats, designated Replication Risk Sequences or RRS, are each 650 kb from the terminus sequence dif and flank the Ter macrodomain. RRS sequence and positioning is highly conserved in enterobacteria. At least one RRS appears to be essential unless a 200 kb region encompassing one of them is amplified. The RRS contain a G-quadruplex on the lagging strand which impedes DNA polymerase extension producing lagging strand ssDNA gaps, $ \le$2000 bp long, upon replisome passage. Deletion of both RRS elements has substantial effects on global genome structure and topology. We hypothesize that RRS elements serve as topological relief valves during chromosome replication and segregation. There have been no screens for genomic sequences that trigger transient gap formation. Functional analogs of RRS could be widespread, possibly including some enigmatic G-quadruplexes in eukaryotes.
Cancer drug sensitivity estimation using modular deep Graph Neural Networks
Authors: Campana Pedro A , Prasse Paul , Lienhard Matthias , Thedinga Kristina , Herwig Ralf , Scheffer Tobias
Published: April 2024

Computational drug sensitivity models have the potential to improve therapeutic outcomes by identifying targeted drugs components that are tailored to the transcriptomic profile of a given primary tumor. The SMILES representation of molecules that is used by state-of-the-art drug-sensitivity models is not conducive for neural networks to generalize to new drugs, in part because the distance between atoms does not generally correspond to the distance between their representation in the SMILES strings. Graph-attention networks, on the other hand, are high-capacity models that require large training-data volumes which are not available for drug-sensitivity estimation. We develop a modular drug-sensitivity graph-attentional neural network. The modular architecture allows us to separately pre-train the graph encoder and graph-attentional pooling layer on related tasks for which more data are available. We observe that this model outperforms reference models for the use cases of precision oncology and drug discovery; in particular, it is better able to predict the specific interaction between drug and cell line that is not explained by the general cytotoxicity of the drug and the overall survivability of the cell line. The complete source code is available at https://zenodo.org/doi/10.5281/zenodo.8020945. All experiments are based on the publicly available GDSC data.
Consensus recommendations on management of selumetinib-associated adverse events in pediatric patients with neurofibromatosis type 1 and plexiform neurofibromas
Authors: Azizi Amedeo A , Hargrave Darren , Passos João , Wolkenstein Pierre , Rosenbaum Thorsten , Santoro Claudia , Rosenmayr Verena , Pletschko Thomas , Ascierto Paolo A , Hernández Héctor Salvador
Published: April 2024

Background

Selumetinib is the first approved treatment for pediatric patients with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN) in the EU and US, as well as in multiple other countries. Evidence for the management of selumetinib-associated adverse events (AEs) is mostly limited to clinical trials and expanded-access programs. We gathered a panel of European healthcare practitioners with clinical experience prescribing selumetinib and/or managing pediatric patients with NF1-PN to provide recommendations on the prevention and management of AEs.

Methods

A modified Delphi approach was used to develop the recommendations among the group of experts. Initial statements were developed from a literature review of current management recommendations and regulatory reports. The panel refined the statements and rated the extent to which they agreed with them in 2 sessions and a follow-up survey. The panel comprised 2 pediatric neuro-oncologists, 1 pediatric oncologist, 1 pediatrician, 1 neuropediatrician, 1 oncologist, 1 neurologist, 2 psychologists, and 1 dermatologist.

Results

The experts agreed on the relative frequency and impact of AEs potentially associated with selumetinib. Consensus-level agreement was reached for 36 statements regarding the prevention and management of AEs potentially associated with selumetinib. Experts recommended treatments for AEs based on their experience.

Conclusions

The development of a variety of consensus statements indicates expert agreement on best practices for the prevention and management of AEs potentially associated with selumetinib in pediatric patients with NF1-PN. These events are generally manageable and should be considered alongside treatment benefit. Information sharing is warranted as further experience is gained.
Incidence of Colon Cancer Among Medicaid Beneficiaries With or Without Human Immunodeficiency Virus Under Comparable Colorectal Cancer Screening Patterns
Authors: Rudolph Jacqueline E , Calkins Keri L , Zhang Xueer , Zhou Yiyi , Pirsl Filip , Xu Xiaoqiang , Wentz Eryka , Lau Bryan , Joshu Corinne E
Published: April 2024

Background

People with human immunodeficiency virus (HIV; PWH) in the United States have a lower incidence of colon cancer than the general population. The lower incidence may be explained by differences in receipt of screening. Thus, we sought to estimate colon cancer incidence under scenarios in which Medicaid beneficiaries, with or without HIV, followed the same screening protocols.

Methods

We used data from 1.5 million Medicaid beneficiaries who were enrolled in 14 US states in 2001–2015 and aged 50–64 years; 72 747 beneficiaries had HIV. We estimated risks of colon cancer and death by age, censoring beneficiaries when they deviated from 3 screening protocols, which were based on Medicaid's coverage policy for endoscopies during the time period, with endoscopy once every 2, 4, or 10 years. We used inverse probability weights to control for baseline and time-varying confounding and informative loss to follow-up. Analyses were performed overall, by sex, and by race/ethnicity.

Results

PWH had a lower incidence of colon cancer than beneficiaries without HIV. Compared with beneficiaries without HIV, the risk difference at age 65 years was −1.6% lower (95% confidence interval, −2.3% to −.7%) among PWH with the 2-year protocol and −0.8% lower (−1.3% to −.3%) with the 10-year protocol. Results were consistent across subgroup and sensitivity analyses.

Conclusions

Our findings suggest that the lower risk of colon cancer that has been observed among PWH aged 50–64 years compared with those without HIV is not due to differences in receipt of lower endoscopy. Keywords: colon cancer, colorectal cancer screening, endoscopy, Medicaid, human immunodeficiency virus
Relating ciliary propulsion morphology and flow to particle acquisition in marine planktonic ciliates II: the oligotrich ciliate Strombidium capitatum
Authors: Jiang Houshuo , Buskey Edward J
Published: April 2024

The marine oligotrich ciliate Strombidium capitatum is a cruise-feeder, relying on ciliary motion and propulsion flow to individually detect and capture particles. High-speed, high-magnification digital imaging revealed that the cell swims forward by sweeping its anterior adoral membranelles (AAMs) backward, achieving a mean path-averaged speed of U = 1.7 mm s−1 (31 cell-lengths per second). Particle detection occurs through either hydrodynamic signal perception or ciliary contact perception, with a mean reaction distance of R = 20.4 μm. While executing a ciliary reversal of AAMs to handle and capture a perceived particle, the cell coordinates the ciliary motion of ventral adoral membranelles (VAMs, the “lapel”) with the ciliary reversal of AAMs (the “collar”), causing a sudden halt of cell motion, thereby functioning as a motion “brake” that is crucial for effective particle capture. The encounter rate with small prey particles is calculated using πR2U (~8.0 μL h−1, equivalent to ~ 3.5 × 106 cell volumes per day). Based on hydrodynamic modeling results, it is hypothesized that spatial structures of the flow velocity vector and acceleration fields in front of the swimming cell are essential for pushing an embedded particle forward, creating a strong enough slip velocity and hydrodynamic signal for prey perception, even for a neutrally buoyant small particle.
Performance-related pain and disability among music students versus professional musicians: a multicenter study using a validated tool
Authors: Zão Ana , Altenmüller Eckart , Azevedo Luís
Published: April 2024

Objective

To evaluate prevalence of performance-related pain among musicians and compare pain characteristics, associated disability and approach to pain management, between music students and professional musicians.

Methods

A multicenter cross-sectional study was performed in a multi-stage stratified cluster random sample of 585 musicians, stratified by music students (294, among which 234 were at pre-university level and 60 at university level) and professional musicians (291). The main outcome was performance-related pain, measured by Performance-related Pain among Musicians Questionnaire (PPAM). Secondary outcomes were: pain management approach, physical activity levels, fatigue, distress, and health-related quality of life.

Results

The lifetime prevalence of performance-related pain was 55.0% (n = 322), being significantly higher among professionals (57.5% vs 42.5%, P < .001). Pain intensity scores were significantly higher in professional musicians (P < .05), but pain interference in performance was higher among music students, who also reported significantly higher levels of fatigue (P = .008) and distress (P < .001), and lower quality of life (P < .001). Regardless of the high levels of pain intensity and interference, fatigue, anxiety and depression, and low levels of quality of life, 33% musicians who developed pain had never looked for healthcare (this proportion is significantly higher for music students, 57%, P < .001).

Conclusions

We present the first multicenter study on performance-related pain among musicians with different backgrounds, using a validated tool, and distinguishing music students from professional musicians. Performance-related pain is a highly prevalent and disabling condition among musicians, however, its proper evaluation and management are still often underappreciated, contributing to significant impairments and reduced quality of life.
Drug-induced impairment of mitochondrial fatty acid oxidation and steatosis: assessment of causal relationship with 45 pharmaceuticals
Authors: Buron Nelly , Porceddu Mathieu , Loyant Roxane , Martel Cécile , Allard Julien A , Fromenty Bernard , Borgne-Sanchez Annie
Published: April 2024

Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number of pharmaceuticals. Hence, 32 steatogenic and 13 nonsteatogenic drugs were tested for their ability to inhibit mtFAO in isolated mouse liver mitochondria. To this end, mitochondrial respiration was measured with palmitoyl-l-carnitine, palmitoyl-CoA + l-carnitine, or octanoyl- l-carnitine. This mtFAO tri-parametric assay was able to predict the occurrence of steatosis in patients with a sensitivity and positive predictive value above 88%. To get further information regarding the mechanism of drug-induced mtFAO impairment, mitochondrial respiration was also measured with malate/glutamate or succinate. Drugs such as diclofenac, methotrexate, and troglitazone could inhibit mtFAO secondary to an impairment of the mitochondrial respiratory chain, whereas dexamethasone, olanzapine, and zidovudine appeared to impair mtFAO directly. Mitochondrial swelling, transmembrane potential, and production of reactive oxygen species were also assessed for all compounds. Only the steatogenic drugs amiodarone, ketoconazole, lovastatin, and toremifene altered all these 3 mitochondrial parameters. In conclusion, our tri-parametric mtFAO assay could be useful in predicting the occurrence of steatosis in patients. The combination of this assay with other mitochondrial parameters could also help to better understand the mechanism of drug-induced mtFAO inhibition.
Leaf morpho-anatomical adjustments in a Quercus pubescens forest after 10 years of partial rain exclusion in the field
Authors: Laoué Justine , Gea-Izquierdo Guillermo , Dupouyet Sylvie , Conde María , Fernandez Catherine , Ormeño Elena
Published: April 2024

In the Mediterranean region, a reduction of annual precipitation and a longer and drier summer season are expected with climate change by the end of the century, eventually endangering forest survival. To cope with such rapid changes, trees may modulate their morpho-anatomical and physiological traits. In the present study, we focused on the variation in leaf gas exchange and different leaf morpho-anatomical functional traits of Quercus pubescens Willd. in summer using a long-term drought experiment in natura consisting of a dynamic rainfall exclusion system where trees have been submitted to amplified drought (AD) (~−30% of annual precipitation) since April 2012 and compared them with trees under natural drought (ND) in a Mediterranean forest. During the study, we analyzed net CO2 assimilation (An), stomatal conductance (gs), transpiration (E), water-use efficiency (WUE), stomatal size and density, density of glandular trichomes and non-glandular trichomes, thickness of the different leaf tissues, specific leaf area and leaf surface. Under AD, tree functioning was slightly impacted, since only An exhibited a 49% drop, while gs, E and WUE remained stable. The decrease in An under AD was regulated by concomitant lower stomatal density and reduced leaf thickness. Trees under AD also featured leaves with a higher non-glandular trichome density and a lower glandular trichome density compared with ND, which simultaneously limits transpiration and production costs. This study points out that Q. pubescens exhibits adjustments of leaf morpho-anatomical traits which can help trees to acclimate to AD scenarios as those expected in the future in the Mediterranean region.
Discovery of optimal cell type classification marker genes from single cell RNA sequencing data
Authors: Liu Angela , Peng Beverly , Pankajam Ajith V. , Duong Thu Elizabeth , Pryhuber Gloria , Scheuermann Richard H. , Zhang Yun
Published: April 2024

The use of single cell/nucleus RNA sequencing (scRNA-seq) technologies that quantitively describe cell transcriptional phenotypes is revolutionizing our understanding of cell biology, leading to new insights in cell type identification, disease mechanisms, and drug development. The tremendous growth in scRNA-seq data has posed new challenges in efficiently characterizing data-driven cell types and identifying quantifiable marker genes for cell type classification. The use of machine learning and explainable artificial intelligence has emerged as an effective approach to study large-scale scRNA-seq data. NS-Forest is a random forest machine learning-based algorithm that aims to provide a scalable data-driven solution to identify minimum combinations of necessary and sufficient marker genes that capture cell type identity with maximum classification accuracy. Here, we describe the latest version, NS-Forest version 4.0 and its companion Python package (https://github.com/JCVenterInstitute/NSForest), with several enhancements to select marker gene combinations that exhibit highly selective expression patterns among closely related cell types and more efficiently perform marker gene selection for large-scale scRNA-seq data atlases with millions of cells. By modularizing the final decision tree step, NS-Forest v4.0 can be used to compare the performance of user-defined marker genes with the NS-Forest computationally-derived marker genes based on the decision tree classifiers. To quantify how well the identified markers exhibit the desired pattern of being exclusively expressed at high levels within their target cell types, we introduce the On-Target Fraction metric that ranges from 0 to 1, with a metric of 1 assigned to markers that are only expressed within their target cell types and not in cells of any other cell types. NS-Forest v4.0 outperforms previous versions on its ability to identify markers with higher On-Target Fraction values for closely related cell types and outperforms other marker gene selection approaches at classification with significantly higher F-beta scores when applied to datasets from three human organs - brain, kidney, and lung.
Short-Term Disruption of TGFβ Signaling in Adult Mice Renders the Aorta Vulnerable to Hypertension-Induced Dissection
Authors: Jiang Bo , Ren Pengwei , He Changshun , Wang Mo , Murtada Sae-Il , Chen Yu , Ramachandra Abhay B. , Li Guangxin , Qin Lingfeng , Assi Roland , Schwartz Martin A. , Humphrey Jay D. , Tellides George
Published: April 2024

Hypertension and transient increases in blood pressure from extreme exertion are risk factors for aortic dissection in patients with age-related vascular degeneration or inherited connective tissue disorders. Yet, the common experimental model of angiotensin II-induced aortopathy in mice appears independent of high blood pressure as lesions do not occur in response to an alternative vasoconstrictor, norepinephrine, and are not prevented by co-treatment with a vasodilator, hydralazine. We investigated vasoconstrictor administration to adult mice 1 week after disruption of TGFβ signaling in smooth muscle cells. Norepinephrine increased blood pressure and induced aortic dissection by 7 days and even within 30 minutes that was rescued by hydralazine; results were similar with angiotensin II. Changes in regulatory contractile molecule expression were not of pathological significance. Rather, reduced synthesis of extracellular matrix yielded a vulnerable aortic phenotype by decreasing medial collagen, most dynamically type XVIII, and impairing cell-matrix adhesion. We conclude that transient and sustained increases in blood pressure cause dissection in aortas rendered vulnerable by inhibition of TGFβ-driven extracellular matrix production by smooth muscle cells. A corollary is that medial fibrosis, a frequent feature of medial degeneration, may afford some protection against aortic dissection.
Phylogeography of bar-tailed godwits: pre-LGM structure in Beringia and westward colonization of post-glacial Europe
Authors: Conklin Jesse R. , Verkuil Yvonne I. , Lefebvre Margaux J.M. , Battley Phil F. , Bom Roeland A. , Gill Robert E. , Hassell Chris J. , ten Horn Job , Ruthrauff Daniel R. , Tibbitts T. Lee , Tomkovich Pavel S. , Warnock Nils , Piersma Theunis , Fontaine Michaël C.
Published: April 2024

In migratory birds, high mobility may reduce population structure through increased dispersal and enable adaptive responses to environmental change, whereas rigid migratory routines predict low dispersal, increased geographic structure, and limited flexibility to respond to change. We used nextRAD sequencing of 14,318 single-nucleotide polymorphisms to explore the population genetics and phylogeographic history of the bar-tailed godwit,Limosa lapponica, a migratory shorebird with six recognized subspecies and known for making the longest non-stop flights of any landbird. Using scenario-testing in an Approximate Bayesian Computation framework, we infer that bar-tailed godwits existed in three main lineages at the Last Glacial Maximum (LGM), when much of their present-day Arctic and sub-Arctic breeding range persisted in a large, unglaciated Siberian-Beringian refugium. Subsequently, population structure developed at both longitudinal extremes: in the east, a genetic cline exists across latitude in the Alaska breeding range of subspeciesL. l. baueri; in the west, one lineage diversified into three extant subspeciesL. l. lapponica,taymyrensis, andyamalensis, the former two of which migrate through previously glaciated western Europe. We also detected unrecognized population structure among bar-tailed godwits wintering in Europe, wherein a significant proportion of purportedlapponicaindividuals were in facttaymyrensis, necessitating a re-assessment of the migrations, ecology, and population estimates for these subspecies. In the global range of this long-distance migrant, we found evidence of both (1) fidelity to rigid behavioral routines promoting fine-scale geographic population structure (in the east), and (2) flexibility to colonize recently available migratory flyways and non-breeding areas (in the west).
Stm1 regulates Ifh1 activity revealing crosstalk between ribosome biogenesis and ribosome dormancy
Authors: Bianco Eliana , Bonassera Martina , Uliana Federico , Tilma Janny , Winkler Martin , Zencir Sevil , Albert Benjamin , Oborská-Oplová Michaela , Dechant Reinhard , Hugener Jannik , Panse Vikram Govind , Pilhofer Martin , Kimmig Philipp , Peter Matthias
Published: April 2024

Ribosome abundance in changing environments is governed by biogenesis and degradation, but the underlying mechanisms regulating these opposing processes remain unknown. Here we show that Suppressor of Tom1 (Stm1), a dormancy factor protecting cytosolic ribosomes during starvation, has an unexpected function to promote ribosome biogenesis during exponential growth conditions. Indeed, Stm1 transiently localizes to the nucleolus and engages with pre-ribosomal particles. Stm1 upregulates transcription of ribosomal protein genes by directly binding the activation domain (AD) of the transcription factor Ifh1. These novel Stm1 functions confer rapamycin-sensitivity and are mediated by its C-terminal intrinsically disordered region (IDR), which is dispensable for ribosome hibernation. We conclude that Stm1 regulates ribosome homeostasis linking ribosome biogenesis and ribosome dormancy.
Quantifying competition between two demersal fish species from spatiotemporal stomach content data
Authors: Lindmark Max , Maioli Federico , Anderson Sean C. , Gogina Mayya , Bartolino Valerio , Sköld Mattias , Ohlsson Mikael , Eklöf Anna , Casini Michele
Published: April 2024

Competition is challenging to quantify in nature and inference is often made on indirect patterns of potential competition (e.g., trends in population trajectories and overlap in spatiotemporal distribution and resource use). However, these indicators are not direct measures of fitness, nor do they say if the contested resource is limited in supply, which are key features of competition. We combine stomach content and biomass density data from scientific bottom trawl surveys to evaluate if food competition is occurring between two dominant demersal fish species in the southern Baltic Sea: Atlantic cod (Gadus morhua) and flounder (Platichthysspp.). We use multivariate generalized linear latent variable models (GLLVMs) to quantify diet similarities across the domain, diet overlap indices to test if predator density drives diet overlap at intermediate spatial scales, and spatiotemporal generalized linear mixed models (GLMMs) fit to individual-level prey weights to evaluate effects of local-scale covariates. We find clear dietary clusters by species and size. The latter is especially pronounced in cod, which shift from benthic to pelagic prey at around 30 cm. The dietary overlap is low and does not decline with predator density. However, signs of resource partitioning to reduce interspecific food competition are evident in the local-scale analysis. As flounder densities increase, small and large cod tend to feed less on the isopodSaduria entomon— an important prey species. However, the benthic prey weight in small cod, and benthic and total prey weight in large cod, are not affected by flounder densities, suggesting that interspecific food competition is not limiting cod feeding but affects their diet composition. We find some support for intraspecific food competition in large cod and flounder. Our study illustrates the importance of local-scale processes when inferring food competition from stomach content data, and such results are important for quantifying ecological interactions.
Interference Length reveals regularity of crossover placement across species
Authors: Ernst Marcel , Mercier Raphael , Zwicker David
Published: April 2024

Crossover interference is a phenomenon that affects the number and positioning of crossovers in meiosis and thus affects genetic diversity and chromosome segregation. Yet, the underlying mechanism is not fully understood, partly because quantification is difficult. To overcome this challenge, we introduce the interference lengthLintthat quantifies changes in crossover patterning due to interference. We show that it faithfully captures known aspects of crossover interference and provides superior statistical power over previous methods. We apply our analysis to empirical data and unveil a similar behavior ofLintacross species, which hints at a common mechanism. A recently proposed coarsening model generally captures these aspects, providing a unified view of crossover interference. Consequently,Lintfacilitates model refinements and general comparisons between alternative models of crossover interference.
Uncovering the bequeathing potential of Apoptotic Mesenchymal Stem Cells via small Extracellular Vesicles for its enhanced immunomodulatory ability
Authors: Mendiratta Meenakshi , Mendiratta Mohini , Sharma Yashvi , Sahoo Ranjit K. , Malhotra Neena , Mohanty Sujata
Published: April 2024

Small Extracellular Vesicles (sEVs) derived from Mesenchymal Stem Cells (MSCs) have emerged as a promising avenue for cell-free therapeutics in regenerative medicine. These vesicles, endowed with regenerative cargo inherited from their parent cells, have attracted attention for their role in immunomodulation and ROS alleviation. Notably, the deliberate induction of apoptosis in MSCs prior to Extracellular Vesicles (EVs) isolation has been identified as a strategy to augment the regenerative capabilities of MSCs-EVs, as certain reports have suggested that MSCs undergo apoptosis to exert their therapeutic effect post-transplantation. Moreover, selecting an optimal tissue source for deriving MSC-sEVs is equally crucial to ensure consistent and improved clinical outcomes.

Multiple attributes of MSCs like their antioxidant, Immunomodulatory & regenerative properties make them particularly appealing for clinical studies, wherein mechanisms such as paracrine secretions and efferocytosis play pivotal roles. This investigation meticulously explores the comparative immunomodulatory & antioxidant capabilities of Apoptotic sEVs (Apo-sEVs) with Viable sEVs (V-sEVs) obtained from both Bone Marrow (BM) and Wharton’s Jelly (WJ)-derived MSCs, using anin vitroliver injury model. The findings from the present study contribute valuable insights into the comparative efficacy of Apo-sEVs and V-sEVs. This will aid in addressing a critical gap in understanding the role of apoptosis in enhancing the reparative capability of MSCs-sEVs. It also aims to shed light on the optimal source of MSCs for generating Apo-sEVs in translational applications.

GRAPHICAL ABSTARCT
Hearing function moderates age-related changes in brain morphometry in the HCP Aging cohort
Authors: Kirschen Robert M , Leaver Amber M
Published: April 2024

Introduction: There are well-established relationships between aging and neurodegenerative changes, and between aging and hearing loss. The goal of this study was to determine how structural brain aging is influenced by hearing loss. Methods: Human Connectome Project Aging (HCP-A) data were analyzed, including T1-weighted MRI and Words in Noise (WIN) thresholds (n=623). Freesurfer extracted gray and white matter volume, and cortical thickness, area, and curvature. Linear regression models targeted (1) interactions between age and WIN threshold and (2) correlations with WIN threshold adjusted for age, both corrected for false discovery rate (pFDR<0.05). Results: WIN threshold moderated age-related increase in volume in bilateral inferior lateral ventricles, with higher threshold associated with increased age-related ventricle expansion. Age-related deterioration in occipital cortex was also increased with higher WIN thresholds. When controlling for age, high WIN threshold was correlated with reduced cortical thickness in Heschl's gyrus, calcarine sulcus, and other sensory regions, and reduced temporal lobe white matter. Older volunteers with poorer hearing and cognitive scores had the lowest volume in left parahippocampal white matter. Conclusions: Preserved hearing abilities in aging associated with a reduction of age-related changes to medial temporal lobe, and preserved hearing at any age associated with preserved cortical tissue in auditory and other sensory regions. Future longitudinal studies are needed to assess the causal nature of these relationships, but these results indicate interventions which preserve hearing function may combat some neurodegenerative changes in aging.
Sample multiplexing for retinal single-cell RNA-sequencing
Authors: Ma Justin , Chu Ting Kuan , Polo Prieto Maria , Park Yong , Li Yumei , Chen Rui , Mardon Graeme , Frankfort Benjamin J , Tran Nicholas M
Published: April 2024

Rare cell populations can be challenging to characterize using microfluidic single-cell RNA sequencing (scRNA-seq) platforms. Typically, the population of interest must be enriched and pooled from multiple biological specimens for efficient collection. However, these practices preclude the resolution of sample origin together with phenotypic data and are problematic in experiments in which biological or technical variation is expected to be high (e.g., disease models, genetic perturbation screens, or human samples). One solution is sample multiplexing whereby each sample is tagged with a unique sequence barcode that is resolved bioinformatically. We have established a scRNA-seq sample multiplexing pipeline for mouse retinal ganglion cells using cholesterol-modified-oligos and utilized the enhanced precision to investigate cell type distribution and transcriptomic variance across retinal samples. As single cell transcriptomics are becoming more widely used to research development and disease, sample multiplexing represents a useful method to enhance the precision of scRNA-seq analysis.
Optimizing Exome Captures in Species with Large Genomes Using Species-specific Repetitive DNA Blocker
Authors: Kesälahti Robert , Kumpula Timo A. , Cervantes Sandra , Kujala Sonja T. , Mattila Tiina M. , Tyrmi Jaakko S. , Niskanen Alina K. , Rastas Pasi , Savolainen Outi , Pyhäjärvi Tanja
Published: April 2024

Large and highly repetitive genomes are common. However, research interests usually lie within the non-repetitive parts of the genome, as they are more likely functional, and can be used to answer questions related to adaptation, selection, and evolutionary history. Exome capture is a cost-effective method for providing sequencing data from protein-coding parts of the genes. C0t-1 DNA blockers consist of repetitive DNA and are used in exome captures to prevent the hybridization of repetitive DNA sequences to capture baits or bait-bound genomic DNA. Universal blockers target repetitive regions shared by many species, while species-specific c0t-1 DNA is prepared from the DNA of the studied species, thus perfectly matching the repetitive DNA contents of the species. So far the use of species-specific c0t-1 DNA has been limited to a few model species. Here, we evaluated the performance of blocker treatments in exome captures ofPinus sylvestris, a widely distributed conifer species with a large (> 20 Gbp) and highly repetitive genome. We compared treatment with a commercial universal blocker to treatments with species-specific c0t-1 (30,000 ng and 60,000 ng). Species-specific c0t-1 captured more unique exons than the initial set of targets, reduced sequencing of tandem repeats, and produced more target regions with high read coverage and narrower depth distribution than the universal blocker. Based on our results, we recommend optimizing exome captures by using at least 60,000 ng species-specific c0t-1 DNA. It is relatively easy and fast to prepare and can also be used with existing bait set designs.
Mind Captioning: Evolving descriptive text of mental content from human brain activity
Authors: Horikawa Tomoyasu
Published: April 2024

A central challenge in neuroscience is decoding brain activity to uncover mental content comprising multiple components and their interactions. Despite progress in decoding language-related information from human brain activity, generating comprehensive descriptions of complex mental content associated with structured visual semantics remains challenging. We present a method that generates descriptive text mirroring brain representations via semantic features computed by a deep language model. Constructing linear decoding models to translate brain activity induced by videos into semantic features of corresponding captions, we optimized candidate descriptions by aligning their features with brain-decoded features through word replacement and interpolation. This process yielded well-structured descriptions faithfully capturing viewed content, even without relying on the canonical language network, thereby revealing explicit representations of fine-grained structured semantic information outside this network. The method also successfully generalized to verbalize recalled content, demonstrating the potential for non-verbal thought-based brain-to-text communication, which could aid individuals with language expression difficulties.
Evolutionary history of the main extracellular matrix polysaccharides in brown algae
Authors: Hervé Lisa , Bouguerba-Collin Ahlem , Cock J. Mark , Denoeud France , Godfroy Olivier , Brillet-Guéguen Loraine , Barbeyron Tristan , Lipinska Agnieszka P. , Delage Ludovic , Corre Erwan , Drula Elodie , Henrissat Bernard , Czjzek Mirjam , Terrapon Nicolas , Hervé Cécile
Published: April 2024

Brown algae belong to the Stramenopiles phylum and are phylogenetically distant from plants and other multicellular organisms. This independent evolutionary history has shaped brown algae with numerous metabolic characteristics specific to this group, including the synthesis of peculiar polysaccharides contained in their extracellular matrix (ECM). Alginates and fucose-containing sulphated polysaccharides (FCSP), the latter including fucans, are the main components of ECMs. However, the metabolic pathways of these polysaccharides remain poorly described due to a lack of genomic data. An extensive genomic dataset has been recently released for brown algae and their close sister species. We performed an expert annotation of key genes involved in ECM-carbohydrate metabolisms, combined with comparative genomics, phylogenetics analyses, and protein modelling. Our analysis indicates that the gene families involved in both the synthesis and degradation of alginate were acquired by the common ancestor of brown algae and their closest sister speciesSchizocladia ischiensis, and subsequently expanded in brown algae. The pathway for the biosynthesis of fucans still remains biochemically unresolved and we identify the most likely fucosyltransferase genes that may harbour a fucan synthase activity in brown algae. Our analysis questions the possible occurrence of FCSPs outside brown algae, notably within their closest sister taxon.
Chloroquine attenuates hypoxia-mediated autophagy to curb thrombosis- anex vivoandin vivostudy
Authors: Bandyopadhyay Propanna , Katakia Yash T. , Mukherjee Sudeshna , Majumder Syamantak , Chowdhury Shibasish , Chowdhury Rajdeep
Published: April 2024

Background

Hypoxia can trigger the activation of blood platelets, leading to thrombosis. If not addressed clinically, it can cause severe complications and fatal consequences as well. The current treatment regime for thrombosis is often palliative and includes long-term administration of anticoagulants, which has the risk of over-bleeding in injury and other secondary effects as well. This demands a deeper understanding of the process and exploration of an alternative therapeutic avenue. Interestingly, recent studies demonstrate that platelets though atypical and enucleated, possess components of autophagy machinery. This cellular homeostatic process though well-studied in non-platelet cells, is under-explored in platelets.

Methods

In this study, we report an activation of autophagy in rat-derived platelets cultured under physiologically relevant hypoxic condition (10% O2)ex vivo. Furthermore, autophagy was triggeredin vivowhen rats were exposed to hypobaric hypoxic conditions. Subsequently, restriction or surgical ligation of the inferior vena cava (IVC) was performed to induce thrombus formation. Post confirming the impact of autophagy induction on platelet functioning, it was inhibited, and then platelet activation and aggregation status were evaluated using light transmission aggregometry, flow cytometry, immunofluorescence and immunoblotting.

Results

Herein, we show that autophagy inhibition with the potent autophagy inhibitor-CQ, a repurposed FDA-approved drug, can significantly reduce platelet activation, both inex vivoandin vivosettings. CQ withdrawal reversed the phenomenon indicating a dynamic effect. Thereafter, in flow restriction or surgical ligation model, interestingly, CQ-pre-treated rats showed reduced clotting ability. Importantly, CQ at the stipulated dose was found to be non-toxic to the tissues, as analyzed through histological staining.

Conclusion

Thus, we propose that the repurpose of the FDA approved drug CQ can attenuate hypoxia-induced thrombosis through inhibition of autophagy and can be explored as an effective therapeutic alternative.

Highlights

Exposure ofex-vivocultured platelets to physiologically relevant hypoxic condition (O2concentration) can induce autophagy causing them to get activated and eventually aggregate.

FDA approved drug chloroquine (CQ) is able to inhibit autophagy in anucleate cellular fragments, platelets, similar to nucleated cells and curb platelet functioning under hypoxic condition in bothex-vivoandin-vivomodel.

Flow restriction model mimicking deep vein thrombosis, emphasizes on the effect of CQ on impeding thrombus formation when used at a non-toxic dosage.
Ferroptosis Inhibition Combats Metabolic Derangements and Improves Cardiac Function in Pulmonary Artery Banded Pigs
Authors: Kazmirczak Felipe , Moon Ryan , Vogel Neal T. , Tollison Walt , T.Lahti Matt , Carney John P. , Mendelson Jenna B , Markowski Todd , Higgins LeeAnn , Murray Kevin , Guerrero Candace , Prins Kurt W.
Published: April 2024

Right heart failure (RHF) is a leading cause of mortality in multiple cardiovascular diseases and preclinical and human data suggest impaired metabolism is a significant contributor to right-sided cardiac dysfunction. Ferroptosis is a nonapopotic form of cell death driven by impaired metabolism. Rodent data suggests ferroptosis inhibition can restore mitochondrial electron transport chain function and enhance cardiac contractility in left heart failure models, but the effects of ferroptosis inhibition in translational large animal models of RHF are unknown. Here, we showed ferrostatin-1 mediated ferroptosis antagonism improve right heart structure and function in pulmonary artery banded pigs. Molecularly, ferrostatin-1 restored mitochondrial cristae structure and combatted downregulation of electron transport chain proteins. Metabolomics and lipidomics analyses revealed ferrostatin-1 improved fatty acid metabolism. Thus, these translational data suggest ferroptosis may be a therapeutic target for RHF.

Graphical Abstract