bluuebunny/crossref_metadata_2025 huggingface dataset:
DNMT1-Mediated Regulation of Inhibitory Interneuron Migration Impacts Cortical Architecture and Function
Authors: Reichard Julia , Wolff Philip , Du Jian , Fullio Camila L. , Dorp Lilli , Yildiz Can Bora , Linde Jenice , Vollmer Johanna , Kempf Shirley , Graff Severin , Nabbefeld Gerion , Singh Minali , Kuo Chao-Chung , Mohan K. Naga , Vogel Tanja , Musall Simon , Zimmer-Bensch Geraldine
Published: September 2024

The fine-tuned establishment of neuronal circuits during the formation of the cerebral cortex is pivotal for its functionality. Developmental abnormalities affecting the composition of cortical circuits, which consist of excitatory neurons and inhibitory interneurons, are linked to a spectrum of neuropsychiatric disorders. Excitatory neurons originate in cortical proliferative zones, while inhibitory interneurons migrate from discrete domains of the basal telencephalon into the cortex. This migration is intricately governed by intrinsic genetic programs and extrinsic cues. Our current study reveals the role of the DNA methyltransferase 1 (DNMT1) in controlling expression of key genes implicated in mouse cortical interneuron development and in guiding the migration of somatostatin-expressing interneurons within the developing cortex.Dnmt1deletion causes interneurons to exit prematurely from the superficial migratory stream. In addition to the perturbed migration pattern and altered gene expression signatures,Dnmt1-deficient interneurons had a discernible non-cell autonomous effect on cortical progenitors, which culminated in nuanced alterations of layer thicknesses in the adult cortex. Our study reveals that an epigenetic mechanism governs the migration of cortical interneurons and through this, their instructive role in sculpting the intricate cortical layer architecture by signaling to cortical progenitors, with pronounced effects on cortical network function.
Is water vole diet consistent with theplant hypothesisfor explaining population fluctuations?
Authors: Lisse Hélène , Buronfosse Marion , Jacquet Cédric , Sobczyk-Moran Gaëlle , Ramadier Etienne , Fafournoux Ambre , Lattard Virginie , Pinot Adrien
Published: September 2024

Rodent population cycles are observed in highly seasonal environments. As most rodents are herbivorous, the availability and the quality of their food resources varies greatly across seasons. Furthermore, it is well documented that herbivore densities have a measurable effect on vegetation and conversely. So, many studies investigated whether rodent population cycles could be induced by bottom-up regulation. A recent review summarized several sub-hypotheses leading to rodent population cycles: cycles may be due to inherent inter-annual variations of plant quantity, to overshoot of carrying capacity by overgrazing (i.e. lack of quantity), to changes in quality of food (decrease of quality of preferred food or switch towards less quality food) in response to rodent grazing (e.g. plant defences). If some sub-hypothesis seems to be more important than others, there is currently a prerequisite to construct scientific consensus: dietary description is still overlooked in many systems and should be more investigated.

This study focuses on fossorial water vole. It shows contrasted population dynamics depending on its geographical locations. It is known to be able to exhibit large outbreaks in grasslands in highly seasonal climate. It is thus a good model species to investigate plant hypotheses, first beginning by diet description.

The diet of water vole was investigated in and out of the outbreak area with a combination of approaches in the field, in different sampling sites and considering seasonality. We demonstrated that voles have a very large fundamental trophic niche, but strong behavioural selection, inducing a narrower realised niche, especially during winter. We created an experimental device based on camera trap and cafeteria tests. We observed a strong preference for dandelion (Taraxacum officinale) in wild water voles, that results in exclusive selection during winter for food stores. These preferences were constant across seasons, altitudes and grassland productivity gradients, despite the scarcity of this species in some experimental sites.

First, we conclude on the importance of using different methods to fully describe the diet of rodents Second, we assess that dandelion is a winter key resource for water vole. It thus might be interesting to investigate the role of dandelion in vole population dynamics.
Environmental antibiotic resistome: selection of HAE-1 efflux pumps in early stages of plant root development
Authors: Simenel Olwen , Nazaret Sylvie , Bodilis Josselin
Published: September 2024

Natural environments are known to be reservoirs for antibiotic resistance genes (ARGs) and human pathogens. Thus, the One Health approach is necessary to fully understand their origin, spread and evolution. Among environments, the rhizosphere – i.e. the volume of soil in contact with plant roots - is of particular interest as it is both a hotspot of bacterial biomass and activity, and ARGs. In this study we investigated the role of the rhizosphere in the selection of antibiotic resistance in its associated bacterial community. We compared the abundance and expression levels of ARGs in seven metagenomes obtained after isotope labeling (DNA-SIP) and eighteen metatranscriptomes of soil and rhizosphere ofAvena fatuafrom six to nine weeks old. ARGs were identified using the CARD database and an in-house HAE-1 (Hydrophobe Amphiphile Efflux-1) efflux pumps database. Our results showed that genes encoding the HAE-1 efflux pumps are enriched in the rhizosphere of six- and nine-week-old plants among the bacteria metabolizing the root exudates, and significantly overexpressed in the rhizosphere of nine-week-old plants. Additionnally, the diversity of HAE-1 pumps expressed in the rhizosphere was observed to be considerable, encompassing the full range of known diversity of these pumps in Gram-negative bacteria. We demonstrated that the environmental conditions in the rhizosphere directly selects for the HAE-1 pumps that is a major multidrug resistance factor in Gram-negative human pathogens. Studying the resistome of the rhizosphere is thus important to understand the emergence of multidrug resistance in human opportunistic pathogens.
Why has the United States of America not ratified the United Nations Convention on the Rights of the Child? The veto fulcrum as a new health policy analysis framework
Authors: Harris Lia
Published: September 2024

The United Nations Convention on the Rights of the Child (CRC) enshrines health as a human right among other rights for children, the fulfillment of which can be advanced by each member state legally endorsing the principles through ratification of the Convention. The most rapidly and widely ratified human rights treaty in history, only the United States of America of all of the UN state parties has not ratified the CRC. This study aimed to determine the reason(s) the CRC has not been ratified by the USA. Method design involved a mapping literature search and in-depth interviews with key stakeholders in the fields of global health, child rights, health policy, and US law. Implementing Walt and Gilson’s health policy triangle to systematize themes into content, context, processes, and actors as opposition or proponents of ratification, finds the literature favors ratification of the CRC. Critically, published literature focuses on pros and cons of ratification of the CRC, rather than reasons why the US has not ratified. Interview informants further expanded themes to elucidate how the history of opposition actors and processes has led to a chilling effect and a status quo of non-ratification, which has become increasingly challenging to overcome. Drawing on Tsebelis’ veto player theory to explain the status quo and introducing a new policy analysis framework of a veto fulcrum reveals that within the process of ratification, single powerful actors at a veto fulcrum have made undemocratic decisions, obstructing CRC ratification. By investigating American non-ratification of the CRC this research has forged a new policy framework, the veto fulcrum, which examines political systems where political actors – who might even be democratically elected – as veto players have extraordinary power to make executive decisions against public opinion, and against good health policy.

Author Summary

Published literature focuses on reasons for or against US ratification of the CRC, rather than reasons why America has not ratified. This study draws from Walt and Gilson’s health policy triangle and Tsebelis’ veto player theory to answerwhythe US has not ratified the CRC. Revising Walt and Gilson’s health policy triangle and drawing on Tsebelis’ veto player theory a new policy analysis framework approach is introduced – the veto fulcrum – which highlights the correlation between actors and processes and their relative importance over content and context factors in the non-ratification of policy. The veto fulcrum underscores the ascendancy of single actors in policy decisions by examining how, by whom, and why these single actors make decisions and/or might be influenced. The veto fulcrum framework can be applied to understand other policy decisions, by identifying and examining barriers to ratification or enactment of health or other good governance policies.
WITHDRAWN: Enhancing Fetal Cardiac Ultrasound Diagnosis: A Multi-Task Hybrid Attention Model for Accurate Standard Plane Detection
Authors: Tian Haodong , Liu Yuxi , Au Frederick , Lin Guannning
Published: September 2024

Withdrawal Statement

The authors have withdrawn this manuscript because it contains fundamental errors and fabricated data. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Impact of 26 Skin Diseases on the Risk of Non-Small Cell Lung Cancer: A Mendelian Randomization Study Using FinnGen R11 Data
Authors: Li Xingyuan , Li Hui
Published: September 2024

Purpose

To determine whether genetic predisposition to various skin diseases influences the risk of non-small cell lung cancer (NSCLC) through Mendelian randomization (MR).

Methods

Single nucleotide polymorphisms (SNPs) associated with 26 skin diseases were extracted from the FinnGen R11 dataset and underwent rigorous quality control. To evaluate the association between these skin diseases and the risk of non-small cell lung cancer (NSCLC), we applied several analytical methods, including inverse-variance weighted (IVW), MR-Egger regression, weighted median, Simple mode, and Weighted mode. The robustness of the findings was further supported by assessing SNP heterogeneity with the Cochran Q test and evaluating horizontal pleiotropy using the MR-Egger intercept test.

Results

Our study revealed that genetically predicted dermatitis herpetiformis (DH) was significantly associated with an elevated risk of squamous cell carcinoma of the lung (SCC). Acne was nominally linked to an increased risk of SCC. Additionally, rhinophyma (RHN), hidradenitis suppurativa (HS), and DH were nominally associated with a higher risk of adenocarcinoma of the lung (ADC). Of the remaining 22 skin diseases analyzed, 7 lacked sufficient instrumental variables to meet inclusion criteria. The other 15 skin diseases showed no statistically significant association with NSCLC.

Conclusion

This study ultimately analyzed the relationship between 19 skin diseases and NSCLC at the genetic level, while 7 other skin diseases could not be analyzed due to insufficient instrumental variables. Dermatitis herpetiformis and acne were associated with an increased risk of squamous cell carcinoma of the lung. Additionally, rhinophyma, hidradenitis suppurativa, and dermatitis herpetiformis were associated with an increased risk of adenocarcinoma of the lung.
Fetal hemoglobin enables malaria parasite growth in sickle cells but augments production of transmission stage parasites
Authors: Lavazec Catherine , Loucoubar Cheikh , Dupuy Florian , Bureau Jean-François , Casadémont Isabelle , Gonçalves Bronner P. , Thein Swee Lay , Lathrop Mark , Laurance Sandrine , Roussel Camille , Le Van Kim Caroline , Colin Yves , De Montalembert Mariane , Sakuntabhai Anavaj , Paul Rick E.
Published: September 2024

Sickle cell trait is the quintessential example of the human response to malaria, providing protection against severe disease, but leading to sickle cell disease (SCD) in the homozygous state. Fetal Hemoglobin (HbF) reduces the pathology of SCD and several mutations lead to the prolonged production of HbF into childhood and adult life. HbF has been suggested to contribute to protection against malaria. Two long-term cohorts were genotyped for three quantitative trait loci associated with HbF production and analyzed for HbF titers, malaria clinical episodes and the production of parasite stages infectious to mosquitoes, gametocytes in asymptomatic infections.Plasmodium falciparumparasites were also grownin vitroin HbSS cells with measured levels of HbF. The genetic determinants of prolonged HbF production were associated with increased HbF titers and that increased HbF afforded protection from malaria disease but increased the production of gametocytes. The presence of HbF in sickled red cells was also shown inin vitroculture to enable parasite persistence in conditions otherwise deleterious for the parasite and enabled complete maturation of gametocytes. The beneficial personal effect of HbF, whether through protection against malaria or alleviating effects of SCD, is offset by increased parasite transmissibility and disease burden for the community. These individuals represent an important reservoir of infection and need to be targeted in elimination strategies.

Key points

Individuals with mutations associated with fetal hemoglobin production had fewer clinical episodes but produced more gametocytes.

HbF in red blood cells enables gametocyte production at tissue level oxygen partial pressures at which normally parasite lysis would occur.
Pediatric brain tumor classification using deep learning on MR-images with age fusion
Authors: Tampu Iulian Emil , Bianchessi Tamara , Blystad Ida , Lundberg Peter , Nyman Per , Eklund Anders , Haj-Hosseini Neda
Published: September 2024

Purpose

To implement and evaluate deep learning-based methods for the classification of pediatric brain tumors in MR data.

Materials and methods

A subset of the “Children’s Brain Tumor Network” dataset was retrospectively used (n=178 subjects, female=72, male=102, NA=4, age-range [0.01, 36.49] years) with tumor types being low-grade astrocytoma (n=84), ependymoma (n=32), and medulloblastoma (n=62). T1w post-contrast (n=94 subjects), T2w (n=160 subjects), and ADC (n=66 subjects) MR sequences were used separately. Two deep-learning models were trained on transversal slices showing tumor. Joint fusion was implemented to combine image and age data, and two pre-training paradigms were utilized. Model explainability was investigated using gradient-weighted class activation mapping (Grad-CAM), and the learned feature space was visualized using principal component analysis (PCA).

Results

The highest tumor-type classification performance was achieved when using a vision transformer model pre-trained on ImageNet and fine-tuned on ADC images with age fusion (MCC: 0.77 ± 0.14 Accuracy: 0.87 ± 0.08), followed by models trained on T2w (MCC: 0.58 ± 0.11, Accuracy: 0.73 ± 0.08) and T1w post-contrast (MCC: 0.41 ± 0.11, Accuracy: 0.62 ± 0.08) data. Age fusion marginally improved the model’s performance. Both model architectures performed similarly across the experiments, with no differences between the pre-training strategies. Grad-CAMs showed that the models’ attention focused on the brain region. PCA of the feature space showed greater separation of the tumor-type clusters when using contrastive pre-training.

Conclusion

Classification of pediatric brain tumors on MR-images could be accomplished using deep learning, with the top-performing model being trained on ADC data, which is used by radiologists for the clinical classification of these tumors.

Key points

The vision transformer model pre-trained on ImageNet and fine-tuned on ADC data with age fusion achieved the highest performance, which was significantly better than models trained on T2w (second-best) and T1w-Gd data.

Fusion of age information with the image data marginally improved classification, and model architecture (ResNet50 -vs -ViT) and pre-training strategies (supervised -vs -self-supervised) did not show to significantly impact models’ performance.

Model explainability, by means of class activation mapping and principal component analysis of the learned feature space, show that the models use the tumor region information for classification and that the tumor type clusters are better separated when using age information.

Deep learning-based classification of pediatric brain tumors can be achieved using single-sequence pre-operative MR data, showing the potential of automated decision support tools that can aid radiologists in the primary diagnosis of these tumors.
Comprehensive analysis of prostate cancer life expectancy, loss of life expectancy, and healthcare expenditures: Taiwan national cohort study spanning 2008 to 2019
Authors: Liu Pin-Chun , Lin Yi-Sheng , Ou Yen-Chuan , Hsu Chao-Yu , Tung Min-Che , Chiu Ying-Ming
Published: September 2024

Prostate cancer (PCa) is the second most commonly diagnosed cancer worldwide and the 5th leading cause of death from cancer for men in Taiwan. The incidence of synchronous metastatic PCa in Taiwan is higher than U.S. and Europe. We aim to present the latest life expectancy (LE), loss of LE, and lifetime cost associated with PCa in Taiwan. The PCa data are based on Taiwan Cancer Registry and National Health Insurance Database. Total 30,207 new cases of PCa were recorded during 2008-2019 nationwide. LE, estimated loss of LE and lifetime cost were stratified by age, cancer stage, Gleason score, grade group and serum PSA level at diagnosis. We compared LE and healthcare cost outcomes between synchronous metastatic PCa patients in 3 age groups. Among the 30,207 new cases, the low to intermediate risk groups, high-risk groups, and regional and metastatic PCa accounted for 54.1%, 13.2%, and 32.6% of cases, respectively. A considerable proportion of synchronous metastatic PCa was noted in Taiwan when compared with the U.S. For synchronous metastatic PCa, the highest LE is 9.22 years for ages 20-64 years, followed by ages 65-74 (8.29 years) and ages 75-89 years (4.58 years). The loss of LE in the three groups is 13.63, 6.75, and 3.87 years, respectively. The healthcare cost of synchronous metastatic PCa in all age groups is higher than the average cost for PCa patients in Taiwan. This study provides real-world evidence to support health care policy-making and clinical decisions regarding PCa. Due to the high proportion of synchronous metastatic PCa in Taiwan, the findings of this analysis emphasize the importance of early detection of PCa, which can save LE and decrease the total cost burden on the healthcare system.
Clinical prediction models to diagnose neonatal sepsis in low-income and middle-income countries: a scoping review
Authors: Neal Samuel R , Sturrock Sarah S , Musorowegomo David , Gannon Hannah , Zaman Michele , Cortina-Borja Mario , Le Doare Kirsty , Heys Michelle , Chimhini Gwendoline , Fitzgerald Felicity
Published: September 2024

Neonatal sepsis causes significant morbidity and mortality worldwide but is difficult to diagnose clinically. Clinical prediction models (CPMs) could improve diagnostic accuracy. Neonates in low-income and middle-income countries are disproportionately affected by sepsis, yet no review has comprehensively synthesised CPMs validated in this setting. We performed a scoping review of CPMs for neonatal sepsis diagnosis validated in low-income and middle-income countries. From 4598 unique records, we included 82 studies validating 44 distinct models. Most studies were set in neonatal intensive or special care units in middle-income countries and included neonates already suspected of sepsis. Three quarters of models were only validated in one study. Our review highlights several literature gaps, particularly a paucity of studies validating models in low-income countries and the WHO African region, and models for the general neonatal population. Furthermore, heterogeneity in study populations, definitions of sepsis and reporting of models may hinder progress in this field.
Descriptives and genetic correlates of eating disorder diagnostic transitions and presumed remission in the Danish registry
Authors: Abdulkadir Mohamed , Larsen Janne Tidselbak , Clausen Loa , Hübel Christopher , Albiñana Clara , Thornton Laura M. , Vilhjálmsson Bjarni J. , Bulik Cynthia M. , Yilmaz Zeynep , Petersen Liselotte Vogdrup
Published: September 2024

Objective

Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. The authors investigated occurrences of ED transitions and presumed remission and their genetic correlates as captured by polygenic scores (PGSs) in a large Danish register-based cohort.

Methods

The sample compromised of 10,565 individuals with a diagnosis of anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (EDNOS) with at least two registered hospital contacts between 1995 and 2018. Based on medical records, occurrence of diagnostic transitions and periods of presumed remission were identified. Associations between 422 PGS and diagnostic transitions and presumed remission were evaluated using Cox proportional hazard models.

Results

A minority of ED cases (14.1%-23.1%) experienced a diagnostic transition. Presumed remission ranged between 86.9%-89.8%. Higher (one SD increase) PGS for major depressive disorder and multisite chronic pain were positively associated with transitioning from AN to either BN or EDNOS. Higher PGS on a measure of body fat percentage and financial difficulties were positively associated with presumed remission from AN. Higher PGS for mood swings was positively associated with presumed remission from EDNOS whereas higher PGS for health rating showed the opposite.

Conclusions

The authors found that most ED patients did not experience diagnostic transitions but were more likely to experience a period of presumed remission. Both diagnostic transitions and presumed remission have significant polygenic component.
Traumatic Amputations - A Nationwide Epidemiological Analysis of a developing country over 16 years
Authors: Ceratti Marcella Moura , Sorbello Carolina Carvalho Jansen , Sunye Isabela Roskamp , Portela Felipe Soares , da Silva Marcelo Fiorelli Alexandrino , Teivelis Marcelo Passos , Neto Miguel Cendoroglo , Wolosker Nelson
Published: September 2024

Background

Defining the impact of amputation is essential for developing cost-effective preventive health policies. Trauma is one of the most common causes of limb loss, affecting mainly the young working population. To date, few studies have investigated the epidemiology of patients undergoing trauma-related amputations and their public health implications in developing countries. The aim of this study was to analyze all limb amputations due to traumatic injuries performed in the Brazilian public health system over a 16-year period, studying their incidence, demographics, hospitalization and costs.

Objective

To analyze the epidemiologic data on traumatic amputations within Brazil’s public health system.

Methods

This study was a cross-sectional and retrospective population-based analysis of traumatic amputations performed in the Brazilian public health system from 2008 to 2023. DATASUS, a public database of the Brazilian public health system, was used to select trauma cases, which were filtered by the traumatic amputation code. The dataset included the number of procedures, regional distribution, patient demographics, length of hospital stay, ICU stay, lethality and financial reimbursement.

Results

There were 202,940 traumatic amputations in Brazil between 2008 and 2023. This condition was most common in males (78.7%), with an average age of 44.77 years, mainly involving fingers (62.7%). Cases involving lower limbs led to longer hospital stays and more ICU admissions. The mean length of hospital stay was 4.57 days, culminating in a lethality of 3.15%, which remained stable during the follow-up period. The estimated total cost to the Brazilian public health system was US$ 54,870,097.79, equivalent to approximately US$ 34,29381 spent per year on traumatic amputations, with the lower limb representing twice as much per patient.

Conclusion

Traumatic amputation is still common in all regions of Brazil and has remained stable over the past 16 years, as has its lethality. Lesions leading to lower limb amputation account for the majority of hospital stays, intensive care unit admissions, and higher lethality and costs.
Impaired spatial dynamic functional network connectivity and neurophysiological correlates in functional stroke mimics
Authors: Premi Enrico , Cantoni Valentina , Benussi Alberto , Iraji Armin , Calhoun Vince , Corbo Daniele , Gasparotti Roberto , Tinazzi Michele , Borroni Barbara , Magoni Mauro
Published: September 2024

The present study investigated spatial dynamic functional network connectivity (dFNC) in patients with functional hemiparesis (i.e., functional stroke mimics, FSM). The aim of this work was to assess dynamic brain states, which represent distinct dFNC patterns that reoccur in time and across subjects. Resting-state fMRI data were collected from 15 patients with FSM (mean age=42.3±9.4, female=80%) and 52 age-matched healthy controls (HC, mean age=42.1±8.6, female=73%). Each patient underwent a resting-state functional MRI scan for spatial dFNC evaluation and transcranial magnetic stimulation protocols for indirect assessment of GABAergic and glutamatergic transmission. We considered three dynamic brain networks, i.e., the somatomotor network (SMN), the default mode network (DMN) and the salience network (SN), each summarized into four distinct recurring spatial configurations. Compared to HC, patients with FSM showed significant decreased dwell time, e.g. the time each individual spends in each spatial state of each network, in state 2 of the SMN (HC vs. FSM, 13.5±27.1 vs. 1.9±4.1, p=0.034). Conversely, as compared to HC, FSM spent more time in state 1 of the DMN (10.8±14.9 vs. 27.3±38.9, p=0.033) and in state 3 of the SN (23.1±23.0 vs. 38.8±38.2, p=0.001). We found a significant correlation between the dwell time of impaired functional state of the SMN and measures of GABAergic neurotransmission (r=0.581, p=0.037). Specifically, longer impaired dwell time was associated with greater GABAergic inhibition. These findings demonstrate that FSM present altered functional brain network dynamics, which correlate with measures of GABAergic neurotransmission. Both dFNC and GABAergic neurotransmission may serve as potential targets for future intervention strategies.
Transcriptome-scale analysis uncovers conserved residues in the hydrophobic core of the bacterial RNA chaperone Hfq required for small regulatory RNA stability
Authors: McQuail Josh , Krepl Miroslav , Katsuya-Gaviria Kai , Tabib-Salazar Aline , Burchell Lynn , Bischler Thorsten , Gräfenhan Tom , Brear Paul , Šponer Jiři , Luisi Ben , Wigneshweraraj Ramesh
Published: September 2024

The RNA-chaperone Hfq plays crucial role in bacterial gene expression and is a major facilitator of small regulatory RNA (sRNA) action. The toroidal molecular architecture of the Hfq hexamer contains three well characterised surfaces which allow it to bind sRNAs to stabilise them and bind to target transcripts. Hfq-interacting sRNAs are categorised into two classes based on the surfaces they use to bind Hfq. By characterising a systematic alanine mutant library of Hfq to identify amino acid residues that impact survival of Escherichia coli experiencing nitrogen starvation, we corroborated the important role of the three RNA binding surfaces for Hfq function. Surprisingly, we uncovered two conserved residues, V22 and G34, in the hydrophobic core of Hfq, to have a significant role in Hfq's RNA binding activity. Alanine substitutions at these residues had no measurable impact on protein stability or equilibrium binding to target sRNAs in vitro. However, transcriptome-scale analysis revealed that V22A and G34A Hfq mutants cause widespread destabilisation of both sRNA classes. We propose that V22 and G34 are key to the cooperative function among the RNA-binding surfaces of Hfq, a mechanism especially critical under cellular conditions when there is an increased demand for Hfq.
Endocytic BDNF secretion through extracellular vesicle-dependent secretory pathways in astrocytes
Authors: Han Jeongho , Park Hyungju
Published: September 2024

Brain-derived neurotrophic factor (BDNF) plays an essential role in regulating diverse neuronal functions in an activity-dependent manner. Although BDNF is synthesized primarily in neurons, astrocytes can also supply BDNF through various routes, including the recycling of neuron-derived BDNF. Despite accumulating evidence for astrocytic BDNF uptake and resecretion of neuronal BDNF, the detailed mechanisms underlying astrocytic BDNF recycling remain unclear. Here, we report that astrocytic resecretion of endocytosed BDNF is mediated by an extracellular vesicle (EV)-dependent secretory pathway. In cultured primary astrocytes, extracellular BDNF was endocytosed into CD63-positive EVs, and stimulation of astrocytes with ATP could evoke the release of endocytosed BDNF from CD63-positive vesicles. Downregulation of vesicle-associated membrane protein 3 (Vamp3) led to an increase in the colocalization of endosomal BDNF and CD63 but a decrease in extracellular vesicle release, suggesting the necessity of Vamp3-dependent signaling for EV-mediated BDNF secretion. Collectively, our findings demonstrate that astrocytic recycling of neuronal BDNF is dependent on the EV-mediated secretory pathway via Vamp3-associated signaling.
Genomic changes are varied across congeneric species pairs
Authors: Francis Warren R. , Vargas Sergio , Wörheide Gert
Published: September 2024

Synteny, the shared arrangement of genes on chromosomes between related species, is a marker of shared ancestry, and synteny-breaking events can result in genomic incompatibilities between populations and ultimately lead to speciation events. Despite its pivotal role as a driver of speciation, the role of synteny breaks on speciation is poorly studied due to a lack of chromosome-level genome assemblies for a taxonomically broad sample of organisms. Here, using 22 congeneric animal genome pairs, we find a link between protein identity, microsynteny, and macrosynteny, but no evidence for a universal path of genomic change during divergence. We observed varied trajectories of synteny conservation relative to protein identity in non-model organisms, with many species pairs showing no karyotypic changes and others displaying large genomic rearrangements. This contrasts with previous studies on model organisms and indicates that the genomic changes preceding or resulting from speciation are likely very contextual between clades.
Subpopulation-specific gene expression inLachancea thermotoleransuncovers distinct metabolic adaptations to wine fermentation
Authors: Vicente Javier , Benito Santiago , Marquina Domingo , Santos Antonio
Published: September 2024

Gene expression is the first step in translating genetic information into quantifiable traits. This study analysed gene expression in 23 strains across six subpopulations ofLachancea thermotolerans, shaped by anthropization, under winemaking conditions to understand the impact of adaptation on transcriptomic profiles and fermentative performance, particularly regarding lactic acid production. By sequencing mRNA during exponential growth and fermentation in synthetic grape must, we identified unique expression patterns linked to the strains originated from wine-related environments. Global expression analysis revealed that anthropized subpopulations, particularly Europe/Domestic-2 and Europe-Mix, exhibited distinct gene expression profiles related to fermentation processes such as glycolysis and pyruvate metabolism. These processes were differentially expressed, along with other important biological processes during fermentation, such as nitrogen and fatty acid metabolism. This study highlights that anthropization has driven metabolic specialization inL. thermotolerans, enhancing traits like lactic acid production, which is a trait of interest in modern winemaking. Correlation analysis further linked lactic acid dehydrogenase genes with key metabolic pathways, indicating adaptive gene expression regulation. Additionally, differences in other metabolites of oenological interest as glycerol or aroma compounds production are highlighted. Here, we provide insights into the evolutionary processes shaping the transcriptomic diversity ofL. thermotolerans, emphasizing the impact of winemaking environments on driving specific metabolic adaptations, including lactic acid production. Understanding the gene expression differences linked to lactic acid production could allow a more rational address of biological acidification while optimizing yeast-specific nutritional requirements during fermentation.

GRAPHICAL ABSTRACT
Genomic characterization of foodborneSalmonella entericaandEscherichia coliisolates from Saboba district and Bolgatanga Municipality Ghana
Authors: Sunmonu Gabriel Temitope , Adzitey Frederick , Odih Erkison Ewomazino , Tibile Boniface Awini , Ekli Rejoice , Aduah Martin , Oaikhena Anderson O , Akinlabi Olabisi C , Abia Akebe Luther King , Amoako Daniel Gyamfi , Okeke Iruka N
Published: September 2024

Salmonella enterica and Escherichia coliare well-known bacteria commonly associated with foodborne illnesses in humans and animals. Genomic characterization of these pathogens provides valuable insights into their evolution, virulence factors and resistance determinants. This study aimed to characterized previously isolatedSalmonella(n = 14) andE. coli(n = 19) from milk, meat and its associated utensils in Ghana using whole-genome sequencing. Most of theSalmonellaserovars (Fresno, Plymouth, Infantis, Give and Orleans) identified in this study are yet to be reported in Ghana. MostSalmonellaisolates were pan-sensitive, but genes conferring resistance to fosfomycin (fosA7.2) and tetracycline(tet(A))were detected in one and three isolates, respectively. Seven of theSalmonellaisolates carry the IncI1-I(Gamma) plasmid replicon. Although antimicrobial resistance was not common amongSalmonellastrains, most (11/19) of theE. colistrains had at least one resistance gene, with nearly half (8/19) being multidrug resistant and carrying mobile elements. Three of the 19E. colistrains belong to serovars commonly associated with enteroaggregativeE. coli(EAEC) pathotype. While strains belonging to virulence-associated lineages lacked key plasmid-encoded virulence plasmids, several plasmid replicons were detected in most of theE. coli(14/19) strains. Food contaminated with these pathogens can serve as a vehicle for disease transmission, posing a significant public health risk and necessitating stringent food safety and hygiene practices to prevent outbreaks. Hence, there is need for continuous surveillance and preventive measures to stop the spread of foodborne pathogens and reduce the risk of associated illnesses in Ghana.
The curse of the red pearl: a fibroblast specific pearl-necklace mitochondrial phenotype caused by phototoxicity
Authors: Hemel Irene MGM , Knoops Kèvin , López-Iglesias Carmen , Gerards Mike
Published: September 2024

The dynamic nature of mitochondria makes live cell imaging an important tool in mitochondrial research. Although imaging using fluorescent probes is the golden standard in studying mitochondrial morphology, these probes might introduce a-specific features. In this study, live cell fluorescent imaging was applied to investigate a pearl-necklace shaped mitochondrial phenotype that arises when mitochondrial fission is restricted. In this fibroblast specific pearl-necklace phenotype, constricted and expanded mitochondrial regions alternate. Imaging studies revealed that the formation time of this pearl-necklace phenotype differs between laser scanning confocal, widefield and spinning disk confocal microscopy. We found that the phenotype formation correlates with the excitation of the fluorescent probe and is the result of phototoxicity. Interestingly, the phenotype only arises in cells stained with red mitochondrial dyes. Serial section electron tomography pearl-necklace mitochondria revealed that the mitochondrial membranes remained intact, while the cristae structure was altered. Furthermore, filaments and ER were present at the constricted sites. This study illustrates the importance of considering experimental conditions for live cell imaging to prevent imaging artefacts that can have a major impact on the obtained results.
Differential gene expression in cells with different p53 mutations identifies genome-wide p53 targets and shows distinct modulation of cellular pathways in response to DNA damage
Authors: Eror Barnes Patricia , de la Concha Maria Jose , Mwikali Kioko , Ng Bee Ling , Ponstingl Hannes , Pance Alena
Published: September 2024

The fundamental transcription factor p53 regulates cellular processes and integrates signals of cellular stress, triggering a coordinated response to ensure survival of cells restored to healthy function and programmed death of those that couldn’t be repaired. Unsurprisingly, this is one of the most mutated genes in human cancers, with most changes occurring in the DNA-binding domain of the protein. In this work, we take a genome-wide approach and use available resources to identify high confidence p53-target genes, that we examine in three breast cancer cell lines with different p53 status, wild type (MCF-7) and different mutations in the DNA-binding domain (MDA-MB231, T47D). Comparison of p53-targets expression in response to DNA damage by RNAseq and cellular assays reveals that MDA-MB231 have a severely impaired p53-dependent pathway functionality while T47D are much less affected. MDA-MB231 are more resistant to DNA damage yet unable to repair and able to override cell cycle arrest leading to survival while T47D are sensitive only to high dose and exposure to genotoxic agents. This data shows the variability of effects of different p53 mutations and highlight the importance of understanding the mechanisms of p53 in the context of genotoxicity-based treatment.
Emergence of resistance to the antiparasitic selamectin inMycobacterium smegmatisis improbable and contingent on cell wall integrity
Authors: Ezquerra-Aznárez José Manuel , Gašparovič Henrich , Chiner-Oms Álvaro , Lucía Ainhoa , Blázquez Jesús , Comas Iñaki , Korduláková Jana , Ainsa José A. , Ramón-García Santiago
Published: September 2024

Tuberculosis remains the deadliest infectious disease of the 21stcentury. New antimicrobials are needed to improve treatment outcomes and enable therapy shortening. Drug repurposing is an alternative to the traditional drug discovery process. The avermectins are a family of macrocyclic lactones with anthelmintic activity active againstMycobacterium tuberculosis. However, their mode of action in mycobacteria remains unknown.

In this study, we employed traditional mutant isolation approaches usingMycobacterium smegmatis, a non-pathogenicMycobacterium tuberculosissurrogate. We were only able to isolate mutants with decreased susceptibility to selamectin using the ΔnucSmutatorM. smegmatisstrain. This phenotype was caused by mutations inmps1andmmpL11. Two of these mutants were used for a second experiment in which high-level selamectin-resistant mutants were isolated; however, specific mutations driving the phenotypic change to high-level resistance could not be identified. The susceptibility to selamectin in these mutants was restored to the basal level by subinhibitory concentrations of ethambutol. The selection of ethambutol resistance in a high-level selamectin-resistant mutant also resulted in multiple colonies becoming susceptible to selamectin again. These colonies carried mutations inembB, suggesting that integrity of the cell envelope is a prerequisite for selamectin resistance. The absence of increased susceptibility to selamectin in anembBdeletion strain demonstrated that the target of selamectin is not cytosolic. Our data show that concurrence of specific multiple mutations and complete integrity of the mycobacterial envelope are necessary for selamectin resistance. Our studies provide first-time insights into the antimycobacterial mode of action of the antiparasitic avermectins.
PPM1D truncation-associated overexpression of the stress-related protein NQO1 confers sensitivity to the bioactivatable drug IB-DNQ in diffuse intrinsic pontine glioma
Authors: Janin Maxime
Published: September 2024

Diffuse intrinsic pontine glioma (DIPG) is a very aggressive brainstem tumor with poor survival and a lack of effective treatments. In this study, I observed the differential overexpression of the stress-related protein NAD(P)H Quinone Dehydrogenase 1 (NQO1) in some patient-derived DIPG cell lines and tumors. I sought to understand how this protein is regulated in DIPG and to investigate the therapeutic potential of the NQO1-bioactivatable drug Isobutyl-deoxynyboquinone (IB-DNQ). Interestingly, the study of the mutational profiles of the cell lines indicated that truncation of PPM1D correlated with NQO1 overexpression. From a functional standpoint, cellular models were utilized to unravel the link between PPM1D phosphatase and NQO1 expression in DIPG by dephosphorylating MDM2 serine 395, leading to NQO1 protein stabilization. From a therapeutic perspective, IB-DNQ treatment showed an NQO1-dependent growth inhibition sensitivity in vitro and induced an extended survival in vivo. Overall, my results reveal a new regulation of NQO1 at the protein level in PPM1D-mutated DIPG indicating a promising therapeutic approach.
Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase
Authors: Skeens Erin , Maschietto Federica , Manjula Ramu , Shillingford Shanelle , Lolis Elias J. , Batista Victor S. , Bennett Anton M. , Lisi George P.
Published: September 2024

Dual-specificity mitogen-activated protein kinase (MAPK) phosphatases (MKPs) directly dephosphorylate and inactivate the MAPKs. Although the catalytic mechanism of dephosphorylation of the MAPKs by the MKPs is established, a complete molecular picture of the regulatory interplay between the MAPKs and MKPs still remains to be fully explored. Here, we sought to define the molecular mechanism of MKP5 regulation through an allosteric site within its catalytic domain. We demonstrate using crystallographic and NMR spectroscopy approaches that residue Y435 is required to maintain the structural integrity of the allosteric pocket. Along with molecular dynamics simulations, these data provide insight into how changes in the allosteric pocket propagate conformational flexibility in the surrounding loops to reorganize catalytically crucial residues in the active site. Furthermore, Y435 contributes to the interaction with p38 MAPK and JNK, thereby promoting dephosphorylation. Collectively, these results highlight the role of Y435 in the allosteric site as a novel mode of MKP5 regulation by p38 MAPK and JNK.
Efficient laser wakefield accelerator in pump depletion dominated bubble regime
Authors: Horný V. , Bleotu P. G. , Ursescu D. , Malka V. , Tomassini P.
Published: September 2024

With the usage of the postcompression technique, few-cycle joule-class laser pulses are nowadays available extending the state of the art of 100 TW-class laser working at 10 Hz repetition. In this Letter, we explore the potential of wakefield acceleration when driven with such pulses. The numerical modeling predicts that 50% of the laser pulse energy can be transferred into electrons with energy above 15 MeV, and with charge exceeding several nanocoulombs for the electrons at hundreds of MeV energy. In such a regime, the laser pulse depletes its energy to plasma rapidly driving a strong cavitated wakefield. The self-steepening effect induces a continuous prolongation of a bubble resulting in a massive continuous self-injection that explains the extremely high charge of the beam rending this approach suitable for promoting Bremsstrahlung emitter and generator of tertiary particles, including neutrons released through photonuclear reactions.

Published by the American Physical Society
2024
Reduction or Enhancement of Stellarator Turbulence by Impurities
Authors: García-Regaña J. M. , Calvo I. , Parra F. I. , Thienpondt H.
Published: September 2024

A systematic study of the impact of impurities on the turbulent heat fluxes is presented for the stellarator Wendelstein 7-X (W7-X) and, for comparison, the Large Helical Device and ITER. By means of nonlinear multispecies gyrokinetic simulations, it is shown that impurities, depending on the sign of their density gradient, can significantly enhance or reduce turbulent ion heat losses. For the relevant scenario of turbulence reduction, an optimal impurity concentration that minimizes the ion heat diffusivity emerges as a universal feature. This result demonstrates the potential of impurities for controlling turbulence and accessing enhanced confinement regimes in fusion plasmas and, in particular, in W7-X.

Published by the American Physical Society
2024
Automatic structural search of tensor network states including entanglement renormalization
Authors: Watanabe Ryo , Ueda Hiroshi
Published: September 2024

Tensor network (TN) states, including entanglement renormalization (ER), can encompass a wider variety of entangled states. When the entanglement structure of the quantum state of interest is nonuniform in real space, accurately representing the state with a limited number of degrees of freedom hinges on appropriately configuring the TN to align with the entanglement pattern. However, a proposal has yet to show a structural search of ER due to its high computational cost and the lack of flexibility in its algorithm. In this study, we conducted an optimal structural search of TN, including ER, based on the reconstruction of their local structures with respect to variational energy. First, we demonstrated that our algorithm for the spin-1/2 tetramer singlets model could calculate exact ground energy using the multiscale entanglement renormalization ansatz (MERA) structure as an initial TN structure. Subsequently, we applied our algorithm to the random XY models with the two initial structures: MERA and the suitable structure underlying the strong disordered renormalization group. We found that, in both cases, our algorithm achieves improvements in variational energy, fidelity, and entanglement entropy. The degree of improvement in these quantities is superior in the latter case compared to the former, suggesting that utilizing an existing TN design method as a preprocessing step is important for maximizing our algorithm's performance.

Published by the American Physical Society
2024