bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unveiling the Virulence Mechanism ofLeptosphaeria maculansin theBrassica napusInteraction: The Key Role of Sirodesmin PL in Cell Death Induction
Authors: Pombo Marina A. , Rosli Hernan G. , Maiale Santiago , Elliott Candace , Stieben Micaela E. , Romero Fernando M. , Garriz Andrés , Ruiz Oscar A. , Idnurm Alexander , Rossi Franco R. 
Published: June 2024

SummaryLeptosphaeria maculansis the causal agent of blackleg disease inBrassica napus, leading to substantial yield losses. Sirodesmin PL, the principal toxin produced byL. maculans, has been implicated in the infective process in plants. However, the precise molecular and physiological mechanisms governing its effects remain elusive. This study investigates the changes induced by Sirodesmin PL at the transcriptomic, physiological, and morphological levels inB. napuscotyledons. Sirodesmin PL treatment upregulates genes associated with plant defense processes, including response to chitin, sulfur compound biosynthesis, toxin metabolism, oxidative stress response, and jasmonic acid/ethylene synthesis and signaling. Validation of these transcriptomic changes is evidenced by several typical defense response processes, such as the accumulation of reactive oxygen species (ROS) and callose deposition. Concomitantly, oxidized Sirodesmin PL induces concentration- and exposure duration-dependent cell death. This cellular death is likely attributed to diminished activity of photosystem II and a reduction in the number of chloroplasts per cell. In agreement, a down-regulation of genes associated with the photosynthesis process is observed following Sirodesmin PL treatment. Thus, it is plausible thatL. maculansexploits Sirodesmin PL as a virulence factor to instigate cell death inB. napusduring its necrotrophic stage, favoring the infective process.HighlightSirodesmin PL, the principal toxin produced by Leptosphaeria maculans, induces cell death and defense mechanisms inBrassica napus, disrupting photosynthesis and facilitating the infective process
TEMR: Trans-ethnic Mendelian Randomization Method using Large-scale GWAS Summary Datasets
Authors: Hou Lei , Wu Sijia , Yuan Zhongshang , Li Hongkai , Xue Fuzhong 
Published: June 2024

AbstractAvailable large-scale GWAS summary datasets predominantly stem from European populations, while sample sizes for other ethnicities, notably Central/South Asian, East Asian, African, Hispanic, etc. remain comparatively limited, which induces the low precision of causal effect estimation within these ethnicities using Mendelian Randomization (MR). In this paper, we propose a Trans-ethnic MR method called TEMR to improve statistical power and estimation precision of MR in the target population using trans-ethnic large-scale GWAS summary datasets. TEMR incorporates trans-ethnic genetic correlation coefficients through a conditional likelihood-based inference framework, producing calibrated p-values with substantially improved MR power. In the simulation study, TEMR exhibited superior precision and statistical power in the causal effects estimation within the target populations than other existing MR methods. Finally, we applied TEMR to infer causal relationships from 17 blood biomarkers to four diseases (hypertension, ischemic stroke, type 2 diabetes and schizophrenia) in East Asian, African and Hispanic/Latino populations leveraging the biobank-scale GWAS summary data from European. We found that causal biomarkers were mostly validated by previous MR methods, and we also discovered 13 new causal relationships that were not identified using previously published MR methods.
Protocol for a randomized cross-over study measuring the effect of reduced protein intake on autophagic flux in healthy adults
Authors: Fourrier Célia , Heilbronn Leonie K. , Teong Xiao Tong , Gore Jemima R. , Sargeant Timothy J. , Bensalem Julien 
Published: June 2024

AbstractAutophagy is a cellular mechanism that degrades damaged or unwanted material from cells and is particularly important during ageing. Autophagy has been widely studied in pre-clinical models and is known to respond to nutrient availability and in particular amino acids. However, clinical data are limited. This protocol paper describes a randomized cross-over clinical study investigating the effect of a four-week long reduction of dietary protein intake on autophagic flux (autophagic degradative activity) measured via a blood test in healthy adults. Sixty-one healthy participants will be recruited. Study participants will be randomly assigned to one of two diets for four weeks, then cross over to the other diet with a four-week washout period between diets. The diets will be: 1) Average Protein Diet: a control comparator diet with a macronutrient profile of 20% of energy from protein, 35% from fat (<10% saturated) and 45% from carbohydrate, with >30 g of fiber/day; 2) Reduced Protein Diet: 10% protein, 35% fat (<10% saturated), 55% carbohydrate, >30 g of fiber/day. This diet will provide 0.7 g of protein per kg of body weight (the recommended minimum daily protein intake). The primary outcome will be the change in autophagic flux between each diet. This study aims to determine whether reducing dietary protein intake in healthy adults can increase autophagy in humans. If positive, it creates the possibility that nutritional strategies could be used to prevent or delay autophagy- related diseases such as Alzheimer disease or atherosclerosis.
A Formal Model of Mood Disorders Based on the Neural Circuit Dynamics of the Triple Network Model
Authors: Rubin Alan Lawrence , Walth Mark 
Published: June 2024

AbstractPsychiatric diagnoses are based on consensus and are not related to pathophysiology, leading to confusion in treatment and in basic and clinical psychiatric research. The pathology of mood disorders arises from the intrinsic function and interactions between key neural circuits of the triple network. These circuits are the central executive network composed of the dorsolateral prefrontal cortex and posterior parietal cortex; the default mode network consisting of the dorsal medial prefrontal cortex, posterior cingulate/precuneus and angular gyrus and the salience network made up of the anterior insula, dorsal anterior cingulate cortex associated with subcortical limbic nodes including the amygdala. In this work, we develop a formal model using nonlinear dynamics and network theory, which captures the dynamic interactions of these three brain networks, allowing us to illustrate how various mood disorders can arise. Recurrent circuit dynamics are modeled on the physio-dynamics of a single neural component and is dependent on a balance of total input (feedforward and feedback) and the sensitivity of activation of its neural components. We use the average percentage of maximal firing rate frequency as a measure of network activity over long periods, which corresponds to fMRI activity.While the circuits function at moderate rates in euthymia, depressive symptoms are due to hypoactivity of the CEN and SN and hyperactivity of the DMN. Mania arises from a hyperactive SN with hypofunction of the CEN and moderate to high activity of the DMN. Functional abnormalities arise from genetic or epigenetic changes, affecting either the weight of neural interconnections or the sensitivity of activation of neurons comprising the network. Decreased excitation in unipolar depressive states is caused by diminished dendritic branches and decreased density of AMPA and NMDA receptors or a decrease in glutamate released by presynaptic neurons. All bipolar states result from heightened neural sensitivity due to altered sodium, calcium, or potassium channel conductance. Our formal model of mood disorders is consistent with fMRI studies, genetic research, as well as preclinical and clinical studies.
Hyperintense Acute Reperfusion Marker Sign in Patients with Diffusion Weighted Image-negative Transient Ischemic Attack HARM Sign in DWI-negative TIA
Authors: Kim Taewoo , Kim Bum Joon , Woo Ho Geol , Lee Kyung Mi , Park Sangil , Chang Dae-il , Heo Sung Hyuk 
Published: June 2024

AbstractBackgroundThe hyperintense acute reperfusion marker (HARM) sign is a hyperintense signal observed on postcontrast fluid-attenuated recovery inversion images and is strongly associated with cerebral ischemic insults. The clinical significance of the HARM sign in transient ischemic attack (TIA) has rarely been studied, unlike that in stroke. This study investigated the association between the HARM sign and clinical factors of diffusion-weighted imaging (DWI)-negative TIA, and the relationship between the HARM sign and recurrence of TIA and ischemic stroke.MethodsWe included 329 consecutive patients with DWI-negative TIA and divided them into two groups according to the HARM sign: 299 patients in the HARM(-) group and 30 patients in the HARM(+) group. Clinical information, brain imaging and follow-up data were collected from medical records and phone calls, and compared using HARM sign.ResultsThe HARM(+) patients were older and had higher systolic blood pressure, shorter symptom duration, and more frequent history of recent TIA or stroke and symptomatic artery stenosis or occlusion. Multivariate logistic regression revealed that recent TIA or stroke within 12 months (OR 6.623), symptom duration under 1 hour (OR 2.735), and relevant artery stenosis or occlusion (OR 2.761) were independently associated with the HARM sign. Cortical symptoms including aphasia were more prevalent in the HARM(+) group. During follow-up, HARM(+) patients showed higher recurrence rates of ischemic stroke (13.3% vs. 3.0%, p = 0.023). However, multivariate Cox analysis indicated that symptomatic stenosis or occlusion, rather than the HARM sign, was independently associated with stroke recurrence.ConclusionThe HARM sign in DWI-negative TIA patients is linked to older age, recent cerebrovascular events, shorter symptom duration, and large artery stenosis or occlusion. While the HARM sign correlates with higher recurrence of ischemic stroke, large artery stenosis or occlusion is the primary independent predictor.
Prevalence and Detection of Obstructive Sleep Apnea Early after Stroke
Authors: Klingman Karen J. , Billinger Sandra A. , Britton-Carpenter Amanda , Bartsch Bria , Duncan Pamela W. , Fulk George D. 
Published: June 2024

ABSTRACTBackgroundObstructive sleep apnea (OSA) negatively impacts post-stroke recovery. This study’s purpose: examine the prevalence of undiagnosed OSA and describe a simple tool to identify those at-risk for OSA in the early phase of stroke recovery.MethodsThis was a cross-sectional descriptive study of people ∼15 days post-stroke. Adults with stroke diagnosis admitted to inpatient rehabilitation over a 3-year period were included if they were alert/arousable, able to consent/assent to participation, and excluded if they had a pre-existing OSA diagnosis, other neurologic health conditions, recent craniectomy, global aphasia, inability to ambulate 150 feet independently pre-stroke, pregnant, or inability to understand English. OSA was deemed present if oxygen desaturation index (ODI) of >=15 resulted from overnight oximetry measures. Prevalence of OSA was determined accordingly. Four participant characteristics comprised the “BASH” tool (body mass index >=35, age>=50, sex=male, hypertension=yes). A receiver operator characteristics (ROC) curve analysis was performed with BASH as test variable and OSA presence as state variable.ResultsParticipants (n=123) were 50.4% male, averaged 64.12 years old (sd 14.08), and self-identified race as 75.6% White, 20.3% Black/African American, 2.4%>1 race, and 1.6% other; 22% had OSA. ROC analysis indicated BASH score >=3 predicts presence of OSA (sensitivity=0.778, specificity=0.656, area under the curve =0.746, p<0.001).ConclusionsPrevalence of undiagnosed OSA in the early stroke recovery phase is high. With detection of OSA post-stroke, it may be possible to offset untreated OSA’s deleterious impact on post-stroke recovery of function. The BASH tool is an effective OSA screener for this application.
Hidden network preserved in Slide-tags data allows reference-free spatial reconstruction
Authors: Dahlberg Simon K. , Bonet David Fernández , Franzén Lovisa , Ståhl Patrik L. , Hoffecker Ian T. 
Published: June 2024

AbstractWe reanalyzed data from the Slide-tags method developed by Russellet al. and discovered a hidden, spatially informative network formed during the transfer of spatial tags to nuclei. The structure of this network conveys sufficient information to infer cell locations entirely without ground truth from spatial indexing, placing Slide-tags among a new generation of optics-free, network-based imaging-by-sequencing approaches, a fundamental departure from classical spatial sequencing technologies based on pre-indexed arrays.
Triadic Dynamics of Gastric Bacterial Microbiome, Phageome, and Host Genotype, with Implications for Disease Associations
Authors: Szymczak Aleksander , Gembara Katarzyna , Majewska Joanna , Miernikiewicz Paulina , Ferenc Stanisław , Gnus Jan , Kłak Marlena , Jędruchniewicz Natalia , Witkiewicz Wojciech , Dąbrowska Krystyna 
Published: June 2024

AbstractThe microbiota plays a key role for human health, and microbiome composition has been linked to specific health disorders many times. Different fractions of the microbiome enter dynamic interactions, particularly bacteria and bacteriophages (phages) – viruses preying on bacteria. Since the microbiome exists inside the human body, the body strongly affects the microbes, although not in a uniform way, but shaped by the extreme diversity of human genetic variants. These triadic dynamics of the bacterial microbiome, phageome, and human host genotype remain poorly understood; hence our goal in this study was to comprehend them as a holistic and interdependent system.Gastric biopsies were the source of the stomach microbiome (bacteria and phages). Genotyping of patients was conducted on blood samples. They were analyzed by next generation sequencing followed by multiway statistical comparisons of identified bacterial and phage taxa, human genetic variants, and medical data from the patients, including gastric disorder diagnostics.Commonly expected associations between presence of bacteriophages and their specific hosts were not found to be a universal principle. With comparable SNP correlations, the strongest associations betweenStaphylococcusand some staphylococcal phages orEnterobacteriaand some enterobacteria phages were discovered. However, many more phage groups were not found to be clearly associated with their bacterial hosts, though often associated with SNPs, particularly those linked to immunological functions and body responses to bacteria and viruses. Thus, in addition to the expected effect on phage communities by shaping the communities of their bacterial hosts, the human body seems to affect phages directly, selecting for phages that survive its specific selective pressure, which can be defined by detection of particular genetic variants.
Synthetic genomes unveil the effects of synonymous recoding
Authors: Nyerges Akos , Chiappino-Pepe Anush , Budnik Bogdan , Baas-Thomas Maximilien , Flynn Regan , Yan Shirui , Ostrov Nili , Liu Min , Wang Meizhou , Zheng Qingmei , Hu Fangxiang , Chen Kangming , Rudolph Alexandra , Chen Dawn , Ahn Jenny , Spencer Owen , Ayalavarapu Venkat , Tarver Angela , Harmon-Smith Miranda , Hamilton Matthew , Blaby Ian , Yoshikuni Yasuo , Hajian Behnoush , Jin Adeline , Kintses Balint , Szamel Monika , Seregi Viktoria , Shen Yue , Li Zilong , Church George M. 
Published: June 2024

AbstractEngineering the genetic code of an organism provides the basis for (i) making any organism safely resistant to natural viruses and (ii) preventing genetic information flow into and out of genetically modified organisms while (iii) allowing the biosynthesis of genetically encoded unnatural polymers1–4. Achieving these three goals requires the reassignment of multiple of the 64 codons nature uses to encode proteins. However, synonymous codon replacement—recoding—is frequently lethal, and how recoding impacts fitness remains poorly explored. Here, we explore these effects using whole-genome synthesis, multiplexed directed evolution, and genome-transcriptome-translatome-proteome co-profiling on multiple recoded genomes. Using this information, we assemble a syntheticEscherichia coligenome in seven sections using only 57 codons to encode proteins. By discovering the rules responsible for the lethality of synonymous recoding and developing a data-driven multi-omics-based genome construction workflow that troubleshoots synthetic genomes, we overcome the lethal effects of 62,007 synonymous codon swaps and 11,108 additional genomic edits. We show that synonymous recoding induces transcriptional noise including new antisense RNAs, leading to drastic transcriptome and proteome perturbation. As the elimination of select codons from an organism’s genetic code results in the widespread appearance of cryptic promoters, we show that synonymous codon choice may naturally evolve to minimize transcriptional noise. Our work provides the first genome-scale description of how synonymous codon changes influence organismal fitness and paves the way for the construction of functional genomes that provide genetic firewalls from natural ecosystems and safely produce biopolymers, drugs, and enzymes with an expanded chemistry.
Nuclear RNA forms an interconnected network of transcription-dependent and tunable microgels
Authors: Marenda Mattia , Michieletto Davide , Czapiewski Rafal , Stocks Jon , Winterbourne Sophie M , Miles Jamilla , Fleming Olivia CA , Lazarova Elena , Chiang Michael , Grimes Graeme R , Becher Hannes , Cook Atlanta , Marenduzzo Davide , Nozawa Ryu-Suke , Gilbert Nick 
Published: June 2024

SummaryThe human cell nucleus is comprised of proteins, chromatin and RNA, yet how they interact to form supramolecular structures and drive key biological processes remains unknown. Conflicting models have proposed either a fluid-like or solid-like nature for the intranuclear microenvironment. To reconcile this discrepancy, we investigated the 3D structure and properties of the nuclear interior using experiments and computer simulations. We reveal a novel mechanism where newly synthesized RNA interacts with SAF-A (scaffold attachment factor A, or HNRNPU), forming interconnected microgels degraded by the exonuclease XRN2, leading to dynamic cycles of gelation and fluidization. This emergent microgel network depends on transcription, and is disrupted by SAF-A depletion. It also decreases protein mobility and regulates chromatin compaction by modulating microphase separation, thereby opening transcriptionally active regions. This tunable intranuclear network exhibits scale-dependent fluid- and solid-like features, that we suggest may regulate transcription by controlling access to regulatory proteins and polymerases.HighlightsRNA and SAF-A interact to form clusters that form a nuclear-spanning network of microgelsEmergent microgel network requires transcription and XRN2 activity to undergo gelation and fluidizationMicrogel network impacts nuclear protein mobilityMolecular dynamics modelling shows RNA/SAF-A microgels regulate chromatin decompaction by steric hinderanceGraphical Abstract
Prime editor-based high-throughput screening reveals functional synonymous mutations in the human genome
Authors: Niu Xuran , Tang Wei , Liu Yongshuo , Liu Ying , Mo Binrui , Yu Ying , Wei Wensheng 
Published: June 2024

AbstractSynonymous mutations are generally considered neutral, while their roles in the human genome remain largely unexplored. Herein, we employed the PEmax system to create a library of 297,900 epegRNAs and performed extensive screening to identify synonymous mutations that impact cell fitness. While most synonymous mutations are neutral, we found that some can elicit phenotypic effects. By developing a specialized machine learning tool, we uncovered their impact on various biological processes such as mRNA splicing and transcription, supported by multifaceted experimental evidence. Notably, synonymous mutations can alter RNA folding and affect translation, as demonstrated by PLK1_S2. By integrating screening data with our model, we successfully predicted clinically deleterious synonymous mutations. This research deepens our understanding of synonymous mutations and provides insights for clinical disease studies.
Intrapartum antibiotic prophylaxis to prevent Group B streptococcal infections in newborn infants: a systematic review and meta-analysis comparing various strategies
Authors: Panneflek Timothy J.R. , Hasperhoven Gea F. , Chimwaza Yamikani , Allen Connor , Lavin Tina , te Pas Arjan B. , Bekker Vincent , van den Akker Thomas 
Published: June 2024

SummaryBackgroundEarly-onset Group B Streptococcus (EOGBS) leads to substantial morbidity and mortality in newborn infants. Intrapartum antibiotic prophylaxis (IAP) prevents EOGBS infection, but IAP strategies vary. The approach to the provision of IAP can be risk-based, universal or a combination of the two strategies. Previous systematic reviews reported that universal strategies might be most optimal in lowering EOGBS infection, but there is no consensus. Therefore, we aimed to provide up-to-date evidence on effectiveness of different strategies by comparing perinatal outcomes.MethodsA systematic search for EOGBS prevention strategies was performed in MEDLINE, Embase and Web of Science. Studies were included if they reported on different strategies and outcomes of interest, including EOGBS infection, IAP administration and antimicrobial resistance. Summary data was extracted from published reports. Study quality was assessed using the ROBINS-I tool. Random-effects meta-analyses were used to determine risk ratios (RR) and 95%-confidence intervals. PROSPERO registration CRD42023411806.FindingsA total of 6050 records were identified, of which 72 observational studies were included for synthesis with more than 10 million live births. Meta-analysis demonstrated that implementation of any strategy (n=34 studies, RR 0.46 (0.36-0.60)), risk-based strategies (n=11 studies, RR 0.65 (0.48-0.87)), or universal strategies (n=16 studies, RR 0.37 (0.25-0.55)) was associated with a reduced risk of EOGBS infection compared to no strategy. In direct comparison, universal strategies were associated with a reduced risk of EOGBS compared to a risk-based strategy (n=17 studies, RR 0.41 (0.30-0.55)), while the proportion of women receiving IAP did not differ between risk-based (16%) and universal (21%) strategies (n=9 studies, RR 1.29 (0.95-1.75)). There was no antimicrobial resistance of EOGBS isolates to penicillin or ampicillin (n=11 studies).InterpretationAny IAP strategy could reduce the risk of EOGBS infection without evidence of increasing antimicrobial resistance. Universal strategies give the largest reduction in the EOGBS burden, while not exposing a significantly higher proportion of pregnancies to IAP compared to risk-based strategies.FundingUNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction, a cosponsored programme executed by the World Health Organisation.