bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalisability of epileptiform patterns across time and patients
Authors: Karimi-Rouzbahani Hamid , McGonigal Aileen
Published: September 2023

Complexity of epileptogenic zone (EZ) localisation contributes to failure of surgical resection to produce seizure freedom. This is to some extent a result of distinct patterns of epileptiform activity between (i.e., interictal) and during seizures (i.e., ictal) and their diversity across patients. This often leads to suboptimal localisation based on inspection of electroencephalography (EEG) features. We asked two open questions. First, whether neural signal reflecting epileptogenicity would be generalisable from interictal to ictal time window within each patient. This would be critical for patients who are monitored in hospital without having a seizure to help with EZ localisation, and more generally for understanding the predictive power of resting state (interictal) EEG data in determining EZ. Second, whether epileptiform patterns would generalise across patients, and if so, which aspects of those patterns are the most generalisable.

We used an intracranial EEG dataset that included fifty-five patients with lesional and non-lesional pathology, who had subsequently undergone cortical resection in frontal or temporal lobe with different levels of seizure freedom. We extracted a large set of simple to complex features from stereo-EEG (SEEG) and electrocorticographic (ECoG) neural signals recorded during interictal and ictal time windows. We fed those features to decision tree classifiers for EZ localisation and to quantify the diversity of ictal and interictal epileptiform patterns through a cross-time and cross-patient generalisation procedure.

We observed significant evidence (Bayes factor>> 10) for generalisability of patterns from interictal to ictal time windows across patients, which were dominantly reflected in signal power and high-frequency network-based features. Majority of patients showed consistent patterns of epileptogenicity across interictal and ictal time windows, reflected in above-chance area-under-curve (meanAUC =0.6). We observed significant evidence (Bayes factor>> 10) that signal features of epileptogenic regions could generalise across patients in both interictal and ictal time windows with significant evidence for higher generalisability in ictal than interictal time window (meanAUC0.75 vs. 0.59;Bayes factor>> 10). While signal power and moment features were the most contributory to the cross-patient generalisation in the interictal window, signal complexity features were the most contributory in the ictal window.

These results provide new insights about features of epileptic neural activity that generalise across interictal-ictal time windows and patients, which can have implications for both qualitative and quantitative EZ localisation. The explainable machine-learning pipeline developed here can guide future developments in epilepsy investigations.
Work Status, Functional Recovery, and Quality of Life of Cardiac Arrest Survivors After Hospital Discharge
Authors: Wu Yi-Wen , Chen Tai-Yuan , Huang Chien-Hua , Chu Yu-Jen , Chen Wei-Ting , Lu Kuan-Ting , Chang Wei-Tien , Ong Hooi-Nee , Chen Wen-Jone , Tsai Min-Shan
Published: September 2023

Background

To investigate the work status, neurological recovery, and quality of life of cardiac arrest survivors within 1 year after hospital discharge.

Methods

A retrospective single center study included 71 non-traumatic adult cardiac arrest patients between 2017 and 2020, who survived more than 1 year after hospital discharge and agreed to participate the study. Questionnaire interviews through telephone visits were conducted with the enrolled patients, assessing their work status, neurological recovery, and quality of life at 3 months and 1 year after hospital discharge. Additionally, their use of medical services was also collected.

Results

Of the enrolled patients, 67 (94.4%) had a cerebral performance category (CPC) of 1 at discharge and the majority of patients (90.1%) returned home. Sixty-seven patients (94.4%) returned for outpatient visits at a median time of 6 days, 23 patients (32.4%) visited the ER at a median time of 74 days, and 22 patients (31.0%) were readmitted to the hospital at a median time of 58 days. In terms of mobility, self-care, usual activities, pain/discomfort, and health state assessed using the EQ-5D-5L, a significant decrease in impairment was observed from 3 months to 1 year. Moreover, patients demonstrated improved work status as well as improved scores for overall quality of life, general health, physical, psychological, social relations, and environmental status evaluated using the WHOQOL-BREF.

Conclusions

Within 1 year following hospital discharge, a considerable number of cardiac arrest survivors require medical support. However, a continual improvement in work status and quality of life were observed.
Metagenomic analysis of the honey bee queen microbiome reveals low bacterial diversity and Caudoviricetes phages
Authors: Caesar Lilian , Rice Danny W. , McAfee Alison , Underwood Robyn , Tarpy David R. , Foster Leonard J. , Newton Irene L. G.
Published: September 2023

In eusocial insects, the health of the queens – the colony founders and sole reproductive females – is a primary determinant for colony success. Queen failure in the honey beeApis mellifera, for example, is a major concern of beekeepers that annually suffer with colony losses, necessitating a greater knowledge of queen health. Several studies on the microbiome of honey bees have characterized its diversity and shown its importance for the health of worker bees, the female non-reproductive caste. However, the microbiome of workers differs from that of queens, which in comparison is still poorly studied. Thus, direct investigations of the queen microbiome are required to understand colony-level microbiome assembly, functional roles, and evolution. Here we used metagenomics to comprehensively characterize the honey bee queen microbiome. Comparing samples from different geographic locations and breeder sources, we show that the microbiome of queens is mostly shaped by the environment experienced since early life, and is predicted to play roles in breakdown of the diet, and protection from pathogens and xenobiotics. We also reveal the microbiome of queens comprises only four core bacterial species,Apilactobacillus kunkeei,Lactobacillus apis, Bombella apisandCommensalibactersp. Interestingly, in addition to bacteria, we show that bacteriophages infect the queen microbiome, for which Lactobacillaceae are predicted to be the main reservoirs. Together, our results provide the basis to understand the honey bee colony microbiome assemblage, can guide improvements in queen rearing processes, and highlight the importance of bacteriophages for queen microbiome health and microbiome homeostasis in eusocial insects.

Importance

The queen caste plays a central role for colony success in eusocial insects, as queens lay eggs, and regulate colony behavior and development. Queen failure can cause colonies to collapse, which is one of the major concerns of beekeepers. Thus, understanding of the biology behind the queen’s health is a pressing issue. Previous studies have shown the bee microbiome plays an important role in worker bee health, but little is known about the queen microbiome and its functionin vivo. Here, we characterized the queen microbiome identifying for the first time present species and their putative functions. We show that the queen microbiome have predicted nutritional and protective roles in queen association, and comprises only four consistently present bacterial species. Additionally, we bring to attention the spread of phages in the queen microbiome, which increased in abundance in failing queens and may impact the fate of the colony.
Water and chloride as allosteric inhibitors in WNK kinase osmosensing
Authors: Teixeira Liliana R. , Akella Radha , Humphreys John M. , He Haixia , Goldsmith Elizabeth J.
Published: September 2023

Osmotic stress and chloride regulate the autophosphorylation and activity of the WNK1 and WNK3 kinase domains. The kinase domain of unphosphorylated WNK1 (uWNK1) is an asymmetric dimer possessing water molecules conserved in multiple uWNK1 crystal structures. Conserved waters are present in two networks, referred to here as conserved water networks 1 and 2 (CWN1and CWN2). Here we show that PEG400 applied to crystals of dimeric uWNK1 induces de-dimerization. Both the WNK1 the water networks and the chloride binding site and are disrupted by PEG400. CWN1 is surrounded by a cluster of pan-WNK-conserved charged residues. Here we mutagenized these charges in WNK3, a highly active WNK isoform kinase domain, and WNK1, the isoform best studied crystallographically. Mutation of E314 in the Activation Loop of WNK3 (WNK3/E314Q and WNK3/E314A, and the homologous WNK1/E388A) enhanced the rate of autophosphorylation, and reduced chloride sensitivity. Other WNK3 Cluster mutants reduced the rate of autophosphorylation activity coupled with greater chloride sensitivity than wild-type. The water and chloride regulation thus appear linked. The lower activity of some mutants may reflect effects on catalysis. Crystallography showed that activating mutants introduced conformational changes in similar parts of the structure to those induced by PEG400. WNK activating mutations and crystallography support a role for CWN1 in WNK inhibition consistent with water functioning as an allosteric ligand.
Saccharomycotina yeasts defy longstanding macroecological patterns
Authors: David Kyle T. , Harrison Marie-Claire , Opulente Dana A. , LaBella Abigail L. , Wolters John F. , Zhou Xiaofan , Shen Xing-Xing , Groenewald Marizeth , Pennell Matt , Hittinger Chris Todd , Rokas Antonis
Published: September 2023

The Saccharomycotina yeasts (“yeasts” hereafter) are a fungal clade of scientific, economic, and medical significance. Yeasts are highly ecologically diverse, found across a broad range of environments in every biome and continent on earth1; however, little is known about what rules govern the macroecology of yeast species and their range limits in the wild2. Here, we trained machine learning models on 12,221 occurrence records and 96 environmental variables to infer global distribution maps for 186 yeast species (∼15% of described species from 75% of orders) and to test environmental drivers of yeast biogeography and macroecology. We found that predicted yeast diversity hotspots occur in mixed montane forests in temperate climates. Diversity in vegetation type and topography were some of the greatest predictors of yeast species richness, suggesting that microhabitats and environmental clines are key to yeast diversification. We further found that range limits in yeasts are significantly influenced by carbon niche breadth and range overlap with other yeast species, with carbon specialists and species in high diversity environments exhibiting reduced geographic ranges. Finally, yeasts contravene many longstanding macroecological principles, including the latitudinal diversity gradient, temperature-dependent species richness, and latitude-dependent range size (Rapoport’s rule). These results unveil how the environment governs the global diversity and distribution of species in the yeast subphylum. These high-resolution models of yeast species distributions will facilitate the prediction of economically relevant and emerging pathogenic species under current and future climate scenarios.
Potassium-mediated bacterial chemotactic response
Authors: Zhang Chi , Zhang Rongjing , Yuan Junhua
Published: September 2023

Bacteria in biofilms secrete potassium ions to attract free swimming cells. However, the basis of chemotaxis to potassium remains poorly understood. Here, using a microfluidic device, we found thatEscherichia colican rapidly accumulate in regions of high potassium concentration on the order of millimoles. Using a bead assay, we measured the dynamic response of individual flagellar motors to stepwise changes in potassium concentration, finding that the response resulted from the chemotaxis signaling pathway instead of the motor response to changes in the proton motive force (PMF). To characterize the chemotactic response to potassium, we exposed the bacteria to a range of potassium concentrations and measured the dose-response curve and adaptation kinetics via a FRET assay, finding that the chemotaxis pathway exhibited a sensitive response and fast adaptation to potassium. We further found that the two major chemoreceptors Tar and Tsr respond differently to potassium. Tar receptors exhibit a biphasic response, whereas Tsr receptors respond to potassium as an attractant. These different responses were consistent with the responses of the two receptors to intracellular pH changes. Therefore, bacteria may sense the change in potassium concentration by sensing the change in intracellular pH. The sensitive response and fast adaptation allow bacteria to sense and localize small changes in potassium concentration. As the ratio of the two major chemoreceptors changes with bacterial growth stages, the differential responses of Tar and Tsr receptors to potassium suggest that cells at different growth stages respond differently to potassium and may have different requirements for potassium.
Cystic fibrosis transmembrane conductance regulator (CFTR) downregulates the excitability of deep pyramidal neurons in the rodent cortex
Authors: Cheng Zongyue , Sun Xuan , Xing Wang , Luo Fei , Chan Hsiao Chang , Gan Wenbiao , Li Baoming
Published: September 2023

The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding chloride channel that is regulated by intracellular cAMP/PKA phosphorylation. CFTR is widely expressed in peripheral tissues and organs of mammals and plays a vital role in maintaining chloride balance and cellular homeostasis. While preliminary studies have identified CFTR expression in the central nervous system (CNS), it is not clear whether this channel also modulates the neural network of the cerebral cortex by regulating the intracellular chloride level of neurons. In this study, we employed immunohistochemical staining, patch-clamp recording, and two-photon imaging techniques to comprehensively analyze the functions of the CFTR channel in the rodent cortex. Our results indicate that CFTR is primarily distributed in the deep pyramidal somata and superficial axons of the cerebral cortex. Regulation of CFTR has the potential to alter the resting membrane potential and evoke action potentials of layer V pyramidal neurons, which produces significant changes in inhibitory synaptic transmission. Furthermore, we found that inhibiting CFTR channels increased the calcium activity of axon boutons and somata of the primary motor cortex in vivo, promoting motor learning. Overall, these findings implicate a crucial role of CFTR in modulating Cl-homeostasis and neuronal excitability in the cerebral cortex, furthering our understanding of the functions of the chloride channel in the central nervous system.
Genetically predicted 25-Hydroxyvitamin D levels on Hypothyroidism: A two-sample Mendelian Randomization
Authors: Akbarzadeh Mahdi , Fateh Sahand Tehrani , Moeinafshar Aysan , Habibi Danial , Ghanooni Amir Hossein , Saeidian Amir Hesam , Riahi Parisa , Zarkesh Maryam , Lanjanian Hossein , Jahangiri Mina , Moazzam-Jazi Maryam , Teymoori Farshad , Azizi Fereidoun , Hedayati Mehdi , Daneshpour Maryam Sadat
Published: September 2023

Background

Alterations in levels of 25-Hydroxyvitamin D have been associated with the risk of thyroid disease. This study uses Mendelian randomization (MR) to infer the possible causal association of 25-Hydroxyvitamin D with hypothyroidism.

Methods

We performed two-sample MR using the summary statistics data from genome-wide association studies (GWAS) from populations with European ancestry to infer the causality of genetically controlled levels of 25-Hydroxyvitamin D on the risk of hypothyroidism, Hashimoto’s thyroiditis, as well as biochemical parameters of thyroid diseases. The inverse-variance method (IVW) was used as the primary method to calculate the combined effect of all SNPs. Other methods were adopted to evaluate the stability and reliability of the results. Comprehensive sensitivity analyses were conducted to ensure that none of the MR analysis’s primary assumptions were violated.

Results

The results of the IVW analysis revealed a significant causal association between higher levels of 25-Hydroxyvitamin D and lower risk of hypothyroidism (beta = −0.197, 95% CI (− 0.301, −0.093); SE = 0.053, Pbeta= 2.256×10-4) as well as increased levels of free T4 (beta = 0.204, 95% CI (0.305, 0.094); SE = 0.056, Pbeta= 3.0506×10−4). On the other hand, no significant causality was determined for higher levels of 25-Hydroxyvitamin D in association with Hashimoto’s thyroiditis (beta=-0.047, 95% CI (−0.245, 0.151), p=0.641) and TSH levels (beta = −0.024, 95% CI (−0.099, - 0.051); Pbeta= 0.524).

Conclusion

The results of this two-sample MR study provide evidence supporting the potential of 25-Hydroxyvitamin D supplementation in reducing the risk of hypothyroidism.
The COVID-19 pandemic has increased health inequalities by altering patterns of engagement with a mass participation event after resumption post-lockdown
Authors: Gilburn Andre S.
Published: September 2023

The global epidemic in physical inactivity has been exacerbated by lockdowns with concerning health inequalities accentuated as a result. Studies are needed of post-lockdown levels of activity to determine if there are lasting impacts beyond lockdown. This study uses parkrun in Scotland as a model system to address this urgent question. Generalised linear mixed models were used to identify patterns in the attendance, gender, age and performance of 500,000+ parkrun participations in Scotland for the year before the pandemic and the first year after lockdown. Total weekly attendance in Scotland had been increasing year-on-year but fell by 13% from 7,649 (95% CI 7,275 to 8.024) in the final-year pre-lockdown to 6,612 (95% CI 6,260 to 6,963) in the first-year post-lockdown. Attendance drops were disproportionately larger at events with larger attendances prior to lockdown. There was a disproportionate loss of female participants in more deprived areas. The gender gap in participation had been narrowing before lockdown but widened from 54.02% (95% CI 53.85 to 54.19%) in the final-year pre-lockdown to 56.29% male (95% CI 56.09 to 56.49%) in the first-year post-lockdown. The age of participants increased from 44.94 (95% CI 44.90 to 44.98) before lockdown to 46.58 (95% CI 46.53 to 46.64) after lockdown. The age gap between the genders widened after lockdown particularly at larger events and in more deprived areas. Performance was declining before lockdown but increased from 55.02% (95% CI 54.96 to 55.06%) to 55.93% (95% CI 55.88 to 55.97%) after lockdown. The pandemic has reduced attendance at parkrun in Scotland and the loss of participants has been non-random increasing health inequalities affecting women, the least fit and those in deprived areas. Some former participants are also now avoiding larger mass participation events. Investment and management strategies will be needed to address these worsening inequalities.
Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort
Authors: Amorim Gustavo , Jaworski James , Cordeiro-Santos Marcelo , Kritski Afrânio L. , Figueiredo Marina C. , Turner Megan , Andrade Bruno B. , Velez Edwards Digna R. , Santos Adalberto R. , Rolla Valeria C. , Sterling Timothy R. , Haas David W. ,   the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil network
Published: September 2023

Background

Genetic polymorphisms have been associated with risk of anti-tuberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil.

Methods

Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015-2019, and who were evaluable for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24 month follow-up. Analyses included 43 polymorphisms in 20 genes related to anti-tuberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset.

Results

Among 903 participants in multivariable genetic association analyses,NAT2slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely amongNAT2rapid acetylators, but not statistically significant at the 5% level. AGSTM1polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity.SLCO1B1polymorphisms were associated with increased risk of treatment- related hepatoxicity and treatment failure/recurrence. Polymorphisms inNR1/2were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism inVTI1A, and the genesMETTL17andPRSS57, but none achieved genome-wide significance.

Conclusions

In a clinical cohort representing three regions of Brazil,NAT2acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations.
Risk Stratification for Ventricular Tachyarrhythmia in Patients with Non-Ischemic Cardiomyopathy
Authors: Goldenberg Ido , Younis Arwa , Huang David T. , Rosero Spencer , Kutyifa Valentina , McNitt Scott , Polonsky Bronislava , Steinberg Jonathan S. , Zareba Wojciech , Goldenberg Ilan , Aktas Mehmet K.
Published: September 2023

Background

The implantable cardioverter defibrillator reduces mortality among patients with heart failure (HF) due to ischemic heart disease. Clinical trial data have called into question the benefit of an ICD in patients with HF due to non-ischemic cardiomyopathy (NICM).

Objective

We developed a risk stratification score for ventricular tachyarrhythmia (VTA) among patients with NICM receiving a primary prevention ICD.

Methods

The study population comprised of 1,515 patients with NICM who were enrolled in the landmark MADIT trials. Fine and Gray analysis was used to develop a model to predict the occurrence of VTAs and ICD therapies while accounting for the competing risk of non-arrhythmic mortality. External validation was carried out in the RAID Trial population.

Results

Four risk factors associated with increased risk for VTA were identified: male sex, left ventricular ejection fraction ≤25%, no indication for cardiac resynchronization therapy with a defibrillator (CRT-D), and Black race. A score was generated based on this model and patients were stratified into low (N=390), intermediate (N=728), and high-risk (N=387) groups. The five-year cumulative incidences of VTA were 15%, 24%, 42% respectively. Application of score groups for the secondary endpoints of Fast VT or VF and Appropriate ICD Shock revealed similar findings. Recurrent event analysis yielded consistent results. The AUC in the validation cohort for the endpoint of Appropriate ICD Shock was 69.3.

Conclusions

Our study shows that patients with NICM can be risk stratified using demographic and clinical variables and may be used when evaluating such patients for a primary prevention ICD.

CONDENSED ABSTRACT

Data regarding the effectiveness of the ICD is lacking in patients with HF and NICM. The purpose of this study was to develop a risk score for ventricular tachyarrhythmia (VTA) among patients with NICM. We included patients from the MADIT trials to generate a risk score. Four risk factors associated with increased risk for VTA were identified and incorporated into the score. Patients were stratified into low, intermediate, and high-risk groups. The five-year cumulative incidences of VTA were 15%, 24%, 42% respectively. Our risk prediction model can support patient-physician shared decision making regarding primary ICD implantation in patients with NICM.
Genetics of cell-type-specific post-transcriptional gene regulation during human neurogenesis
Authors: Aygün Nil , Krupa Oleh , Mory Jessica , Le Brandon , Valone Jordan , Liang Dan , Love Michael I. , Stein Jason L.
Published: September 2023

The function of some genetic variants associated with brain-relevant traits has been explained through colocalization with expression quantitative trait loci (eQTL) conducted in bulk post-mortem adult brain tissue. However, many brain-trait associated loci have unknown cellular or molecular function. These genetic variants may exert context-specific function on different molecular phenotypes including post-transcriptional changes. Here, we identified genetic regulation of RNA-editing and alternative polyadenylation (APA), within a cell-type-specific population of human neural progenitors and neurons. More RNA-editing and isoforms utilizing longer polyadenylation sequences were observed in neurons, likely due to higher expression of genes encoding the proteins mediating these post-transcriptional events. We also detected hundreds of cell-type-specific editing quantitative trait loci (edQTLs) and alternative polyadenylation QTLs (apaQTLs). We found colocalizations of a neuron edQTL inCCDC88Awith educational attainment and a progenitor apaQTL inEP300with schizophrenia, suggesting genetically mediated post-transcriptional regulation during brain development lead to differences in brain function.
Sm-like protein Rof inhibits transcription termination factor ρ by binding site obstruction and conformational insulation
Authors: Said Nelly , Finazzo Mark , Hilal Tarek , Wang Bing , Selinger Tim Luca , Gjorgjevikj Daniela , Artsimovitch Irina , Wahl Markus C.
Published: September 2023

Transcription termination factor ρ is a hexameric, RNA-dependent NTPase that can adopt active closed-ring and inactive open-ring conformations. The Sm-like protein Rof, a homolog of the RNA chaperone Hfq, inhibits ρ-dependent terminationin vivobut recapitulation of this activityin vitrohas proven difficult and the precise mode of Rof action is presently unknown. Our electron microscopic structures of ρ-Rof and ρ-RNA complexes show that Rof undergoes pronounced conformational changes to bind ρ at the protomer interfaces, undercutting ρ conformational dynamics associated with ring closure and occluding extended primary RNA-binding sites that are also part of interfaces between ρ and RNA polymerase. Consistently, Rof impedes ρ ring closure, ρ-RNA interactions, and ρ association with transcription elongation complexes. Structure-guided mutagenesis coupled with functional assays confirmed that the observed ρ-Rof interface is required for Rof-mediated inhibition of cell growth and ρ-terminationin vitro. Bioinformatic analyses revealed that Rof is restricted to Pseudomonadota and that the ρ-Rof interface is conserved. Genomic contexts ofrofdiffer betweenEnterobacteriaceaeandVibrionaceae,suggesting distinct modes of Rof regulation. We hypothesize that Rof and other cellular anti-terminators silence ρ under diverse, but yet to be identified, stress conditions when unrestrained transcription termination by ρ would be lethal.
Myelin dystrophy in the aging prefrontal cortex leads to impaired signal transmission and working memory decline: a multiscale computational study
Authors: Ibañez Sara , Sengupta Nilapratim , Luebke Jennifer I. , Wimmer Klaus , Weaver Christina M.
Published: September 2023

Normal aging leads to myelin alternations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are often correlated with cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First we built a multicompartment pyramidal neuron model fit to monkey dlPFC data, with axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions, to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination in a population of neurons. Lasso regression identified distinctive parameter sets likely to modulate an axon’s susceptibility to CV changes following demyelination versus remyelination. Next we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from electron microscopy up to behavior on aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.
Neural activity is modulated by spontaneous and volitionally controlled breathing
Authors: Karjalainen Suvi , Kujala Jan , Parviainen Tiina
Published: September 2023

Recent studies have provided evidence regarding respiration-brain coupling, but how continuously varying dynamics of breathing modulate neural activity is not known. We examined whether the neural state differs between spontaneous and volitionally controlled breathing and across the phases of breathing, inspiration and expiration. Magnetoencephalography with a respiratory belt was used to record cortical oscillatory activity during spontaneous, deep, and square breathing (n=33). Alpha power was suppressed during inspiration and increased during expiration (p<0.01) indicating dynamically fluctuating neural states across the respiratory cycle. Compared to spontaneous and square breathing, alpha power increased during deep breathing (p<0.01). We also observed a steeper aperiodic slope and a broadband shift in the power spectrum during square breathing in comparison with spontaneous breathing suggesting that spectral characteristics of neural activity are modulated by the rate, depth, and pattern of breathing. Altogether, we demonstrate that neural activity is modulated by breathing techniques and phases of breathing.
Chromatin priming elements direct tissue-specific gene activity prior to hematopoietic specification
Authors: Maytum Alexander , Edginton-White Benjamin , Keane Peter , Cockerill Peter N , Cazier Jean-Baptiste , Bonifer Constanze
Published: September 2023

Tissue-specific gene regulation during development involves the interplay between transcription factors and epigenetic regulators binding to enhancer and promoter elements. The pattern of active enhancers defines the cellular differentiation state. However, developmental gene activation involves a previous step called chromatin priming which is not fully understood. We recently developed a genome-wide functional assay that allowed us to functionally identify enhancer elements integrated in chromatin regulating each of five stages spanning the in vitro differentiation of embryonic stem cells to blood. We also measured global chromatin accessibility, histone modifications and transcription factor binding. The integration of these data identified and characterised cis-regulatory elements which become activated prior to the onset of gene expression, some of which are primed in a signalling-dependent fashion. Deletion of such a priming element leads to a delay in the upregulation of its associated gene in development. Our work uncovers the details of a complex network of regulatory interactions with the dynamics of early chromatin opening being at the heart of dynamic tissue-specific gene expression control.

Summary blurb

In this manuscript, we exploited a new dataset of functionally characterised enhancer elements active at five stages of differentiation from mouse embryonic stem cells to blood to determine the developmental stages at which these elements are being activated. We show that many enhancer elements are activated at the level of chromatin prior to the activation of their associated genes (priming), which can be associated with signalling events. Elimination of priming elements within a gene locus leads to a delay in cellular development.
Omix: A Multi-Omics Integration Pipeline
Authors: Schneegans Eléonore , Fancy Nurun , Thomas Michael , Willumsen Nanet , Matthews Paul M , Jackson Johanna
Published: September 2023

TheOmixpipeline offers an integration and analysis framework for multiomics intended to preprocess, analyse, and visualise multimodal data flexibly to address various research questions. From biomarker discovery and patient stratification to the investigation of complex biological processes,Omixempowers researchers to derive valuable insights from omics data. Using Alzheimer’s Disease (AD) bulk proteomics and transcriptomics datasets generated from two distinct regions derived from post-mortem brains, we demonstrate the utility ofOmixin generating an integrated pseudo-temporal multi-omics profile of AD.

Availability and Implementation

Omixis implemented as a software package in R. The code for theOmixpackage is available athttps://github.com/eleonoreschneeg/Omix. Reference documentation and online tutorials are available athttps://eleonore-schneeg.github.io/Omix. All code is open-source and available under the GNU General Public License v3.0 (GPL-3).

Contact

eleonore.schneegans17@imperial.ac.uk,johanna.jackson@imperial.ac.uk
Epidemiological modeling of SARS-CoV-2 in white-tailed deer (Odocoileus virginianus) reveals conditions for introduction and widespread transmission
Authors: Rosenblatt Elias , Cook Jonathan D. , DiRenzo Graziella V. , Grant Evan H.C. , Arce Fernando , Pepin Kim M. , Rudolph F. Javiera , Runge Michael C. , Shriner Susan , Walsh Daniel P. , Mosher Brittany A.
Published: September 2023

Emerging infectious diseases with zoonotic potential often have complex socioecological dynamics and limited ecological data, requiring integration of epidemiological modeling with surveillance. Although our understanding of SARS-CoV-2 has advanced considerably since its detection in late 2019, the factors influencing its introduction and transmission in wildlife hosts, particularly white-tailed deer (Odocoileus virginianus), remain poorly understood. We use a Susceptible-Infected-Recovered-Susceptible epidemiological model to investigate the spillover risk and transmission dynamics of SARS-CoV-2 in wild and captive white-tailed deer populations across various simulated scenarios. We found that captive scenarios pose a higher risk of SARS-CoV-2 introduction from humans into deer herds and subsequent transmission among deer, compared to wild herds. However, even in wild herds, the transmission risk is often substantial enough to sustain infections. Furthermore, we demonstrate that the strength of introduction from humans influences outbreak characteristics only to a certain extent. Transmission among deer was frequently sufficient for widespread outbreaks in deer populations, regardless of the initial level of introduction. We also explore the potential for fence line interactions between captive and wild deer to elevate outbreak metrics in wild herds that have the lowest risk of introduction and sustained transmission. Our results indicate that SARS-CoV-2 could be introduced and maintained in deer herds across a range of circumstances based on testing a range of introduction and transmission risks in various captive and wild scenarios. Our approach and findings will aid One Health strategies that mitigate persistent SARS-CoV-2 outbreaks in white-tailed deer populations and potential spillback to humans.
The antigenic landscape of human influenza N2 neuraminidases from 2009 until 2017
Authors: Catani João Paulo Portela , Smet Anouk , Ysenbaert Tine , Vuylsteke Marnik , Bottu Guy , Mathys Janick , Botzki Alexander , Cortes-Garcia Guadalupe , Strugnell Tod , Gomila Raul , Hamberger John , Catalan John , Ustyugova Irina V. , Farrell Timothy , Stegalkina Svetlana , Ray Satyajit , LaRue Lauren , Saelens Xavier , Vogel Thorsten U.
Published: September 2023

Human H3N2 influenza viruses are subject to rapid antigenic evolution which translates into frequent updates of the composition of seasonal influenza vaccines. Despite these updates, the effectiveness of influenza vaccines against H3N2-associated disease is suboptimal. Seasonal influenza vaccines primarily induce hemagglutinin-specific antibody responses. However, antibodies directed against influenza neuraminidase (NA) also contribute to protection. Here, we analyzed the antigenic diversity of a panel of N2 NAs derived from human H3N2 viruses that circulated between 2009 and 2017. The antigenic breadth of these NAs was determined based on the NA inhibition (NAI) of a broad panel of ferret and mouse immune sera that were raised by infection and recombinant N2 NA immunization. This assessment allowed us to distinguish at least 4 antigenic groups in the N2 NAs derived from human H3N2 viruses that circulated between 2009 and 2017. Computational analysis further revealed that the amino acid residues in N2 NA that have a major impact on susceptibility to NAI by immune sera are in proximity of the catalytic site. Finally, a machine learning method was developed that allowed to accurately predict the impact of mutations that are present in our N2 NA panel on NAI. These findings have important implications for the renewed interest to develop improved influenza vaccines based on the inclusion of a protective NA antigen formulation.
Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS
Authors: Mosegaard Signe , Twayana Krishna S. , Denis Simone W. , Kroon Jeffrey , Schomakers Bauke V. , van Weeghel Michel , Houtkooper Riekelt H. , Olsen Rikke K. J. , Holm Christian K.
Published: September 2023

Stimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in the activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for the subsequent release of pro-inflammatory cytokines. This has become particularly clear for enzymes of the tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS-induced formation of IL-1β. If enzymes involved in beta-oxidation of fatty acids are important for sufficient responses to LPS is currently not clear.

Using cells from various patients with inborn fatty acid oxidation disorders, we report that disease-causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl-CoA Dehydrogenase (ACADVL), both cause insufficient responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6. The insufficient responses to LPS were reproduced in cells from normal healthy controls by targeted loss-of-function of eitherETFDHorACADVL,supporting that the deleteriousETFDHandACADVLvariants cause the attenuated responses to LPS.

ETFDHandACADVLencode two distinct enzymes both involved in fatty acid beta-oxidation, and patients with these deficiencies cannot sufficiently metabolize long-chain fatty acids. With this report, we therefore provide genetic evidence from two genetically distinct but phenotypically similar human metabolic diseases, that genes important for beta-oxidation of long-chain fatty acids are also important for inflammatory responses to LPS.
Nested neural circuits generate distinct acoustic signals during Drosophila courtship
Authors: Lillvis Joshua L. , Wang Kaiyu , Shiozaki Hiroshi M. , Xu Min , Stern David L. , Dickson Barry J.
Published: September 2023

Many motor control systems generate multiple movements using a common set of muscles. How are premotor circuits able to flexibly generate diverse movement patterns? Here, we characterize the neuronal circuits that drive the distinct courtship songs ofDrosophila melanogaster. Male flies vibrate their wings towards females to produce two different song modes – pulse and sine song – which signal species identity and male quality. Using cell-type specific genetic reagents and the connectome, we provide a cellular and synaptic map of the circuits in the male ventral nerve cord that generate these songs and examine how activating or inhibiting each cell type within these circuits affects the song. Our data reveal that the song circuit is organized into two nested feed-forward pathways, with extensive reciprocal and feed-back connections. The larger network produces pulse song, the more complex and ancestral song form. A subset of this network produces sine song, the simpler and more recent form. Such nested organization may be a common feature of motor control circuits in which evolution has layered increasing flexibility on to a basic movement pattern.
Five-year Efficacy and Safety of TiNO-Coated Stents Versus Drug-Eluting Stents in Acute Coronary Syndrome. A meta-analysis
Authors: Daoud Frederic C. , Catargi Bogdan , Karjalainen Pasi P. , Gerbaud Edouard
Published: September 2023

(1) Background: Percutaneous Coronary Interventions (PCI) in patients with acute coronary syndrome (ACS) are performed with titanium-nitride-oxide-coated stents (TiNOS) or drug-eluting stents (DES). This prospective systematic literature review (SLR) of prospective, randomized, controlled trials (RCTs) showed TiNOS is non-inferior to DES in major adverse cardiac events (MACE) rates and presents a lower risk of recurrent myocardial infarction (MI) at 1-year follow-up. (2) Methods: The previously described SLR and meta-analysis protocol, per PRISMA, Cochrane methods, and GRADE, applied here to 5-year follow-up outcomes. (3) Results: Three RCTs were eligible, comprising 1,620 patients with TiNOS vs. 1,123 with DES. The pooled risk ratios (RRs) and 95% confidence intervals were: MACE 0.82 [0.68, 0.99], MI 0.58 [0.44, 0.78], cardiac death (CD) 0.46 [0.28, 0.76], ischemia-driven target lesion re-vascularization (TLR) 1.03 [0.79, 1.33], probable or definite stent thrombosis (ST) 0.32 [0.21, 0.59], and all-cause mortality (TD) 0.84 [0.63, 1.12]. Evidence certainty was high in MACE, CD, MI, and ST. Certainty was moderate in TLR and TD. (4) Conclusions: TiNOS in ACS at 5-year follow-up appears safer than DES and equally efficacious. Stratified pooled outcomes by clinical presentation would facilitate clinical validity benchmarking and generalization to target populations.
DIAGNOSTIC ACCURACY OF ARTIFICIAL INTELLIGENCE FOR ANALYSIS OF 1.3 MILLION MEDICAL IMAGING STUDIES: THE MOSCOW EXPERIMENT ON COMPUTER VISION TECHNOLOGIES
Authors: Morozov Sergey , Vladzymyrskyy Anton , Ledikhova Natalia , Andreychenko Anna , Arzamasov Kirill , Omelyanskaya Olga , Reshetnikov Roman , Gelezhe Pavel , Blokhin Ivan , Turavilova Elena , Kozhikhina Daria , Anikina Daria , Bondarchuk Dmitry
Published: September 2023

Objective

to assess the diagnostic accuracy of services based on computer vision technologies at the integration and operation stages in Moscow’s Unified Radiological Information Service (URIS).

Methods

this is a multicenter diagnostic study of artificial intelligence (AI) services with retrospective and prospective stages. The minimum acceptable criteria levels for the index test were established, justifying the intended clinical application of the investigated index test. The Experiment was based on the infrastructure of the URIS and United Medical Information and Analytical System (UMIAS) of Moscow. Basic functional and diagnostic requirements for the artificial intelligence services and methods for monitoring technological and diagnostic quality were developed. Diagnostic accuracy metrics were calculated and compared.

Results

based on the results of the retrospective study, we can conclude that AI services have good result reproducibility on local test sets. The highest and at the same time most balanced metrics were obtained for AI services processing CT scans. All AI services demonstrated a pronounced decrease in diagnostic accuracy in the prospective study. The results indicated a need for further refinement of AI services with additional training on the Moscow population datasets.

Conclusions

the diagnostic accuracy and reproducibility of AI services on the reference data are sufficient, however, they are insufficient on the data in routine clinical practice. The AI services that participated in the experiment require a technological improvement, additional training on Moscow population datasets, technical and clinical trials to get a status of a medical device.
Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19
Authors: Padi Sathish K.R. , Vos Margaret R. , Godek Rachel J. , Fuller James R. , Kruse Thomas , Hein Jamin B. , Nilsson Jakob , Kelker Matthew S. , Page Rebecca , Peti Wolfgang
Published: September 2023

Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation.1Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases,2while mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B55.3While the role of kinases in mitotic entry is well-established, recent data have shown that mitosis is only successfully initiated when the counterbalancing phosphatases are also inhibited.4For PP2A:B55, inhibition is achieved by the two intrinsically disordered proteins (IDPs), ARPP19 (phosphorylation-dependent)6,7and FAM122A5(inhibition is phosphorylation-independent). Despite their critical roles in mitosis, the mechanisms by which they achieve PP2A:B55 inhibition is unknown. Here, we report the cryo-electron microscopy structures of PP2A:B55 bound to phosphorylated ARPP19 and FAM122A. Consistent with our complementary NMR spectroscopy studies both IDPs bind PP2A:B55, but do so in highly distinct manners, unexpectedly leveraging multiple distinct binding sites on B55. Our extensive structural, biophysical and biochemical data explain how substrates and inhibitors are recruited to PP2A:B55 and provides a molecular roadmap for the development of therapeutic interventions for PP2A:B55 related diseases.
A synthetic biology approach to transgene expression
Authors: Leftwich Philip T. , Purcell Jessica C. , Anderson Michelle A.E. , Fragkoudis Rennos , Basu Sanjay , Lycett Gareth , Alphey Luke
Published: September 2023

The ability to control gene expression is pivotal in genetic engineering and synthetic biology. However, in most non-model and pest insect species, empirical evidence for predictable modulation of gene expression levels is lacking. This knowledge gap is critical for genetic control systems, particularly in mosquitoes, where transgenic methods offer novel routes for pest control. Commonly, the choice of RNA polymerase II promoter (Pol II) is the primary method for controlling gene expression, but the options are limited.

To address this, we developed a systematic approach to characterize modifications in translation initiation sequences (TIS) and 3’ untranslated regions (UTR) of transgenes, enabling the creation of a toolbox for gene expression modulation in mosquitoes and potentially other insects. The approach demonstrated highly predictable gene expression changes across various cell lines and promoter sequences, representing a significant advancement in mosquito synthetic biology gene expression. tools.

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