bluuebunny/crossref_metadata_2025 huggingface dataset:
Latent Epigenetic Programs in Müller Glia Contribute to Stress, Injury, and Disease Response in the Retina
Authors: Norrie Jackie L. , Lupo Marybeth , Shirinifard Abbas , Djekidel Nadhir , Ramirez Cody , Xu Beisi , Dundee Jacob M. , Dyer Michael A.
Published: October 2023

Previous studies have demonstrated the dynamic changes in chromatin structure during retinal development that correlate with changes in gene expression. However, a major limitation of those prior studies was the lack of cellular resolution. Here, we integrate single-cell (sc) RNA-seq and scATAC-seq with bulk retinal data sets to identify cell type–specific changes in the chromatin structure during development. Although most genes’ promoter activity is strongly correlated with chromatin accessibility, we discovered several hundred genes that were transcriptionally silent but had accessible chromatin at their promoters. Most of those silent/accessible gene promoters were in the Müller glial cells. The Müller cells are radial glia of the retina and perform a variety of essential functions to maintain retinal homeostasis and respond to stress, injury, or disease. The silent/accessible genes in Müller glia are enriched in pathways related to inflammation, angiogenesis, and other types of cell-cell signaling and were rapidly activated when we tested 15 different physiologically relevant conditions to mimic retinal stress, injury, or disease in human and murine retinae. We refer to these as “pliancy genes” because they allow the Müller glia to rapidly change their gene expression and cellular state in response to different types of retinal insults. The Müller glial cell pliancy program is established during development, and we demonstrate that pliancy genes are necessary and sufficient for regulating inflammation in the murine retina in vivo. In zebrafish, Müller glia can de-differentiate and form retinal progenitor cells that replace lost neurons. The pro-inflammatory pliancy gene cascade is not activated in zebrafish Müller glia following injury, and we propose a model in which species-specific pliancy programs underly the differential response to retinal damage in species that can regenerate retinal neurons (zebrafish) versus those that cannot (humans and mice).
Fine-grained descending control of steering in walkingDrosophila
Authors: Yang Helen H. , Brezovec Luke E. , Serratosa Capdevila Laia , Vanderbeck Quinn X. , Adachi Atsuko , Mann Richard S. , Wilson Rachel I.
Published: October 2023

Locomotion involves rhythmic limb movement patterns that originate in circuits outside the brain. Purposeful locomotion requires descending commands from the brain, but we do not understand how these commands are structured. Here we investigate this issue, focusing on the control of steering in walkingDrosophila. First, we describe different limb “gestures” associated with different steering maneuvers. Next, we identify a set of descending neurons whose activity predicts steering. Focusing on two descending cell types downstream from distinct brain networks, we show that they evoke specific limb gestures: one lengthens strides on the outside of a turn, while the other attenuates strides on the inside of a turn. Notably, a single descending neuron can have opposite effects during different locomotor rhythm phases, and we identify networks positioned to implement this phase-specific gating. Together, our results show how purposeful locomotion emerges from brain cells that drive specific, coordinated modulations of low-level patterns.
Ecological and Evolutionary Characteristics of Anthropogenic Roosting Ability in Bats of the World
Authors: Betke Briana A. , Gottdenker Nicole L. , Meyers Lauren Ancel , Becker Daniel J.
Published: October 2023

Although the global conversion of wildlife habitat to built environments often has negative impacts on biodiversity, some wildlife have the ability to cope by living in human-made structures. However, the determinants of this adaptation on a global scale are not well understood and may signify species with unique conservation needs at the human–wildlife interface. Here, we identify the trait profile associated with anthropogenic roosting in bats globally and characterize the evolution of this phenotype using an original dataset of roosting behavior developed across 1,279 extant species. Trait-based analyses showed that anthropogenic roosting is predictable across bats and is associated with habitat generalism, small geographic ranges, small body size, temperate zone distributions, and insectivory. We identified moderate phylogenetic signal in this complex phenotype, which has undergone both gains and losses across bat evolution and for which speciation rates are lower compared to natural roosting bats.
A Non-invasive Detection of Parkinson’s Disease using PitArray: An Integrative Meta-Analysis and Machine Learning Approach
Authors: Bhattacharjee Arittra , Jamal Tabassum Binte , Ahammad Ishtiaque , Lamisa Anika Bushra , Arefin Md. Shamsul , Chowdhury Zeshan Mahmud , Hossain Mohammad Uzzal , Das Keshob Chandra , Keya Chaman Ara , Salimullah Md
Published: October 2023

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting the central nervous system, often diagnosed in its advanced stages due to the absence of sensitive biomarkers. With this objective in mind, our study conducted a comprehensive analysis of differentially expressed genes (DEGs) sourced from blood-based microarray datasets to uncover potential biomarkers and developed a machine learning based classifier to conduct two step validations. By analyzing gene expression of three projects, we identified 678 DEGs, consisting of 337 genes showing upregulation and 341 genes presenting downregulation. Additionally, insights from functional enrichment and the protein-protein network analysis indicate thatHLA-F,IRF-1, andRPS28have the potential to serve as biomarkers for diagnosing PD. Simultaneously, we employed feature selection techniques such as Least Absolute Shrinkage and Selection Operator with Cross Validation (LassoCV) followed by Recursive Feature Elimination with Cross Validation (REFCV) to filter our initial dataset of 13,249 genes down to 43 genes, which were subsequently used to train the machine learning-based classifier models. These 43 genes formed the basis for training and testing various machine learning models, including logistic regression, random forest, naive Bayes, k-nearest neighbors, support vector machine, and deep learning based artificial neural networks. Our models demonstrated robust performance, with Support Vector Machine outperforming others by 0.65 accuracy (95%CI: 0.58-0.66), 0.70 AUC-ROC (95%CI: 0.70-0.71) and 0.35 MCC (95%CI: 0.34-0.39). The model was implemented to develop the PitArray tool for non-invasive detection of PD from blood. PitArray is available at:https://github.com/Arittra95/PitArray.

Key Points

HLA-F, IRF-1,andRPS28were identified as potential biomarkers for Parkinson’s disease diagnosis.

Several sophisticated feature selection methods recognized 43 genes which were then used to build a machine learning model.

A Support Vector Machine based tool named PitArray was developed which could distinguish Parkinson’s disease patients from healthy people based on blood transcriptome data.
Assessing the limits of zero-shot foundation models in single-cell biology
Authors: Kedzierska Kasia Z. , Crawford Lorin , Amini Ava P. , Lu Alex X.
Published: October 2023

The advent and success of foundation models such as GPT has sparked growing interest in their application to single-cell biology. Models like Geneformer and scGPT have emerged with the promise of serving as versatile tools for this specialized field. However, the efficacy of these models, particularly in zero-shot settings where models are not fine-tuned but used without any further training, remains an open question, especially as practical constraints require useful models to function in settings that preclude fine-tuning (e.g., discovery settings where labels are not fully known). This paper presents a rigorous evaluation of the zero-shot performance of these proposed single-cell foundation models. We assess their utility in tasks such as cell type clustering and batch effect correction, and evaluate the generality of their pretraining objectives. Our results indicate that both Geneformer and scGPT exhibit limited reliability in zero-shot settings and often underperform compared to simpler methods. These findings serve as a cautionary note for the deployment of proposed single-cell foundation models and highlight the need for more focused research to realize their potential.2
Cortical mapping of sensory responses reveals strong brain-state dependence of the late component
Authors: Montagni E , Resta F , Tort-Colet N , Scaglione A , Mazzamuto G , Destexhe A , Pavone FS , Allegra Mascaro AL
Published: October 2023

Sensory information must be integrated across a distributed brain network for stimulus processing and perception. Recent studies have revealed specific spatiotemporal patterns of cortical activation for the early and late components of sensory-evoked responses, which are associated with stimulus features and perception, respectively. However, our understanding of how the brain state influences the sensory-evoked activation across the mouse cortex remains limited.

In this study, we utilized isoflurane to modulate the brain state and conducted wide-field calcium imaging of Thy1-GCaMP6f mice to monitor the distributed activation evoked by multi-whisker stimulation. Our findings reveal that the level of anesthesia strongly shapes the spatiotemporal features and the functional connectivity of the sensory-activated network. As anesthesia levels decrease, we observe increasingly complex responses, accompanied by the emergence of the late component within the sensory-evoked response. The persistence of the late component under anesthesia raises new questions regarding the potential existence of perception during unconscious states.
Structural insights into the distinct protective mechanisms of human antibodies targeting ZIKV NS1
Authors: Pan Qi , Xing Xiaomin , Yu Jianhai , Chen Qiang , Jiao Haizhan , Zhang Wanqin , Wen Yingfen , Gao Ming , Zhao Wei , Yu Lei , Hu Hongli
Published: October 2023

Zika virus (ZIKV) Non-structural protein 1 (NS1) plays an essential role in viral replication and immune evasion. Our understanding of the differential protective mechanism of NS1-targeting antibodies is limited. Here, we determined the cryoEM structures of ZIKV NS1 in complex with two group antibodies at 2.6-2.9Å. Group I antibodies (3G2 and 4B8) potently recognize cell surface form of NS1 and multiple oligomeric forms of NS1 by occupy the epitopes on outer surface of dimeric NS1. IgG and Fab from group I antibodies completely abrogate sNS1-mediated endothelial dysfunction in vitro. Group II antibodies (4F10, 2E11, and 14G5) recognize the previously reported epitopes in distal end of theβ-ladder domain of monomeric NS1, and their blockade efficiency depends on the affinity with NS1 protein. These findings elucidate the correlation between the epitope recognition and the protective efficacy of anti-NS1 antibodies and highlight the distinct mechanisms of therapeutic potential of 3G2 and 4B8.
Computational Modeling of Hyperpolarizing Astrocytic Influence on Cortical Up-Down State Transitions
Authors: Verma Jay , Garg Pranjal
Published: October 2023

The Up-Down dynamics seen in cortical structures during non-rapid-eye-movement (NREM) sleep, anesthetized states, and quiet wakefulness is the spontaneous alternation between phases of heightened firing activity (referred to as the Up state) and periods of neuronal inactivity (termed the Down state) within neural networks. By leveraging bistable dynamics imposed by a depolarising astrocyte population, in the current paper, we introduced a hyperpolarising astrocyte population to an existing model of Up-Down dynamics to account for biological relevance. We created a computational rate model that includes populations of depolarizing and hyperpolarizing astrocytes and neurons. To optimize model parameters, we used the Elementary Effects (EE) test. It was followed by linear stability analysis to locate bistable regimes in the parameter hyperspace. The addition of hyperpolarizing gliotransmission perturbed model dynamics, indicating its sensitivity to qualitatively differing architectures. We then identified a bistable regime within the dynamics spectrum. According to the EE test, the strength of cell population coupling is a low-sensitivity parameter, possibly due to neuroplastic changes. We also found that the threshold of excitatory cell populations and the strength of adaptation are high-sensitivity parameters, whereas the threshold of inhibitory cell populations is low-sensitivity. Our model enables the possibility of testing biologically relevant theories of hyperpolarizing gliotransmission, where data remains scant.
CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells
Authors: Oestreicher David , Chepurwar Shashank , Kusch Kathrin , Rankovic Vladan , Jung Sangyong , Strenzke Nicola , Pangrsic Tina
Published: October 2023

To encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3 calcium channels. Mutations in theCABP2gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. InCabp1/2double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neuronsin vivoare strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage and calcium-dependent inactivation of IHC CaV1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding.
Plasmid partitioning driven by collective migration of ParA between nucleoid lobes
Authors: Köhler Robin , Murray Seán M.
Published: October 2023

The ParABS system is crucial for the faithful segregation and inheritance of many bacterial chromosomes and low-copy number plasmids. However, despite extensive research, the spatio-temporal dynamics of the ATPase ParA and its connection to the dynamics and positioning of the ParB-coated cargo has remained unclear. In this study, we utilise high-throughput imaging, quantitative data analysis, and computational modelling to explore thein vivodynamics of ParA and its interaction with ParB-coated plasmids and the nucleoid. As previously observed, we find that F-plasmid ParA undergoes collective migrations (‘flips’) between cell halves multiple times per cell cycle. We reveal that a constricting nucleoid is required for these migrations and that they are triggered by a plasmid crossing into the cell half with greater ParA. Using simulations, we show that these dynamics can be explained by the combination of nucleoid constriction and cooperative ParA binding to the DNA, in line with the behaviour of other ParA proteins. We further show that these ParA flips act to equally partition plasmids between the two lobes of the constricted nucleoid and are therefore important for plasmid stability, especially in fast growth conditions for which the nucleoid constricts early in the cell cycle. Overall our work identifies a second mode of action of the ParABS system and deepens our understanding of how this important segregation system functions.
Data-driven motif discovery in biological neural networks
Authors: Matelsky Jordan K. , Robinette Michael S. , Wester Brock , Gray-Roncal William R. , Johnson Erik C. , Reilly Elizabeth P.
Published: October 2023

Abstract

Data from a variety of domains are represented as graphs, including social networks, transportation networks, computer networks, and biological networks. A key question spans these domains: are there meaningful repeated subgraphs, or motifs, within the structure of these larger networks? This is a particularly relevant problem when searching for repeated neural circuits in networks of biological neurons, as the field now regularly produces large brain connectivity maps of neurons and synapses, or connectomes. Given acquisition costs, however, these neuron-synapse connectivity maps are mostly one-of-a-kind. With current graph analysis techniques, it is very challenging to discover new “interesting” subgraphsa priorigiven small sample sizes of host graphs. Another challenge is that for even relatively modest graph sizes, an exhaustive search of all possible subgraphs is computationally intractable. For these reasons, motif discovery in biological graphs remains an unsolved challenge in the field. In this work, we present a motif discovery approach that can derive a list of undirected or directed motifs, with occurrence counts which are statistically significant compared to randomized graphs, from a single graph example. We first address common pitfalls in the current most common approaches when testing for motif statistical significance, and outline a strategy to ameliorate this problem with improved graph randomization techniques. We then propose a progressive-refinement approach for motif discovery, which addresses issues of computational cost. We demonstrate that our sampling correction technique allows for significance testing of target motifs while highlighting misleading conclusions from standard random graph models. Finally, we share our reference implementation, which is available as an open-source Python package, and demonstrate real-world preliminary results on theC. elegansconnectome and the ellipsoid body of theDrosophila melanogasterfruit fly connectome.
Diurnal fluctuations in steroid hormones tied to variation in intrinsic functional connectivity in a densely sampled male
Authors: Grotzinger Hannah , Pritschet Laura , Shapturenka Pavel , Santander Tyler , Murata Elle , Jacobs Emily G.
Published: October 2023

Most of mammalian physiology is under the control of biological rhythms, including the endocrine system with time-varying hormone secretion. Precision neuroimaging studies provide unique insights into the means through which our endocrine system regulates dynamic properties of the human brain. Recently, we established estrogen’s ability to drive widespread patterns of connectivity and enhance the functional efficiency of large-scale brain networks in a woman sampled every 24h across 30 consecutive days, capturing a complete menstrual cycle. Steroid hormone production also follows a pronounced sinusoidal pattern, with a peak in testosterone between 6-7am and nadir between 7-8pm. To capture the brain’s response to diurnal changes in hormone production, we carried out a companion precision imaging study of a healthy adult man who completed MRI and venipuncture every 12-24 hours across 30 consecutive days. Results confirmed robust diurnal fluctuations in testosterone, cortisol, and estradiol. Standardized regression analyses revealed predominantly positive associations between testosterone, cortisol, and estradiol concentrations and whole-brain patterns of coherence. In particular, functional connectivity in Dorsal Attention and Salience/Ventral Attention Networks were coupled with diurnally fluctuating hormones. Further, comparing dense-sampling datasets between a man and naturally-cycling woman revealed that fluctuations in sex hormones are tied to patterns of whole-brain coherence to a comparable degree in both sexes. Together, these findings enhance our understanding of steroid hormones as rapid neuromodulators and provide evidence that diurnal changes in steroid hormones are tied to patterns of whole-brain functional connectivity.

Significance Statement

Diurnal variation is an essential biorhythm, yet the relationship between diurnal fluctuations in steroid hormones and the functional architecture of the human brain is virtually unknown. This precision neuroimaging study suggests that endogenous fluctuations in testosterone, estradiol, and cortisol concentrations are tied to rhythmic changes in coherence across the brain. Precision imaging studies that track individuals across major endocrine transitions (e.g. the diurnal cycle and menstrual cycle) demonstrate steroid hormones’ ability to modulate the functional architecture of the brain in both sexes, and provide a starting point for future studies to probe the functional significance of these rhythms for behavior.
Complete genome sequence of thermophilic cellulolytic actinobacteriumThermobifida fuscastrain UPMC 901 producing thermostable cellulases
Authors: Zainudin Mohd Huzairi Mohd , Gan Han Ming , Tokura Mitsunori
Published: October 2023

Thermophilic cellulolytic bacteria producing thermostable cellulase have multiple potential industrial and biotechnological applications. In this study, we reported the complete genome sequence of the speciesThermobifida fuscaUPMC 901 by using nano-pore sequencing technology. The represented genome is 3.76 Mb with a G + C content of 67.4%. The genome is composed of 1 scaffold with 3,193 protein-coding genes. The results indicated that the genome of theThermobifida fuscagene encodes at least 109 genes for carbohydrate-active enzymes. Of these genes, 38 glycoside hydrolases (GHs), 36 glycosylTransferases (GTs), 21 carbohydrate-binding modules (CBMs), 9 carbohydrate esterases (CEs), and 3 polysaccharide lyases (PL) were identified. In addition, two genes encoding for lytic polysaccharide monooxygenase (LPMO), the copper-dependent enzymes that catalyse oxidative cleavage of recalcitrant crystalline cellulose, that is auxiliary activity (AAs) were also detected in theT. fuscagenome. This study represented the ninth genome of the speciesT. fusca, and the cellulase genes identified will facilitate the exploration of potential sources fromT. fuscafor industrial and agricultural applications.
Forecasting regional-level COVID-19 hospitalisation in England as an ordinal variable using the machine learning method
Authors: Wang Haowei , Kwok Kin On , Li Ruiyun , Riley Steven
Published: October 2023

Background

COVID-19 causes substantial pressure on healthcare, with many healthcare systems now needing to prepare for and mitigate the consequences of surges in demand caused by multiple overlapping waves of infections. Therefore, public health agencies and health system managers also now benefit from short-term forecasts for respiratory infections that allow them to manage services better. However, the availability of easily implemented effective tools for generating precise forecasts at the individual regional level still needs to be improved.

Methods

We extended prior work on influenza to forecast regional COVID-19 hospitalisations in England for the period from 19th March 2020 to 31st December 2022, treating the number of hospital admissions in each region as an ordinal variable. We further developed the XGBoost model used previously to forecast influenza to enable it to exploit the ordering information in ordinal hospital admission levels. We incorporated different types of data as predictors: epidemiological data including weekly region COVID-19 cases and hospital admissions, weather conditions and mobility data for multiple categories of locations (e.g., parks, workplaces, etc). The impact of different discretisation methods and the number of ordinal levels was also considered.

Results

We find that the inclusion of weather data consistently increases the accuracy of our forecasts compared with models that rely only on the intrinsic epidemiological data, but only by a small amount. Mobility data brings about a more substantial increase in our forecasts. When both weather and mobility data are used in addition to the epidemiological data, the results are very similar to the model with only epidemiological data and mobility data.

Conclusion

Accurate ordinal forecasts of COVID-19 hospitalisations can be obtained using XGBoost and mobility data. While uniform ordinal levels show higher apparent accuracy, we recommend N-tile ordinal levels which contain far richer information.

Author Summary

At the regional level, we address the pressing need for precise short-term forecasts of respiratory infections, particularly COVID-19. We focus on the specific context of England and cover the period from January 1 to December 31, 2022. We introduced an enhanced XGBoost model that leverages the ordinal nature of hospital admission data, utilising a combination of predictors, including epidemiological data, weather conditions, and mobility data across various location categories. Our findings indicate that the inclusion of weather data marginally improves forecasting accuracy, while mobility data yields more significant enhancements. This research contributes valuable insights for public health agencies and healthcare system managers in their ongoing efforts to manage and respond to the complexities of the COVID-19 pandemic.
Expert panel identified health-related social needs and methodological considerations for a polysocial risk score
Authors: Vest Joshua R , McNamee Cassidy , Musey Paul I
Published: October 2023

Objectives

A polysocial risk score, which summaries multiple different health-related social needs (HRSNs) into a single likelihood of risk, could support more effective patient and population health management. Nevertheless, developing a polysocial risk score faces uncertainties and challenges due the HRSNs’ differing etiologies and interventions, cooccurrence, and variation in information availability.

Methods

A 3-round Delphi technique to elicit expert opinion and develop a preliminary polysocial risk score approach. Expert panel members included physicians (n=8), social service professionals & staff (n=9), and patients (n=6). For physicians, the primary qualification was direct patient care experience in screening or asking about patients’ health-related social needs. Social service professionals & staff had titles of: nurse, patient care assistant, patient advocate, community health worker, director of community services. Round 1 obtained an initial importance of HRSNs on general health & well-being and total healthcare cost. Panelists also suggested additional HRSNs Responses served as discussion points for Round 2. Five focus groups explored how HRSNs should be ranked; additional HRSNs to include; timing of measurements; management of non-response and missing data; and concerns about bias and equity. We analyzed the transcripts using a consensus coding approach. Panelists then completed a follow-up survey.

Results

Panelists identified 17 HRSNs relevant to health and well-being for inclusion in a polysocial risk score. Methodology concerns ranging from the sources and quality of data, non-random missing information, data timeliness, and the need for different risk scores by population. Panelist also raised concerns about potential bias and missaplication of a polysocial risk score.

Conclusion

A polysocial risk score is a potentially useful addition to the growing methodologies to better understand and address HRSNs. Nevertheless, development is potentially complicated and fraught with challenges.
iSCORED: nanopore-based random genomic sampling for intraoperative molecular diagnosis
Authors: Emiliani Francesco E. , Ould Ismail Abdol Aziz , Hughes Edward G. , Tsongalis Gregory J. , Zanazzi George J , Lin Chun-Chieh
Published: October 2023

Copy number variations (CNVs) are almost ubiquitous in cancer. In many cases, somatic CNV analysis has led to the identification of oncogenic pathways and suggested molecular-defined therapeutic targets. Here, we develop iSCORED, a one-step random genomic DNA reconstruction method that enables efficient, unbiased quantification of CNVs using a real-time Nanopore sequencer. By leveraging the long concatenated reads, we generate approximately 1-2 million genomic fragments within one hour of MinION sequencing, allowing for high-resolution genomic dosage comparisons. In our cohort of 26 malignant brain tumors, we demonstrated 100% concordance in CNV detections, including chromosomal alterations and oncogene amplifications when compared to clinically validated next generation sequencing and chromosomal microarray results. In addition, iSCORED allows concurrent brain tumor methylation classification without additional tissue preparation. The integrated methylation information revealed promoter hypomethylation in all detected amplified oncogenes. The entire workflow, including the automatic generation of CNV and methylation reports, can be accomplished within 120-140 minutes. Ultrafast molecular analysis can enhance clinical decision-making, optimize surgical planning and identify potential molecular therapies within surgical timeframes.
Short-term Functional Outcomes of Patients with acute intracerebral hemorrhage in the Native and Expatriate Population
Authors: Akhtar Naveed , Kate Mahesh , Kamran Saadat , Joseph Sujatha , Morgan Deborah , Uy Ryan , Babu Blessy , Shanti Shobhna , Shuaib Ashfaq
Published: October 2023

Objectives

Functional outcomes in patients with intracerebral hemorrhage (ICH) have not been well characterized in the Middle East and North Africa Region. We report the 30 and 90-day clinical outcomes in the native and expatriate of Qatar with ICH.

Methods

We evaluated the Glasgow Coma Scale (GCS), NIHSS, and imaging in the Qatar Stroke Registry (2013–22). The outcome measures were a modified Rankin Scale (mRS) at 90 days and mortality at 30 and 90 days. Unfavourable outcome was defined as mRS of 4-6. We performed non-parametric ROC analyses to measure the concordance index (C-index) to assess the goodness-of-fit of ICH score for predicting 30 day and 90-day mortality and functional outcome.

Results

1660 patients (median age of 49 (41.5-58) years; male 83.1%, expatriates 77.5%) with ICH, including supratentorial deep in 65.2%, cortical in 16.2%, infratentorial 16% and primary intraventricular in 2.5% were studied. The median baseline ICH volume was 7.5 (3.2-15.8) ml. An unfavorable outcome was seen in 673 (40.5%) patients at 90 days. Mortality at 30 days and 90 days was 10.4% and 15.1%. Increasing age (OR (95% CI), 1.02 (1.00-1.03)), lower GCS (0.77 (0.73-0.80)), prior use of antiplatelet medications (1.82 (1.19-2.08)), higher ICH volume (1.03 (1.02-1.04)), and presence of any intraventricular hemorrhage (1.57(1.19-2.08)), were associated with unfavorable outcome.

Conclusions

In this relatively younger ICH cohort more than 75% were expatriates, had smaller ICH volume and had better functional outcomes. Prognostic scoring systems may have to be modified in this population to avoid early withdrawal of care.
Non-evoked frequencies: Retinotopic position modulation induces SSVEP signals without intrinsic neural signal processing
Authors: Duymaz İlker , Kogo Naoki , Alp Nihan
Published: October 2023

Steady-state visually evoked potentials (SSVEPs) are defined as periodic EEG responses elicited by periodic modulations in visual stimuli. These periodic responses can be extracted as narrowband frequency components by employing frequency domain analyses. Frequency components extracted this way are traditionally attributed to modulations in neuronal activity, particularly of neurons sensitive to a modulated stimulus property. Here, we demonstrate a scenario in which frequency components arise solely due to retinotopic variations in signal strength without representing the activity of any specific neural mechanism. Specifically, we present evidence from two EEG experiments for the existence of signal fluctuations that depend solely on retinotopic stimulus position, which are also able to yield identifiable frequency components in the face of a position-modulated stimulus. Given the large extent of positional variation in our stimulus, these position-dependent fluctuations likely reflect the factors that impact the strength of the measured responses from different retinotopic areas. These results offer a counterexample to the conventional approach of associating frequency components with neuronal activity, and underscore potentially confounding interactions between stimuli and the brain’s architecture.
Global regulation via modulation of ribosome pausing by the ABC-F protein EttA
Authors: Ousalem Farès , Ngo Saravuth , Oïffer Thomas , Omairi-Nasser Amin , Hamon Marion , Monlezun Laura , Boël Grégory
Published: October 2023

Having multiple rounds of translation of the same mRNA creates dynamic complexities along with opportunities for regulation related to ribosome pausing and stalling at specific sequences. Yet, mechanisms controlling these critical processes and the principles guiding their evolution remain poorly understood. Through genetic, genomic, physiological, and biochemical approaches, we demonstrate that regulating ribosome pausing at specific amino acid sequences can produce ∼2-fold changes in protein expression levels which strongly influence cell growth and therefore evolutionary fitness. We demonstrate, bothin vivoandin vitro,that the ABC-F protein EttA directly controls the translation of mRNAs coding for a subset of enzymes in the tricarboxylic acid (TCA) cycle and its glyoxylate shunt, which modulates growth in some chemical environments. EttA also modulates expression of specific proteins involved in metabolically related physiological and stress-response pathways. These regulatory activities are mediated by EttA rescuing ribosomes paused at specific patterns of negatively charged residues within the first 30 amino acids of nascent proteins. We thus establish a unique global regulatory paradigm based on sequence-specific modulation of translational pausing.
Spatio-temporal organization of network activity patterns in the hippocampus
Authors: Lopes-dos-Santos Vítor , Brizee Demi , Dupret David
Published: October 2023

The hippocampus is a layered brain network, composed of diverse cell types arranged in multiple microcircuits with anatomically structured inputs, all working in concert to support memory. This intricate organization generates a myriad of electrophysiological signatures. While specific aspects of these activity patterns have been explored, a comprehensive understanding of the hippocampal layer-embedded dynamics remains elusive. Here, we developed a low-dimensional manifold to capture electrophysiological patterns, mapping their anatomical trajectory along the CA1-to-DG axis, and distinguishing layers based on sharp-wave and theta profiles. This profiling led to the characterization of selective theta-nested gamma signatures for each layer. It further revealed spike patterns associated with gamma rhythms, which highlight specific firing motifs between principal cells and interneurons, and differential firing properties within pyramidal sub-layers. These findings support a holistic understanding of the spatio-temporal activity patterns across hippocampal layers for unraveling the network operations that drive memory-guided behavior.
Chemical-LTP induces confinment of BDNF mRNA under dendritic spines and BDNF protein accumulation inside the spines
Authors: Bimbi Giorgia , Tongiorgi Enrico
Published: October 2023

The neurotrophin brain-derived neurotrophic factor (BDNF) plays a key role in neuronal development and synaptic plasticity. The discovery that BDNF mRNA can be transported in neuronal dendrites in an activity-dependent manner has suggested that its local translation may support synapse maturation and plasticity. However, a clear demonstration that BDNF mRNA is locally transported and translated at activated synapses in response to long-term potentiation (LTP) is still lacking. Here, we study the dynamics of BDNF mRNA dendritic trafficking following induction of chemical-LTP (cLTP). Dendritic transport of BDNF transcripts was analysed using the MS2 system for mRNA visualization, and chimeric BDNF-GFP constructs were used to monitor protein synthesis in living neurons. We found that within 15’ following cLTP induction, most BDNF mRNA granules become stationary and transiently accumulate in the dendritic shaft at the basis of the spines similarly to the control CamkIIα mRNA which increased also inside the spines, at 60’ post-cLTP. At 60’ but not at 15’ from cLTP induction, we observed an increase in BDNF protein levels within the spine. Taken together, these findings suggest that BDNF mRNA trafficking is arrested in the early phase of cLTP, providing a local source of mRNA for translation of BDNF at the basis of the spine followed in the late LTP phase, by translocation of the BDNF protein within the spine head.

Statement

Brain-derived neurotrophic factor (BDNF) plays a key role in neuronal development and synaptic plasticity. In this study, we investigate two unresolved questions in neuronal plasticity: a) whether the post-synaptically released BDNF can be locally synthesized in this compartment, and b) whether the local translation of BDNF occurs in dendrites, or within the spine. Using chimeric constructs ectopically expressed in living primary hippocampal neurons, we tracked BDNF mRNA trafficking within the dendrites and its local translation following induction of chemical-LTP (cLTP) by forskolin. We show that in the early phase of cLTP induction (15’), BDNF mRNA becomes confined at the basis of the spines providing a local source for translation of the protein followed in the late LTP phase (60’), by translocation of the BDNF protein within the spine head.
Microglia are dispensable for experience-dependent refinement of visual circuitry
Authors: Brown Thomas C. , Crouse Emily C. , Attaway Cecilia A. , Oakes Dana K. , Minton Sarah W. , Borghuis Bart G. , McGee Aaron W.
Published: October 2023

Microglia are proposed to be critical for the refinement of developing neural circuitry. However, evidence identifying specific roles for microglia has been limited and often indirect. Here we examined whether microglia are required for the experience-dependent refinement of visual circuitry and visual function during development. We ablated microglia by administering the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622, and then examined the consequences for retinal function, receptive field tuning of neurons in primary visual cortex (V1), visual acuity, and experience-dependent plasticity in visual circuitry. Eradicating microglia by treating mice with PLX5622 beginning at postnatal day (P) 14 did not alter visual response properties of retinal ganglion cells examined three or more weeks later. Mice treated with PLX5622 from P14 lacked more than 95% of microglia in V1 by P18, prior to the opening of the critical period. Despite the absence of microglia, the receptive field tuning properties of neurons in V1 were normal at P32. Similarly, eradicating microglia did not affect the maturation of visual acuity. Mice treated with PLX5622 displayed typical ocular dominance plasticity in response to brief monocular deprivation. Thus, none of these principal measurements of visual circuit development and function detectibly differed in the absence of microglia. We conclude that microglia are dispensable for experience-dependent refinement of visual circuitry. These findings challenge the proposed critical role of microglia in refining neural circuitry.
Phages Produce Persisters
Authors: Fernández-García Laura , Kirigo Joy , Huelgas-Méndez Daniel , Tomás María , García-Contreras Rodolfo , Wood Thomas K.
Published: October 2023

Bacteria primarily encounter stress, and, arguably, their greatest threats are phages. It is often assumed that those bacteria that escape phage attack have mutated; however, another possibility is that a subpopulation forms the dormant persister state, in a manner similar to that demonstrated for bacterial cells undergoing nutritive, oxidative, and antibiotic stress. Persister cells do not undergo mutation and survive lethal conditions by ceasing growth transiently. Slower growth and dormancy play a key physiological role as they allow host phage defense systems more time to clear the phage infection. Here we investigated how bacteria survive lytic phage infection by isolating surviving cells from the plaques of T2, T4, and lambda (cI mutant) virulent phages. We found that bacteria in plaques can escape phage attack both by mutation (i.e., become resistant) and without mutation (i.e., become persistent). Specifically, whereas T4-resistant and lambda-resistant bacteria with over a 100,000-fold less sensitivity were isolated from plaques with obvious genetic mutations (e.g., causing mucoidy), cells were also found after T2 infection that undergo no significant mutation, retain wild-type phage sensitivity, and survive lethal doses of antibiotics. Corroborating this, adding T2 phage to persister cells resulted in 137,000-fold more survival compared to that of addition to exponentially-growing cells. Phage treatments withKlebsiella pneumoniaandPseudomonas aeruginosaalso generated persister cells. Hence, along with resistant strains, bacteria also form persister cells during phage infection.
A Histomorphometric and Computational Investigation of the Stabilizing Role of Pectinate Ligaments in the Aqueous Outflow Pathway
Authors: Safa Babak N. , Fraticelli Guzmán Nina Sara , Li Guorong , Stamer W. Daniel , Feola Andrew J. , Ethier C. Ross
Published: October 2023

Murine models are commonly used to study glaucoma, the leading cause of irreversible blindness. Glaucoma is associated with elevated intraocular pressure (IOP), which is regulated by the tissues of the aqueous outflow pathway. In particular, pectinate ligaments (PLs) connect the iris and trabecular meshwork (TM) at the anterior chamber angle, with an unknown role in maintenance of the biomechanical stability of the aqueous outflow pathway, thus motivating this study. We conducted histomorphometric analysis and optical coherence tomography-based finite element (FE) modeling on three cohorts of C57BL/6 mice: ‘young’ (2-6 months), ‘middle-aged’ (11-16 months), and ‘elderly’ (25-32 months). We evaluated the age-specific morphology of the outflow pathway tissues. Further, because of the known pressure-dependent Schlemm’s canal (SC) narrowing, we assessed the dependence of the SC lumen area to varying IOPs in age-specific FE models over a physiological range of TM/PL stiffness values. We found age-dependent changes in morphology of outflow tissues; notably, the PLs were more developed in older mice compared to younger ones. In addition, FE modeling demonstrated that murine SC patency is highly dependent on the presence of PLs, and that increased IOP caused SC collapse only with sufficiently low TM/PL stiffness values. Moreover, the elderly model showed more susceptibility to SC collapse compared to the younger models. In conclusion, our study elucidated the previously unexplored role of PLs in the aqueous outflow pathway, indicating their function in supporting TM and SC under elevated IOP.
Mechanism of 2’-Fucosyllactose degradation by Human-AssociatedAkkermansia
Authors: Padilla Loren , Fricker Ashwana D. , Luna Estefani , Choudhury Biswa , Hughes Elizabeth R. , Panzetta Maria E. , Valdivia Raphael H. , Flores Gilberto E.
Published: October 2023

Among the first microorganisms to colonize the human gut of breastfed infants are bacteria capable of fermenting human milk oligosaccharides (HMOs). One of the most abundant HMOs, 2’-fucosyllactose (2’-FL), may specifically drive bacterial colonization of the intestine. Recently, differential growth has been observed across multiple species ofAkkermansiaon various HMOs including 2’FL. In culture, we found growth of two species,A. muciniphilaMucTandA. biwaensisCSUN-19, in HMOS corresponded to a decrease in the levels of 2’-FL and an increase in lactose, indicating that the first step in 2’-FL catabolism is the cleavage of fucose. Using phylogenetic analysis and transcriptional profiling, we found that the number and expression of fucosidase genes from two glycoside hydrolase (GH) families, GH29 and GH95, varies between these two species. During mid-log phase growth, the expression of several GH29 genes was increased by 2’-FL in both species, whereas the GH95 genes were induced only inA. muciniphila. We further show that one putative fucosidase and a β-galactosidase fromA. biwaensisare involved in the breakdown of 2’-FL. Our findings indicate that that plasticity of GHs of human associatedAkkermansiasp. enable access to additional growth substrates present in HMOs, including 2’-FL. Our work highlights the potential forAkkermansiato influence the development of the gut microbiota early in life and expands the known metabolic capabilities of this important human symbiont.

IMPORTANCE

Akkermansiaare mucin degrading specialists widely distributed in the human population.Akkermansia biwaensishas recently been observed to have enhanced growth relative to other human associatedAkkermansiaon multiple human milk oligosaccharides (HMOs). However, the mechanisms for enhanced growth are not understood. Here, we characterized the phylogenetic diversity and function of select genes involved in growth ofA. biwaensison 2’-fucosyllactose (2’-FL), a dominant HMO. Specifically, we demonstrate that two genes in a genomic locus, a putative β-galactosidase and α-fucosidase, are likely responsible for the enhanced growth on 2’-FL. The functional characterization ofA. biwaensisgrowth on 2’-FL delineates the significance of a single genomic locus that may facilitate enhanced colonization and functional activity of selectAkkermansiaearly in life.
The influence of skin pigmentation on pulse oximetry readings: a protocol for systematic review and meta-analysis
Authors: Ahmed Shabbir , Afrin Sadia , Hasan SK Mehedi , Sarker Sharmishtha Sonalika , Azrin Farhia , Jahan Esrat , Rahman Ahmed Ehsanur
Published: October 2023

Background

Pulse oximeters are widely used crucial devices to triage and monitor sign of diseases and make informed decisions on patients’ health. Various studies have found a bias in pulse oximetry readings based on skin pigmentation/ ethnicity. This protocol outlines a systematic review and meta-analysis approach that will assess the effect of different skin pigmentation levels on the accuracy of pulse oximetry readings.

Methods and analysis

We will conduct search in Medline, Embase, CINAHL, and Web of Science database. Studies carried out either on healthy population or population with critical illness measuring pulse oximetry (SpO2) versus SaO2 obtained by standard CO-oximetry based on skin pigmentation and/or ethnicity and reported in the form of overall accuracy, bias, precision, or agreement will be included in this study. Four dedicated reviewers will independently assess and extract data from the included studies in a pre-specified excel format for further analysis. Any discordance in the way will be resolved by discussion until consensus is reached. JBI’s critical appraisal tool for diagnostic test accuracy test will be used to assess study quality for the included studies.

Ethics and dissemination

Ethical approval is not required because no original data will be collected as part of this review. The final review will be submitted to a peer-reviewed journal for publication and presented at conferences.