bluuebunny/crossref_metadata_2025 huggingface dataset:
Anesthesia alters cortical spike sequences in rodent visual cortex
Authors: Tanabe Sean , Lee Heonsoo , Wang Shiyong , Hudetz Anthony G.
Published: December 2022

Recurring spike sequences are thought to underlie cortical computations and may be essential for information processing in the conscious state. How anesthesia at graded levels may influence spontaneous and stimulus-related spike sequences in visual cortex has not been systematically examined. We recorded extracellular single-unit activity in the rat primary visual cortexin vivoduring wakefulness and three levels of anesthesia produced by desflurane. The latencies of spike sequences within 0~200ms from the onset of spontaneous UP states and visual flash-evoked responses were compared. During wakefulness, spike latency patterns linked to the local field potential theta cycle were similar to stimulus-evoked patterns. Under anesthesia, spontaneous UP state sequences differed from flash-evoked sequences due to the recruitment of low-firing excitatory neurons to the UP state. Flash-evoked spike sequences showed higher reliability and longer latency when stimuli were applied during DOWN states compared to UP states. At deeper levels, anesthesia altered both UP state and flash-evoked spike sequences by selectively suppressing inhibitory neuron firing. The results reveal anesthesia-induced complex changes in cortical firing sequences that may influence visual information processing.
Air-seq: Measuring air metagenomic diversity in an agricultural ecosystem
Authors: Giolai Michael , Verweij Walter , Pearson Neil , Nicholson Paul , Leggett Richard M. , Clark Matthew D.
Published: December 2022

Background

All species shed DNA into their environment during life or in death providing an opportunity to monitor biodiversity via its environmental DNA. Biodiversity monitoring using environmental DNA based technologies has become an important tool in understanding ecosystems. In recent years promising progress for non-invasive and, more importantly, non-destructive monitoring has been made by combining the retrieval of information transmitted by released environmental DNA with high-throughput sequencing technologies. Important ecosystems under continuous threat by disease but essential for food supplies are agricultural systems, often farmed as large monocultures and so highly vulnerable to disease outbreaks. Pest and pathogen monitoring in agricultural ecosystems is therefore key for efficient and early disease prevention and management. Air is rich in biodiversity, but has the lowest DNA concentration of all environmental media and yet it is required for windborne spread by many of the world’s most damaging crop pathogens. Our work and recent research suggests that ecosystems can be monitored efficiently using airborne nucleic acid information.

Results

Here we show that the airborne DNA of microbes can be recovered, sequenced and taxonomically classified, including down to the species level. Monitoring a field growing key crops we show that Air-seq can identify the presence of agriculturally significant pathogens and quantify their changing abundance over a period of 1.5 months often correlating with weather variables.

Conclusion

We add to the evidence that aerial environmental DNA can be used as a source for biomonitoring in agricultural and more general terrestrial ecosystems. The ability to detect fluxes and occurrence patterns of species and strains with high throughput sample processing and analysis technologies highlights the value of airborne environmental DNA in monitoring biodiversity changes and tracking of taxa of human interest or concern.
Effect of field strength on RF power deposition near conductive leads: A simulation study of SAR in DBS lead models during MRI at 1.5 T - 10.5 T
Authors: Kazemivalipour Ehsan , Sadeghi-Tarakameh Alireza , Keil Boris , Eryaman Yigitcan , Atalar Ergin , Golestanirad Laleh
Published: December 2022

Background

Since the advent of magnetic resonance imaging (MRI) nearly four decades ago, there has been a quest for ever-higher magnetic field strengths. Strong incentives exist to do so, as increasing the magnetic field strength increases the signal-to-noise ratio of images. However, ensuring patient safety becomes more challenging at high and ultrahigh field MRI (i.e., ≥3 T) compared to lower fields. The problem is exacerbated for patients with conductive implants, such as those with deep brain stimulation (DBS) devices, as excessive local heating can occur around implanted lead tips. Despite extensive effort to assess radio frequency (RF) heating of implants during MRI at 1.5 T, a comparative study that systematically examines the effects of field strength and various exposure limits on RF heating is missing.

Purpose

This study aims to perform numerical simulations that systematically compare RF power deposition near DBS lead models during MRI at common clinical and ultra-high field strengths, namely 1.5, 3, 7, and 10.5 T. Furthermore, we assess the effects of different exposure constraints on RF power deposition by imposing limits on either the B1+or global head specific absorption rate (SAR) as these two exposure limits commonly appear in MRI guidelines.

Methods

We created 33 unique DBS lead models based on postoperative computed tomography (CT) images of patients with implanted DBS devices and performed electromagnetic simulations to evaluate the SAR of RF energy in the tissue surrounding lead tips during RF exposure at frequencies ranging from 64 MHz (1.5 T) to 447 MHz (10.5 T). The RF exposure was implemented via realistic MRI RF coil models created based on physical prototypes built in our institutions. We systematically examined the distribution of local SAR at different frequencies with the input coil power adjusted to either limit the B1+or the global head SAR.

Results

The MRI RF coils at higher resonant frequencies generated lower SARs around the lead tips when the global head SAR was constrained. The trend was reversed when the constraint was imposed on B1+.

Conclusion

At higher static fields, MRI is not necessarily more dangerous than at lower fields for patients with conductive leads. Specifically, when a conservative safety criterion, such as constraints on the global SAR, is imposed, coils at a higher resonant frequency tend to generate a lower local SAR around implanted leads due to the decreased B1+and, by proxy,Efield levels.
De novo protein design by inversion of the AlphaFold structure prediction network
Authors: Goverde Casper , Wolf Benedict , Khakzad Hamed , Rosset Stéphane , Correia Bruno E.
Published: December 2022

De novoprotein design enhances our understanding of the principles that govern protein folding and interactions, and has the potential to revolutionize biotechnology through the engineering of novel protein functionalities. Despite recent progress in computational design strategies,de novodesign of protein structures remains challenging, given the vast size of the sequence-structure space. AlphaFold2 (AF2), a state-of-the-art neural network architecture, achieved remarkable accuracy in predicting protein structures from amino acid sequences. This raises the question whether AF2 has learned the principles of protein folding sufficiently for de novo design. Here, we sought to answer this question by inverting the AF2 network, using the prediction weight set and a loss function to bias the generated sequences to adopt a target fold. Initial design trials resulted in de novo designs with an overrepresentation of hydrophobic residues on the protein surface compared to their natural protein family, requiring additional surface optimization. In silico validation of the designs showed protein structures with the correct fold, a hydrophilic surface and a densely packed hydrophobic core. In vitro validation showed that several designs were folded and stable in solution with high melting temperatures. In summary, our design workflow solely based on AF2 does not seem to fully capture basic principles of de novo protein design, as observed in the protein surface’s hydrophobic vs. hydrophilic patterning. However, with minimal post-design intervention, these pipelines generated viable sequences as assessed experimental characterization. Thus such pipelines show the potential to contribute to solving outstanding challenges in de novo protein design.
Albatrosses employ orientation and routing strategies similar to yacht racers
Authors: Goto Yusuke , Weimerskirch Henri , Fukaya Keiichi , Yoda Ken , Naruoka Masaru , Sato Katsufumi
Published: December 2022

The way goal-oriented birds adjust their travel direction and route in response to wind significantly affects their travel costs. This is expected to be particularly pronounced in pelagic seabirds, which utilize a wind-dependent flight style called dynamic soaring. Dynamic soaring seabirds in situations without a definite goal, e.g. searching for prey, are known to preferentially fly with tail-to-side winds to increase the speed and search area, and reduce travel costs. However, little is known about their reaction to wind when heading to a definite goal, such as homing. Homing tracks of wandering albatrosses (Diomedea exulans) vary from beelines to zigzags, which are similar to those of sailboats. Here, given that both albatrosses and sailboats travel slower in headwinds and tailwinds, we tested whether the time-minimizing strategies used by yacht racers can be compared to the locomotion patterns of wandering albatrosses. We predicted that when the goal is located upwind or downwind, albatrosses should deviate their travel directions from the goal on the microscale and increase the number of turns on the macroscale. Both hypotheses were supported by track data from albatrosses and racing yachts in the Southern Ocean confirming that albatrosses qualitatively employ the same strategy as yacht racers. Nevertheless, albatrosses did not strictly minimize their travel time, likely making their flight robust against wind fluctuations to reduce flight costs. Our study provides the first empirical evidence of tacking in albatrosses and demonstrates that man-made movement strategies provide a new perspective on the laws underlying wildlife movement.
Role of HAO2 in rats with chronic kidney disease by regulating fatty acid metabolic processes in renal tissue
Authors: Li Xunjia , Liu Chengxuan , Yang Aimin , Shen Youfeng , Xu Jian , Zuo Deyu
Published: December 2022

Fibrosis is a progressive, often irreversible histologic manifestation of chronic and end-stage renal disease. In this study, single-cell transcriptome sequencing technology was used to sequence and analyze blood and kidney tissue cells in normal control rats and rats with chronic kidney disease (CKD), focusing on key cell populations and functional enrichment to explore the pathogenesis of CKD. Oil red O staining and ELISA were used to detect lipid droplets and free fat acid (FFA). RT-PCR, WB were used to verify the differential gene HAO2 and fatty acid metabolic process in tissue to ensure the reliability of single-cell sequencing results. We successfully established a single-cell transcriptome atlas of blood and kidney tissue in rats with CKD, which were annotated into 14 cell subsets (MPCs, PT, Tc, DCT, B-IC, A-IC, CNT, ALOH, BC, Neu, Endo, Pla, NKT, Baso) according to marker gene, and the integrated single-cell atlas of rats showed a significant increase and decrease of MPCs and PTs in the model group, respectively. Functional analysis found extensive enrichment of metabolic-related pathways in PT cells, includes fatty acid metabolic process, cellular amino acid metabolic process and generation of precursor metabolites and energy. Immunohistochemical experiments determined that the differential gene HAO2 was localized in the renal tubules, and its expression was significantly reduced in model group compared with control, and oil red O staining showed that lipid droplets increased in the model group. ELISA assay showed that ATP content decreased in the model group and FFA increased in the model group. ACOX1, PPARα, PGC1α were decreased in the model group, while genes and proteins were increased after overexpression of HAO2, and the AMPK and ACC phosphorylated proteins were increased. Therefore, HAO2 may be an important regulator of fatty acid metabolic processes in CKD, and overexpression of HAO2 can enhance fatty acid metabolism by promoting fatty acid oxidation pathway.
Using Social Media to Help Understand Long COVID Patient Reported Health Outcomes: A Natural Language Processing Approach
Authors: Dolatabadi Elham , Moyano Diana , Bales Michael , Spasojevic Sofija , Bhambhoria Rohan , Bhatti Junaid , Debnath Shyamolima , Hoell Nicholas , Li Xin , Leng Celine , Nanda Sasha , Saab Jad , Sahak Esmat , Sie Fanny , Uppal Sara , Vadlamudi Nirma Khatri , Vladimirova Antoaneta , Yakimovich Artur , Yang Xiaoxue , Kocak Sedef Akinli , Cheung Angela M.
Published: December 2022

Background

There remains significant uncertainty in the definition of the long COVID disease, its expected clinical course, and its impact on daily functioning. Social media platforms can generate valuable insights into patient-reported health outcomes as the content is produced at high resolution by patients and caregivers, representing experiences that may be unavailable to most clinicians.

Objective

We aim to determine the validity and effectiveness of advanced NLP approaches built to derive insight into Long COVID-related patient-reported health outcomes from social media platforms.

Methodology

We use Transformer-based BERT models to extract and normalize long COVID Symptoms and Conditions (SyCo) from English posts on Twitter and Reddit. Furthermore, we estimate the occurrence and co-occurrence of SyCo terms at any point or across time and locations. Finally, we compare the extracted health outcomes with human annotations and highly utilized clinical outcomes grounded in the medical literature.

Result

Based on our findings, the top three most commonly occurring groups of long COVID symptoms are systemic (such as “fatigue”), neuropsychiatric (such as “anxiety” and “brain fog”), and respiratory (such as “shortness of breath”). Regarding the co-occurring symptoms, the pair of ‘fatigue & headaches’ is most common. In addition, we show that other conditions, such as infection, hair loss, and weight loss, as well as mentions of other diseases, such as flu, cancer, or Lyme disease, are among the top reported terms by social media users.

Conclusion

The outcome of our social media-derived pipeline is comparable with the outcomes of peer-reviewed articles relevant to long COVID symptoms. Overall, this study provides unique insights into patient-reported health outcomes from long COVID and valuable information about the patient’s journey that can help healthcare providers anticipate future needs.
Expression of substance P, NPY and their Receptors Is Altered in Major Depression
Authors: Barde Swapnali , Aguila Julio , Zhong Wen , Solarz Anna , Mei Irene , Prud’homme Josee , Palkovits Miklos , Turecki Gustavo , Mulder Jan , Uhlén Mathias , Nagy Corina , Mechawar Naguib , Hedlund Eva , Hökfelt Tomas
Published: December 2022

BACKGROUND

Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems, including substance P(SP)/tachykinin, neuropeptide Y(NPY) and their G protein-coupled receptors are involved in mood regulation.

METHODS

We assessed the transcript levels (qPCR) of SP/tachykinin and NPY systems in five regions from postmortem brains of male and female depressed subjects who committed suicide (DSS) and controls: dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), the dorsal raphe nucleus (DRN), locus coeruleus (LC) and medullary raphe nuclei (MRN). We also analysed human LC neurons isolated using LCM with Smart-seq2 RNA sequencing.

RESULTS

Transcripts for all nine members were detected in male and female controls with marked regional variations of the raw CT values and with the highest levels for several tachykinin and tachykinin receptor transcripts in the DRN and forNPYandNPYRtranscripts in the PFC regions. Significant sex differences for controls were recorded only in the DRN (NPYR2>in females)andLC (TAC3andNPY>in females). Elevated expression in DSS was recorded in (i) DLPFC forSP, TACandTAC3in females,SPin males, andNPYR1in both sexes; and (ii) LC for all tachykinin family transcripts in females,SP, TACR1andTACR3in males,NPYin both sexes, andNPYR1in males.

CONCLUSIONS

The selective perturbation of neuropeptide systems in MDD patients may assist in the search for novel treatment strategies for subjects afflicted by this grave disorder.
Transcriptional Responses of Cancer Cells to Heat Shock-Inducing Stimuli Involve Amplification of Robust HSF1 Binding
Authors: Dastidar Sayantani Ghosh , De Kumar Bony , Lauckner Bo , Parrello Damien , Perley Danielle , Vlasenok Maria , Tyagi Antariksh , Koney Nii Koney-Kwaku , Abbas Ata , Nechaev Sergei
Published: December 2022

Responses of cells to signals are increasingly discovered to involve the binding of sequence-specific transcription factors outside of known target genes. We wanted to determine to what extent the genome-wide binding and function of a transcription factor are shaped by the cell type versus the stimulus. To do so, we induced the Heat Shock Response pathway in two distant cell lines with two different stimuli and related the binding of its master regulator HSF1 to nascent RNA and chromatin accessibility. We show that HSF1 binding patterns robustly retain their identity under different magnitudes of activation so that common HSF1 binding is globally associated with stimulus-specific transcription outcomes. HSF1-induced increase in DNA accessibility was modest in scale but occurred predominantly at remote genomic sites. Apart from regulating transcription at existing elements including promoters and enhancers, responses to heat shock may directly engage inactive chromatin.
Is mild ADHD beneficial? Brain criticality peaks at intermediate ADHD symptom scores across the population
Authors: Haque Hamed , Hirvonen Jonni , Wang Sheng H. , Simola Jaana , Morales-Muñoz Isabel , Cowley Benjamin U. , Palva J. Matias , Palva Satu
Published: December 2022

Attention-deficit/hyperactivity disorder (ADHD) is characterized by a continuum of symptoms including inattentiveness, hyperfocus, and hyperactivity, that are manifested,e.g., in increased reaction-time variability in continuous performance tasks (CPTs). Framework of brain criticality posits that brains operate in an extended regime of critical-like dynamics where neuronal and behavioral processes exhibit scale-free long-range temporal correlations (LRTCs) across hundreds of seconds. Whether shifts across critical-like brain states and parallel changes in LRTCs underlie ADHD symptoms has remained unexplored. We investigated whether brain-state shifts towards excitation-dominated dynamics and associated changes in LRTCs could explain ADHD symptoms and their continuum across individuals. We measured brain activity with magnetoencephalography (MEG) during resting and two CPTs from adult participants diagnosed with ADHD (N= 34) and neurotypical controls (NC) (N= 36) and characterized criticality with LRTCs of neuronal oscillations. ADHD patients exhibited stronger LRTCs than NC in low (5-20 Hz) and high (30-100 Hz) frequencies and dichotomous task effects. High-frequency LRTCs were positively correlated with ADHD symptoms, while beta-band (20-30 Hz) activity exhibited a quadratic correlation, peaking at moderate scores across the ADHD and NC cohorts being smaller for low and high scores. We demonstrate that ADHD is associated with shifts in brain criticality in resting-and task-state brain dynamics. Individuals with intermediate symptom scores across the NC and ADHD cohorts operated at peak criticality that is associated with a several functional benefits The progressive shift towards the supercritical side of the critical regime becomes detrimental only at moderate and severe symptoms.
GABA excitatory actions in cerebrospinal-fluid contacting neurones of adult mouse spinal cord
Authors: Riondel Priscille , Jurčić Nina , Trouslard Jérôme , Wanaverbecq Nicolas , Seddik Riad
Published: December 2022

Spinal cerebrospinal fluid-contacting neurons (CSF-cNs) form an evolutionary conserved bipolar cells population localized around the central canal of all vertebrates. CSF-cNs were shown to express molecular markers of neuronal immaturity into adulthood, however the functional relevance of their incomplete maturation remains unknown. Neuronal maturation is classically associated with the expression of the K+-Cl-cotransporter 2 (KCC2), allowing chloride (Cl-) extrusion and hyperpolarising GABA transmission. Here, we show no detectable expression of KCC2 in CSF-cNs of adult mouse spinal cord. Accordingly, lack of KCC2 expression results in low Cl-extrusion capacity in CSF-cNs under high Cl-load in whole-cell patch-clamp. Using cell-attached recordings, we found that activation of ionotropic GABAAreceptors induced a dominant depolarising effect in 70% of CSF-cNs recorded with intact intracellular chloride concentration. Moreover, in these cells, depolarising GABA-responses can drive action potentials as well as intracellular calcium elevations by activating voltage-gated calcium channels. CSF-cNs express the Na+-K+-Cl-cotransporter 1 (NKCC1) involved in Cl-uptake and its inhibition by bumetanide blocked the GABA-induced calcium transients in CSF-cNs. Finally, we show that activation of metabotropic GABABreceptors did not mediate hyperpolarisation in spinal CSF-cNs, presumably due to the lack of expression of G protein-coupled inwardly rectifying potassium (GIRK) channels. Together, these findings outline CSF-cNs as a unique neuronal population in adult spinal cord with immature Cl-homeostasis and no hyperpolarising GABAergic signalling but rather generation of excitation and intracellular calcium modulation. GABA may therefore promote CSF-cNs maturation and integration into the existing spinal circuit.

Key points

CSF contacting neurones (CSF-cNs) are located around the central canal of spinal cord across all vertebrates.

CSF-cNs express canonical markers of immature neurons during adulthood in mice but the impact of such persistent immaturity on their chloride (Cl-) homeostasis as well as GABAergic signalling were not addressed yet.

Here, we show that spinal CSF-cNs express the Na+-K+-Cl-cotransporter 1 (NKCC1) involved in Cl-uptake but not the K+-Cl-cotransporter 2 (KCC2) classically allowing Cl-extrusion.

As a result of intracellular Cl-accumulation, GABA does not mediate inhibition in most CSF-cNs but rather excitation and intracellular Ca2+elevations through the activation of voltage-gated Ca2+channels.

Excitatory GABAergic signalling associated with intracellular calcium modulation may underlie the maturation and integration of CSF-cNs into the spinal circuit of adult mice.
BioASQ-QA: A manually curated corpus for Biomedical Question Answering
Authors: Krithara Anastasia , Nentidis Anastasios , Bougiatiotis Konstantinos , Paliouras Georgios
Published: December 2022

The BioASQ question answering (QA) benchmark dataset contains questions in English, along with golden standard (reference) answers and related material. The dataset has been designed to reflect real information needs of biomedical experts and is therefore more realistic and challenging than most existing datasets. Furthermore, unlike most previous QA benchmarks that contain only exact answers, the BioASQ-QA dataset also includes ideal answers (in effect summaries), which are particularly useful for research on multi-document summarization. The dataset combines structured and unstructured data. The material linked with each question comprise documents and snippets, which are useful for Information Retrieval and Passage Retrieval experiments, as well as concepts that are useful in concept-to-text Natural Language Generation. Researchers working on paraphrasing and textual entailment can also measure the degree to which their methods improve the performance of biomedical QA systems. Last but not least, the dataset is continuously extended, as the BioASQ challenge is running and new data are generated.
A Versatile Deep Graph Contrastive Learning Framework for Single-cell Proteomics Embedding
Authors: Li Wei , Yang Fan , Wang Fang , Rong Yu , Wu Bingzhe , Zhang Han , Yao Jianhua
Published: December 2022

The advance of single-cell proteomics sequencing technology sheds light on the research in revealing the protein-protein interactions, the post-translational modifications, and the proteoform dynamics of proteins in a cell. However, the uncertainty estimation for peptide quantification, data missingness, severe batch effects and high noise hinder the analysis of single-cell proteomic data. It is a significant challenge to solve this set of tangled problems together, where existing methods tailored for single-cell transcriptome do not address. Here, we proposed a novel versatile framework scPROTEIN, composed of peptide uncertainty estimation based on a multi-task heteroscedastic regression model and cell embedding learning based on graph contrastive learning designed for single-cell proteomic data analysis. scPROTEIN estimated the uncertainty of peptide quantification, denoised the protein data, removed batch effects and encoded single-cell proteomic-specific embeddings in a unified framework. We demonstrate that our method is efficient for cell clustering, batch correction, cell-type annotation and clinical analysis. Furthermore, our method can be easily plugged into single-cell resolved spatial proteomic data, laying the foundation for encoding spatial proteomic data for tumor microenvironment analysis.
Experimental study of modified human tendon stem cells to promote graft ligamentation and tendon-bone healing after anterior cruciate ligament reconstruction
Authors: Zhao Haibo , Chen Jinli , Qi Chao , Wang Tianrui , Liang Tongda , Hao Xiaokun , Li Xiang , Yin Xiangzhi , Yu Tengbo , Zhang Yingze
Published: December 2022

Restoring the normal structure and function of injured tendons is one of the biggest challenges faced by the Department of Orthopedics and Sports Medicine. Tendon-derived stem cells (TDSCs), a new type of pluripotent stem cells with multidirectional differentiation potential, are expected to be promising cell seeds for the treatment of tendon injury and tendon-bone healing in the future. In this study, tendon stem cells were successfully isolated from human tissues, which were positive for markers CD44, CD90, and CD105, and exhibited clonality and multilineage differentiation ability. Analysis of single-cell sequencing results and mass spectrometry identification results showed that there were differences in protein expression during CTGF-induced TDSC tendon differentiation. Reverse Co-IP, qPCR, WB, and immunofluorescence detection all confirmed that CTGF directly interacts with KIT, thereby mediating the transcription factor HES1 to regulate the Wnt/β-catenin signaling pathway (GSK3β, β-catenin, TCF4). ChIP-qPCR and dual-luciferase reporter gene assays indicated that HES1 regulates stem cell differentiation by directly regulating the expression of GSK3β in the Wnt/β-catenin pathway. Rats were treated with TDSCs overexpressing the KIT gene after repair surgery. This method had a more ideal recovery effect than other methods through animal behavioral scores, mechanical properties testing, and HE staining tissue observation. This study found that the use of modified human tendon stem cells (hTDSC) could promote graft ligamentization and tendon-bone healing after ACL reconstruction, which could provide an effective way for faster and better recovery from tendon injury.
Non-specific vs specific DNA binding free energetics of a transcription factor domain protein for target search and recognition
Authors: Masri Carmen Al , Wan Biao , Yu Jin
Published: December 2022

Transcription factor (TF) proteins regulate gene expression by binding to specific sites on the genome. In the facilitated diffusion model, an optimized search process is achieved by the TF protein alternating between 3D diffusion in the bulk and 1D diffusion along DNA. While undergoing 1D diffusion, the protein can switch from a search mode for fast diffusion along non-specific DNA to a recognition mode for stable binding to specific DNA. It was recently noticed that for a small TF domain protein, re-orientations on DNA other than conformational changes happen between the non-specific and specific DNA binding. We here conducted all-atom molecular dynamics simulations with steering forces to reveal the protein-DNA binding free energetics, with a difference between the non-specific and specific binding about 10kBT, confirming that the search and recognition modes are distinguished only by protein orientations on the DNA. As the binding free energy difference differs from that being estimated from experimental measurements about 4-5kBTon 15-bp DNA constructs, we hypothesize that the discrepancy comes from DNA sequences flanking the 6-bp central binding sites impacting on the dissociation kinetics measurements. The hypothesis is supported by a simplified spherical protein-DNA model along with stochastic simulations and kinetic modeling.
Identification of plant exclusive lipid transfer SMP proteins at membrane contact sites in Arabidopsis and Tomato
Authors: Huercano Carolina , Percio Francisco , Sanchez-Vera Victoria , Morello-López Jorge , Botella Miguel A , Ruiz-Lopez Noemi
Published: December 2022

Membrane contact sites (MCS) are regions where two membranes of different organelles are close but not fused; they coordinate non-vesicular communication between organelles and are involved in a wide variety of physiological functions, including membrane lipid homeostasis. Amongst proteins localized at MCS are those containing a lipid transport domain known as synaptotagmin-like mitochondrial-lipid binding protein (SMP), being the mammalian Extended Synaptotagmins, the yeast Tricalbins and the plant Synaptotagmin 1 (SYT1) the best SMP proteins characterized so far. They are all localized at endoplasmic reticulum-plasma membrane contact sites (ER-PM CS). We have carried outin-silicogenome-wide identification of genes encoding SMP proteins in Arabidopsis and tomato. We have identified the plant exclusive NTMC2T5 proteins as ER-chloroplast CS components which make them extremely interesting as the route for lipid trafficking into and out of chloroplasts remains unknown. Additionally,NTMC2T5over-expressions caused a significant clustering of chloroplast around nucleus. Moreover, SYT6, NTMC2T6 and TEX2 have been identified as ER-Trans-Golgi Network CS proteins. These proteins associated between them and with the exocytosis related proteins VAMP721 and VAMP727. Since the functional roles of many of these genes are unknown, this gene collection provides a useful resource for future studies.

HIGHLIGHT

Plant exclusive lipid transport proteins were identified at membrane contact sites. SYT6, TEX2 and NTMC2T6 proteins are localized at ER-TGN. NTMC2T5 proteins are localized at ER-Chloroplast and induced chloroplast-nucleus clustering.
Processing and evaluating the quality of genome-wide nascent transcription profiling libraries
Authors: Scott Thomas G. , Martins André L. , Guertin Michael J.
Published: December 2022

Precision genomic run-on assays (PRO-seq) quantify nascent RNA at single nucleotide resolution with strand specificity. Here we deconstruct a recently published genomic nascent RNA processing pipeline (PEPPRO) into its components and link the analyses to the underlying molecular biology. PRO-seq experiments are evolving and variations can be found throughout the literature. The analyses are presented as individual code chunks with comprehensive details so that users can modify the framework to accommodate different protocols. We present the framework to quantify the following quality control metrics: library complexity, nascent RNA purity, nuclear run-on efficiency, alignment rate, sequencing depth, and RNA degradation.
Experimental Data Connector (XDC): Integrating the Capture of Experimental Data and Metadata Using Standard Formats and Digital Repositories
Authors: Samineni Sai P. , Vidal Gonzalo , Vidal-Céspedes Carlos , Yañez-Feliú Guillermo , Rudge Timothy J. , Myers Chris J. , Mante Jeanet
Published: December 2022

Accelerating the development of synthetic biology applications requires reproducible experimental findings. Different standards and repositories exist to exchange experimental data and metadata. However, the associated software tools often do not support a uniform data capture, encoding, and exchange of information. A connection between digital repositories is required to prevent siloing and loss of information. To this end, we developed the Experimental Data Connector (XDC). It captures experimental data and related metadata by encoding it in standard formats and storing the converted data in digital repositories. Experimental data is then uploaded to Flapjack and the metadata to SynBioHub in a consistent manner linking these repositories. This produces complete connected experimental datasets that are exchangeable. The information is captured using a single template Excel Workbook, which can be integrated into existing experimental workflow automation processes.

TOC Graphic
Comparative transcriptome revealed potential genes related with drug resistance in Melanoma
Authors: Zhao Bei , Liu Yinghua , Tang Xuemei , Cheng Shi
Published: December 2022

Chemotherapy remains a relatively ineffective and unsatisfactory treatment because of drug resistance in melanoma (whether due to intrinsic resistance or the use of cytostatic drugs). In order to explore the genes and signaling pathways related to melanoma drug resistance, the study presented here obtained drug-resistant melanoma cell lines of A375 and M14 by gradually increasing the concentration of dacarbazine (DTIC), followed by comparative transcriptomics studies (RNA-seq) and real-time quantitative PCR (RT-qPCR) and Western Blotting validation. The results showed that after 8 months of continuous treatment, the IC50 values of A375 and M14 to DTIC were increased by more than 5 folds. Meanwhile, flow cytometry analysis found that drug-resistant melanoma cells have a significant ability to resist apoptosis induced by DTIC. Subsequently, RNA-seq revealed high expression ofSENP1and abnormal activation of the Hippo signaling pathway in drug-resistant cells. Finally, we found that compared with wild-type cells, the expressions ofSENP1andYAPwere both up-regulated in drug-resistant cells via RT-qPCR and Western Blotting. Roles of SENP1 in drug resistance was finally verified via its overexpression in normal A375 cell lines. Therefore, this paper infers that there is a positive correlation between the ubiquitin-specific protease SENP1 and the drug resistance of melanoma. Meanwhile, the up-regulation of its expression may lead to changes in the Hippo signaling pathway and increase the resistance of melanoma to DTIC.
Streptococcus pneumoniaere-emerges as a cause of community-acquired pneumonia, including frequent co-infection with SARS-CoV-2, in Germany, 2021
Authors: Ankert Juliane , Hagel Stefan , Schwarz Claudia , Pan Kaijie , Wang Liz , Eiff Christof von , Gessner Bradford D. , Theilacker Christian , Pletz Mathias W.
Published: December 2022

Background

The COVID-19 pandemic and the associated containment measures had a substantial impact on pathogens causing pneumonia in adults. The objective of this study was to determine the etiology of hospitalized community-acquired pneumonia (CAP) among adults in Germany in 2021, the second year of the COVID-19 pandemic.

Methods

Since January 2021, this on-going, prospective, population-based surveillances study enrolled adult patients with clinically and radiographically confirmed CAP at three hospitals in Thuringia, Germany, serving a population of approximately 280,000. Urine samples were collected from patients and tested forS. pneumoniaeusing the pneumococcal urinary antigen test (PUAT, BinaxNOWS. pneumoniae) and the proprietary serotype-specific urinary antigen detection (UAD) assays. Nasopharyngeal swabs were tested for 10 respiratory viruses by PCR.

Results

A total of 797 patients were enrolled, of whom 760 were included in the analysis. The median age of patients with CAP was 67 years; in-hospital case-fatality rate was 8.4%. A respiratory pathogen was detected in 553 (72.8%) patients. The most common pathogen was SARS-CoV-2 (n=498, 68.2%), followed byS. pneumoniae(n=40, 6.4%). Serotypes contained in the 13-valent, 15-valent and 20-valent pneumococcal conjugate vaccine were detected in 42.5%, 45.0%, and 70.0% of the pneumococcal CAP cases. Between the first and second half of 2021, the proportion of CAP cases associated withS. pneumoniaeincreased from 1.1% to 5.6% in patients aged 18-59 years and from 2.5% to 12.4% in those aged ≥60 years; coinfection of SARS-CoV-2 andS. pneumoniaeamong COVID-19 patients increased from 0.7% (2/283 cases) to 6.0% (13/215) in patients aged ≥18 years, and from 1.0% (2/195) to 8.7% (11/127) in those aged ≥60 years.

Conclusion

In Germany, the proportion of CAP cases associated withS. pneumoniaerebounded to a near-pandemic level in the second half of 2021 and many pneumococcal infections occurred in patients with COVID-19. Vaccination uptake against respiratory pathogens, includingS. pneumoniae, should be strengthened.
Clinical Characteristic of a Haitian Stroke Cohort and a scoping review of the literature of stroke among the Haitian population
Authors: Paul Axler Jean , Charles Jude Hassan , Gedner Gandhi Marius Edwitch , Roche Richardson , Andre Wislet , Saint Croix Garly Rushler , Perue Gillian Gordon
Published: December 2022

Background

There is staggering evidence of stroke care disparities in Low- and Middle-Income countries compared to developed countries. Haiti like those countries suffer from lack of resources for acute stroke management. To our knowledge, we conducted the first study reporting the epidemiological profile of the Haitian population presenting with stroke symptoms in the largest academic hospital of the nation.

Methods

This is an observational study conducted over a period of five months from April to August 2021 in the Internal Medicine Department of the State University Hospital of Haiti including 51 consecutive patients suspected to have acute stroke. Descriptive statistical analysis was conducted. A scoping review of the literature on Haitian population stroke was also conducted.

Result

More than 50% of our patients are in the age range [19-65] years, 96.1% are older than 35 years. Mean age at presentation was 61 years, predominantly female (64.74 %). Severe motor deficit was more prevalent 96 %, with presenting NIHSS of 12 on average. Only 15% of patients (8/51) had a CT scan during their hospitalization. The majority were delays with a median time to CT of 84 hours after symptoms onset. About 80% of those with complications took more than 24 hours to arrive at the hospital after the onset of symptoms. There was a significant association between the modified Rankin Score and the occurrence of complications (F=6.33; p=0.016). 11% of the patient had complications with a mortality rate of 3.9%. NIHSS score has a very highly significant association with the Glasgow score (p<0.001) where an inverse proportional correlation was measured (r=-0.7; p<0.001) and a proportional correlation with the Rankin prediction score (r=0.3, p=0.04).

Conclusion

Stroke affect the most economically active portion of the Haitian population and there is a salient lack of equipped healthcare facilities and appropriate treatment for stroke management in Haiti. Urgent assistance in both personnel and infrastructural resources dedicated to stroke care is needed. Neurological assessment based on NIHSS and Rankin score should be systematic in stroke Evaluation.
Investigating social deprivation and comorbid mental health diagnosis as predictors of treatment access among patients with an opioid use disorder using substance use services: a prospective cohort study
Authors: Adams Emma A , Yang Justin C , O’Donnell Amy , Minot Sarah , Osborn David , Kirkbride James B
Published: December 2022

Purpose

We investigated the role of social deprivation and comorbid mental health diagnoses in predicting re-engagement with substance use services or contact with crisis and inpatient services for individuals with opioid use disorder in secondary mental health care in inner-city London.

Methods

We conducted a prospective cohort study which followed individuals diagnosed with a first episode of opioid use disorder who accessed substance use services between September 2015 and May 2020 for up to 12 months, using anonymised electronic health records. We employed Poisson regression and Cox proportional survival analyses to assess associations between exposures and outcomes.

Results

Comorbid mental health diagnoses were associated with higher contact rates with crisis/inpatient services among people with opioid use disorder: incidence rate ratios (IRR) and 95% confidence intervals (CI) were 3.37 (2.11-5.53) for non-opioid substance use comorbidity, 7.02 (3.63-13.31) for a single comorbid mental health diagnosis, and 11.68 (7.53-18.71) for multiple comorbid mental health diagnoses. Social deprivation was not associated with contact rates with crisis/inpatient services. Similar patterns were found with time to first crisis/inpatient contact. Social deprivation and comorbid mental health diagnoses were not associated with re-engagement with substance use services.

Conclusion

Comorbid substance and mental health difficulties amongst people who use opioids led to earlier and more frequent contact with crisis/inpatient services during the first 12 months of follow up. Given the common co-occurrence of mental health and substance use disorders among those who use opioids, a better understanding of their needs will ensure they are supported in their treatment journeys.
Genetic modifiers of rare variants in monogenic developmental disorder loci
Authors: Kingdom Rebecca , Beaumont Robin N. , Wood Andrew R. , Weedon Michael N. , Wright Caroline F.
Published: December 2022

Rare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DD), and have been shown to cause milder sub-clinical phenotypes in population cohorts. To investigate potential genetic modifiers, we identified individuals in UK Biobank with predicted deleterious variants in 599 autosomal dominant DD genes, and found that carrying multiple rare variants in these genes had an additive adverse effect on numerous cognitive and socio-economic traits, which could be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS). Amongst rare DD variant carriers, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without. Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may influence whether an individual reaches the threshold for clinical disease.
Invasive Mechanical Ventilation Duration Prediction using Survival Analysis
Authors: Kobara Yawo , Rodrigues Felipe F. , de Souza Camila P. E. , Wismer Megan
Published: December 2022

Invasive mechanical ventilation is one of the leading life support machines in the intensive care unit (ICU). By identifying the predictors of ventilation time upon arrival, important information can be gathered to improve decisions regarding capacity planning.

In this study, first-day ventilated patients’ ventilation time was analyzed using survival analysis. The probabilistic behaviour of ventilation time duration was analyzed and the predictors of ventilation time duration were determined based on available first-day covariates.

A retrospective analysis of ICU ventilation time in Ontario was performed with data from ICU patients obtained from the Critical Care Information System (CCIS) in Ontario between July 2015 and December 2016. As part of the protocol for inclusion, a patient must have been connected to an invasive ventilator upon arrival to the ICU. Parametric survival methods were used to characterize ventilation time and to determine associated covariates. Parametric and non-parametric methods were used to determine predictors of ventilation duration for first-day ventilated patients.

A total of 128,030 patients visited the ICUs between July 2015 and December 2016. 51,966 (40.59%) patients received invasive mechanical ventilation on arrival. Analysis of ventilation duration suggested that the log-normal distribution provided the best fit to ventilation time, whereas the log-logistic Accelerated Failure Time model best describes the association between the covariates and ventilation duration. ICU site, admission source, admission diagnosis, scheduled admission, scheduled surgery, referring physician, central venous line treatment, arterial line treatment, intracranial pressure monitor treatment, extra-corporeal membrane oxygen treatment, intraaortic balloon pump treatment, other interventions, age group, pre-ICU LOS, and MODS score were significant predictors of the ICU ventilation time.

The results show substantial variability in ICU ventilation duration for different ICUs, patient’s demographics, and underlying conditions, and highlight mechanical ventilation as an important driver of ICU costs.

The predictive performance of the proposed model showed that both the model and the data can be used to predict an individual patient’s ventilation time and to provide insight into predictors.
Human retina trades single-photon detection for high-fidelity contrast encoding
Authors: Kilpeläinen Markku , Westö Johan , Laihi Anton , Takeshita Daisuke , Rieke Fred , Ala-Laurila Petri
Published: December 2022

We lack a fundamental understanding of how the spike output of the retina enables human visual perception. Here we show that human vision at its ultimate sensitivity limit depends on the spike output of ON but not OFF parasol (magnocellular) ganglion cells. Surprisingly, nonlinear signal processing in the retinal ON pathway precludes perceptual detection of single photons in darkness, but enables quantal-resolution discrimination of differences in light intensity.