bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved Resolution of Highly Pathogenic Avian Influenza Virus Haemagglutinin Cleavage Site Using Oxford Nanopore R10 Sequencing Chemistry
Authors: Ratcliff Jeremy D , Merritt Brian , Gooden Hannah , Siegers Jurre Y , Srikanth Abhi , Yann Sokhoun , Kol Sonita , Sin Sarath , Tok Songha , Karlsson Erik A , Thielen Peter M 
Published: October 2023

AbstractHighly pathogenic avian influenza viruses continue to pose global risks to One Health, including agriculture, public, and animal health. Rapid and accurate genomic surveillance is critical for monitoring viral mutations, tracing transmission, and guiding interventions in near real-time. Oxford Nanopore sequencing holds promise for real-time influenza genotyping, but data quality from R9 chemistry has limited its adoption due to challenges resolving low-complexity regions such as the biologically critical hemagglutinin cleavage site, a homopolymer of basic amino acids that distinguish highly pathogenic strains. In this study, human and avian influenza isolates (n=45) from Cambodia were sequenced using both R9.4.1 and R10.4.1 flow cells and chemistries to evaluate performance between approaches. Overall, R10.4.1 yielded increased data output with higher average quality compared to R9.4.1, producing improved consensus sequences using a reference-based bioinformatics approach. R10.4.1 had significantly lower minor population insertion and deletion frequencies, driven by improved performance in low sequence complexity regions prone to insertion and deletion errors, such as homopolymers. Within the hemagglutinin cleavage site, R10.4.1 resolved the correct motif in 90% of genomes compared to only 60% with R9.4.1. Further examination showed reduced frameshift mutations in consensus sequences generated with R10.4.1 that could result in incorrectly classified virulence. Improved consensus genome quality from nanopore sequencing approaches, especially across biologically important low-complexity regions, is critical to reduce subjective hand-curation and will improve local and global genomic surveillance responses.
A prospective controlled study for EEG records comparison between Scalp-EEG and Ear-EEG wearable device, for subsequent analysis by an artificial intelligence-based system: SERAS-EEG study
Authors: Torres-Gaona G. , Blánquez D. , Valls A. , Raurich X. , Valls J. , Munsó L. , Arcos J.L. , Trejo A. , Aledo-Serrano A. 
Published: October 2023

ABSTRACTmjn-SERAS is an earpiece shaped as a hearing-aid device, which continuously records the electrical brain activity in two channels placed in the external auditory. It uses an artificial intelligence algorithm (AI), based system for early detection of preictal period of seizures. Sixteen patients with drug-resistant focal epilepsy and 14 control subjects were simultaneously studied with the mjn-SERAS device and a standard 24-channel EEG using the 10-20 system. Data from channels F8-T4 or F7-T3, according to the laterality of the epileptic focus was extracted from the standard EEG. We analyzed the average signal correlation (AC) between the two types of records, with and without artefact removal (filtered records [FR]), comparing inter-subject and subjects recordings (SR), as well between ictal and interictal periods in epilepsy patients.AC was 0.90 [0.88 - 0.91] and 0.88 [0.86 - 0.90] in the FR and the whole cohort, respectively. No differences in the correlation of signals were found between controls and patients in the FR (-0.01 [-0.04;0.01], p=0.261) or the SR (-0.03 [-0.06;0.01], p=0.09). In addition, in the subset of patients with epilepsy, no differences in AC were noted between interictal activity and seizures (-0.02 [- 0.06; 0.02], p=0.352). Only AC during sleep in controls was found to be smaller compared to repose (-0.04 [-0.08;-0.01], p=0.01). No adverse events were reported. Our study supports an adequate correlation between the information recorded with both methods, providing technical support for use of the mjn-SERAS to record EEG signals.
DNA i-motif levels are overwhelmingly depleted in living human cells: insights from in-cell NMR
Authors: Víšková Pavlína , Ištvánková Eva , Ryneš Jan , Džatko Šimon , Loja Tomáš , Živković Martina Lenarčič , Rigo Riccardo , El-Khoury Roberto , Serrano-Chacón Israel , Damha Masad J. , González Carlos , Mergny Jean-Louis , Foldynová-Trantírková Silvie , Trantírek Lukáš 
Published: October 2023

AbstractI-Motifs (iM) are non-canonical DNA structures potentially forming in accessible, single-stranded, cytosine-rich genomic regions, with regulatory roles. Chromatin, protein interactions, and intracellular properties seem to govern iM formation at sites with i-motif formation propensity (iMFPS) in human cells, yet their specific contributions remain unclear. Using in-cell NMR with oligonucleotide iMFPS models, we monitored iM-associated structural equilibria in asynchronous and cell cycle-synchronized HeLa cells at 37°C. Our findings show that iMFPS displaying pHT<7 under reference in vitro conditions occur predominantly in unfolded states in cells, while those with pHT>7 occur as a mix of folded and unfolded states depending on the cell cycle phase. Comparing these results with previous data obtained using an iM-specific antibody (iMab) revealed that cell cycle-dependent iM formation has a dual origin and iM formation concerns only a small fraction (possibly 1%) of genomic sites with iM formation propensity. We propose a comprehensive model aligning observations from iMab and in-cell NMR and enabling the identification of iMFPS capable of adopting iM structures under physiological conditions in living human cells. Our results suggest that many iMFPS may have biological roles linked to their unfolded states.
Atrial t-tubules adopt a specialist developmental state while alterations to Ca2+buffering maintain systolic Ca2+during postnatal development
Authors: Smith CER , Clarke JD , Quinn CJ , Sultan Z , Najem H , Denham NC , Hutchings DC , Madders GWP , Caldwell JL , Toms LK , Pinali C , Eisner DA , Trafford AW , Dibb KM 
Published: October 2023

AbstractTransverse (t)-tubules ensure a uniform rise in calcium (Ca2+) and thus contraction in cardiac cells. Though more extensively studied in the ventricle, t-tubules also play a key role in the atria of large mammals, such as human, and their loss in heart failure is associated with impaired Ca2+release and thus contractility. T-tubule restoration is therefore an ideal therapeutic target but the process of t-tubule formation is not understood. The aim of this study was to determine how t-tubules develop in the healthy atria and the impact this has on Ca2+handling. Postnatal development was assessed in sheep from newborn through to adulthood. Atrial t-tubules were present at birth in the sheep atria and increased in density up until 3 months of age. In the latter part of development (3 months to adult) a lack of t-tubule growth but increase in cell width results in t-tubule density decreasing. In the newborn, despite reduced t-tubule density, we found the amplitude of the Ca2+transient was maintained and this was associated with increases in the L-type Ca2+current (ICa-L) and the Ca2+content of the sarcoplasmic reticulum (SR). We suggest these changes are sufficient to overcome the elevated cytosolic Ca2+buffering in the newborn and the decreased t-tubule density. We have shown the neonate atria is highly specialised to negate reduced central Ca2+release through enhanced surfaceICa-Land SR load. This maintains atrial function despite immature t-tubules highlighting important differences in Ca2+handling in the newborn and heart failure atria where t-tubules are sparse.
Membrane positioning across antigen-induced synaptic contacts tunes CAR-T cell signaling and effector responses
Authors: Li Fenglei , Choudhuri Kaushik 
Published: October 2023

AbstractTumor antigen recognition by chimeric antigen receptors (CAR) triggers phosphorylation of their cytoplasmic portions resulting in CAR-T cell activation. We and others have shown that immunoreceptor triggering depends on the formation of close synaptic contacts, determined by the span of immunoreceptor-ligand complexes, from which large inhibitory phosphatases such as CD45 are sterically excluded. Here, we show, varying CAR-antigen complex span, that CAR-T cell activation depends on a formation of close contacts with target cells. CAR-antigen complexes with a span of 4 immunoglobulin superfamily (IgSF) domains maximize CAR-T cell activation, closely matching the span of endogenous TCR-pMHC complexes. Longer CAR-antigen complexes precipitously reduced triggering and cytokine production, but notably, anti-tumor cytotoxicity was largely preserved due to a ∼10-fold lower signaling threshold for mobilization of cytolytic effector function. Increased intermembrane spacing disrupted short-spanned PD-1-PD- L1 interactions, reducing CAR-T cell exhaustion. Together, our results show that membrane positioning across the immunological synapse can be engineered to generate CAR-T cells with clinically desirable functional profilesin vitroandin vivo.
Changes in high-frequency aperiodic 1/f slope and periodic activity reflect post-stimulus functional inhibition in the visual cortex
Authors: Manyukhina Viktoriya O. , Prokofyev Andrey O. , Obukhova Tatiana S. , Stroganova Tatiana A. , Orekhova Elena V. 
Published: October 2023

AbstractIt has been shown that cessation of intensive sensory stimulation is associated with a transient increase in functional inhibition in the sensory cortical areas. However, the electrophysiological correlates of this post-stimulus inhibition in the human brain have not been properly investigated.To investigate post-stimulus inhibition, we recorded magnetoencephalogram (MEG) at rest and after cessation of visual stimulation of varying intensity (high-contrast gratings drifting at a slow, medium, or high rate) in 25 healthy women aged 18-40 years. We analyzed condition- and intensity-related changes in MEG parameters sensitive to functional inhibition: periodic alpha-beta power, peak alpha frequency (PAF), and 1/f aperiodic slope. We also investigated the association of these parameters with sensory sensitivity and avoidance assessed by a questionnaire. To evaluate the influence of hormonal status on the studied parameters, participants were examined twice, during the follicular and luteal phases of the menstrual cycle (MC).Regardless of MC phase, increasing intensity of the preceding visual stimulation resulted in increased posterior post-stimulus alpha-beta power, PAF, and a more negative/steeper aperiodic (1/f) slope of the power spectrum in the 35-45 Hz range. Compared to rest, the post-stimulus period was characterized by higher PAF, a steeper 35-45 Hz 1/f slope in posterior cortical areas, and a widespread increase in beta power. While condition- and intensity-dependent changes in alpha-beta power and 1/f slope were correlated, changes in PAF did not correlate with either of them. Greater intensity-dependent increase in visual alpha-beta power predicted higher subjective sensory sensitivity/avoidance, suggesting stronger regulatory top-down modulation of visual cortex in individuals with heightened sensitivity.Our results show that several MEG parameters concordantly indicate a post-stimulus enhancement of inhibition that is proportional to the intensity of the preceding visual stimulation. While post-stimulus changes in alpha-beta power and 1/f slope may share some common mechanisms, changes in PAF reflect a distinct aspect of inhibitory regulation. Our results inform potential inhibition-based biomarkers for clinical and translational research.Key points:The cessation of visual stimulation leads to a transient increase in functional inhibition.Changes in MEG parameters reflect post-stimulus enhancement of inhibition.These changes scale with the intensity of the preceding stimulation.
Daptomycin forms a stable complex with phosphatidylglycerol for selective uptake to bacterial membrane
Authors: Machhua Pragyansree , Unnithan Vignesh Gopalakrishnan , Liu Yu , Jiang Yiping , Zhang Lingfeng , Guo Zhihong 
Published: October 2023

AbstractDaptomycin is a potent lipopeptide antibiotic used in the treatment of live-threatening Gram-positive infections, but the molecular mechanism of its interaction with bacterial membrane remains unclear. Here we show that this interaction is divided into two stages, of which the first is a fast and reversible binding of the drug to phospholipid membrane in milliseconds and the second is a slow and irreversible insertion into membrane in minutes, only in the presence of the bacteria-specific lipid phosphatidylglycerol, to a saturating point where the ratio of the drug to phosphatidylglycerol is 1:2. Fluorescence-based titration showed that the antibiotic simultaneously binds two molecules of phosphatidylglycerol with a nanomolar binding affinity in the presence of calcium ion. The resulting stable complex is easily formed in a test tube and readily isolated from the membrane of drug-treated bacterial cells, strongly supporting a unique drug uptake mechanism in which daptomycin forms a stable multi-component complex with calcium and phosphatidylglycerol. Revelation of this novel uptake mechanism provides fresh insights into the mode of action of daptomycin and paves the way to new strategies to attenuate resistance to the drug.
On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity
Authors: Edgar Rebecca C.S. , Malcolm Tess R. , Siddiqui Ghizal , Giannangelo Carlo , Counihan Natalie A. , Challis Matthew , Duffy Sandra , Chowdhury Mrittika , Marfurt Jutta , Dans Madeline , Wirjanata Grennady , Noviyanti Rintis , Daware Kajal , Suraweera Chathura D. , Price Ric N , Wittlin Sergio , Avery Vicky M. , Drinkwater Nyssa , Charman Susan A. , Creek Darren J. , de Koning-Ward Tania F. , Scammells Peter J. , McGowan Sheena 
Published: October 2023

ABSTRACTTo combat the global burden of malaria, development of new drugs to replace or complement current therapies are urgently required. As drug resistance to existing treatments and clinical failures continue to rise, compounds targeting multiple life cycle stages and species need to be developed as a high priority. Here we show that the compoundMMV1557817is a nanomolar inhibitor of bothPlasmodium falciparumandPlasmodium vivaxaminopeptidases M1 and M17, leading to inhibition of end stage haemoglobin digestion in asexual parasites. Multi-stage analysis confirmed thatMMV1557817can also kill sexual stageP. falciparum, while cross-resistance studies confirmed the compound targets a mechanism of action distinct to current drug resistance mechanisms. Analysis of cross reactivity to homologous human enzymes shows the compound exhibits a high level of selectivity, whilst safety as well as druggability was confirmed in the murine modelP. berghei.MMV1557817-resistantP. falciparumparasites displayed only low-level resistance (<3-fold) and exhibited a slow growth rate that was quickly outcompeted by wild type parasites.MMV1557817-resistant parasites digest significantly more haemoglobin and possess a mutation inPfA-M17 that induces partial destabilisation of thePfA-M17 homohexamer, resulting in high-level resistance to specificPfA-M17 inhibition, but enhanced sensitivity to specificPfA-M1 inhibition, and importantly, these parasites were highly sensitive to artemisinin. Overall, these results confirmMMV1557817as a potential lead compound for further drug development and highlight the potential of dual inhibition of M1 and M17 as an effective multi-species drug targeting strategy.
Investigation of normalization procedures for transcriptome profiles of compounds oriented toward practical study design
Authors: Mizuno Tadahaya , Kusuhara Hiroyuki 
Published: October 2023

AbstractThe transcriptome profile is a representative phenotype-based descriptor of compounds, widely acknowledged for its ability to effectively capture compound effects. However, the presence of batch differences is inevitable. Despite the existence of sophisticated statistical methods, many of them presume a substantial sample size. How should we design a transcriptome analysis to obtain robust compound profiles, particularly in the context of small datasets frequently encountered in practical scenarios? This study addresses this question by investigating the normalization procedures for transcriptome profiles, focusing on the baseline distribution employed in deriving biological responses as profiles. Firstly, we investigated two large GeneChip datasets, comparing the impact of different normalization procedures. Through an evaluation of the similarity between response profiles of biological replicates within each dataset and the similarity between response profiles of the same compound across datasets, we revealed that the baseline distribution defined by all samples within each batch under batch-corrected condition is a good choice for large datasets. Subsequently, we conducted a simulation to explore the influence of the number of control samples on the robustness of response profiles across datasets. The results offer insights into determining the suitable quantity of control samples for diminutive datasets. It is crucial to acknowledge that these conclusions stem from constrained datasets. Nevertheless, we believe that this study enhances our understanding of how to effectively leverage transcriptome profiles of compounds and promotes the accumulation of essential knowledge for the practical application of such profiles.
Barriers and Facilitators to Trustworthy and Ethical AI-enabled Medical Care From Patient’s and Healthcare Provider’s Perspectives: A Literature Review
Authors: Mooghali Maryam , Stroud Austin M. , Yoo Dong Whi , Barry Barbara A , Grimshaw Alyssa A. , Ross Joseph S. , Zhu Xuan , Miller Jennifer E. 
Published: October 2023

ABSTRACTBackgroundArtificial intelligence (AI) and machine learning (ML) are increasingly used for prevention, diagnosis, monitoring, and treatment of cardiovascular diseases. Despite the potential for AI/ML to improve care, ethical concerns and mistrust in AI-enabled health care exist among the public and medical community. To inform practice guidelines and regulatory policies that facilitate ethical and trustworthy use of AI in medicine, we conducted a literature review to identify key ethical and trust barriers and facilitators from patients’ and healthcare providers’ perspectives when using AI in cardiovascular care.MethodsIn this rapid literature review, we searched six bibliographic databases to identify publications discussing transparency, trust, or ethical concerns (outcomes of interest) associated with AI/ML-based medical devices (interventions of interest) in the context of cardiovascular care from patients’, caregivers’, or healthcare providers’ perspectives. The search was completed on May 24, 2022 and was not limited by date or study design.ResultsAfter reviewing 7,925 papers from six databases and 3,603 papers identified through citation chasing, 145 articles were included. Key ethical concerns included privacy, security, or confidentiality issues; risk of healthcare inequity or disparity; risk of patient harm; accountability and responsibility concerns; problematic informed consent and potential loss of patient autonomy; and issues related to data ownership. Major trust barriers included data privacy and security concerns, potential risk of patient harm, perceived lack of transparency about AI-enabled medical devices, concerns about AI replacing human aspects of care, concerns about prioritizing profits over patients’ interests, and lack of robust evidence related to the accuracy and limitations of AI-based medical devices. Ethical and trust facilitators included ensuring data privacy and data validation, conducting clinical trials in diverse cohorts, providing appropriate training and resources to patients and healthcare providers and improving their engagement in different phases of AI implementation, and establishing further regulatory oversights.ConclusionThis review revealed key ethical concerns and barriers and facilitators of trust in AI-enabled medical devices from patients’ and healthcare providers’ perspectives. Mitigation strategies, including enhancing regulatory oversight on the use of patient data and promoting AI safety and transparency are needed for effective implementation of AI in cardiovascular care.
Patient-reported predictors of post-discharge mortality after cardiac hospitalization
Authors: Nair Devika , Schildcrout Jonathan S. , Shi Yaping , Trochez Ricardo , Nwosu Sam , Bell Susan P. , Mixon Amanda S. , Welch Sarah A. , Goggins Kathryn , Bachmann Justin M. , Vasilevskis Eduard E. , Cavanaugh Kerri L. , Rothman Russell L. , Kripalani Sunil B. 
Published: October 2023

AbstractBackgroundAdults hospitalized for cardiovascular events are at high risk for post-discharge mortality. Hospital-based screening of health-related psychosocial risk factors is now prioritized by the Joint Commission and the National Quality Forum to achieve equitable, high-quality care. We tested our hypothesis that key patient-reported psychosocial and behavioral measures could predict post-hospitalization mortality in a cohort of adults hospitalized for a cardiovascular event.MethodsThis was a prospective cohort of adults hospitalized at Vanderbilt University Medical Center. Validated patient-reported measures of health literacy, social support, disease self-management, and socioeconomic status were used as predictors of interest. Cox survival analyses of mortality were conducted over a median 3.5-year follow-up (range: 1.25 – 5.5 years).ResultsAmong 2,977 adults, 1,874 (63%) were hospitalized for acute coronary syndrome and 1,103 (37%) were hospitalized for acute decompensated heart failure; 60% were male; and the mean age was 53 years. After adjusting for demographic, clinical, and other psychosocial factors, mortality risk was greatest among patients who reported being unable to work due to disability (Hazard Ratio (HR) 2.36, 95% Confidence Interval (CI): 1.73-3.21), who were retired (HR 2.14, 95% CI 1.60-2.87), and who reported unemployment (HR 1.99, 95% CI 1.30-3.06) as compared to those who were employed. Patient-reported measures of disease self-management, perceived health competence and exercise frequency, were also associated with mortality risk after full covariate adjustment (HR 0.86, 95% CI 0.73-1.00 per four-point increase), (HR 0.86, 95% CI 0.77-0.96 per three-day change), respectively.ConclusionsPatient-reported measures of employment status independently predict post-discharge mortality after a cardiac hospitalization. Measure of disease self-management also have prognostic modest utility. Hospital-based screening of psychosocial risk is increasingly prioritized in legislative policy. Incorporating brief, valid measures of employment status and disease self-management factors may help target patients for psychosocial, financial, and rehabilitative resources during post-discharge transitions of care.