Miracle-dz/UniFAR-FTUs huggingface dataset:
Individual and joint associations of anxiety disorder and depression with cardiovascular disease: A UK Biobank prospective cohort study

Abstract Background Growing evidence suggests that individuals with anxiety disorder have an elevated risk of cardiovascular disease (CVD) but few studies have assessed this association independently of or jointly with depression. Methods We conducted a prospective cohort study using UK Biobank. Diagnoses of anxiety disorder, depression, and CVDs were ascertained through linked hospital admission and mortality data. Individual and joint associations between anxiety disorder and depression and CVD overall, as well as each of myocardial infarction, stroke/transient ischemic attack, and heart failure, were analyzed using Cox proportional hazard models and interaction tests. Results Among the 431,973 participants, the risk of CVD was higher among those who had been diagnosed with anxiety disorder only (hazard ratio [HR] 1.72; 95% confidence interval [CI] 1.32–2.24), depression only (HR 2.07; 95% CI 1.79–2.40), and both conditions (HR 2.89; 95% CI 2.03–4.11) compared to those without these conditions, respectively. There was very little evidence of multiplicative or additive interaction. Results were similar for myocardial infarction, stroke/transient ischemic attack, and heart failure. Conclusions Having anxiety is associated with the same magnitude of increased risk of CVD among people who do not have depression and those who do. Anxiety disorder should be considered for inclusion in CVD risk prediction and stratification, in addition to depression.
SViT: A Spectral Vision Transformer for the Detection of REM Sleep Behavior Disorder

REM sleep behavior disorder (RBD) is a parasomnia with dream enactment and presence of REM sleep without atonia (RSWA). RBD diagnosed manually via polysomnography (PSG) scoring, which is time intensive. Isolated RBD (iRBD) is also associated with a high probability of conversion to Parkinson's disease. Diagnosis of iRBD is largely based on clinical evaluation and subjective PSG ratings of REM sleep without atonia. Here we show the first application of a novel spectral vision transformer (SViT) to PSG signals for detection of RBD and compare the results to the more conventional convolutional neural network architecture. The vision-based deep learning models were applied to scalograms (30 or 300 s windows) of the PSG data (EEG, EMG and EOG) and the predictions interpreted. A total of 153 RBD (96 iRBD and 57 RBD with PD) and 190 controls were included in the study and 5-fold bagged ensemble was used. Model outputs were analyzed per-patient (averaged), with regards to sleep stage, and the SViT was interpreted using integrated gradients. Models had a similar per-epoch test F1 score. However, the vision transformer had the best per-patient performance, with an F1 score 0.87. Training the SViT on channel subsets, it achieved an F1 score of 0.93 on a combination of EEG and EOG. EMG is thought to have the highest diagnostic yield, but interpretation of our model showed that high relevance was placed on EEG and EOG, indicating these channels could be included for diagnosing RBD.
IChrom-Deep: An Attention-Based Deep Learning Model for Identifying Chromatin Interactions

Identification of chromatin interactions is crucial for advancing our knowledge of gene regulation. However, due to the limitations of high-throughput experimental techniques, there is an urgent need to develop computational methods for predicting chromatin interactions. In this study, we propose a novel attention-based deep learning model, termed IChrom-Deep, to identify chromatin interactions using sequence features and genomic features. The experimental results based on the datasets of three cell lines demonstrate that the IChrom-Deep achieves satisfactory performance and is superior to the previous methods. We also investigate the effect of DNA sequence and associated features and genomic features on chromatin interactions, and highlight the applicable scenarios of some features, such as sequence conservation and distance. Moreover, we identify a few genomic features that are extremely important across different cell lines, and IChrom-Deep achieves comparable performance with only these significant genomic features versus using all genomic features. It is believed that IChrom-Deep can serve as a useful tool for future studies that seek to identify chromatin interactions.
A single amino acid change led to structural and functional differentiation of PvHd1 to control flowering in switchgrass

Abstract Switchgrass, a forage and bioenergy crop, occurs as two main ecotypes with different but overlapping ranges of adaptation. The two ecotypes differ in a range of characteristics, including flowering time. Flowering time determines the duration of vegetative development and therefore biomass accumulation, a key trait in bioenergy crops. No causal variants for flowering time differences between switchgrass ecotypes have, as yet, been identified. In this study, we mapped a robust flowering time quantitative trait locus (QTL) on chromosome 4K in a biparental F2 population and characterized the flowering-associated transcription factor gene PvHd1, an ortholog of CONSTANS in Arabidopsis and Heading date 1 in rice, as the underlying causal gene. Protein modeling predicted that a serine to glycine substitution at position 35 (p.S35G) in B-Box domain 1 greatly altered the global structure of the PvHd1 protein. The predicted variation in protein compactness was supported in vitro by a 4 °C shift in denaturation temperature. Overexpressing the PvHd1-p.35S allele in a late-flowering CONSTANS-null Arabidopsis mutant rescued earlier flowering, whereas PvHd1-p.35G had a reduced ability to promote flowering, demonstrating that the structural variation led to functional divergence. Our findings provide us with a tool to manipulate the timing of floral transition in switchgrass cultivars and, potentially, expand their cultivation range.
Digital Technologies for Women’s Pelvic Floor Muscle Training to Manage Urinary Incontinence Across Their Life Course: Scoping Review

Background Women with urinary incontinence (UI) may consider using digital technologies (DTs) to guide pelvic floor muscle training (PFMT) to help manage their symptoms. DTs that deliver PFMT programs are readily available, yet uncertainty exists regarding whether they are scientifically valid, appropriate, and culturally relevant and meet the needs of women at specific life stages. Objective This scoping review aims to provide a narrative synthesis of DTs used for PFMT to manage UI in women across their life course. Methods This scoping review was conducted in accordance with the Joanna Briggs Institute methodological framework. A systematic search of 7 electronic databases was conducted, and primary quantitative and qualitative research and gray literature publications were considered. Studies were eligible if they focused on women with or without UI who had engaged with DTs for PFMT, reported on outcomes related to the use of PFMT DTs for managing UI, or explored users’ experiences of DTs for PFMT. The identified studies were screened for eligibility. Data on the evidence base for and features of PFMT DTs using the Consensus on Exercise Reporting Template for PFMT, PFMT DT outcomes (eg, UI symptoms, quality of life, adherence, and satisfaction), life stage and culture, and the experiences of women and health care providers (facilitators and barriers) were extracted and synthesized by ≥2 independent reviewers. Results In total, 89 papers were included (n=45, 51% primary and n=44, 49% supplementary) involving studies from 14 countries. A total of 28 types of DTs were used in 41 primary studies, including mobile apps with or without a portable vaginal biofeedback or accelerometer-based device, a smartphone messaging system, internet-based programs, and videoconferencing. Approximately half (22/41, 54%) of the studies provided evidence for or testing of the DTs, and a similar proportion of PFMT programs were drawn from or adapted from a known evidence base. Although PFMT parameters and program compliance varied, most studies that reported on UI symptoms showed improved outcomes, and women were generally satisfied with this treatment approach. With respect to life stage, pregnancy and the postpartum period were the most common focus, with more evidence needed for women of various age ranges (eg, adolescent and older women), including their cultural context, which is a factor that is rarely considered. Women’s perceptions and experiences are often considered in the development of DTs, with qualitative data highlighting factors that are usually both facilitators and barriers. Conclusions DTs are a growing mechanism for delivering PFMT, as evidenced by the recent increase in publications. This review highlighted the heterogeneity in types of DTs, PFMT protocols, the lack of cultural adaptations of most of the DTs reviewed, and a paucity in the consideration of the changing needs of women across their life course.
Combination of PD-1 Checkpoint Blockade and Botulinum Toxin Type A1 Improves Antitumor Responses in Mouse Tumor Models of Melanoma and Colon Carcinoma

ABSTRACT Background Tumor innervation has been shown to be utilized by some solid cancers to support tumor initiation, growth, progression, and metastasis, as well as confer resistance to immune checkpoint blockade through suppression of antitumor immunologic responses. Since botulinum neurotoxin type A1 (BoNT/A1) blocks neuronal cholinergic signaling, its potential use as an anticancer drug in combination with anti-PD-1 therapy was investigated in four different syngeneic mouse tumor models. Methods Mice implanted with breast (4T1), lung (LLC1), colon (MC38), and melanoma (B16-F10) tumors were administered a single intratumoral injection of 15 U/kg BoNT/A1, repeated intraperitoneal injections of 5 mg/kg anti-PD-1 (RMP1-14), or both. Results Compared to the single-agent treatments, anti-PD-1 and BoNT/A1 combination treatment elicited significant reduction in tumor growth among B16-F10 and MC38 tumor-bearing mice. The combination treatment also lowered serum exosome levels in these mice compared to the placebo control group. In the B16-F10 syngeneic mouse tumor model, anti-PD-1 + BoNT/A1 combination treatment lowered the proportion of MDSCs, negated the increased proportion of Treg cells, and elicited a higher number of tumor-infiltrating CD4+ and CD8+ T lymphocytes into the tumor microenvironment compared to anti-PD-1 treatment alone. Conclusion Our findings demonstrate the synergistic antitumor effects of BoNT/A1 and PD-1 checkpoint blockade in mouse tumor models of melanoma and colon carcinoma. These findings provide some evidence on the potential application of BoNT/A1 as an anticancer drug in combination with immune checkpoint blockade and should be further explored.
Teaching medical students to apply deliberate reflection

Abstract Purpose Deliberate reflection on initial diagnosis has been found to repair diagnostic errors. We investigated the effectiveness of teaching students to use deliberate reflection on future cases and whether their usage would depend on their perception of case difficulty. Method One-hundred-nineteen medical students solved cases either with deliberate-reflection or without instructions to reflect. One week later, all participants solved six cases, each with two equally likely diagnoses, but some symptoms in the case were associated with only one of the diagnoses (discriminating features). Participants provided one diagnosis and subsequently wrote down everything they remembered from it. After the first three cases, they were told that the next three would be difficult cases. Reflection was measured by the proportion of discriminating features recalled (overall; related to their provided diagnosis; related to alternative diagnosis). Results The deliberate-reflection condition recalled more features for the alternative diagnosis than the control condition (p = .013) regardless of described difficulty. They also recalled more features related to their provided diagnosis on the first three cases (p = .004), but on the last three cases (described as difficult), there was no difference. Conclusion Learning deliberate reflection helped students engage in more reflective reasoning when solving future cases.
Advances in the stochastic and deterministic analysis of multistable biochemical networks

This dissertation is concerned with the potential multistability of protein concentrations in the cell that can arise in biochemical networks. That is, situations where one, or a family of, proteins may sit at one of two or more different steady state concentrations in otherwise identical cells, and in spite of them being in the same environment. Models of multisite protein phosphorylation have shown that this mechanism is able to exhibit unlimited multistability. Nevertheless, these models have not considered enzyme docking, the binding of the enzymes to one or more substrate docking sites, which are separate from the motif that is chemically modified. Enzyme docking is, however, increasingly being recognised as a method to achieve specificity in protein phosphorylation and dephosphorylation cycles. Most models in the literature for these systems are deterministic i.e. based on Ordinary Differential Equations, despite the fact that these are accurate only in the limit of large molecule numbers. For small molecule numbers, a discrete probabilistic, stochastic, approach is more suitable. However, when compared to the tools available in the deterministic framework, the tools available for stochastic analysis offer inadequate visualisation and intuition. We firstly try to bridge that gap, by developing three tools: a) a discrete ‘nullclines’ construct applicable to stochastic systems an analogue to the ODE nullcines, b) a stochastic tool based on a Weakly Chained Diagonally Dominant M-matrix formulation of the Chemical Master Equation and c) an algorithm that is able to construct non-reversible Markov chains with desired stationary probability distributions. We subsequently prove that, for multisite protein phosphorylation and similar models, in the deterministic domain, enzyme docking and the consequent substrate enzyme-sequestration must inevitably limit the extent of multistability, ultimately to one steady state. In contrast, bimodality can be obtained in the stochastic domain even in situations where bistability is not possible for large molecule numbers. We finally extend our results to cases where we have an autophosphorylating kinase, as for example is the case with Ca2+/calmodulin-dependent protein kinase II (CaMKII), a key enzyme in synaptic plasticity.
Radiotherapy trend in elderly hepatocellular carcinoma: retrospective analysis of patients diagnosed between 2005 and 2017

Purpose To report the trends of radiotherapy in the management of elderly patients with hepatocellular carcinoma (HCC). Materials and Methods We retrospectively reviewed patients who entered HCC registry of Samsung Medical Center between 2005 and 2017. Patients who were 75 years or older at the time of registration were defined as elderly. They were categorized into three groups based on the year of registration. Radiotherapy characteristics were compared between the groups to observe differences by age groups and period of registration. Results Out of 9,132 HCC registry patients, elderly comprised 6.2% (566 patients) of the registry, and the proportion increased throughout the study period (from 3.1% to 11.4%). Radiotherapy was administered to 107 patients (18.9%) in elderly group. Radiotherapy utilization in the early treatment process (within 1 year after registration) has rapidly increased from 6.1% to 15.3%. All treatments before 2008 were delivered with two-dimensional or three-dimensional conformal radiotherapy, while more than two-thirds of treatments after 2017 were delivered with advanced techniques such as intensity-modulated radiotherapy, stereotactic body radiotherapy, or proton beam therapy. Overall survival (OS) of elderly was significantly worse than younger patients. However, for patients who received radiotherapy during the initial management (within one month after registration), there was no statistically significant difference in OS between age groups. Conclusion The proportion of elderly HCC is increasing. Radiotherapy utilization and adoption of advanced radiotherapy technique showed a consistently increasing trend for the group of patients, indicating that the role of radiotherapy in the management of elderly HCC is expanding.
Antibody‐dependent NK‐cell and neutralizing antibody responses against the Spike protein of Wuhan‐Hu‐1 and Omicron BA.1 SARS‐CoV‐2 variants in vaccinated experienced and vaccinated naïve individuals

Antibodies triggering Fc‐mediated NK cell activity may contribute to protection against disease caused by SARS‐CoV‐2 infection in humans. However, how these Fc‐mediated humoral responses compare between individuals displaying hybrid immunity (Vac‐ex) and those fully vaccinated with no history of SARS‐CoV‐2 infection (Vac‐n) and whether they correlate with neutralizing antibody (NtAb) responses remains largely undetermined. In this retrospective study serum samples from 50 individuals (median age, 44.5 years; range, 11–85; 25 males), 25 Vac‐ex and 25 Vac‐n were studied. A flow‐cytometry‐based antibody‐mediated NK‐cell activation assay was used to quantitate effector NK‐cells stimulated to express LAMP1 (lysosomal associated membrane protein 1), MIP1 (Macrophage inflammatory protein 1), and interferon‐γ (IFNγ); NK cells isolated from two donors (D1 and D2) were used. NtAb levels targeting the Spike protein of Wuhan‐Hu‐1 and Omicron BA.1 SARS‐CoV‐2 variants were quantitated using a SARS‐CoV‐2 S pseudotyped neutralization assay. Regardless of the SARS‐CoV‐2 variant S antigen used in the NK‐cell activation assay, the frequency of NK cells stimulated to express LAMP‐1, MIP1β, and IFNγ was higher in Vac‐ex compared with Vac‐n (p values ranging from 0.07 to 0.006) for D1; this was only seen for BA.1 when NK cells from D2 were employed. The frequency of functional NK cells activated by antibody binding to either Wuhan‐Hu‐1 or Omicron BA.1 S protein was not significantly different for both VAC‐ex and VAC‐n. In contrast, NtAb titers against BA.1 were around 10‐fold lower than that against Wuhan‐Hu‐1. Vac‐ex displayed higher NtAb titers against both (sub)variants than Vac‐n. NK‐cell responses correlated poorly with NtAb titers (ρ ≤ 0.30). The data demonstrate higher cross‐reactivity across variants of concern for antibodies triggering Fc‐mediated NK cell than for NtAb. Moreover, Vac‐Ex seemed to display more robust functional antibody responses as compared with Vac‐n.
The effects of weight bearing after ACL reconstruction on joint contracture in rats

ABSTRACT Purpose Joint contractures after anterior cruciate ligament (ACL) reconstruction are a serious problem. Given the uncertain effects of weight bearing after ACL reconstruction on contractures, this study was conducted to examine such effects. Materials and methods To control the amount of weight bearing, ACL-reconstructed rats were reared with either untreated (small weight bearing; weight bearing during locomotion was 54% of pre-surgery at minimum), hindlimb unloading (non-weight bearing), or sustained morphine administration (large weight bearing; weight bearing during locomotion was maintained at 80% or more of pre-surgery) conditions. Untreated rats were used as controls. Knee extension range of motions (ROMs) before (includes myogenic and arthrogenic factors) and after myotomy (includes arthrogenic factor only) and fibrotic reactions in the joint capsule were assessed 7 and 14 days post-surgery. Results ACL reconstruction significantly reduced ROMs both before and after myotomy and induced fibrosis in the joint capsule accompanying upregulation of fibrosis-related genes (i.e., type I and III collagens and transforming growth factor-β1) at both time points. Morphine administration increased the ROM before myotomy, but not after myotomy 7 days post-surgery. Unloading after ACL reconstruction improved ROMs both before and after myotomy at both time points. In addition, unloading after ACL reconstruction attenuated fibrotic reactions in the joint capsule. Conclusions Our results suggest that morphine administration improves myogenic contractures in parallel with an increase in the amount of weight bearing. Unloading after ACL reconstruction is effective in reducing both myogenic and arthrogenic contractures.
Serum neutralization of SARS‐CoV‐2 Omicron BA.2, BA.2.75, BA.2.76, BA.5, BF.7, BQ.1.1 and XBB.1.5 in individuals receiving Evusheld

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron variant is undergoing continuous evolution and convergent mutation. These new subvariants are raising concerns that they may evade neutralizing monoclonal antibodies (mAbs). We investigated the serum neutralization efficacy of Evusheld (cilgavimab and tixagevimab) against SARS‐CoV‐2 Omicron BA.2, BA.2. 75, BA.2. 76, BA.5, BF.7, BQ.1. 1, and XBB.1. 5. A total of 90 serum samples from healthy individuals were collected in Shanghai. Anti‐RBD antibodies were measured and symptoms of infection with COVID‐19 were compared among those individuals. The neutralizing activity of serum against Omicron variants was analyzed by pseudovirus neutralization assays in 22 samples. Evusheld retained neutralizing activity against BA.2, BA.2. 75, and BA.5, albeit with somewhat reduced titers. However, the neutralizing activity of Evusheld against BA.2. 76, BF.7, BQ.1. 1, and XBB.1. 5 significantly decreased, with XBB.1. 5 showing the greatest escape activity among the subvariants. We also observed that Evusheld recipients displayed elevated antibody levels in their serum, which efficiently neutralized the original variant, and exhibited different characteristics of infection than those who did not receive Evusheld. The mAb has partial neutralization activity against Omicron sublineages. However, the increasing doses of mAb and a larger size of population should be further investigated.
Length and saturation of fatty acids in phosphatidylserine determine the rate of lysozyme aggregation simultaneously altering the structure and toxicity of amyloid oligomers and fibrils

Abrupt aggregation of misfolded proteins is the underlying molecular cause of numerous severe pathologies including Alzheimer's and Parkinson's diseases. Protein aggregation yields small oligomers that can later propagate into amyloid fibrils, β‐sheet‐rich structures with a variety of topologies. A growing body of evidence suggests that lipids play an important role in abrupt aggregation of misfolded proteins. In this study, we investigate the roles of length and saturation of fatty acids (FAs) in phosphatidylserine (PS), an anionic lipid that is responsible for the recognition of apoptotic cells by macrophages, in lysozyme aggregation. We found that both the length and saturation of FAs in PS contribute to the aggregation rate of insulin. PS with 14‐carbon‐long FAs (14:0) enabled a much stronger acceleration of protein aggregation compared to PS with 18‐carbon‐long FAs (18:0). Our results demonstrate that the presence of double bonds in FAs accelerated the rate of insulin aggregation relative to PS with fully saturated FAs. Biophysical methods revealed morphological and structural differences in lysozyme aggregates grown in the presence of PS with varying lengths and FA saturation. We also found that such aggregates exerted diverse cell toxicities. These results demonstrate that the length and saturation of FAs in PS can uniquely alter the stability of misfolded proteins on lipid membranes.