Miracle-dz/UniFAR-FTUs huggingface dataset:
CD8+ cell somatic mutations in multiple sclerosis patients and controls—Enrichment of mutations in STAT3 and other genes implicated in hematological malignancies

Somatic mutations have a central role in cancer but their role in other diseases such as common autoimmune disorders is not clear. Previously we and others have demonstrated that especially CD8+ T cells in blood can harbor persistent somatic mutations in some patients with multiple sclerosis (MS) and rheumatoid arthritis. Here we concentrated on CD8+ cells in more detail and tested (i) how commonly somatic mutations are detectable, (ii) does the overall mutation load differ between MS patients and controls, and (iii) do the somatic mutations accumulate non-randomly in certain genes? We separated peripheral blood CD8+ cells from newly diagnosed relapsing MS patients (n = 21) as well as matched controls (n = 21) and performed next-generation sequencing of the CD8+ cells’ DNA, limiting our search to a custom panel of 2524 immunity and cancer related genes, which enabled us to obtain a median sequencing depth of over 2000x. We discovered nonsynonymous somatic mutations in all MS patients’ and controls’ CD8+ cell DNA samples, with no significant difference in number between the groups (p = 0.60), at a median allelic fraction of 0.5% (range 0.2–8.6%). The mutations showed statistically significant clustering especially to the STAT3 gene, and also enrichment to the SMARCA2, DNMT3A, SOCS1 and PPP3CA genes. Known activating STAT3 mutations were found both in MS patients and controls and overall 1/5 of the mutations were previously described cancer mutations. The detected clustering suggests a selection advantage of the mutated CD8+ clones and calls for further research on possible phenotypic effects.
Anticachectic regulator analysis reveals Perp-dependent antitumorigenic properties of 3-methyladenine in pancreatic cancer

Approximately 80% of pancreatic cancer patients suffer from cachexia, and one-third die due to cachexia-related complications such as respiratory failure and cardiac arrest. Although there has been considerable research into cachexia mechanisms and interventions, there are, to date, no FDA-approved therapies. A major contributing factor for the lack of therapy options could be the failure of animal models to accurately recapitulate the human condition. In this study, we generated an aged model of pancreatic cancer cachexia to compare cachexia progression in young versus aged tumor-bearing mice. Comparative skeletal muscle transcriptome analyses identified 3-methyladenine (3-MA) as a candidate antiwasting compound. In vitro analyses confirmed antiwasting capacity, while in vivo analysis revealed potent antitumor effects. Transcriptome analyses of 3-MA–treated tumor cells implicated Perp as a 3-MA target gene. We subsequently (a) observed significantly higher expression of Perp in cancer cell lines compared with control cells, (b) noted a survival disadvantage associated with elevated Perp, and (c) found that 3-MA–associated Perp reduction inhibited tumor cell growth. Finally, we have provided in vivo evidence that survival benefits conferred by 3-MA administration are independent of its effect on tumor progression. Taken together, we report a mechanism linking 3-MA to Perp inhibition, and we further implicate Perp as a tumor-promoting factor in pancreatic cancer.
Determining Risk Factors That Affect Progression in Patients with Nonproliferative Diabetic Retinopathy

Purpose To determine risk factors that affect nonproliferative diabetic retinopathy (NPDR) progression and establish a predictive model to estimate the probability of and time to progression in NPDR. Patients and Methods. Charts of diabetic patients who received an initial eye exam between 2010 and 2017 at our county hospital were included. Patients with proliferative diabetic retinopathy (PDR), fewer than 2 years of follow-up, or fewer than 3 clinic visits were excluded. Demographics and baseline systemic and ocular characteristics were recorded. Follow-up mean annual HbA1c and blood pressure, best-corrected visual acuity, and the number of antivascular endothelial growth factor treatments were recorded. Stage and date of progression were recorded. A 5-state nonhomogeneous continuous-time Markov chain with a backward elimination model was used to identify risk factors and estimate their effects on progression. Results Two hundred thirty patients were included. Initially, 65 eyes (28.3%) had no retinopathy; 73 (31.7%) mild NPDR; 60 (26.1%) moderate NPDR; and 32 (13.9%) severe NPDR. Patients were followed for a mean of 5.8 years (±2.0 years; range 2.1–9.4 years). 164 (71.3%) eyes progressed during the follow-up. Time-independent risk factors affecting progression rate were age (hazard ratio (HR) = 0.99, P=0.047), duration of diabetes (HR = 1.02, P=0.018), and Hispanic ethnicity (HR = 1.31, P=0.068). Mean sojourn times at mean age, duration of diabetes, and annual HbA1c for a non-Hispanic patient were estimated to be 3.03 (±0.97), 4.63 (±1.21), 6.18 (±1.45), and 4.85 (±1.25) years for no retinopathy, mild NPDR, moderate NPDR, and severe NPDR, respectively. Each 1% increase in HbA1c annually diminished sojourn times by 15%, 10%, 7%, and 10% for no retinopathy, mild NPDR, moderate NPDR, and severe NPDR, respectively. Conclusion HbA1c level is a significant modifiable risk factor in controlling the progression of DR. The proposed model could be used to predict the time and rate of progression based on an individual's risk factors. A prospective multicenter study should be conducted to further validate our model.
Size Effect on Shear Strength of Deep Beams: Investigating with Strut-and-Tie Model

Since a diagonally cracked deep beam behaves as a tied arch, the conventional plane section remaining plane approach is not applicable to analyses of deep beams. Besides, for beams without web reinforcement, it has been shown that shear strength decreases as member size increases. This is associated with a phenomenon called size effect. In this study, the causes of size effect on shear strength of deep beams are investigated using both the strut-and-tie model (STM) and finite element model. The study shows that size effect in concrete beam arises primarily from an inappropriate adoption of the shear transfer concept for steel beams. In addition, size effect also depends on secondary factors such as the geometry of strut, and the spacing and diameter of web reinforcement. The modified STM is verified with three published case studies comprising a total of 36 beams. Generally, the predictions are accurate and consistent, with a uniform safety margin for different member sizes considered.
Automated classification of cytogenetic abnormalities in hematolymphoid neoplasms

MOTIVATION Algorithms for classifying chromosomes, like convolutional deep neural networks (CNNs), show promise to augment cytogeneticists' workflows, however, a critical limitation is their inability to accurately classify various structural chromosomal abnormalities. In hematopathology, recurrent structural cytogenetic abnormalities herald diagnostic, prognostic, and therapeutic implications, but are laborious for expert cytogeneticists to identify. Non-recurrent cytogenetic abnormalities also occur frequently cancerous cells. Here, we demonstrate the feasibility of using CNNs to accurately classify many recurrent cytogenetic abnormalities while being able to reliably detect non-recurrent, spurious abnormal chromosomes, as well as provide insights into dataset assembly, model selection, and training methodology that improve overall generalizability and performance for chromosome classification. RESULTS Our top-performing model achieved a mean weighted F1 score of 96.86% on the validation set and 94.03% on the test set. Gradient class activation maps indicated that our model learned biologically-meaningful feature maps, reinforcing the clinical utility of our proposed approach. Altogether, this work: proposes a new dataset framework for training chromosome classifiers for use in a clinical environment, reveals that residual CNNs and cyclical learning rates confer superior performance, and demonstrates the feasibility of using this approach to automatically screen for many recurrent cytogenetic abnormalities while adeptly classifying non-recurrent abnormal chromosomes. AVAILABILITY AND IMPLEMENTATION Software is freely available at https://github.com/DaehwanKimLab/Chromosome-ReAd. The data underlying this article cannot be shared publicly due to it being protected patient information. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
Association between intimate partner violence and male alcohol use and the receipt of perinatal care: Evidence from Nepal demographic and health survey 2011–2016

The utilization of perinatal care services among women experiencing intimate partner violence (IPV) and male alcohol use is a major problem. Adequate and regular perinatal care is essential through the continuum of pregnancy to mitigate pregnancy and birth complications. The aim of this study is to determine the association between IPV and male alcohol use and the receipt of perinatal care in Nepal. This study used pooled data from 2011 and 2016 Nepal Demographic and Health Surveys (NDHS). A total of 3067 women who interviewed for domestic violence module and had most recent live birth 5 years prior surveys were included in the analysis. Multivariable logistic regression analysis was performed to determine the association between IPV and male alcohol use and the receipt of perinatal care. Of the total women interviewed, 22% reported physical violence, 14% emotional violence, and 11% sexual violence. Women who were exposed to physical violence were significantly more likely to report non-usage of institutional delivery [adjusted Odds Ratio (aOR) = 1.30 (95% Cl: 1.01, 1.68)] and skilled delivery assistants [aOR = 1.43 (95% Cl: 1.10, 1.88)]. Non-attendance of 4 or more skilled antenatal care visits was associated with a combination of alcohol use by male partner and exposure to emotional [aOR = 1.42 (95% Cl: 1.01, 2.00)] and physical violence [aOR = 1.39 (95% Cl: 1.03, 1.88)]. The negative association between IPV and perinatal care suggests it is essential to develop comprehensive community-based interventions which integrates IPV support services with other health services to increase the uptake of perinatal care through the continuum of pregnancy.
Online survey on factors influencing patients' motivation to undergo bariatric surgery

Given the worldwide increasing prevalence of severe obesity and considering the amount of scientific evidence demonstrating the beneficial effects of bariatric surgery (BS), it is surprising that only a fraction of patients with obesity undergo BS. We therefore conducted an anonymized online survey among individuals with a history of BS to understand factors influencing the deciding process leading to BS. Respondents were recruited on a voluntary basis from obesity‐related social media groups between April and June 2020. The self‐designed, non‐validated questionnaire consisted of 20 questions and was open to any participants with a history of BS. Of 851 participants who started the survey, 665 completed the questionnaire (completion rate of 78.1%). Five years after BS, still 70% of the survey‐participants were very satisfied or satisfied with the surgical result. However, the majority (73.3%) would have undergone BS earlier. The main motivation to choose BS was related to health status or quality of life. Important characteristics for a bariatric surgeon to obtain patients' trust are “taking time and listen” (74.7%), empathy (64%) and sympathy (56%). Post‐operative satisfaction with the surgical outcome was high and long‐lasting in this large cohort of BS patients. However, most participants would retrospectively have undergone BS earlier. The main reason to choose BS as treatment for their obesity were impaired physical health or reduced quality of life. Nearby location to patients' residence and availability of surgeons with empathy were decisive motives for bariatric centre selection.
Racial biases in healthcare: Examining the contributions of Point of Care tools and unintended practitioner bias to patient treatment and diagnosis

Sophisticated algorithms are used daily to search through hundreds of medical journals in order to package updated medical insights into commercial databases. Healthcare practitioners can access these searchable databases—called Point of Care (PoC) tools—as downloadable apps on their smartphones or tablets to comprehensively and efficiently inform patient diagnosis and treatment. Because racist biases are unintentionally incorporated into the search reports that the companies generate and that practitioners regularly access, the aim of this article is to examine how healthcare practitioners’ “pre-existing” racial stereotypes interact with pithy conclusions about race and ethnicity in PoC tools. I use qualitative research methods (content analysis, discourse analysis, open-ended semi-structured interviews, and role play) to frame the analysis within the Public Health Critical Race Praxis (PHCRP). This approach facilitates an understanding of how biological racism—the use of scientific evidence to support inherent differences between races—that is embedded in PoC algorithms informs a practitioner’s assessment of a patient, and converges with persistent racial bias in medical training, medical research and healthcare. I contextualize the study with one semi-structured interview with an Editor of a leading PoC tool, MedScope (pseudonomized), and 10 semi-structured interviews with healthcare practitioners in S.E. Ontario, Canada. The article concludes that PoC tools and practitioners’ personal biases contribute to racial prejudices in healthcare provision. This warrants further research on racial bias in medical literature and curriculum design in medical school.
A new generation high speed low loss IGBT module

By virtue of simulation and advanced process technologies the IGBT and the fast recovery diode chip structures have been modified to develop new generation low-loss power chips. These newly structured chips have been integrated into a moduler housing to form a 100A,600V dual type IGBT module that has exhibited superior characteristics, particularly in terms of reducing operational power loss over the conventional second generation counterpart. This paper will give details of this new generation IGBT module development and describe its characteristical superiority.
ENHANCED MODELING OF MOISTURE EQUILIBRIUM AND TRANSPORT IN CEMENTITIOUS MATERIALS UNDER ARBITRARY TEMPERATURE AND RELATIVE HUMIDITY HISTORY

This paper focuses on behaviors of moisture dispersed in nano‐macro scale pores under various temperature and relative humidity conditions. The authors formulated an equilibrium relationship between liquid and vapor phases and a moisture flux driven by pore pressure, vapor pressure and temperature gradients. In addition, liquid and interlayer water were measured separately by ethanol in order to reveal each temperature sensitivity in saturation‐humidity paths. Based on the experiments, a modified hysteresis model for moisture isotherm was proposed. Verifications with experimental data showed that the proposed method can simulate moisture behaviors under various temperature conditions.
Model-Value Inconsistency as a Signal for Epistemic Uncertainty

Using a model of the environment and a value function, an agent can construct many estimates of a state's value, by unrolling the model for different lengths and bootstrapping with its value function. Our key insight is that one can treat this set of value estimates as a type of ensemble, which we call an \emph{implicit value ensemble} (IVE). Consequently, the discrepancy between these estimates can be used as a proxy for the agent's epistemic uncertainty; we term this signal \emph{model-value inconsistency} or \emph{self-inconsistency} for short. Unlike prior work which estimates uncertainty by training an ensemble of many models and/or value functions, this approach requires only the single model and value function which are already being learned in most model-based reinforcement learning algorithms. We provide empirical evidence in both tabular and function approximation settings from pixels that self-inconsistency is useful (i) as a signal for exploration, (ii) for acting safely under distribution shifts, and (iii) for robustifying value-based planning with a learned model.
Primordial black hole dark matter in the presence of p-wave WIMP annihilation

We study the allowed primordial black hole (PBH) dark matter abundance in the mixed dark matter scenarios consisting of PBHs and self-annihilating weakly interacting massive particles (WIMPs) with a velocity dependent annihilation cross section. We first briefly illustrate how the WIMP dark matter halo profile changes for the velocity suppressed p-wave annihilation scenarios, compared with the familiar s-wave annihilation scenarios, and then discuss the PBH mass dependent upper bound on the allowed PBH dark matter abundance. The WIMPs can accrete onto a PBH to form an ultracompact minihalo with a spiky density profile. Such a spike is moderated in the central region of a halo because the WIMPs are annihilated away and this moderation is less effective for a smaller annihilation cross section. The WIMP core density becomes larger while the core radius becomes smaller for a velocity suppressed p-wave annihilation cross section than those for the s-wave annihilation scenarios. The annihilation cross section is dependent on the velocity which varies across the halo, and, in addition to the change of the WIMP density profile, another interesting feature is the PBH mass dependent bound on PBH dark matter abundance. This is in stark contrast to the s-wave annihilation scenarios where the PBH abundance bound is independent of the PBH mass. The allowed PBH dark matter fraction (with respect to the total dark matter abundance) is of order f PBH ≲ 𝒪(10−7)(M⊙/MPBH)(−6+2γsp)/(3γsp+3) for the thermal relic p-wave dark matter with the mass 100 GeV where γsp is the slope index of the spike profile, to be compared with f PBH ≲ 𝒪(10−9) for the corresponding thermal relic s-wave dark matter scenarios.
The 'Doomsday' Effect in Climate Policies: Why is the Present Decade so Crucial to Tackling the Climate Challenge?

Despite growing scientific evidence that passing a 2°C temperature increase may trigger tipping points in climate dynamics, most Integrated Assessment Models (IAM) based on Cost Benefit Analysis (CBA) with smooth quadratic damage functions are unable to account for the possibility of strong increase in climate damage. Our IAM RESPONSE makes it possible to bridge this gap by integrating a threshold effect damage function which sets a threshold of temperature increase from which climate damages increase significantly. To fit with on-going climate negotiations, this threshold is set at 2°C. Regardless of the bleak prospect of passing the threshold, it turns out that among a broad set of scenarios accounting for the diversity of worldviews in the climate debate, overshooting the 2°C target and then facing the resulting damage may become an optimal strategy for many economic agents who are struck by what we call a “doomsday effect”. We show that this effect happens for any level of jump in damage and dramatically increases if the beginning of mitigation efforts is postponed till the decade 2010-2020 on. In light of these results, we believe that any further delay in reaching a clear international agreement will close the window of opportunity for meeting the 2°C target with a reasonable chance of diplomatic success.
Fast Thermal Actuators for Soft Robotics.

Thermal actuation is a common actuation method for soft robots. However, a major limitation is the relatively slow actuation speed. Here we report significant increase in the actuation speed of a bimorph thermal actuator by harnessing the snap-through instability. The actuator is made of silver nanowire/polydimethylsiloxane composite. The snap-through instability is enabled by simply applying an offset displacement to part of the actuator structure. The effects of thermal conductivity of the composite, offset displacement, and actuation frequency on the actuator speed are investigated using both experiments and finite element analysis. The actuator yields a bending speed as high as 28.7 cm-1/s, 10 times that without the snap-through instability. A fast crawling robot with locomotion speed of 1.04 body length per second and a biomimetic Venus flytrap were demonstrated to illustrate the promising potential of the fast bimorph thermal actuators for soft robotic applications.
Simultaneous sampling of multiple transition channels using adaptive paths of collective variables

We present a molecular simulation method to simultaneously find multiple transition pathways, and their associated freeenergy profiles. The scheme extends path-metadynamics (PMD) [Phys. Rev. Lett. 109, 020601 (2012)] with multiple paths and repulsive walkers (multiPMD). We illustrate multiPMD for two C7eq →C7ax paths in Ace-Ala-Nme and six PPII→PPII paths in Ace-(Pro)4-Nme. We also show a scheme to render an interpretable “PathMap”, showing the free energy ridges between paths, as well as the branching and merging of the transition channels. MultiPMD is a flexible and promising method for systems with competing or controversial pathways, which appear in many biomolecular systems, including proteins and nucleic acids.
Peaceful coexistence of thermal equilibrium and the emergence of time

We consider a quantum Universe composed by a small system S and a large environment. It has been demonstrated that, for the vast majority of randomly chosen wave-functions of the Universe satisfying a total energy constraint, the reduced density matrix of the system S is given by the canonical statistical distribution. Here, through the Page and Wootters mechanism, we show that time and non-equilibrium dynamics can emerge as a consequence of the entanglement between the system and the environment present in the (randomly chosen) global wave-function of the Universe. The clock is provided by the environment, which ticks the temporal evolution of S. The paradox of the peaceful coexistence of statistical equilibrium and non-equilibrium dynamics is solved by identifying the trace over the environment degrees of freedom with the temporal trace over the entire history of the system S.
Nonlinear analysis research in biomedical engineering

In this book, the authors present current research on nonlinear analysis, from across the globe. Topics include modelling of the characteristics of inelastic members of reinforced concrete structures in seismic nonlinear analysis; automatic estimation of the apnea-hypopnea index from oxygen saturation recordings using non-linear regression analysis; nonlinearity in bridge structural analysis; nonlinear analysis of spontaneous MEG activity in Alzheimer's disease; mesh free-enriched finite element methods for nonlinear analysis of path-independent and path-dependent problems in solids; nonlinear analysis research in biomedical engineering; and nonlinear evolution analysis for flow during alloy crystallization.