Miracle-dz/UniFAR-FTUs huggingface dataset:
Promutagenicity of 8-Chloroguanine, A Major Inflammation-Induced Halogenated DNA Lesion

Chronic inflammation is closely associated with cancer development. One possible mechanism for inflammation-induced carcinogenesis is DNA damage caused by reactive halogen species, such as hypochlorous acid, which is released by myeloperoxidase to kill pathogens. Hypochlorous acid can attack genomic DNA to produce 8-chloro-2′-deoxyguanosine (ClG) as a major lesion. It has been postulated that ClG promotes mutagenic replication using its syn conformer; yet, the structural basis for ClG-induced mutagenesis is unknown. We obtained crystal structures and kinetics data for nucleotide incorporation past a templating ClG using human DNA polymerase β (polβ) as a model enzyme for high-fidelity DNA polymerases. The structures showed that ClG formed base pairs with incoming dCTP and dGTP using its anti and syn conformers, respectively. Kinetic studies showed that polβ incorporated dGTP only 15-fold less efficiently than dCTP, suggesting that replication across ClG is promutagenic. Two hydrogen bonds between syn-ClG and anti-dGTP and a water-mediated hydrogen bond appeared to facilitate mutagenic replication opposite the major halogenated guanine lesion. These results suggest that ClG in DNA promotes G to C transversion mutations by forming Hoogsteen base pairing between syn-ClG and anti-G during DNA synthesis.
Parallel Traversal of Large Ensembles of Decision Trees

Machine-learnt models based on additive ensembles of regression trees are currently deemed the best solution to address complex classification, regression, and ranking tasks. The deployment of such models is computationally demanding: to compute the final prediction, the whole ensemble must be traversed by accumulating the contributions of all its trees. In particular, traversal cost impacts applications where the number of candidate items is large, the time budget available to apply the learnt model to them is limited, and the users’ expectations in terms of quality-of-service is high. Document ranking in web search, where sub-optimal ranking models are deployed to find a proper trade-off between efficiency and effectiveness of query answering, is probably the most typical example of this challenging issue. This paper investigates multi/many-core parallelization strategies for speeding up the traversal of large ensembles of regression trees thus obtaining machine-learnt models that are, at the same time, effective, fast, and scalable. Our best results are obtained by the GPU-based parallelization of the state-of-the-art algorithm, with speedups of up to 102.6x.
Effect of mirabegron on erectile function in sexually active men with bothersome overactive bladder symptoms

Background: To evaluate the change of erectile function (EF) in sexually active male overactive bladder (OAB) patients treated with Mirabegron. Mirabegron, a selective β3 adrenoceptor agonist, approved for the treatment of OAB, has been reported to relax human and rat corpus cavernosum and might have beneficial effect on EF. Methods: A total of 128 consecutive men with lower urinary tract symptoms attended urology outpatient clinic were evaluated for OAB and EF. Thirty-four sexually active OAB patients were prospectively enrolled in this study and received mirabegron 50 mg oral once a day. The evaluation of EF and OAB was based on a self-administered questionnaire containing International Index of Erectile Function (IIEF-5) and OAB symptom score (OABSS), respectively. Men with an OABSS urgency score of ≥2 and sum score of ≥3 were considered to have OAB. The therapeutic outcomes were assessed at baseline, 4, and 12 weeks. Results: Mirabegron usage was associated with a statistically significant improvement of OAB symptoms (OABSS 32.1% decrease) at 4-week follow-up and the therapeutic effects were maintained at 12-week follow-up. Mirabegron usage did not improve EF (IIEF-5 4.9% decrease at 4-week; p = 0.106, and 9.1% decrease at 12-week follow-up; p = 0.077). However, the IIEF-5 was significantly decreased in the higher baseline IIEF-5 (≥17) group (11.7% decrease; p = 0.044), noncoronary artery disease (13.2%; p = 0.007), or non-DM group (13.9% decrease; p = 0.021) at 12-week follow-up. Conclusion: This preliminary study demonstrates that mirabegron treatment of men with OAB improved OAB symptoms, but has no beneficial effect on EF.
Generalizability of machine learning for classification of schizophrenia based on resting‐state functional MRI data

Machine learning has increasingly been applied to classification of schizophrenia in neuroimaging research. However, direct replication studies and studies seeking to investigate generalizability are scarce. To address these issues, we assessed within‐site and between‐site generalizability of a machine learning classification framework which achieved excellent performance in a previous study using two independent resting‐state functional magnetic resonance imaging data sets collected from different sites and scanners. We established within‐site generalizability of the classification framework in the main data set using cross‐validation. Then, we trained a model in the main data set and investigated between‐site generalization in the validated data set using external validation. Finally, recognizing the poor between‐site generalization performance, we updated the unsupervised algorithm to investigate if transfer learning using additional unlabeled data were able to improve between‐site classification performance. Cross‐validation showed that the published classification procedure achieved an accuracy of 0.73 using majority voting across all selected components. External validation found a classification accuracy of 0.55 (not significant) and 0.70 (significant) using the direct and transfer learning procedures, respectively. The failure of direct generalization from one site to another demonstrates the limitation of within‐site cross‐validation and points toward the need to incorporate efforts to facilitate application of machine learning across multiple data sets. The improvement in performance with transfer learning highlights the importance of taking into account the properties of data when constructing predictive models across samples and sites. Our findings suggest that machine learning classification result based on a single study should be interpreted cautiously.
Toward Cultural Competency in Health Care: A Scoping Review of the Diversity and Inclusion Education Literature

Supplemental Digital Content is available in the text. Purpose To explore best practices for increasing cultural competency and reducing health disparities, the authors conducted a scoping review of the existing literature. Method The review was guided by 2 questions: (1) Are health care professionals and medical students learning about implicit bias, health disparities, advocacy, and the needs of diverse patient populations? (2) What educational strategies are being used to increase student and educator cultural competency? In August 2016 and July 2018, the authors searched 10 databases (including Ovid MEDLINE, Embase, and Scopus) and MedEdPORTAL, respectively, using keywords related to multiple health professions and cultural competency or diversity and inclusion education and training. Publications from 2005 to August 2016 were included. Results were screened using a 2-phase process (title and abstract review followed by full-text review) to determine if articles met the inclusion or exclusion criteria. Results The search identified 89 articles that specifically related to cultural competency or diversity and inclusion education and training within health care. Interventions ranged from single-day workshops to a 10-year curriculum. Eleven educational strategies used to teach cultural competency and about health disparities were identified. Many studies recommended using multiple educational strategies to develop knowledge, awareness, attitudes, and skills. Less than half of the studies reported favorable outcomes. Multiple studies highlighted the difficulty of implementing curricula without trained and knowledgeable faculty. Conclusions For the field to progress in supporting a culturally diverse patient population, comprehensive training of trainers, longitudinal evaluations of interventions, and the identification and establishment of best practices will be imperative.
Flow cytometric features of incidental indolent T lymphoblastic proliferations

Indolent T lymphoblastic proliferations have been reported rarely in extramedullary and extrathymic tissues. Recent work has identified these indolent T lymphoblast populations to be mostly CD4+/CD8+ (characterized by immunohistochemistry), with only limited immunophenotypic evaluation of these populations by flow cytometry (FC). We retrospectively reviewed our institutional FC archives and identified 12 samples from 10 patients with incidental T lymphoblastic populations. Samples were characterized with respect to expression of T‐cell antigens, CD45, TdT, CD1a, and T/NK antigens, and light scatter properties. Overall, the proportion of T lymphoblasts was small (range 0.01–8.8% of white cells; mean, 1.7%). Histologic correlation showed scattered immature T lymphoblasts in samples without overt distortion of underlying architecture. T lymphoblasts were identified most frequently in association with Castleman disease (four) or tissues with Castleman features (four), marginal zone B‐cell lymphoma (one), or tissue with reactive/atypical changes (three cases). Although three cases were composed predominantly of CD4+/CD8+ T cells, the majority of cases in our cohort (eight) included a major subset of CD4−/CD8− T lymphoblasts by FC (one case CD8+/CD4−), which has not been described previously. There was no evidence of subsequent progression to T lymphoblastic leukemia. Incidental, indolent T lymphoblastic proliferations may be detected by clinical FC. In contrast to reports, we find that these proliferations in clinical samples may contain not only CD4+/CD8+ immature T cells but also CD4−/CD8− immature T cells, expanding the immunophenotypic spectrum of this entity.
How internal cavities destabilize a protein

Significance Proteins exist as ensembles of microstates governed by a free energy landscape, with multiple “excited” states coexisting with the minimum energy structure. These alternate folded and partially disordered states are continuously being accessed through protein dynamics and are key elements required for a comprehensive understanding of protein function and stability. Unfortunately, their low abundance makes these “invisible” states hard to characterize experimentally. A unique view of the hierarchy of unfolding states on the protein energy landscape was obtained here using pressure perturbation. Furthermore, pressure perturbation can directly identify empty protein cavities and determine the energetic penalty of filling these with water. Although many proteins possess a distinct folded structure lying at a minimum in a funneled free energy landscape, thermal energy causes any protein to continuously access lowly populated excited states. The existence of excited states is an integral part of biological function. Although transitions into the excited states may lead to protein misfolding and aggregation, little structural information is currently available for them. Here, we show how NMR spectroscopy, coupled with pressure perturbation, brings these elusive species to light. As pressure acts to favor states with lower partial molar volume, NMR follows the ensuing change in the equilibrium spectroscopically, with residue-specific resolution. For T4 lysozyme L99A, relaxation dispersion NMR was used to follow the increase in population of a previously identified “invisible” folded state with pressure, as this is driven by the reduction in cavity volume by the flipping-in of a surface aromatic group. Furthermore, multiple partly disordered excited states were detected at equilibrium using pressure-dependent H/D exchange NMR spectroscopy. Here, unfolding reduced partial molar volume by the removal of empty internal cavities and packing imperfections through subglobal and global unfolding. A close correspondence was found for the distinct pressure sensitivities of various parts of the protein and the amount of internal cavity volume that was lost in each unfolding event. The free energies and populations of excited states allowed us to determine the energetic penalty of empty internal protein cavities to be 36 cal⋅Å−3.
Permanent Pancreatic Duct Occlusion With Neoprene-based Glue Injection After Pancreatoduodenectomy at High Risk of Pancreatic Fistula

Objective: The aim of this study was to assess safety and efficacy of pancreatic duct occlusion (PDO) with neoprene-based glue in selected patients undergoing pancreatoduodenectomy (PD) at high risk of postoperative pancreatic fistula (POPF). Background Data: PD is the reference standard approach for tumors of the pancreaticoduodenal region. POPF is the most relevant complication after PD. PDO has been proposed as an alternative to anastomosis to manage the pancreatic stump. Methods: A single-center, prospective, nonrandomized trial enrolled 100 consecutive PD for cancer. Patients at high risk for POPF according to Fistula Risk Score (FRS) >15% (≥6 points) were treated with PDO using neoprene glue (study cohort); patients with FRS ≤15% (≤5 points) received pancreaticojejunal anastomosis (PJA: control cohort). Primary endpoint was complication rate grade ≥3 according to Dindo–Clavien Classification (DCC). Other postoperative outcomes were monitored (ClinicalTrials.gov NCT03738787). Results: Fifty-one patients underwent PDO and 49 PJA. DCC ≥3, postoperative mortality, and POPF grade B-C were 25.5% versus 24.5% (P = 0.91), 5.9% versus 2% (P = 0.62), and 11.8% versus 16.3% (P = 0.51) in the study versus control cohort, respectively. At 1 and 3 years, new-onset diabetes was diagnosed in 13.7% and 36.7% of the study cohort versu 4.2% and 12.2% in controls (P = 0.007). Conclusions: PDO with neoprene-based glue is a safe technique that equalizes early outcome of selected patients at high risk of POPF to those at low risk undergoing PJA. Neoprene-based PDO, however, triples the risk of diabetes at 1 and 3 years.
Incidence and Outcomes of Sepsis in Korea: A Nationwide Cohort Study From 2007 to 2016.

OBJECTIVES This study aimed to estimate the incidence and clinical outcomes of sepsis in Korea from 2007 to 2016. DESIGN Retrospective observational study. SETTING Nationwide study with population-based healthcare reimbursement claims database. PATIENTS Using data from the National Health Insurance Service of Korea, patients who were hospitalized with a diagnosis of sepsis from 2007 to 2016 were analyzed. The incidence of sepsis was calculated using mid-year census population and analyzed according to year, age, and sex. The Elixhauser Comorbidity Index score was calculated to adjust for the impact of comorbidities on clinical outcome. In-hospital mortality, hospital length of stay, ICU admission rates, and risk factors for in-hospital mortality were also analyzed. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The incidence of sepsis increased from 173.8 per 100,000 population in 2007 to 233.6 per 100,000 population in 2016. In-hospital mortality decreased from 30.9% in 2007 to 22.6% in 2016 (p < 0.0001). From 2007 to 2016, hospital length of stay and ICU admission rates associated with sepsis decreased from 26.0 ± 33.5 days to 21.3 ± 24.4 days (p < 0.0001) and from 16.2% to 12.7% (p < 0.0001), respectively. Male sex, age greater than 50 years, Elixhauser Comorbidity Index greater than 10, and mechanical ventilation were identified as risk factors for in-hospital mortality after adjusting for baseline characteristics. CONCLUSIONS The incidence of sepsis in Korea increased from 2007 to 2016, while the associated in-hospital mortality, hospital length of stay, and ICU admission rates decreased.
Effect of physical therapy for chronic obstructive pulmonary disease

Abstract Background: Previous studies have reported that physical therapy (PT) can be used for the treatment of chronic obstructive pulmonary disease (COPD). However, its effectiveness is still inconclusive. This systematic review will aim to assess its effectiveness and safety for the treatment of patients with COPD. Methods: All randomized controlled trials (RCTs) literatures of PT for COPD will be searched from the databases of Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDILINE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP Information, and Wanfang Data from inception to the present without any language restrictions. Two reviewers will independently perform the study selection, data extraction, and methodological quality assessment. A third reviewer will be invited to resolve any disagreements occurred between 2 reviewers. Results: The primary outcome is lung function. The secondary outcomes include symptoms, health-related quality of life, mortality, and adverse events. The outcome data will be pooled by using the models of random-effects or fixed-effects according to the detected heterogeneity. Conclusion: The findings of this study will provide up-todated summary evidence for assessing the effectiveness and safety of PT for COPD.
Effects of Locomotion on Visual Responses in the Mouse Superior Colliculus

Visual responses are extensively shaped by internal factors. This effect is drastic in the primary visual cortex (V1), where locomotion profoundly increases visually-evoked responses. Here we investigate whether a similar effect exists in another major visual structure, the superior colliculus (SC). By performing two-photon calcium imaging of head-fixed male and female mice running on a treadmill, we find that only a minority of neurons in the most superficial lamina of the SC display significant changes during locomotion. This modulation includes both increase and decrease in response amplitude and is similar between excitatory and inhibitory neurons. The overall change in the SC is small, whereas V1 responses almost double during locomotion. Additionally, SC neurons display lower response variability and less spontaneous activity than V1 neurons. Together, these experiments indicate that locomotion-dependent modulation is not a widespread phenomenon in the early visual system and that the SC and V1 use different strategies to encode visual information. SIGNIFICANCE STATEMENT Visual information captured by the retina is processed in parallel through two major pathways, one reaching the primary visual cortex through the thalamus, and the other projecting to the superior colliculus. The two pathways then merge in the higher areas of the visual cortex. Recent studies have shown that behavioral state such as locomotion is an essential component of vision and can strongly affect visual responses in the thalamocortical pathway. Here we demonstrate that neurons in the mouse superior colliculus and primary visual cortex display striking differences in their modulation by locomotion, as well as in response variability and spontaneous activity. Our results reveal an important “division of labor” in visual processing between these two evolutionarily distinct structures.
Differential Regulation of TLE3 in Sertoli Cells of the Testes during Postnatal Development

Spermatogenesis is a process by which haploid cells differentiate from germ cells in the seminiferous tubules of the testes. TLE3, a transcriptional co-regulator that interacts with DNA-binding factors, plays a role in the development of somatic cells. However, no studies have shown its role during germ cell development in the testes. Here, we examined TLE3 expression in the testes during spermatogenesis. TLE3 was highly expressed in mouse testes and was dynamically regulated in different cell types of the seminiferous tubules, spermatogonia, spermatids, and Sertoli cells, but not in the spermatocytes. Interestingly, TLE3 was not detected in Sertoli cells on postnatal day 7 (P7) but was expressed from P10 onward. The microarray analysis showed that the expression of numerous genes changed upon TLE3 knockdown in a Sertoli cell line TM4. These include 1597 up-regulated genes and 1452 down-regulated genes in TLE3-knockdown TM4 cells. Ingenuity Pathway Analysis (IPA) showed that three factors were up-regulated and two genes were down-regulated upon TLE3 knockdown in TM4 cells. The abnormal expression of the three factors is associated with cellular malfunctions such as abnormal differentiation and Sertoli cell formation. Thus, TLE3 is differentially expressed in Sertoli cells and plays a crucial role in regulating cell-specific genes involved in the differentiation and formation of Sertoli cells during testicular development.
Inhibition of TOR in Chlamydomonas reinhardtii Leads to Rapid Cysteine Oxidation Reflecting Sustained Physiological Changes

The target of rapamycin (TOR) kinase is a Ser/Thr kinase and master regulator, with roles in the regulation of nutritional sensing, protein translation, and autophagy, among others. In Chlamydomonas reinhardtii, a unicellular green algae and model organism for biofuel production and optimization, TOR has been linked to increased triacylglycerol (TAG) accumulation, suggesting that TOR or a downstream target is responsible for the elusive “lipid switch,” the protein or proteins responsible for increasing TAG formation under nutrient limitation and environmental stressors. However, when this lipid switch is activated, overall culture growth is arrested, truncating the alga’s ability to continuously produce TAGs at a level needed for widespread biofuel use.
Diverse deep-sea anglerfishes share a genetically reduced luminous symbiont that is acquired from the environment

Deep-sea anglerfishes are relatively abundant and diverse, but their luminescent bacterial symbionts remain enigmatic. The genomes of two symbiont species have qualities common to vertically transmitted, host-dependent bacteria. However, a number of traits suggest that these symbionts may be environmentally acquired. To determine how anglerfish symbionts are transmitted, we analyzed bacteria-host codivergence across six diverse anglerfish genera. Most of the anglerfish species surveyed shared a common species of symbiont. Only one other symbiont species was found, which had a specific relationship with one anglerfish species, Cryptopsaras couesii. Host and symbiont phylogenies lacked congruence, and there was no statistical support for codivergence broadly. We also recovered symbiont-specific gene sequences from water collected near hosts, suggesting environmental persistence of symbionts. Based on these results we conclude that diverse anglerfishes share symbionts that are acquired from the environment, and that these bacteria have undergone extreme genome reduction although they are not vertically transmitted.