Miracle-dz/UniFAR-FTUs huggingface dataset:
Kinetics of trifurcated electron flow in the decaheme bacterial proteins MtrC and MtrF

Significance Certain bacteria survive in anoxic environments by switching from aerobic to anaerobic respiration: in place of O2, they reduce diverse substrates outside the cell. Multiheme cytochromes spanning the outer membrane have been identified as the essential building blocks for this process. Here, we provide molecular-level insight into the electron flow in two decaheme proteins. Our study reveals that electron hopping through these proteins is strongly enhanced by cysteines at heme junctions that trifurcate the electron flow. We believe this to be a general design principle in multiheme cytochromes for acceleration of electron transfer (ET) steps that would otherwise be too slow for respiration. Our study uncovers a natural design principle of significance to an entire class of proteins involved in biological ET. The bacterium Shewanella oneidensis has evolved a sophisticated electron transfer (ET) machinery to export electrons from the cytosol to extracellular space during extracellular respiration. At the heart of this process are decaheme proteins of the Mtr pathway, MtrC and MtrF, located at the external face of the outer bacterial membrane. Crystal structures have revealed that these proteins bind 10 c-type hemes arranged in the peculiar shape of a staggered cross that trifurcates the electron flow, presumably to reduce extracellular substrates while directing electrons to neighboring multiheme cytochromes at either side along the membrane. Especially intriguing is the design of the heme junctions trifurcating the electron flow: they are made of coplanar and T-shaped heme pair motifs with relatively large and seemingly unfavorable tunneling distances. Here, we use electronic structure calculations and molecular simulations to show that the side chains of the heme rings, in particular the cysteine linkages inserting in the space between coplanar and T-shaped heme pairs, strongly enhance electronic coupling in these two motifs. This results in an ≈103-fold speedup of ET steps at heme junctions that would otherwise be rate limiting. The predicted maximum electron flux through the solvated proteins is remarkably similar for all possible flow directions, suggesting that MtrC and MtrF shuttle electrons with similar efficiency and reversibly in directions parallel and orthogonal to the outer membrane. No major differences in the ET properties of MtrC and MtrF are found, implying that the different expression levels of the two proteins during extracellular respiration are not related to redox function.
The independent influence of apathy and depression on cognitive functioning in Parkinson's disease.

OBJECTIVE The purpose of the present study was to examine the independent influence of symptoms of depression and apathy, two of the most common neuropsychiatric symptoms in Parkinson's disease (PD), on executive functioning and memory in PD patients using measures designed to discriminate between these symptoms. METHOD Participants included 68 nondemented, idiopathic PD patients, ages 56-82 years. The Apathy Evaluation Scale-Self-Rating and select items of the Beck Depression Inventory II were used to assess symptoms of apathy and depression, respectively. Cognitive function was assessed using the Wisconsin Card Sorting Test and Hopkins Verbal Learning Test-Revised. Correlations and hierarchical regressions were conducted to investigate the relationships between apathy, depression, and cognitive function. Hierarchical regression analyses were conducted to evaluate the degree of influence of depression and apathy on cognitive function. RESULTS Results revealed that symptoms of apathy, but not depression, were significantly and negatively associated with executive functioning. Immediate memory was significantly and negatively associated with both apathy and depression. However, apathy accounted for additional variance in memory performance after controlling for depression at a level approaching significance. CONCLUSIONS Apathy is not only associated with cognitive impairment, but also with impaired daily functioning, caregiver burden and distress, medication noncompliance, and increased mortality. Differentiating apathy and depression, understanding their unique effects, and appropriately identifying apathy symptoms in patients have robust implications for the development of neuropsychological models of these effects in PD as well as practical implications in guiding improvements to patient care and enhancing quality of life in patients and caregivers.
Comparison of Human and Murine Enteroendocrine Cells by Transcriptomic and Peptidomic Profiling

Enteroendocrine cells (EECs) produce hormones such as glucagon-like peptide 1 and peptide YY that regulate food absorption, insulin secretion, and appetite. Based on the success of glucagon-like peptide 1–based therapies for type 2 diabetes and obesity, EECs are themselves the focus of drug discovery programs to enhance gut hormone secretion. The aim of this study was to identify the transcriptome and peptidome of human EECs and to provide a cross-species comparison between humans and mice. By RNA sequencing of human EECs purified by flow cytometry after cell fixation and staining, we present a first transcriptomic analysis of human EEC populations and demonstrate a strong correlation with murine counterparts. RNA sequencing was deep enough to enable identification of low-abundance transcripts such as G-protein–coupled receptors and ion channels, revealing expression in human EECs of G-protein–coupled receptors previously found to play roles in postprandial nutrient detection. With liquid chromatography–tandem mass spectrometry, we profiled the gradients of peptide hormones along the human and mouse gut, including their sequences and posttranslational modifications. The transcriptomic and peptidomic profiles of human and mouse EECs and cross-species comparison will be valuable tools for drug discovery programs and for understanding human metabolism and the endocrine impacts of bariatric surgery.
Effects of Different Comorbidities on Health-Related Quality of Life among Respiratory Patients in Vietnam

Comorbidities are common in respiratory disease patients and have been well-known to impact their quality of life. The objective of this study is to estimate the minimal clinically important difference (MCID) of the health-related quality of life (HRQOL) among respiratory disease patients with different comorbidities in a Vietnamese tertiary hospital. We performed a cross-sectional study from October to November 2016 at the Respiratory Center of Bach Mai Hospital, Hanoi, with a total of 508 participants. Information about socio-economic characteristics, HRQOL and comorbidities of participants was collected. ANOVA was used to identify MCID between patients with and without specific comorbid conditions. Tobit regression was used to explore the associations between comorbidities and the HRQOL. Results showed that the prevalence of cardiovascular comorbidities was 23.8%, followed by musculoskeletal diseases (12.0%), digestive diseases (11.8%), endocrine diseases (10.0%), kidney diseases (5.1%) and ear, nose, and throat diseases (4.5%). Regarding HRQOL, having a problem in pain/discomfort was observed in 61.0% of participants, followed by anxiety/depression (48.2%). Mean EQ-5D index was 0.66 (SD (Standard Deviation) = 0.31). The significant MCID (p < 0.05) was found between patients with and without cardiovascular diseases, musculoskeletal diseases, kidney diseases, and endocrine diseases. The multivariate regression model showed that only musculoskeletal diseases were found to be related with the marked decrement of EQ-5D index score (Coef. = −0.13; 95% CI (Confident Interval) = −0.23; −0.02). Suffering at least one chronic illness was correlated to the marked decrease of EQ-5D index score (Coef. = −0.09; 95% CI = −0.17; −0.01). These results underline the importance of appropriate pain management as well as the provision of an interprofessional care approach to patients in order to alleviate the burden of comorbidities to their treatment outcomes and HRQOL.
8-Oxo-guanine DNA damage induces transcription errors by escaping two distinct fidelity control checkpoints of RNA polymerase II

RNA polymerase II (Pol II) has an intrinsic fidelity control mechanism to maintain faithful genetic information transfer during transcription. 8-Oxo-guanine (8OG), a commonly occurring damaged guanine base, promotes misincorporation of adenine into the RNA strand. Recent structural work has shown that adenine can pair with the syn conformation of 8OG directly upstream of the Pol II active site. However, it remains unknown how 8OG is accommodated in the active site as a template base for the incoming ATP. Here, we used molecular dynamics (MD) simulations to investigate two consecutive steps that may contribute to the adenine misincorporation by Pol II. First, the mismatch is located in the active site, contributing to initial incorporation of adenine. Second, the mismatch is in the adjacent upstream position, contributing to extension from the mismatched bp. These results are supported by an in vitro transcription assay, confirming that 8OG can induce adenine misincorporation. Our simulations further suggest that 8OG forms a stable bp with the mismatched adenine in both the active site and the adjacent upstream position. This stability predominantly originates from hydrogen bonding between the mismatched adenine and 8OG in a noncanonical syn conformation. Interestingly, we also found that an unstable bp present directly upstream of the active site, such as adenine paired with 8OG in the canonical anti conformation, largely disrupts the stability of the active site. Our findings have uncovered two main factors contributing to how 8OG induces transcriptional errors and escapes Pol II transcriptional fidelity control checkpoints.
Tooth movement rate and anchorage lost during canine retraction: A maxillary and mandibular comparison.

OBJECTIVES To investigate the canine retraction rate and anchorage loss during canine retraction using self-ligating (SL) brackets and conventional (CV) brackets. Differences between maxillary and mandibular rates were computed. MATERIALS AND METHODS Twenty-five subjects requiring four first premolar extractions were enrolled in this split-mouth, randomized clinical trial. Each patient had one upper canine and one lower canine bonded randomly with SL brackets and the other canines with CV brackets but never on the same side. NiTi retraction springs were used to retract canines (100 g force). Maxillary and mandibular superimpositions, using cephalometric 45° oblique radiographs at the beginning and at the end of canine retraction, were used to calculate the changes and rates during canine retraction. Paired t-tests were used to compare side and jaw effects. RESULTS The SL and CV brackets did not show differences related to monthly canine movement in the maxilla (0.71 mm and 0.72 mm, respectively) or in the mandible (0.54 mm and 0.60 mm, respectively). Rates of anchorage loss in the maxilla and in the mandible also did not show differences between the SL and CV brackets. Maxillary canines showed greater amount of tooth movement per month than mandibular canines (0.71 mm and 0.57 mm, respectively). CONCLUSIONS SL brackets did not show faster canine retraction compared with CV brackets nor less anchorage loss. The maxillary canines showed a greater rate of tooth movement than the mandibular canines; however, no difference in anchorage loss between the maxillary and mandibular posterior segments during canine retraction was found.
Association of Behavior in Boys From Low Socioeconomic Neighborhoods With Employment Earnings in Adulthood

Importance Identifying early childhood behavioral problems associated with economic success/failure is essential for the development of targeted interventions that enhance economic prosperity through improved educational attainment and social integration. Objective To test the association between kindergarten teacher–rated assessments of inattention, hyperactivity, opposition, aggression, and prosociality in boys with their employment earnings at age 35 to 36 years as measured by government tax return data. Design, Setting, and Participants A 30-year prospective follow-up study analyzing low socioeconomic neighborhoods in Montreal, Quebec, Canada. Boys aged 5 to 6 years attending kindergarten in low socioeconomic neighborhoods were recruited. Teacher-rated behavioral assessments were obtained for 1040 boys. Data were collected from April 1984 to December 2015. Analysis began January 2017. Main Outcomes and Measures Mixed-effects linear regression models were used to examine the association between teacher ratings of inattention, hyperactivity, opposition, aggression, and prosociality at age 6 years and individual earnings obtained from government tax returns at age 35 to 36 years. The IQ of the child and family adversity were adjusted for in the analysis. Results Complete data were available for 920 study participants (mean age at follow-up was 36.3 years). Mean (SD) personal earnings at follow-up were $28 865.53 ($24 103.45) (range, $0-$142 267.84). A 1-unit increase in inattention (mean [SD], 2.66 [2.34]; range, 0-8) at age 6 years was associated with decrease in earnings at age 35 to 36 years of $1295.13 (95% CI, −$2051.65 to −$538.62), while a unit increase in prosociality (mean [SD], 8.0 [4.96]; range, 0-20) was associated with an increase in earnings of $406.15 (95% CI, $172.54-$639.77). Hyperactivity, opposition, and aggression were not significantly associated with earnings. Child IQ was associated with higher earnings and family adversity with lower earnings in all models. A 1-SD reduction in inattention at age 6 years was associated with a theoretical increase in annual earnings of $3040.41, a similar magnitude to an equivalent increase in IQ. Conclusions and Relevance Teacher ratings of inattention and prosociality in kindergarten boys from low socioeconomic neighborhoods are associated with earnings in adulthood after adjustment for hyperactivity, aggression, and opposition, which were not associated with earnings. Interventions beginning in kindergarten that target boys’ inattention and enhance prosociality could positively impact workforce integration and earnings.
Candida auris Clinical Isolates from South Korea: Identification, Antifungal Susceptibility, and Genotyping

Candida auris is an emerging worldwide fungal pathogen. Over the past 20 years, 61 patient isolates of C. auris (4 blood and 57 ear) have been obtained from 13 hospitals in Korea. ABSTRACT Candida auris is an emerging worldwide fungal pathogen. Over the past 20 years, 61 patient isolates of C. auris (4 blood and 57 ear) have been obtained from 13 hospitals in Korea. Here, we reanalyzed those molecularly identified isolates using two matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) systems, including Biotyper and Vitek MS, followed by antifungal susceptibility testing, sequencing of the ERG11 gene, and genotyping. With a research-use-only (RUO) library, 83.6% and 93.4% of the isolates were correctly identified by Biotyper and Vitek MS, respectively. Using an in vitro diagnostic (IVD) library of Vitek MS, 96.7% of the isolates were correctly identified. Fluconazole-resistant isolates made up 62.3% of the isolates, while echinocandin- or multidrug-resistant isolates were not found. Excellent essential (within two dilutions, 96.7%) and categorical agreements (93.4%) between the Clinical and Laboratory Standards Institute (CLSI) and Vitek 2 (AST-YS07 card) methods were observed for fluconazole. Sequencing ERG11 for all 61 isolates revealed that only 3 fluconazole-resistant isolates showed the Erg11p amino acid substitution K143R. All 61 isolates showed identical multilocus sequence typing (MLST). Pulsed-field gel electrophoresis (PFGE) analyses revealed that both blood and ear isolates had the same or similar patterns. These results show that MALDI-TOF MS and Vitek 2 antifungal susceptibility systems can be reliable diagnostic tools for testing C. auris isolates from Korean hospitals. The Erg11p mutation was seldom found among Korean isolates of C. auris, and multidrug resistance was not found. Both MLST and PFGE analyses suggest that these isolates are genetically similar.
Risk Score to Predict Dental Caries in Adult Patients for Use in the Clinical Setting

Background: There is a need for risk prediction tools in caries research. This investigation aimed to estimate and evaluate a risk score for prediction of dental caries. Materials and Methods: This case-cohort study included a random sample of 177 cases (with dental caries) and 220 controls (randomly sampled from the study population at baseline), followed for 3 years. The risk ratio (RR) for each potential predictor was estimated using a logistic regression model. The level of significance was 5%. Results: The risk model for dental caries included the predictors: “presence of bacterial plaque/calculus” (RR = 4.1), “restorations with more than 5 years” (RR = 2.3), “>8 teeth restored” (RR = 2.0), “history/active periodontitis” (RR = 1.7) and “presence of systemic condition” (RR = 1.4). The risk model discrimination (95% confidence interval) was 0.78 (0.73; 0.82) (p < 0.001, C-statistic). Patients were distributed into three risk groups based on the pre-analysis risk (54%): low risk (<half the pre-analysis risk; caries incidence = 6.8%), moderate risk (half-to-less than the pre-analysis risk; caries incidence = 20.4%) and high risk (≥the pre-analysis risk; caries incidence = 27%). Conclusions: The present study estimated a simple risk score for prediction of dental caries retrieved from a risk algorithm with good discrimination.
Collagen Fiber Array of Peritumoral Stroma Influences Epithelial-to-Mesenchymal Transition and Invasive Potential of Mammary Cancer Cells

Interactions of cancer cells with matrix macromolecules of the surrounding tumor stroma are critical to mediate invasion and metastasis. In this study, we reproduced the collagen mechanical barriers in vitro (i.e., basement membrane, lamina propria under basement membrane, and deeper bundled collagen fibers with different array). These were used in 3D cell cultures to define their effects on morphology and behavior of breast cancer cells with different metastatic potential (MCF-7 and MDA-MB-231) using scanning electron microscope (SEM). We demonstrated that breast cancer cells cultured in 2D and 3D cultures on different collagen substrates show different morphologies: i) a globular/spherical shape, ii) a flattened polygonal shape, and iii) elongated/fusiform and spindle-like shapes. The distribution of different cell shapes changed with the distinct collagen fiber/fibril physical array and size. Dense collagen fibers, parallel to the culture plane, do not allow the invasion of MCF-7 and MDA-MB-231 cells, which, however, show increases of microvilli and microvesicles, respectively. These novel data highlight the regulatory role of different fibrillar collagen arrays in modifying breast cancer cell shape, inducing epithelial-to-mesenchymal transition, changing matrix composition and modulating the production of extracellular vesicles. Further investigation utilizing this in vitro model will help to demonstrate the biological roles of matrix macromolecules in cancer cell invasion in vivo.
Association Between Urinary Sodium and Potassium Excretion and Blood Pressure Among Adults in the United States: National Health and Nutrition Examination Survey, 2014

Background: Higher levels of sodium and lower levels of potassium intake are associated with higher blood pressure. However, the shape and magnitude of these associations can vary by study participant characteristics or intake assessment method. Twenty-four–hour urinary excretion of sodium and potassium are unaffected by recall errors and represent all sources of intake, and were collected for the first time in a nationally representative US survey. Our objective was to assess the associations of blood pressure and hypertension with 24-hour urinary excretion of sodium and potassium among US adults. Methods: Cross-sectional data were obtained from 766 participants age 20 to 69 years with complete blood pressure and 24-hour urine collections in the 2014 National Health and Nutrition Examination Survey, a nationally representative survey of the US noninstitutionalized population. Usual 24-hour urinary electrolyte excretion (sodium, potassium, and their ratio) was estimated from ⩽2 collections on nonconsecutive days, adjusting for day-to-day variability in excretion. Outcomes included systolic and diastolic blood pressure from the average of 3 measures and hypertension status, based on average blood pressure ≥140/90 and antihypertensive medication use. Results: After multivariable adjustment, each 1000-mg difference in usual 24-hour sodium excretion was directly associated with systolic (4.58 mm Hg; 95% confidence interval [CI], 2.64–6.51) and diastolic (2.25 mm Hg; 95% CI, 0.83–3.67) blood pressures. Each 1000-mg difference in potassium excretion was inversely associated with systolic blood pressure (–3.72 mm Hg; 95% CI, –6.01 to –1.42). Each 0.5 U difference in sodium-to-potassium ratio was directly associated with systolic blood pressure (1.72 mm Hg; 95% CI, 0.76–2.68). Hypertension was linearly associated with progressively higher sodium and lower potassium excretion; in comparison with the lowest quartile of excretion, the adjusted odds of hypertension for the highest quartile was 4.22 (95% CI, 1.36–13.15) for sodium, and 0.38 (95% CI, 0.17–0.87) for potassium (P<0.01 for trends). Conclusions: These cross-sectional results show a strong dose-response association between urinary sodium excretion and blood pressure, and an inverse association between urinary potassium excretion and blood pressure, in a nationally representative sample of US adults.
Geographic Distribution of HCV-GT3 Subtypes and Naturally Occurring Resistance Associated Substitutions

Background: Little is known about the frequency or geographic distributions of naturally occurring resistance-associated substitutions (RASs) in the nonstructural protein 5A (NS5A) domain of hepatitis-C virus (HCV) genotype-3 (GT-3) different subtypes. We investigated naturally occurring GT-3 RASs that confer resistance to NS5A inhibitors. Methods: From a publicly accessible database, we retrieved 58 complete GT-3 genomes and an additional 731 worldwide NS5A sequences from patients infected with GT-3 that were naive to direct-acting antiviral treatment. Results: We performed a phylogenetic analysis of NS5A domains in complete HCV genomes to determine more precisely HCV-GT-3 subtypes, based on commonly used target regions (e.g., 5′untranslated region and NS5B partial domain). Among 789 NS5A sequences, GT-3nonA subtypes were more prevalent in Asia than in other geographic regions (p < 0.0001). The A30K RAS was detected more frequently in HCV GT-3nonA (84.6%) than in GT-3A subtypes (0.8%), and the amino acid change was polymorphic in isolates from Asia. Conclusions: These results provided information on the accuracy of HCV-3 subtyping with a phylogenetic analysis of the NS5A domain with data from the Los Alamos HCV genome database. This information and the worldwide geographic distribution of RASs according to HCV GT-3 subtypes are crucial steps in meeting the challenges of treating HCV GT-3.