Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of a Hotspot Residue for Improving the Thermostability of a Flavin‐Dependent Monooxygenase

HadA is a flavin‐dependent monooxygenase that can catalyze the denitration and dehalogenation of a wide variety of toxicants such as pesticides. Although these enzymatic reactions are useful for bioremediation or biocatalysis, the application of HadA for these purposes is not yet possible because of its low thermostability. In this work we have engineered HadA to be more thermostable through the use of structural, in silico, and rational approaches. The X‐ray structure of HadA was solved to obtain a reliable three‐dimensional protein model for further prediction of thermostable variants. In silico analysis by using two bioinformatic tools—FireProt and Disulfide by Design—suggested 102 variants that we then further refined by applying rational criteria including the location of a particular residue and its nearby interactions, as well as other biophysical parameters to narrow down the list to six candidates. The G513Y variant was found to be an optimal engineered candidate because it has significantly improved stability relative to the wild‐type enzyme and equivalent activity. G513Y has an activity half‐life 72 (50 °C) and 160 times (45 °C) longer than that of the wild‐type enzyme. Coupled together with thermostable reactions of reduced flavin and NADH‐regenerating systems, the G513Y variant can be used to catalyze denitration of 4nitrophenol at 45 °C. Structure/sequence alignments of HadA and its homologues indicate that several flavin‐dependent monooxygenases also contain amino acid residues homologous to the G513 of HadA, hence opening up the possibility of applying this engineering approach to improving their thermostabilities as well. Molecular dynamics (MD) simulations confirmed that the improved thermostability of the G513Y variant was due to aromatic hydrocarbon interactions between Y513 and N359, L347, G348, and F349.
Postpartum problems in primary care: focus on postpartum depression and diabetes.

Postpartum depression and diabetes are common diagnoses affecting many childbearing women annually. Nevertheless, disease management by the primary care provider can be complicated by late entry or insufficient care. Pharmacotherapeutic interventions must be initiated appropriately to address the disease progression, while supporting breastfeeding. This study explores the course of postpartum depression and diabetes in a woman with postpartum using the case study application and analysis along with interventions and education that can help primary care providers in reducing the complications that come from undiagnosed depression and diabetes in the postpartum period.
Estimated Contributions of Emissions Controls, Meteorological Factors, Population Growth, and Changes in Baseline Mortality to Reductions in Ambient PM2.5 and PM2.5-Related Mortality in China, 2013–2017

Background: In 2013, China released the Air Pollution Prevention and Control Action Plan (Action Plan), which set the roadmap for national air pollution control actions for the period of 2013 to 2017. A decrease in the fine particulate matter with aerodynamic diameter ≤2. 5μm (PM2.5) concentration may lead to a substantial benefit for human health. Objective: We aimed to quantify the relative contributions four factors: emission reductions, changed meteorology, population growth, and a change in baseline mortality rates to the reduced PM2.5-related mortality (PM2.5-mortality) during the 2013–2017 period and evaluate the importance of emission controls for human health protection in China. Methods: The integrated exposure–response function was adopted to estimate the chronic health effects of PM2.5. The annual PM2.5 concentrations were estimated from chemical transport model simulations combined with surface observations for 2013 and 2017. Relative contributions to PM2.5-mortality from emission reductions and the three factors were individually quantified through scenario analysis. Results: The estimated total PM2.5-mortality in China was 1.389 million [95% confidence interval (CI): 1.005 million, 1.631 million] in 2013 but was substantially reduced to 1.102 million (95% CI: 0.755 million, 1.337 million) in 2017. Emission controls contributed 88.7% to this reduction in PM2.5-mortality, while changed meteorology, the change in baseline mortality rates, and population growth during 2013–2017 contributed 9.6, 3.8, and −2.2%, respectively. Conclusions: The implementation of the Action Plan has significantly reduced the PM2.5 concentration in regions of China where population density is high, dominating the decline in PM2.5-mortality during 2013–2017. However, the health burden of PM2.5 pollution in China is still extremely high compared with that in other developed countries. An aggressive air pollution control strategy should be implemented in densely populated areas to further reduce the health burden. https://doi.org/10.1289/EHP4157
Cognitive compensatory mechanisms in normal aging: a study on verbal fluency and the contribution of other cognitive functions

Verbal fluency has been widely studied in cognitive aging. However, compensatory mechanisms that maintain its optimal performance with increasing age are not completely understood. Using cross-sectional data, we investigated differentiation and dedifferentiation processes in verbal fluency across the lifespan by analyzing the association between verbal fluency and numerous cognitive measures within four age groups (N=446): early middle-age (32-45 years), late middle-age (46-58 years), early elderly (59-71 years), and late elderly (72-84 years). ANCOVA was used to investigate the interaction between age and fluency modality. Random forest models were conducted to study the contribution of cognition to semantic, phonemic, and action fluency. All modalities declined with increasing age, but semantic fluency was the most vulnerable to aging. The most prominent reduction in performance was observed during the transition from middle-age to early elderly, when cognitive variables stopped contributing (differentiation), and new cognitive variables started contributing (dedifferentiation). Lexical access, processing speed, and executive functions were among the most contributing functions. We conclude that the association between age and verbal fluency is masked by age-specific influences of other cognitive functions. Differentiation and dedifferentiation processes can coexist. This study provides important data for better understanding of cognitive aging and compensatory processes.
Evaluating Immunopathogenic Biomarkers During Severe Malaria Illness as Modifiers of the Neuropsychologic Benefits of Computer Cognitive Games Rehabilitation in Ugandan Children.

BACKGROUND We explored 3 immunopathogenic biomarkers collected during acute malaria illness as potential moderators of gains from a computerized cognitive rehabilitation training (CCRT) intervention. METHOD Von Willebrand Factor (vWF), tumor necrosis factor (TNF) and Regulated on Activation, Normal T Expressed and Secreted (RANTES) were assayed from plasma and cerebral spinal fluid (CSF) of children during acute severe malaria anemia or cerebral malaria. Two years after acute malaria illness, 150 surviving children and 150 nonmalaria community controls (CCs) from their households 6-12 years old entered a 3-arm randomized controlled trial of titrating and nontitrating CCRT against no CCRT. Tests of cognition [Kaufman Assessment Battery for Children (KABC)], Tests of Variables of Attention and Achenbach Child Behavior Checklist (CBCL) were administered before and after 24 CCRT sessions over a 3-month period, and at 1-year follow-up. Differences in outcomes by trial arms and biomarker levels were evaluated using linear mixed effects models. RESULTS Severe malaria survivors with lower levels of vWF, lower CSF levels of TNF and higher levels of plasma and CSF RANTES had better KABC cognitive performance after both titrating and nontitrating CCRT compared to no CCRT. For the CBCL, high plasma RANTES was associated with no benefit from either the titrating and nontitrating CCRT, whereas high TNF plasma was predictive of the benefit for both interventions. These biomarker moderating effects were not evident for CC children. CONCLUSIONS Severe malaria immunopathogenic biomarkers may be related to poorer long-term brain/behavior function as evidenced by diminished benefit from a computerized cognitive rehabilitation intervention.
A systematic review protocol

Background: Chronic urticaria (CU) is a common and easily recurring skin disease in the world. Many trials have shown that autologous whole-blood or autologous serum acupoint injection therapy is effective in treating CU. There is currently no systematic review of this therapy. The program aims to evaluate the effectiveness and safety of this therapy in patients with CU. Methods: Literature search will be conducted at Medline, PubMed, Excerpt Medica Database, Springer, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal Database, and other databases. The search date is until May 2019. We will search for popular terms including CU and this therapy. Import the literature electronically. Duplicate documents will be deleted. The primary outcome is the urticaria activity score or other validated scales. Secondary outcomes included response rate, quality of life scale, recurrence rate, and adverse events. A systematic review and search for a randomized controlled trial of this therapy for CU. Implement the Cochrane RevMan V5.3 bias assessment tool to assess bias assessment risk, data integration risk, meta-analysis risk, and subgroup analysis risk (if conditions are met). The mean difference, standard MD, and binary data will be used to represent continuous results. Results: This study will provide a comprehensive review of the available evidence for the treatment of CU with this therapy. Conclusion: This study will provide new evidence for assessing the effectiveness and side effects of this therapy for CU. Since the data is not individualized, there is no need for formal ethical approval. PROSPERO registration number: CRD42019128364. Abbreviations: AS = autologous serum, AWB = autologous whole-blood, CBM = China biomedical literature database, CI = confidence interval, CNKI = China National Knowledge Infrastructure, CSU = chronic spontaneous urticarial, CU = chronic urticarial, EMBASE = excerpt medica database, ICTRP = international clinical trials registry platform, IU = inducible urticaria, MD = mean difference, RCT = randomized controlled trial, RR = relative risk, SMD = standard mean difference, TCMD = traditional Chinese medicine databases, UAS = urticaria activity score, VIP = Chinese scientific journal database.
Independent Functioning in Nonagenarians Living in a Rural Italian Community: The Mugello Study

Nonagenarians are a fast-growing population deserving specific research. We explored the prevalence and characteristics of functionally independent nonagenarians from a rural community-dwelling Italian population. Data were collected in the Mugello Study; 475 persons aged ≥90 years (median age, 92) underwent a home-based clinical and functional assessment, including psychosocial, clinical, functional, and lifestyle history and status and physical and instrumental examinations. Sixty-eight (15%) persons reported no need for help in basic and instrumental daily living activities. Among variables significantly associated with independent functionality after age- and gender-adjusted cross-sectional analysis, lower body mass index (BMI; p = .034) and depressive symptoms (p = .028), higher current physical activity (p < .001), better cognitive status (p = .033), and lower medication intake (p = .048) were associated with reporting no disability in the logistic regression analysis. Disability was mainly associated with current lifestyle-related potentially modifiable factors. Thus, lifestyle-oriented multidimensional interventions, should be developed and evaluated for their potential effects on functionality, even in the oldest old.
Novel protein microarray for the detection of avian influenza virus antibodies and simultaneous distinction of antibodies against H5 and H7 subtypes

ABSTRACT Avian influenza virus (AIV) can cause serious zoonotic disease, thereby threatening the poultry industry and human health. An efficient and rapid detection approach is crucial to prevent and control the spread of avian influenza. In this study, a novel protein microarray was developed. Haemagglutinin proteins of H5 and H7 subtypes and nucleoprotein (NP) were purified and spotted onto the initiator-integrated poly-(dimethylsiloxane) as antigens. Monoclonal antibodies with inhibition effect were screened and utilized for the synchronous detection of three avian influenza antibodies in different species. In the protein microarray, the cut-off values were 40%, 50% and 30% inhibition for H5 antibody detection; 50%, 50% and 20% for NP antibody detection; 40%, 50% and 40% for H7 antibody detection in chicken, peacock and duck sera, respectively. The 95 serum samples were detected by microarray, and results were compared with the findings of AIV antibody test enzyme-linked immunosorbent assay (ELISA) or haemagglutination inhibition (HI) test. NP antibody detection in the microarray showed 100% (55/55) agreement ratio in chicken using ELISA. Compared with HI, H5 antibody detection in the microarray showed 100% (95/95) agreement ratio in chicken, peacock and duck, whilst those of H7 displayed 98.18% (54/55) agreement in chicken, 100% (20/20) in peacock and 90% (18/20) in duck. In conclusion, this novel protein microarray is a high-throughput and specific method for the detection of AIV antibodies and simultaneous distinction of antibodies against H5 and H7 subtypes. It can be applied to the serological diagnosis and epidemiological investigation of AIV. RESEARCH HIGHLIGHTS A novel protein microarray method has been developed. The microarray can detect AIV antibodies and distinguish between H5 and H7 subtypes. The study lays the foundation for simultaneous identification of multiple pathogens.
Hydrocortisone Continuous Infusion Versus Bolus Dose on Glycemic Control in Critically Ill Subjects

Background: Corticosteroid therapy in patients with septic shock can improve hemodynamics but can also cause hyperglycemia. Continuous infusion (CI) hydrocortisone has limited evidence that it may reduce hyperglycemia relative to bolus dose (BD) therapy, but CI can be cumbersome and requires attention to intravenous access and drug incompatibilities. Objective: To compare the effects of CI hydrocortisone with BD on glycemic control. Methods: A matched, retrospective cohort study of blood glucose, insulin requirements, and glycemic variability was performed between patients with shock receiving CI and BD hydrocortisone. Patients were matched based on history of type 2 diabetes and intensive care unit (ICU) admission. Results: Baseline blood glucose was similar between groups, with higher baseline hourly insulin requirements in the CI group (CI: 12 [12.8] units, BD: 6.7 [7] units, P = .0012). For the first 72 hours of treatment, there was no difference in mean blood glucose with higher average hourly insulin requirements in the CI group (CI 7.8 [7.7] units, BD: 5.5 [6.9] units, P < .0001). There was no difference in glycemic variability between groups. Conclusions: CI hydrocortisone therapy for septic shock does not appear to have a favorable impact on mean blood glucose or influence glycemic variability relative to BD therapy.
Identification of conserved peptides containing B-cell epitopes of Babesia bovis AMA-1 and their potential as diagnostics candidates.

The apical membrane antigen 1 (AMA-1) is a protein of the micronemes that is present in all organisms of the phylum Apicomplexa; it has been shown that AMA-1 plays an essential role for parasite invasion to target cells. It has been reported that AMA-1 is conserved among different isolates of Babesia; however, it is unknown whether the protein contains conserved B-cell epitopes and whether these epitopes are recognized by antibodies from cattle in endemic areas. In this research, using an in silico analysis, four peptides were designed containing exposed and conserved linear B-cell epitopes from the extracellular region of Babesia bovis AMA-1. The selected peptides were chemically synthesized, and then each peptide was emulsified and used to immunize two bovines per peptide. The antibodies produced against these peptides were able to recognize intra-erythrocytic parasites in an IFAT, except peptide 4, which was insoluble. The synthetic peptides were covalently fixed to the wells of an ELISA plate and incubated with sera from B. bovis naturally infected cattle. Peptides P2AMA and P3AMA were recognized by the sera of naturally infected cattle from different regions of Mexico. Statistical analysis showed that the ELISA test for peptides P2AMA and P3AMA had a concordance of 91.2% and 61.1% compared to the IFAT, a sensitivity of 94.56% and 71.74%, and a specificity of 76.19% and 14.2%, respectively. The presence of antibodies in bovine sera from endemic areas that bind to the identified peptides indicates that AMA-1 from B. bovis has conserved B-cell epitopes involved in the immune response under natural conditions. However, to propose their use as vaccine or diagnostics candidates, a further characterization of the humoral immune response elicited in cattle by these peptides is needed.
Iterative allogamy-autogamy transitions drive actual and incipient speciation during the ongoing evolutionary radiation within the orchid genus Epipactis (Orchidaceae).

BACKGROUND AND AIMS The terrestrial orchid genus Epipactis has become a model system for the study of speciation via transitions from allogamy to autogamy, but close phylogenetic relationships have proven difficult to resolve through Sanger sequencing. METHODS We analysed with RAD-seq 108 plants representing 29 named taxa that together span the genus, focusing on section Epipactis. Our filtered matrix of 12,543 single nucleotide polymorphisms was used to generate an unrooted network and a rooted, well-supported likelihood tree. We further inferred genetic structure through a co-ancestry heat-map and admixture analysis, and estimated inbreeding coefficients per sample. KEY RESULTS The 27 named taxa of the ingroup were resolved as 11 genuine, geographically widespread species: four dominantly allogamous and seven dominantly autogamous. A single comparatively allogamous species, E. helleborine, is the direct ancestor of most of the remaining species, though one of the derived autogams has generated one further autogamous species. An assessment of shared ancestry suggested only sporadic hybridisation between the re-circumscribed species. Taxa with greatest inclination towards autogamy show less if any admixture, whereas the gene pools of more allogamous species contain a mixture alleles found in the autogams. CONCLUSIONS This clade is presently undergoing an evolutionary radiation driven by a wide spectrum of genotypic, phenotypic and environmental factors. Epipactishelleborine has also frequently generated many local variants showing inclinations toward autogamy (and occasionally cleistogamy) best viewed as incipient speciation from within the genetic background provided by Epipactis helleborine, which thus becomes an example of a convincingly paraphyletic species. Autogams are often as widespread and ecologically successful as allogams.
First-Days Reduction of Plasma and Skin Advanced Glycation End Products is Related to Outcome in Septic Patients.

BACKGROUND Advanced glycation end products (AGEs) are a result of non-enzymatic glycation of proteins and lipids, which can attach to either their cell surface receptor (RAGE) or its soluble form (sRAGE). Evidence exists for the implication of AGE-RAGE axis in sepsis, but data are still insufficient and conflicting. We aimed to analyse the kinetics of plasma and skin AGEs and sRAGE during sepsis, and their association with outcome in septic patients. METHODS We performed a prospective observational study. We enrolled 90 consecutive patients with severe sepsis or septic shock, within the first 24 hours of Intensive Care Unit admission. During the first 5 days of sepsis, we measured plasma autofluorescence (PAF) and skin autofluorescence (SAF) as surrogates of circulating and skin AGEs, respectively. sRAGE was measured on days 1, 3 and 5. Delta values were defined as the difference between the PAF, SAF or sRAGE on a specific day and the value on day 1. RESULTS 28-day mortality was 18%. Bivariate analysis found that ΔPAF3-1, ΔPAF4-1, ΔPAF5-1 and ΔSAF5-1 were significantly associated with 28-day mortality. Additionally, sRAGE1 was inversely correlated to ΔPAF4-1 (r = -0.250, p = 0.019) and ΔPAF5-1 (r = -0.246, p = 0.024), and significantly associated with 28-day mortality. In an adjusted multivariate logistic regression analysis, ΔPAF2-1, ΔPAF3-1, ΔPAF4-1, ΔPAF5-1 and ΔSAF5-1 were associated with 28-day mortality. CONCLUSIONS Kinetics of plasma and skin AGEs during the first days of sepsis are independently associated with mortality, where a decrease of plasma and skin AGEs are related to higher mortality.
Effect of ambient temperature and intracellular pigmentation on photothermal damage rate kinetics

Abstract. Computational models predicting cell damage responses to transient temperature rises generated by exposure to lasers have implemented the damage integral (Ω), which time integrates the chemical reaction rate constant described by Arrhenius. However, few published reports of empirical temperature histories (thermal profiles) correlated with damage outcomes at the cellular level are available to validate the breadth of applicability of the damage integral. In our study, an analysis of photothermal damage rate processes in cultured retinal pigment epithelium cells indicated good agreement between temperature rise, exposure duration (τ), and threshold cellular damage. Full-frame thermograms recorded at high magnification during laser exposures were overlaid with fluorescence damage images taken 1 h postexposure. From the image overlays, pixels of the thermogram correlated with the boundary of cell death were used to extract threshold thermal profiles. Assessing photothermal responses at these boundaries standardized all data points, irrespective of laser irradiance, damage size, or optical and thermal properties of the cells. These results support the hypothesis that data from boundaries of cell death were equivalent to a minimum visible lesion, where the damage integral approached unity (Ω = 1) at the end of the exposure duration. Empirically resolved Arrhenius coefficients for use in the damage integral determined from exposures at wavelengths of 2 μm and 532 nm and durations of 0.05–20 s were consistent with literature values. Varying ambient temperature (Tamb) between 20°C and 40°C during laser exposure did not change the τ-dependent threshold peak temperature (Tp). We also show that, although threshold laser irradiance varied due to pigmentation differences, threshold temperatures were irradiance independent.
Geophysical Signal Analysis

“This text, an introduction to geophysical signal analysis, is concerned with the construction, analysis, and interpretation of mathematical and statistical models. In general, it is intended to provide material of interest to upper undergraduate students in mathematics, science, and engineering. Much of this book requires only a knowledge of elementary algebra. However, at some points, a familiarity with elementary calculus and matrix algebra is needed. The practical use of the concepts and techniques developed is illustrated by numerous applications. Care has been taken to choose examples that are of interest to a variety of readers. Therefore, the book contains material of interest to both geophysicists and those engaged in digital signal analysis in disciplines other than geophysics. This book is a reprint of the 1980 Prentice-Hall volume of the same title. ”