Miracle-dz/UniFAR-FTUs huggingface dataset:
Multilevel genome typing: genomics-guided scalable resolution typing of microbial pathogens

Background Both long- and short-term epidemiology are fundamental to disease control and require accurate bacterial typing. Genomic data resulting from implementation of whole genome sequencing in many public health laboratories can potentially provide highly sensitive and accurate descriptions of strain relatedness. Previous typing efforts using these data have mainly focussed on outbreak detection. Aim We aimed to develop multilevel genome typing (MGT), using consecutive multilocus sequence typing (MLST) schemes of increasing sizes, stepping up from seven-gene MLST to core genome MLST, to allow examination of genetic relatedness at multiple resolution levels. Methods The system was applied to Salmonella enterica serovar Typhimurium. The MLST scheme used at each step (MGT level), defined a given MGT-level specific sequence type (ST). The list of STs generated from all of these increasing MGT levels, was named a genome type (GT). Using MGT, we typed 9,096 previously characterised isolates with publicly available data. Results Our approach could identify previously described S. Typhimurium populations, such as the DT104 multidrug resistance lineage (GT 19-2-11) and two invasive lineages of African isolates (GT 313-2-3 and 313-2-752). Further, we showed that MGT-derived clusters can accurately distinguish five outbreaks from each other and five background isolates. Conclusion MGT provides a universal and stable nomenclature at multiple resolutions for S. Typhimurium strains and could be implemented as an internationally standardised strain identification system. While established so far only for S. Typhimurium, the results here suggest that MGT could form the basis for typing systems in other similar microorganisms.
Isoenzymatic variation in the germplasm of Brazilian races of maize (Zea mays L.)

There are more than 200 races of maize (Zea mays L.) divided into three groups (ancient commercial races, the recent commercial races, and indigenous races). Although the indigenous races have no commercial value, they have many important characteristics which can be incorporated into maize breeding programs. Most Brazilian indigenous germplasm race stocks were collected at least 40 years ago, and nothing is known of the genetic variability present in this germplasm. The genetic variability was assayed in 15 populations from four indigenous races of maize (Caingang, Entrelacado, Lenha and Moroti) and five indigenous cultivars, using five isoenzymatic systems encoded by 14 loci. The analysis revealed a low level of variability among the samples studied. Overall, the mean number of alleles/polymorphic locus was three, 64.3% of the loci analyzed being polymorphic and the estimated heterozygosity was 0.352. The mean number of alleles/polymorphic locus per population was 1.6. A mean of 47.5% of the loci were polymorphic. The mean expected heterozygosity was 0.195, the mean genetic identity was 0.821 and the proportion of total genetic diversity partitioned among populations (Gst) was 0.156. A founder effect could explain the low variability detected.
Structural insights into sodium transport by the oxaloacetate decarboxylase sodium pump

The oxaloacetate decarboxylase sodium pump (OAD) is a unique primary-active transporter that utilizes the free energy derived from oxaloacetate decarboxylation for sodium transport across the cell membrane. It is composed of 3 subunits: the α subunit catalyzes carboxyl-transfer from oxaloacetate to biotin, the membrane integrated β subunit catalyzes the subsequent carboxyl-biotin decarboxylation and the coupled sodium transport, the γ subunit interacts with the α and β subunits and stabilizes the OAD complex. We present here structure of the Salmonella typhimurium OAD βγ sub-complex. The structure revealed that the β and γ subunits form a β3γ3 hetero-hexamer with extensive interactions between the subunits and shed light on the OAD holo-enzyme assembly. Structure-guided functional studies provided insights into the sodium binding sites in the β subunit and the coupling between carboxyl-biotin decarboxylation and sodium transport by the OAD β subunit.
Association of Single Nucleotide Polymorphisms of the Bile Salt Export Pump Gene with Intrahepatic Cholestasis of Pregnancy

Background: We determined whether genetic variability in the gene encoding the bile salt export pump ( BSEP ) contributes to individual differences in susceptibility to the development of intrahepatic cholestasis of pregnancy (ICP). Methods: The study involved 57 affected and 115 healthy control pregnant women who were genotyped for two single nucleotide polymorphisms (SNPs) in the BSEP gene. Chi-square analysis was used to assess genotype and allele frequency differences between the cholestatic and control groups. In addition, single locus analysis was expanded to pair of loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, among the cholestatic and control groups. Estimated haplotype frequencies were assessed using the maximum-likelihood method, employing an expectation-maximization (EM) algorithm. Results: The genotype and allele frequency distribution of the two intragenic SNPs in the ICP and control groups revealed significant evidence of association with the exon 28 SNP ( P r = r 0.04 and P r = r 0.02, respectively). In addition, a borderline allele association was noted with the intron 19 SNP ( P r = r 0.08). Although the overall distribution of estimated haplotypes of intron 19 and exon 28 SNPs did not differ between the ICP and control groups, the most common haplotype, A-G, was significantly overrepresented in the ICP group ( P r = r 0.02), at an odds ratio of 1.73 (95% CI: 1.08-2.74). Conclusions: The use of two intragenic SNPs in both single locus and haplotype analyses of association suggests that the BSEP gene is a susceptibility gene in intrahepatic cholestasis of pregnancy.
Multilevel model for airborne transmission of foot-and-mouth disease applied to Swedish livestock

The foot-and-mouth disease is an ever-present hazard to the livestock industry due to the huge economic consequences following an outbreak that necessitates culling of possibly infected animals in vast numbers. The disease is highly contagious and previous epizootics have shown that it spreads by many routes. One such route is airborne transmission, which has been investigated in this study by means of a detailed multilevel model that includes all scales of an outbreak. Local spread within an infected farm is described by a stochastic compartment model while the spread between farms is quantified by atmospheric dispersion simulations using a network representation of the set of farms. The model was applied to the Swedish livestock industry and the risk for an epizootic outbreak in Sweden was estimated using the basic reproduction number of each individual livestock-holding farm as the endpoint metric. The study was based on comprehensive official data sets for both the current livestock holdings and regional meteorological conditions. Three species of farm animals are susceptible to the disease and are present in large numbers: cattle, pigs and sheep. These species are all included in this study using their individual responses and consequences to the disease. It was concluded that some parts of southern Sweden are indeed preconditioned to harbor an airborne epizootic, while the sparse farm population of the north renders such events unlikely to occur there. The distribution of the basic reproduction number spans over several orders of magnitudes with low risk of disease spread from the majority of the farms while some farms may act as very strong disease transmitters. The results may serve as basic data in the planning of the national preparedness for this type of events.
HRP2–DPF3a–BAF complex coordinates histone modification and chromatin remodeling to regulate myogenic gene transcription

Abstract Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we discover an HRP2–DPF3a–BAF epigenetic pathway that coordinates methylated histone H3 lysine 36 (H3K36me) and ATP-dependent chromatin remodeling to regulate chromatin dynamics and gene transcription during myogenic differentiation. Using siRNA screening targeting epigenetic modifiers, we identify hepatoma-derived growth factor-related protein 2 (HRP2) as a key regulator of myogenesis. Knockout of HRP2 in mice leads to impaired muscle regeneration. Mechanistically, through its HIV integrase binding domain (IBD), HRP2 associates with the BRG1/BRM-associated factor (BAF) chromatin remodeling complex by interacting directly with the BAF45c (DPF3a) subunit. Through its Pro-Trp-Trp-Pro (PWWP) domain, HRP2 preferentially binds to H3K36me2. Consistent with the biochemical studies, ChIP-seq analyses show that HRP2 colocalizes with DPF3a across the genome and that the recruitment of HRP2/DPF3a to chromatin is dependent on H3K36me2. Integrative transcriptomic and cistromic analyses, coupled with ATAC-seq, reveal that HRP2 and DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of BRG1, the ATPase subunit of the BAF complex. Taken together, these results illuminate a key role for the HRP2-DPF3a-BAF complex in the epigenetic coordination of gene transcription during myogenic differentiation.
Octahydroquinoxalin-2(1H)-One-Based Aminophosphonic Acids and Their Derivatives—Biological Activity towards Cancer Cells

In the search for new antitumor agents, aminophosphonic acids and their derivatives based on octahydroquinoxalin-2(1H)-one scaffold were obtained and their cytotoxic properties and a mechanism of action were evaluated. Phosphonic acid and phosphonate moieties increased the antiproliferative activity in comparison to phenolic Mannich bases previously reported. Most of the obtained compounds revealed a strong antiproliferative effect against leukemia cell line (MV-4-11) with simultaneous low cytotoxicity against normal cell line (mouse fibroblasts-BALB/3T3). The most active compound was diphenyl-[(1R,6R)-3-oxo-2,5-diazabicyclo[4.4. 0]dec-4-yl]phosphonate. Preliminary evaluation of the mechanism of action showed the proapoptotic effect associated with caspase 3/7 induction.
An Application of Ensemble and Deep Learning Models in Predictive Analytics

Predictive analytics stands for prediction of future demand with the help of historical data. An accurate prediction of future demand is the need for a competitive and challenging market. Thus a robust and accurate model is required to cater to such needs. This paper proposes two novel approaches for taxi demand prediction that is about to come in the next ten-minutes interval. The first model is a three-stage ensemble model for prediction where the first stage consists of data cleaning and exploratory data analysis (EDA) and then Mini-Batch K-Means clustering is applied, followed by time-binning in the second stage and in the final stage the processed data is fed to the Ensemble Model. The second model is a four-stage deep learning model where the first two stages are common as the proposed ensemble model. In the third stage, the Fourier Transform of the time series data is used to extract and add more features to the training set and in the final stage, the processed training set is fed to the deep neural network (DNN) for prediction. The NYC TLC trip dataset is used for the experiments, and the results clearly indicate that the proposed models perform better than the existing models and the deep learning model performs the best among all.
Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma.

PURPOSE Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma. METHODS We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS). RESULTS Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare. CONCLUSION Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).
Neuroprotective and Anti-Inflammatory Effects of Low–Moderate Dose Ionizing Radiation in Models of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-β (Aβ) deposition and hyperphosphorylated tau accumulation. Although several clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been identified thus far. Recently, the potential use of non-pharmacological interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients. However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been established. In this study, we examined the effect of LDIR on Aβ accumulation and Aβ-mediated pathology. To investigate the short-term effects of low–moderate dose ionizing radiation (LMDIR), a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term exposure to LMDIR did not affect Aβ accumulation in the brain, but significantly ameliorated synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and cerebral cortex. In addition, a direct neuroprotective effect was confirmed in SH-SY5Y neuronal cells treated with Aβ1–42 (2 μM) after single irradiation (1 Gy). In BV-2 microglial cells exposed to Aβ and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory molecules and activation of the nuclear factor-kappa B (NF-κB) pathway. These results indicate that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro. Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by its neuroprotective and anti-inflammatory effects.
Analysis of Effectiveness, Safety, and Bleeding Related to Rivaroxaban in Elderly Patients

This study explored the efficacy and safety of rivaroxaban in elderly patients, at different doses and age of patients, and analyzed risk factors of bleeding. A retrospective analysis was conducted of 299 patients aged 60 years or older who were admitted to the First Hospital of Jilin University between January 2016 and August 2018. It was found that the rate of bleeding events (but not embolism) significantly increased as the dose of oral rivaroxaban increased (P < .001), and with age, especially in patients aged ≥80 years (P = .001, both). The multivariate logistic regression analysis indicated that age (odds ratio [OR]: 2.963, 95% CI: 1.627-5.396) and the daily dose of rivaroxaban (OR: 2.325, 95% CI: 1.483-3.645) were independent risk factors for bleeding. The study determined that rivaroxaban anticoagulant therapy is effective in the elderly patients, but the risk of bleeding increases with age, and is a concern especially in the most old patients. The recommended daily dose of rivaroxaban is effective, but a lower dose is safer for the elderly patients.
The Psychometric Characteristic of the Taekwondo Electronic Protector Cognition Scale: The Application of the Rasch Model

This research was to investigate the psychometric characteristics of the electronic protector cognition scale by the infit and outfit of taekwondo athletes. Participants were 216 athletes (male = 109; female = 117) from 19 countries competed at the 19th Taekwondo World Championships. The electronic protector cognition scale consisting of 24-item with four subscales was utilized. The electronic protector cognition scale used a five-point Likert grading with 1 (not at all) to 5 (very likely). Analysis using IBM SPSS STATISTICS version 23 (IBM SPSS, Inc., Chicago, IL, USA) was conducted for the 226 data sets collected. WINSTEPS 3.74 (Linacre, 2015) was used for calculating subject reliability, item goodness-of-fit, scale propriety, and item level of difficulty, in order to apply the item response theory to the psychometric characteristics of electronic protectors. The research results showed that it was suitable for subject infit/outfit in taekwondo electronic protector cognition scale as 1.00~1.01 and the input/output of taekwondo electronic protector cognition scale as 1.00~1.01. Secondly, five-point scales were reviewed to be suitable for scale propriety, resulting from stage index judgment. Thirdly, 8 items showed problems in item goodness-of-fit. Finally, scale propriety was reported to be suitable considering the ability distribution of taekwondo players and the level of scale difficulty.
A Phase II Prospective, Randomized, Double‐Blind, Placebo‐Controlled and Multicenter Clinical Trial to Assess the Safety of 0.005% Estriol Vaginal Gel in Hormone Receptor‐Positive Postmenopausal Women with Early Stage Breast Cancer in Treatment with Aromatase Inhibitor in the Adjuvant Setting

Abstract Lessons Learned The levels of circulating follicle‐stimulating hormone, luteinizing hormone, estriol, estradiol, and estrone remained unchanged after a 12‐week treatment with 0.005% estriol vaginal gel in postmenopausal women receiving nonsteroidal aromatase inhibitors for hormone receptor‐positive early breast cancer. These results support the safety of 0.005% estriol vaginal gel for the treatment of bothering symptoms of vulvovaginal atrophy in breast cancer survivors. The results provide clinicians with confidence in the use of this product in women who do not experience symptom relief with nonhormonal remedies. Background Symptoms of vulvovaginal atrophy associated with treatment with nonsteroidal aromatase inhibitors (NSAIs) negatively impact patients’ quality of life and may affect adherence to NSAIs. Vaginal estrogens effectively improve these symptoms, although their safe use in breast cancer survivors remains unclear. Methods Postmenopausal women with hormone receptor‐positive early breast cancer receiving NSAI and moderate‐to‐severe vaginal dryness were randomized to 0.005% estriol vaginal gel or placebo for 12 weeks. Circulating estrogens, follicle‐stimulating hormone (FSH), and luteinizing hormone (LH), were analyzed at baseline and at weeks 1, 3, 8, and 12. The primary safety outcome was the variation in serum FSH from baseline to week 12. Results Sixty‐one women (mean age, 59 years) enrolled in the study. Small oscillations were observed in FSH and LH, although they were always maintained within the postmenopausal range. No significant differences were found in the variation of FSH and LH between baseline and week 12 from the physiological variation observed before treatment. Women receiving 0.005% estriol vaginal gel had slightly increased estriol levels at weeks 1 and 3, with a subsequent reduction until normalizing at week 12; estradiol and estrone remained the below limit‐of‐quantitation in almost all samples. Conclusion Ultralow‐dose 0.005% estriol vaginal gel did not significantly influence estrogens, FSH, and LH levels in women with breast cancer receiving NSAI. A transient negligible absorption of estriol and a nonsignificant variation of FSH after 12 weeks were observed. These findings provide confidence for the safe use of 0.005% estriol vaginal gel in women with breast cancer with an indication for treatment with vaginal estrogens.
An emerging technology in lipid research for targeting hydrophilic drugs to the skin in the treatment of hyperpigmentation disorders: kojic acid-solid lipid nanoparticles

Abstract Kojic acid (KA) as tyrosinase inhibitor shows insufficient skin penetration and several adverse events due topical administration. KA solid lipid nanoparticles (KA-SLNs) were prepared using high speed homogenisation followed by ultra-probe sonication method for improve its effectiveness. KA-SLNs was optimised by Glyceryl mono-stearate (GMS) and Cholesterol (Chol) as lipid excipients and span 60 (SP 60) and Tween 20 (Tw 20) as co-emulsifiers (particle size 156.97 ± 7.15 nm, encapsulation efficiency 59.02 ± 0.74%, drug loading 14.755 ± 1.63%, polydispersity index (PDI) of 0.388 ± 0.004 and zeta potential (ZP) of -27.67 ± 1.89 mV). Optimum formulation (KA-SLN3 dispersion) was stable at 4 and 25 °C for 3 months. Also, TEM image confirmed these results. The results of XRD, DSC and ATR-FTIR analysis indicated that KA was well encapsulated within the SLNs either in molecularly dispersed state and stabilised in amorphous form and there was no chemical interaction between drug and other ingredients. Controlled release was achieved with this formulation. KA-SLN3 dispersion have more tyrosinase inhibition potency in comparison with pure KA. Also, the results of the ex vivo and in vitro percutaneous absorption show that KA-SLN3 dispersion improved percutaneous delivery of KA as a promising and potential novel topical preparation and might open new avenues for treatment of hyperpigmentation disorders.