Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of prolonged type 2 diabetes on mitochondrial function in cerebral blood vessels.

One of the major characteristics of hyperglycemic states such as type 2 diabetes is increased reactive oxygen species generation. Since mitochondria are a major source of ROS, it is vital to understand the involvement of these organelles in the pathogenesis of ROS mediated conditions. Therefore, we investigated mitochondrial function and ROS production in cerebral blood vessels of 21-week-old Zucker diabetic fatty obese rats and their lean controls. We have previously shown that in the early stages of insulin resistance, and short periods of T2DM, only mild differences exist in mitochondrial function. In the present study, we examined mitochondrial respiration, mitochondrial protein expression, and ROS production in large surface cerebral arteries as well as within intracortical microvessels. We used 21-week-old animals exposed to peak glucose levels for seven weeks and compared them with our previous studies on younger diabetic animals. We found that the same segments of mitochondrial respiration (basal respiration and proton leak) were diminished in diabetic groups, as they were in younger diabetic animals. Levels of rattin, a rat humanin analogue, tended to decrease in the diabetic group, but did not reach statistical significance (P = 0.08). Other mitochondrial proteins were unaffected, which might indicate the existence of compensatory mechanisms with extension of this relatively mild form of diabetes. Superoxide levels were significantly higher in large cerebral vessels of diabetic animals compared with the control group. In conclusion, prolonged dietary diabetes leads to stabilization, rather than deterioration of metabolic status in the cerebral circulation, despite continued overproduction of ROS.
In Situ Synthesis of Silicon–Carbon Composites and Application as Lithium-Ion Battery Anode Materials

Silicon can be used in a variety of applications. Particularly, silicon particles are attracting increased attention as energy storage materials for lithium-ion batteries. However, silicon has a limited cycling performance owing to its peeling from the current collector and the volume expansion that occurs during alloying with lithium in the charging process. Significant contributors to this problem are the even distribution of silicon nanoparticles within the carbon matrix and their deep placement in the internal structure. In this study, we synthesized silicon nanoparticles and carbon materials via a bottom-up approach using a new method called plasma in solution. Silicon nanoparticles and the carbon matrix were synthesized in a structure similar to carbon black. It was confirmed that the silicon particles were evenly distributed in the carbon matrix. In addition, the evaluation of the electrochemical performance of the silicon–carbon matrix (Si–C) composite material showed that it exhibited stable cycling performance with high reversible capacity.
Data for the dosimetry of low- and medium-energy kV x rays

Following the publication of the ICRU Report 90 (2016) on key data for measurement standards in radiation dosimetry, where ionometric air-kerma standards for kilovoltage (kV) x-ray beams are estimated to change by up to about 0.5%, an update of the backscatter factors and water/air ratios of mass energy-absorption coefficients in kV dosimetry protocols was deemed necessary for consistency through the entire dosimetry chain. In addition, numerical methods and Monte Carlo (MC) systems that did not exist at the time when air-kerma protocols were developed, are currently available. Calculations of the chamber-independent quantities required for the dosimetry of low- and medium-energy kV x rays were carried out using a consistent set of key data throughout the complete process. The quantities were based on MC calculations of a database for a dense grid of monoenergetic photons for different beam diameters and source-to-surface distances, followed by an averaging procedure to compute water/air energy-absorption coefficient ratios and backscatter factors for 342 experimental and calculated kV spectra. It was found that for a given HVL and field size the variation of backscatter factors for different kVs can be up to about 5%, a trend confirmed with independent calculations that shows the limitation of using only the HVL for the beam quality specification of kV x rays. Extensive tables as a function of beam quality in terms of kV and HVL were developed for configurations that might be encountered in clinical practice; the data are also available in the form of a GUI web app at http://52.233. 195.208. Results were compared with data used at PTB for deriving low-energy ion chamber calibration coefficients, finding agreement within about 0.5%, and with independent full MC kerma calculations that agreed within better than about 1%. Compared with the data in the AAPM TG-61 protocol (Ma et al 2001 Med. Phys. 28 868–93) there was in general good agreement for the ratios of mass energy-absorption coefficients, although differences of up to 1.5% resulted when both kV and HVL were taken into account; more significant discrepancies, within about 2%–6%, were obtained for backscatter factors, the present values being generally higher.
Cardioprotective Melatonin: Translating from Proof-of-Concept Studies to Therapeutic Use

In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most clinical trials investigating a cardioprotective therapeutic role of melatonin are in phase 2a. Selective melatonin receptor agonists Tasimelteon, Ramelteon, and combined melatonergic-serotonin Agomelatine, and other agonists with registered structures in CHEMBL were not yet investigated as cardioprotective or cardiovascular drugs. As drug-able for these therapeutic targets, melatonin receptor agonists have the benefit over melatonin of well-characterized pharmacologic profiles and extensive safety data. Recent reports of the X-ray crystal structures of MT1 and MT2 receptors shall lead to the development of highly selective melatonin receptor agonists. Predictive models using machine learning could help to identify cardiovascular targets for melatonin. Selecting ChEMBL scores > 4.5 in cardiovascular assays, and melatonin scores > 4, we obtained 284 records from 162 cardiovascular assays carried out with 80 molecules with predicted or measured melatonin activity. Melatonin activities (agonistic or antagonistic) found in these experimental cardiovascular assays and models include arrhythmias, coronary and large vessel contractility, and hypertension. Preclinical proof-of-concept and early clinical studies (phase 2a) suggest a cardioprotective benefit from melatonin in various heart diseases. However, larger phase 3 randomized interventional studies are necessary to establish melatonin and its agonists’ actions as cardioprotective therapeutic agents.
Improvement of Epitope Prediction Using Peptide Sequence Descriptors and Machine Learning

In this work, we improved a previous model used for the prediction of proteomes as new B-cell epitopes in vaccine design. The predicted epitope activity of a queried peptide is based on its sequence, a known reference epitope sequence under specific experimental conditions. The peptide sequences were transformed into molecular descriptors of sequence recurrence networks and were mixed under experimental conditions. The new models were generated using 709,100 instances of pair descriptors for query and reference peptide sequences. Using perturbations of the initial descriptors under sequence or assay conditions, 10 transformed features were used as inputs for seven Machine Learning methods. The best model was obtained with random forest classifiers with an Area Under the Receiver Operating Characteristics (AUROC) of 0.981 ± 0.0005 for the external validation series (five-fold cross-validation). The database included information about 83,683 peptides sequences, 1448 epitope organisms, 323 host organisms, 15 types of in vivo processes, 28 experimental techniques, and 505 adjuvant additives. The current model could improve the in silico predictions of epitopes for vaccine design. The script and results are available as a free repository.
Long Noncoding RNA SChLAP1 Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma through Stabilization of ACTN4 and Activation of NF-κB Signaling

Purpose: Long noncoding RNAs (lncRNA) have essential roles in diverse cellular processes, both in normal and diseased cell types, and thus have emerged as potential therapeutic targets. A specific member of this family, the SWI/SNF complex antagonist associated with prostate cancer 1 (SChLAP1), has been shown to promote aggressive prostate cancer growth by antagonizing the SWI/SNF complex and therefore serves as a biomarker for poor prognosis. Here, we investigated whether SChLAP1 plays a potential role in the development of human glioblastoma (GBM). Experimental Design: RNA-ISH and IHC were performed on a tissue microarray to assess expression of SChLAP1 and associated proteins in human gliomas. Proteins complexed with SChLAP1 were identified using RNA pull-down and mass spectrometry. Lentiviral constructs were used for functional analysis in vitro and in vivo. Results: SChLAP1 was increased in primary GBM samples and cell lines, and knockdown of the lncRNA suppressed growth. SChLAP1 was found to bind heterogeneous nuclear ribonucleoprotein L (HNRNPL), which stabilized the lncRNA and led to an enhanced interaction with the protein actinin alpha 4 (ACTN4). ACTN4 was also highly expressed in primary GBM samples and was associated with poorer overall survival in glioma patients. The SChLAP1–HNRNPL complex led to stabilization of ACTN4 through suppression of proteasomal degradation, which resulted in increased nuclear localization of the p65 subunit of NF-κB and activation of NF-κB signaling, a pathway associated with cancer development. Conclusions: Our results implicated SChLAP1 as a driver of GBM growth as well as a potential therapeutic target in treatment of the disease.
Mammalian kinetochores count attached microtubules in a sensitive and switch-like manner

Kinetochores monitor their attachment to spindle microtubules to control spindle assembly checkpoint (SAC) signaling and cell cycle progression. Kuhn and Dumont show that individual mammalian kinetochores monitor the number of attached microtubules as a single unit in a sensitive and switch-like manner.
Association between heart rate recovery after exercise and renal function in patients referred for treadmill exercise test

Introduction Heart rate recovery (HRR) is a marker of parasympathetic activity recovery after exercise, and it is associated with cardiovascular mortality and total mortality. Impaired renal function is also associated with cardiac mortality. The aim of this study was to investigate the association between HRR after exercise and renal function in patients referred for a treadmill exercise test. Patients and methods This cross-sectional study was conducted at a regional hospital in southern Taiwan. Patients who completed a symptom-limited treadmill exercise test from January 2015 to February 2018 were recruited. Before the treadmill exercise test, patients were asked to complete a questionnaire on the past disease history and lifestyle factors. Serum creatinine measurement within two years prior to or after the date of the treadmill exercise test of the patients was also obtained from the medical records for these patients. Estimated glomerular filtration rate (eGFR) was calculated. Simple and multiple linear regression analyses were performed to investigate the association between one-minute HRR and eGFR. Results A total of 2,825 patients completed the treadmill exercise test, and serum creatinine measurement was identified from medical records for 2,153 patients (76.2%). Multiple linear regression analysis revealed that a lower eGFR was significantly associated with lower one-minute HRR (P< 0.001), adjusting for other significant independent factors, including age, waist circumference, type 2 diabetes mellitus, and smoking. Conclusions In this cross-sectional observational study, a lower eGFR was significantly and independently associated with decreased one-minute HRR, suggesting that parasympathetic activity recovery after exercise could be impaired by a decrease in renal function.
STAT5 and STAT5 Inhibitors in Hematological Malignancies.

The JAK-STAT pathway is an important physiologic regulator of different cellular functions including proliferation, apoptosis, differentiation, and immunological responses. Out of six different STAT proteins, STAT5 plays its main role in hematopoiesis and constitutive STAT5 activation seem to be a key event in the pathogenesis of several hematological malignancies. This has led many researchers to develop compounds capable of inhibiting STAT5 activation or interfering with its functions. Several anti-STAT5 molecules have shown potent STAT5 inhibitory activity in vitro. However, compared to the large amount of clinical studies with JAK inhibitors that are currently widely used in the clinics to treat myeloproliferative disorders, the clinical trials with STAT5 inhibitors are very limited. At present, a few STAT5 inhibitors are in phase I or II clinical trials for the treatment of leukemias and graft vs host disease. These studies seem to indicate that such compounds could be well tolerated and useful in reducing the occurrence of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia. Of interest, STAT5 seems to play an important role in the regulation of hematopoietic stem cell self-renewal suggesting that combination therapies including STAT5 inhibitors can erode the cancer stem cell pool and possibly open the way for the complete cancer eradication. In this review we discuss the implication of STAT5 in hematological malignancies and the results obtained with the novel STAT5 inhibitors.
Chitinase-like1 Plays a Role in Stalk Tensile Strength in Maize1

Phenotypic, histological, and biochemical characterization of loss-of-function mutant and overexpression lines of Chitinase-like1 support a role for ZmCtl1 in tensile strength enhancement in maize. Stalk lodging in maize (Zea mays) causes significant yield losses due to breaking of stalk tissue below the ear node before harvest. Here, we identified the maize brittle stalk4 (bk4) mutant in a Mutator F2 population. This mutant was characterized by highly brittle aerial parts that broke easily from mechanical disturbance or in high-wind conditions. The bk4 plants displayed a reduction in average stalk diameter and mechanical strength, dwarf stature, senescence at leaf tips, and semisterility of pollen. Histological studies demonstrated a reduction in lignin staining of cells in the bk4 mutant leaves and stalk, and deformation of vascular bundles in the stalk resulting in the loss of xylem and phloem tissues. Biochemical characterization showed a significant reduction in p-coumaric acid, Glc, Man, and cellulose contents. The candidate gene responsible for bk4 phenotype is Chitinase-like1 protein (Ctl1), which is expressed at its highest levels in elongated internodes. Expression levels of secondary cell wall cellulose synthase genes (CesA) in the bk4 single mutant, and phenotypic observations in double mutants combining bk4 with bk2 or null alleles for two CesA genes, confirmed interaction of ZmCtl1 with CesA genes. Overexpression of ZmCtl1 enhanced mechanical stalk strength without affecting plant stature, senescence, or fertility. Biochemical characterization of ZmCtl1 overexpressing lines supported a role for ZmCtl1 in tensile strength enhancement. Conserved identity of CTL1 peptides across plant species and analysis of Arabidopsis (Arabidopsis thaliana) ctl1-1 ctl2-1 double mutants indicated that Ctl1 might have a conserved role in plants.
Exploring the Lived Experiences of Staff Nurses Transitioning to the Nurse Manager Role.

OBJECTIVE The objective of this study was to discover the experience of nurse managers (NMs) who had transitioned from a staff nurse position BACKGROUND: Nurses who become NMs may receive little or no training or support during the transition process. This study sought to gain the perspective of NMs who transitioned into the role. METHODS A phenomenology method was used to interview 10 NMs regarding their experience of transitioning into the NM role. Meleis Role Transition theory provided the theoretical framework. RESULTS Five themes were identified that related to the research questions: expectations, essential knowledge and skills, graduate education prepared, sought support and mentoring from colleagues, and role mastery not possible. Participants experienced role insufficiency due to lack of support and resources. CONCLUSIONS Further research is needed to understand nurses' experience after completing an NM developmental program, contributing to role mastery.
Outcomes of transcatheter aortic valve implantation for intermediate-risk patients in Australia: the SOLACE-AU trial

Abstract Background: Few studies have examined the safety and efficacy of transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS) in Australian patients. SOLACE-AU was a single-arm, open-label clinical trial conducted in Australian hospitals to determine the safety, performance, and cost implications of TAVI in patients with severe, symptomatic AS at intermediate surgical risk. Methods: This was a prospective, pragmatic, single-arm, multi-center, observational trial of 199 patients with severe, symptomatic AS treated with transfemoral TAVI using the SAPIEN XT transcatheter heart valve (THV) at 11 hospitals in Australia. The primary outcome was Valve Academic Research Consortium-2 (VARC-2) criteria – a composite of seven safety endpoints. Kaplan–Meier (KM) estimates and descriptive analyses were used to evaluate the impact of transfemoral TAVI on safety and valve performance. We also evaluated patient health-related quality of life (QoL) and healthcare resources used throughout the trial. Results: The valve was successfully implanted in 88% of patients. The VARC-2 outcome at 30 days was 12.1% (95% CI: 8.3–17.5%), and almost 90% of patients had improved heart failure symptoms at 1 year based on New York Heart Association functional class criteria. Patient QoL remained stable over time, with mean EQ-5D-3L scores being 0.71 ± 0.20 at baseline and 0.71 ± 0.21 at 2 years. Duration of post-procedure hospitalization (mean: 6.9 ± 4.7 days) decreased as procedural familiarity increased. The median total cost of TAVI decreased 10.1% at 3 years after introduction of the procedure at the sites. Conclusions: The SOLACE-AU trial demonstrated favorable safety and performance of the SAPIEN XT valve in patients with AS at intermediate risk of surgical complications.
Psychometric properties of the perceived stigma towards substance users scale: factor structure, internal consistency, and associations with help-seeking variables

ABSTRACT Background: Stigma toward substance users is a barrier to seeking treatment. Objective: The aim for this paper was to examine the psychometric properties of the Perceived Stigma Toward Substance Users (PSAS) and its relationship with help-seeking variables. Methods: College students (N = 791; nfemales = 557, 70%) responded to the PSAS and other help-seeking-related measures in an online study. Results: Confirmatory factor analysis supported a unidimensional factor structure and acceptable model fit after modifications (CFI = .961; TLI = .937; RMSEA = .067, 90% C.I. = .050 to .085; SRMR = .035). Results indicated good internal consistency estimates (α = .80; ω = .80). The PSAS was negatively associated with intent to seek treatment for substance issues and willingness to self-disclose negative emotions. The PSAS was also positively correlated with stigma associated with seeking help for mental health issues, attitudes concerning risk associated with help-seeking, self-concealment, anticipated risks associated with seeking treatment. When embedded within a larger path model that predicts intent to seek treatment for substance use issues (CFI = .925; TLI = .895; RMSEA = .061, 90%C.I. = .052 to .069; p close fit = .019; SRMR = .049), the PSAS had an incremental contribution to predicting the criterion variable even after accounting for frequency of alcohol use-related problems, and stigma and attitudes associated with seeking help for general mental health issues. Conclusion: These findings provide further reliability and validity evidence for PSAS, especially in relation to help-seeking variables. Reducing stigma toward substance users can help increase treatment utilization.
The Plasmodium falciparum rhoptry bulb protein RAMA plays an essential role in rhoptry neck morphogenesis and host red blood cell invasion

The malaria parasite Plasmodium falciparum invades, replicates within and destroys red blood cells in an asexual blood stage life cycle that is responsible for clinical disease and crucial for parasite propagation. Invasive malaria merozoites possess a characteristic apical complex of secretory organelles that are discharged in a tightly controlled and highly regulated order during merozoite egress and host cell invasion. The most prominent of these organelles, the rhoptries, are twinned, club-shaped structures with a body or bulb region that tapers to a narrow neck as it meets the apical prominence of the merozoite. Different protein populations localise to the rhoptry bulb and neck, but the function of many of these proteins and how they are spatially segregated within the rhoptries is unknown. Using conditional disruption of the gene encoding the only known glycolipid-anchored malarial rhoptry bulb protein, rhoptry-associated membrane antigen (RAMA), we demonstrate that RAMA is indispensable for blood stage parasite survival. Contrary to previous suggestions, RAMA is not required for trafficking of all rhoptry bulb proteins. Instead, RAMA-null parasites display selective mislocalisation of a subset of rhoptry bulb and neck proteins (RONs) and produce dysmorphic rhoptries that lack a distinct neck region. The mutant parasites undergo normal intracellular development and egress but display a fatal defect in invasion and do not induce echinocytosis in target red blood cells. Our results indicate that distinct pathways regulate biogenesis of the two main rhoptry sub-compartments in the malaria parasite.