Miracle-dz/UniFAR-FTUs huggingface dataset:
SGLT2 Inhibitors: Emerging Roles in the Protection Against Cardiovascular and Kidney Disease Among Diabetic Patients

Purpose of Review Type 2 diabetes mellitus (T2DM) is a prevalent disease with the severe clinical implications including myocardial infarction, stroke, and kidney disease. Therapies focusing on glycemic control in T2DM such as biguanides, sulfonylureas, thiazolidinediones, and insulin-based regimens have largely failed to substantially improve cardiovascular and kidney outcomes. We review the recent findings on sodium-glucose co-transporter type 2 (SGLT2) inhibitors which have shown to have beneficial cardiovascular and kidney-related effects. Recent Findings SGLT2 inhibitors are a new class of diabetic medications that reduce the absorption of glucose in the kidney, decrease proteinuria, control blood pressure, and are associated with weight loss. SGLT2 inhibitors provide complementary therapy independent of insulin secretion or action with proved glucose-lowering effects. Recent placebo-controlled clinical trials have demonstrated that these medications can decrease cardiovascular death, progression of kidney disease, and all-cause mortality in diabetic and non-diabetic patients. Interestingly, SGT2 inhibitors such as dapagliflozin have also proven to decrease heart failure admissions and cardiovascular endpoints in non-diabetic patients, suggesting pleiotropic effects. The exact mechanisms responsible for reductions in atherosclerotic heart disease, need for kidney replacement therapy, and progressive kidney disease remain unknown. While regulation of glomerular hyperfiltration, albuminuria, and natriuresis may be part of the explanation, it is possible that complex cellular effects including energy balance optimization, downregulation of oxidative stress, and modulation of pro-inflammatory signaling pathways are associated with favorable outcomes observed in large clinical studies. Conclusion SGLT2 inhibitors are novel antidiabetic medications with immense utility in the management of patients with T2DM. Furthermore, SGLT2 inhibitors have demonstrated to reduce the progression to advanced forms of kidney disease and its associated complications. These medications should be front and center in the management of patients with diabetic kidney disease with and without chronic kidney disease as they confer protection against cardiovascular/renal death and improve all-cause mortality. Future studies should evaluate the benefits and implications of early initiation of SGLT2 inhibitors, as well as the long-term effects of this therapy.
Bilirubin Can Be Used as a Prognostic Factor for Lung Adenocarcinoma Patients with EGFR Mutations

Background and Objectives Non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation demonstrate only a median progression-free survival (PFS) of 8 to 10 months and undergo EGFR tyrosine kinase inhibitors (EGFR-TKIs) therapy. For decades, bilirubin has been reported to be associated with the onset and prognosis of lung cancer as a prooxidant. This study aimed to investigate the prediction of pretreatment circulating bilirubin for PFS in lung adenocarcinoma (LAC) patients who underwent EGFR-TKIs targeted therapy. Patients and Methods LAC cases diagnosed and undergone EGFR-TKIs targeted therapy at The First Affiliated Hospital of Zhengzhou University between 2013 and 2015 were retrospectively reviewed. A total of 180 patients were studied according to inclusion and exclusion criteria. Follow-up data were collected for all patients until the disease progressed. Results Univariate analysis showed that the levels of pretreatment total bilirubin (TBIL), indirect bilirubin (IBIL) and direct bilirubin (DBIL) were related to PFS (all p<0.05). Considering the close relationship among the three factors, we combined TBIL, IBIL and DBIL into one total factor, which is called bilirubin. Kaplan–Meier survival curves and Log rank tests indicated that patients with lower bilirubin levels had a shorter median PFS than those with higher bilirubin levels (8 vs. 15 months; p=0.002). Multivariate analysis demonstrated that pretreatment bilirubin is an independent prognostic factor (HR=0.454, CI: 0.267–0.773, p=0.004). Conclusion This study confirms that bilirubin can predict the prognosis of LAC patients who had undergone EGFR-TKIs targeted therapy.
LncRNA MEG3 Reduces Hippocampal Neuron Apoptosis via the PI3K/AKT/mTOR Pathway in a Rat Model of Temporal Lobe Epilepsy

Purpose Temporal lobe epilepsy (TLE) is a common neurological disorder, which is characterized by recurrent spontaneous seizures. Exploring the mechanisms of epileptogenesis has been considered as a priority. The aim of this study is to investigate the effects of LncRNA MEG3 in spontaneous recurrent epileptiform discharges (SREDs) and rats with TLE. Methods Rat model of TLE was produced by intraperitoneal injection of lithium chloride and pilocarpine. Rat hippocampal neuronal model of SREDs was established by Mg2+-free treatment. MEG3 was overexpressed by transfection of AAV-MEG3 in TLE and SREDs model. The expression of MEG3, interleukin-1β (IL-1β), interleukin-6 (IL-6) and recombinant human tumor necrosis factor-alpha (TNF-α) was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were detected by corresponding kit. The apoptosis of hippocampal neurons was detected by terminal deoxynucleotidyl transferase transfer‑mediated dUTP nick end‑labeling (TUNEL) assay and flow cytometry. The expression of proteins related to apoptosis (Caspase-3, Bax, and Bcl-2) and the PI3K/AKT/mTOR pathway was detected by Western blot. Results MEG3 expression was downregulated in SREDs and rats with TLE. Overexpression of MEG3 reduced the expression of IL-1β, IL-6, and TNF-α, MDA content, apoptosis rate of hippocampal neuron, increased SOD activity, and inhibited the PI3K/AKT/mTOR pathway in rats with TLE. In addition, overexpression of MEG3 enhanced cell viability and inhibited apoptosis through the activation of the PI3K/AKT/mTOR pathway in SREDs. Conclusion MEG3 reduced proinflammatory cytokines, oxidative stress, and apoptosis rate of hippocampal neuron and enhanced cell viability through the activation of the PI3K/AKT/mTOR pathway in SREDs and rats with TLE. Our findings may contribute to find a new therapeutic target for the treatment of epilepsy.
Asymptomatic Hyperuricemia Associates with Cardiometabolic Risk Indicators in Overweight/Obese but Not in Lean Adolescents

Purpose In overweight/obese adolescents, asymptomatic hyperuricemia is associated with increased prevalence of metabolic syndrome, its components, and a higher cardiometabolic risk. Whether similar associations exist in lean hyperuricemic adolescents is unknown. Subjects and Methods In 2424 adolescents (51.9% females) aged 16–19 years, anthropometric variables, blood pressure, uric acid, glucose, insulin, lipid profile, inflammatory markers, and renal function were determined. Continuous cardiometabolic score was calculated. Normouricemic vs hyperuricemic subjects were compared among lean and overweight/obese individuals of both sexes. Results Females (5.4%) and males (13.3%) presented with hyperuricemia; among them 63% of females and 53% of males were lean. In both sexes, hyperuricemic lean and hyperuricemic overweight/obese adolescents displayed similar uric acid concentrations (eg, males: 455±30 vs 461±32 µmol/L, respectively, p=0.933). Lean normouricemic adolescents manifested significantly lower uric acid levels than their overweight/obese peers (eg, males: 333±46 vs 357±41 µmol/L, respectively, p<0.001). Lean normouricemic and hyperuricemic subjects presented similar cardiometabolic score (eg, males: 2.60±0.67 vs 2.64±0.60, respectively, p=0.998); among overweight/obese adolescents those with hyperuricemia displayed higher scores compared with their normouricemic counterparts (eg, males: 3.36±1.04 vs 4.21±1.65, respectively, p<0.001). A decision-tree model revealed phenotypes associated with higher uricemia, however, distribution of individuals with hyperuricemia among phenotypes was random. Conclusion In lean adolescents, hyperuricemia is not associated with cardiometabolic profile indicating an increased risk. Existence of this rather prevalent phenotype remains undetected unless lean and overweight/obese subjects are analyzed separately. Longitudinal studies are needed to elucidate the potential clinical consequences of asymptomatic hyperuricemia in lean subjects in later life.
Comparison of Hemodialysis Using a Medium Cutoff Dialyzer versus Hemodiafiltration: A Controlled Cross-Over Study

Purpose Conventional hemodialysis (HD) treatment has an acceptable removal of small uremic molecules, but so-called “middle molecules” in the range of 0.5–60 kDa are poorly cleared with HD compared to a native kidney, which may contribute to morbidity in the dialysis population. Hemodiafiltration (HDF) has a better removal of middle molecules compared to HD but is technically demanding and requires well-functioning dialysis access. The newly introduced medium cutoff (MCO) filters have been developed to enhance middle molecule clearance in HD-mode. The aim of this study was to compare reduction ratios (RRs) of molecules with different molecular weights (0.06–150 kDa) during dialysis with MCO dialyzer (used in HD-mode) compared to online-hemodiafiltration (ol-HDF) treatment with a conventional high-flux dialyzer. Patients and Methods This is a prospective controlled single-center cross-over study, including 16 patients in Malmö, Sweden. All patients had ongoing post-dilution ol-HDF treatment before the study. The study compared reduction ratios of small-, middle-, and large-sized molecules during a single 4h dialysis treatment with post-dilution ol-HDF (Polyflux 210H) to a 4h dialysis treatment with MCO dialyzer (Theranova 500) in HD-mode. Between treatments, the patients had a washout period of at least two weeks of their ordinary HDF treatment to reach their ordinary steady state. Results ol-HDF had significantly higher RR for cystatin C (13 kDa), compared to MCO (RR 68.1 vs 65.8, p=0.003), during a 4h dialysis treatment (mean convection volume of 24.5 L for HDF, and mean Qb of 324 mL/min for HDF and 323 mL/min for MCO). There was no significant difference in the RR for other middle molecules, or for smaller or larger molecules. Conclusion Overall, the RRs were comparable for ol-HDF and MCO-HD. There was a slightly higher RR of cystatin C (a small middle molecule) for HDF compared to MCO but no difference in other measured molecules.
Visual duration bisection in profoundly deaf individuals

Background Previous research has been designed to study the effect of hearing loss on supra-second duration estimation in the visual channel and position effect of visual abilities among deaf populations. The current study aimed to investigate the sub-second duration perception of different visual fields in profoundly deaf individuals. Methods A total of 16 profoundly deaf undergraduates and 16 hearing undergraduates completed a visual duration bisection task in which participants made judgments about whether a series of probe durations that were linearly spaced from 200 ms to 800 ms at 100 ms intervals were more similar to a standard short duration (200 ms) or a standard long duration (800 ms). The probe stimuli were presented in the center, left, or right of the screen. A repeated measure analysis of variance (ANOVA) with a between-participants factor of group and a within-participants factor of position, and a one-sample t-test were conducted. Results The Weber ratio (WR) values of deaf participants were significantly higher than those of hearing participants, regardless of the presented positions of the visual stimulus. The bisection point (BP) value of deaf participants was significantly lower than 500 ms (average mean of 200/800 ms) and the BP value of hearing participants did not significantly differ from 500 ms, although the overall difference of BP values between the deaf group and hearing group did not reach significance. For deaf participants, the BP value in the center condition was significantly lower than 500 ms; however, the difference between the BP value in the left condition and 500 ms did not reach significance, indicating that their duration discrimination accuracy in the left visual field was better than that in the center visual field. Conclusions Hearing loss impaired visual sub-second duration perception, and deaf individuals showed a left visual field advantage of duration discrimination accuracy during the visual duration bisection task.
Constitution of a comprehensive phytochemical profile and network pharmacology based investigation to decipher molecular mechanisms of Teucrium polium L. in the treatment of type 2 diabetes mellitus

Background Type 2 diabetes mellitus (T2DM) is a metabolic disease affecting a huge population worldwide. Teucrium polium L. has been used as a folk medicine for the treatment of T2DM in Anatolia, Turkey. The antihyperglycemic effect of the plant was reported previously. However, there was no detailed study on the underlying molecular mechanisms. In this study, we generated a research plan to clarify the active constituents of the extract and uncover the molecular mechanisms using network pharmacology analysis. Methods For this purpose, we composed a dataset of 126 compounds for the phytochemical profile of the aerial parts of T. polium. Drug-likeness of the compounds was evaluated, and 52 compounds were selected for further investigation. A total of 252 T2DM related targets hit by selected compounds were subjected to DAVID database. Results The KEGG pathway analysis showed enrichment for the TNF signaling pathway, insulin resistance, the HIF-1 signaling pathway, apoptosis, the PI3K-AKT signaling pathway, the FOXO signaling pathway, the insulin signaling pathway, and type 2 diabetes mellitus which are related to T2DM . AKT1, IL6, STAT3, TP53, INS, and VEGFA were found to be key targets in protein-protein interaction. Besides these key targets, with this study the role of GSK3β, GLUT4, and PDX1 were also discussed through literature and considered as important targets in the antidiabetic effect of T. polium. Various compounds of T. polium were shown to interact with the key targets activating PI3K-AKT and insulin signaling pathways. Conclusions According to these findings, mainly phenolic compounds were identified as the active components and IRS1/PI3K/AKT signaling and insulin resistance were identified as the main pathways regulated by T. polium. This study reveals the relationship of the compounds in T. polium with the targets of T2DM in human. Our findings suggested the use of T. polium as an effective herbal drug in the treatment of T2DM and provides new insights for further research on the antidiabetic effect of T. polium.
Effect of L-carnitine on health-related quality of life in patients with liver cirrhosis

L-carnitine (4-N-trimethylammonium-3-hydroxybutyric acid) is the physiologically active form of carnitine and is a natural compound that has been shown to exhibit antioxidant activity. L-carnitine is used as a supplementary treatment in patients with cirrhosis with hepatic encephalopathy, hyperammonemia or muscle cramps. In the present study, the effect of L-carnitine supplementation on health-related quality of life in 30 patients with cirrhosis was prospectively examined. L-carnitine (1,800 mg/day) was administered orally for 6 months. To assess the effects of L-carnitine on chronic fatigue, patients filled out a self-report questionnaire regarding their physical and mental health. The levels of total and free carnitine, and acylcarnitine were found to be significantly higher 1, 3 and 6 months after therapy initiation compared with before treatment. Serum albumin levels were significantly increased 3 and 6 months after initiation of therapy. L-carnitine supplementation significantly increased the BAP/d-ROM ratio, a marker of antioxidant status in patients with cirrhosis. Changes in serum carnitine concentrations were positively correlated with changes in serum albumin levels (R2=0.369; P=0.012), but not with changes in serum ammonia levels (R2= 0.005; P=0.78). Total and mental health scores improved significantly, and physical scores improved marginally 3 and 6 months after initiation of L-carnitine. These findings may be attributed to the enhanced serum albumin levels and oxidative stress rather than the reduced serum ammonia levels. Based on these results, it is suggested that L-carnitine can potentially alleviate chronic fatigue, along with the increased BAP/d-ROM ratio, which were involved in increased oxidative stress in patients with cirrhosis. The specific mechanisms by which L-carnitine ameliorates chronic fatigue is not fully understood and requires further investigation.
Research on the Impact and Mechanism for the Inhibition of Micrococcus Catalase Activity by Typical Tetracyclines

As potential inhibitors target to biological enzymes, antibiotics may have certain impacts on the biochemical treatment process. With micrococcus catalase (CAT) served as the target molecule, the impact and inhibition mechanism for typical tetracyclines (TCs) were evaluated. Toxicity experiments showed that TCs had significant inhibition on CAT in the sequence of tetracycline>chlortetracycline>oxytetracycline>doxycycline. To clarify the inhibition mechanism between TCs and CAT which was explored with the assistance of fluorescence spectroscopy and MOE molecule simulation. According to fluorescence analysis, TCs quenched the fluorescence signal of CAT by the mode of static quenching. Combined with toxicity data, it could be presumed that TCs combined with the catalytic active center and thus inhibited CAT. Above presumption was further verified by the molecular simulation data. When TCs combined with the catalytic center of CAT, the compounds have increased combination areas and prominent energy change (compared with the compounds formed by TCs and noncatalytic center recommend by MOE software). IBM SPSS statistics showed that TC toxicity positively correlated with the hydrogen bonds such as O13→Glu252, O1←Arg195, and O6→Asp249, but negatively correlated with the hydrogen bonds such as O10→Pro363, O10→Lys455, and O12 → Asn127. TC toxicity also positively correlated with the ion bonds ofN4-Glu252, but negatively correlated with the ion bonds of N4-Asp379. Hydrogen bonds and ion bonds for above key sites were closely related to the inhibition effect of TCs on CAT.
Fitness outcomes in relation to individual variation in constitutive innate immune function

Although crucial for host survival when facing persistent parasite pressure, costly immune functions will inevitably compete for resources with other energetically expensive traits such as reproduction. Optimizing, but not necessarily maximizing, immune function might therefore provide net benefit to overall host fitness. Evidence for associations between fitness and immune function is relatively rare, limiting our potential to understand ultimate fitness costs of immune investment. Here, we assess how measures of constitutive immune function (haptoglobin, natural antibodies, complement activity) relate to subsequent fitness outcomes (survival, reproductive success, dominance acquisition) in a wild passerine (Malurus coronatus). Surprisingly, survival probability was not positively linearly predicted by any immune index. Instead, both low and high values of complement activity (quadratic effect) were associated with higher survival, suggesting that different immune investment strategies might reflect a dynamic disease environment. Positive linear relationships between immune indices and reproductive success suggest that individual heterogeneity overrides potential resource reallocation trade-offs within individuals. Controlling for body condition (size-adjusted body mass) and chronic stress (heterophil-lymphocyte ratio) did not alter our findings in a sample subset with available data. Overall, our results suggest that constitutive immune components have limited net costs for fitness and that variation in immune maintenance relates to individual differences more closely.
Multivariate Visualization of Game Metrics: An Evaluation of Hexbin Maps

Visualizations have become a relevant instrument in games user research and analytics as well as for players to facilitate the analysis of behavioral data, including the evaluation of spatial game metrics. A fundamental task in this respect is to understand how different metrics vary across the game environment and how they relate to each other. In this paper, we evaluate a visualization based on hexagonal binning paired with visual glyphs to represent multivariate information. To study how much information can be encoded in a reasonable manner we created variants with varying complexity and measured correctness and efficiency for different types of tasks through an online study (N = 197). Our results indicate that players appreciated the clear display of multivariate data but that correctness and efficiency were also largely influenced by the visual coding and the task at hand. Based on gained insights, we discuss implications for the design of such and similar gameplay visualizations.
IGF Bioregulation System in Benign and Malignant Thyroid Nodular Disease: A Systematic Review

Background/Aim: The insulin-like growth factor bioregulation system is implicated in cancer biology. Herein, we aim to review the evidence on the expression of the insulin-like growth factor 1 and 2 (IGF1 and IGF2), their receptors (IGF-Rs) and IGF-binding proteins (IGFBPs) in thyroid tissue and their possible association with benign and malignant thyroid nodular diseases. Materials and Methods: We systematically reviewed Pubmed and Scopus databases up to May 2020. A total of 375 articles were retrieved and analyzed. Results: Among 375 articles, 45 were included in this systematic review study. IGF1 was investigated in 31 studies, IGF2 in 1, IGF1 receptor in 15 and IGF-binding proteins in 13 articles. IGF1 expression in humans was dependent on the number and compound of benign nodules as well as the method of measurement. In differentiated thyroid carcinoma, a positive correlation between IGF1 and immunohistological stage was documented in some studies while in others only a positive trend was observed. IGF-1R and IGFBPs expression was higher in malignant rather than benign lesions. There was only a positive trend for increased IGF2 expression in malignancy, while IGFBPs were in most studies statistically increased in various cancer types compared to benign nodular disease. Conclusion: The present data demonstrate that in most studies there is statistically positive expression of IGF-1 and less of IGF-2 in thyroid cancer compared to normal thyroid tissue.
"Let's Get Physiological, Physiological!": A Systematic Review of Affective Gaming

Physiological sensing has been a prominent fixture in games user research (GUR) since the late 1990s, when researchers started to explore its potential to enhance and understand experience within digital game play. Since these early days, is has been widely argued that "affective gaming"---in which gameplay is influenced by a player's emotional state---can enhance player experience by integrating physiological sensors into play. Reflecting in 2020 on these last 20 years of progress, we systematically review the field of affective gaming to answer whether or not it has met this promise. We create a framework (the affective game loop) to classify 162 publications (included from an initial search set of 52,834 results) within affective gaming, present findings on the current state of the field, and discuss how our findings, contextualized within the affective game loop, can guide the future of affective gaming.