Miracle-dz/UniFAR-FTUs huggingface dataset:
Transcription Factor EB Activation Rescues Advanced αB‐Crystallin Mutation‐Induced Cardiomyopathy by Normalizing Desmin Localization

Background Mutations in αB‐crystallin result in proteotoxic cardiomyopathy with desmin mislocalization to protein aggregates. Intermittent fasting (IF) is a novel approach to activate transcription factor EB (TFEB), a master regulator of the autophagy‐lysosomal pathway, in the myocardium. We tested whether TFEB activation can be harnessed to treat advanced proteotoxic cardiomyopathy. Methods and Results Mice overexpressing the R120G mutant of αB‐crystallin in cardiomyocytes (Myh6‐CryABR120G) were subjected to IF or ad‐lib feeding, or transduced with adeno‐associated virus–TFEB or adeno‐associated virus—green fluorescent protein after development of advanced proteotoxic cardiomyopathy. Adeno‐associated virus–short hairpin RNA–mediated knockdown of TFEB and HSPB8 was performed simultaneously with IF. Myh6‐CryABR120G mice demonstrated impaired autophagic flux, reduced lysosome abundance, and mammalian target of rapamycin activation in the myocardium. IF resulted in mammalian target of rapamycin inhibition and nuclear translocation of TFEB with restored lysosome abundance and autophagic flux; and reduced aggregates with normalized desmin localization. IF also attenuated left ventricular dilation and myocardial hypertrophy, increased percentage fractional shortening, and increased survival. Adeno‐associated virus–TFEB transduction was sufficient to rescue cardiomyopathic manifestations, and resulted in reduced aggregates and normalized desmin localization in Myh6‐CryABR120G mice. CryABR120G‐expressing hearts demonstrated increased interaction of desmin with αB‐crystallin and reduced interaction with chaperone protein, HSPB8, compared with wild type, which was reversed by both IF and TFEB transduction. TFEB stimulated autophagic flux to remove protein aggregates and transcriptionally upregulated HSPB8, to restore normal desmin localization in CryABR120G‐expressing cardiomyocytes. Short hairpin RNA–mediated knockdown of TFEB and HSPB8 abrogated IF effects, in vivo. Conclusions IF and TFEB activation are clinically relevant therapeutic strategies to rescue advanced R120G αB‐crystallin mutant‐induced cardiomyopathy by normalizing desmin localization via autophagy‐dependent and autophagy‐independent mechanisms.
Evolution of an insect immune barrier through horizontal gene transfer mediated by a parasitic wasp

Genome sequencing data have recently demonstrated that eukaryote evolution has been remarkably influenced by the acquisition of a large number of genes by horizontal gene transfer (HGT) across different kingdoms. However, in depth-studies on the physiological traits conferred by these accidental DNA acquisitions are largely lacking. Here we elucidate the functional role of Sl gasmin, a gene of a symbiotic virus of a parasitic wasp that has been transferred to an ancestor of the moth species Spodoptera littoralis and domesticated. This gene is highly expressed in circulating immune cells (haemocytes) of larval stages, where its transcription is rapidly boosted by injection of microorganisms into the body cavity. RNAi silencing of Sl gasmin generates a phenotype characterized by a precocious suppression of phagocytic activity by haemocytes, which is rescued when these immune cells are incubated in plasma samples of control larvae, containing high levels of the encoded protein. Proteomic analysis demonstrates that the protein Sl gasmin is released by haemocytes into the haemolymph, where it opsonizes the invading bacteria to promote their phagocytosis, both in vitro and in vivo. Our results show that important physiological traits do not necessarily originate from evolution of pre-existing genes, but can be acquired by HGT events, through unique pathways of symbiotic evolution. These findings indicate that insects can paradoxically acquire selective advantages with the help of their natural enemies.
Paradoxical Roles of Oxidative Stress Response in the Digestive System before and after Carcinogenesis

Oxidative stress is recognized as a cancer-initiating stress response in the digestive system. It is produced through mitochondrial respiration and induces DNA damage, resulting in cancer cell transformation. However, recent findings indicate that oxidative stress is also a necessary anticancer response for destroying cancer cells. The oxidative stress response has also been reported to be an important step in increasing the anticancer response of newly developed molecular targeted agents. Oxidative stress might therefore be a cancer-initiating response that should be downregulated in the precancerous stage in patients at risk of cancer but an anticancer cell response that should not be downregulated in the postcancerous stage when cancer cells are still present. Many commercial antioxidant agents are marketed as “cancer-eliminating agents” or as products to improve one’s health, so cancer patients often take these antioxidant agents. However, care should be taken to avoid harming the anticancerous oxidative stress response. In this review, we will highlight the paradoxical effects of oxidative stress and antioxidant agents in the digestive system before and after carcinogenesis.
Short pressure reactivity index versus long pressure reactivity index in the management of traumatic brain injury.

OBJECT The pressure reactivity index (PRx) correlates with outcome after traumatic brain injury (TBI) and is used to calculate optimal cerebral perfusion pressure (CPPopt). The PRx is a correlation coefficient between slow, spontaneous changes (0.003-0.05 Hz) in intracranial pressure (ICP) and arterial blood pressure (ABP). A novel index-the so-called long PRx (L-PRx)-that considers ABP and ICP changes (0.0008-0.008 Hz) was proposed. METHODS The authors compared PRx and L-PRx for 6-month outcome prediction and CPPopt calculation in 307 patients with TBI. The PRx- and L-PRx-based CPPopt were determined and the predictive power and discriminant abilities were compared. RESULTS The PRx and L-PRx correlation was good (R = 0.7, p < 0.00001; Spearman test). The PRx, age, CPP, and Glasgow Coma Scale score but not L-PRx were significant fatal outcome predictors (death and persistent vegetative state). There was a significant difference between the areas under the receiver operating characteristic curves calculated for PRx and L-PRx (0.61 ± 0.04 vs 0.51 ± 0.04; z-statistic = -3.26, p = 0.011), which indicates a better ability by PRx than L-PRx to predict fatal outcome. The CPPopt was higher for L-PRx than for PRx, without a statistical difference (median CPPopt for L-PRx: 76.9 mm Hg, interquartile range [IQR] ± 10.1 mm Hg; median CPPopt for PRx: 74.7 mm Hg, IQR ± 8.2 mm Hg). Death was associated with CPP below CPPopt for PRx (χ(2) = 30.6, p < 0.00001), and severe disability was associated with CPP above CPPopt for PRx (χ(2) = 7.8, p = 0.005). These relationships were not statistically significant for CPPopt for L-PRx. CONCLUSIONS The PRx is superior to the L-PRx for TBI outcome prediction. Individual CPPopt for L-PRx and PRx are not statistically different. Deviations between CPP and CPPopt for PRx are relevant for outcome prediction; those between CPP and CPPopt for L-PRx are not. The PRx uses the entire B-wave spectrum for index calculation, whereas the L-PRX covers only one-third of it. This may explain the performance discrepancy.
DNA Repair Gene ZmRAD51A Improves Rice and Arabidopsis Resistance to Disease

RAD51 (DNA repair gene) family genes play ubiquitous roles in immune response among species from plants to mammals. In this study, we cloned the ZmRAD51A gene (a member of RAD51) in maize and generated ZmRAD51A overexpression (ZmRAD51A-OE) in rice, tobacco, and Arabidopsis. The expression level of ZmRAD51A was remarkably induced by salicylic acid (SA) application in maize, and the transient overexpression of ZmRAD51A in tobacco induced a hypersensitive response. The disease resistance was significantly enhanced in ZmRAD51A- OE (overexpressing) plants, triggering an increased expression of defense-related genes. High-performance liquid chromatography (HPLC) analysis showed that, compared to control lines, ZmRAD51A-OE in rice plants resulted in higher SA levels, and conferred rice plants resistance to Magnaporthe oryzae. Moreover, the ZmRAD51A-OE Arabidopsis plants displayed increased resistance to Pseudomonas syringae pv. tomato DC3000 when compared to wild types. Together, our results provide the evidence that, for the first time, the maize DNA repair gene ZmRAD51A plays an important role in in disease resistance.
Utility of optical coherence tomography angiography in detecting vascular retinal damage caused by arterial hypertension

Objective: To evaluate the potential utility of perfusion density measurements to discriminate patients with arterial hypertension by cardiovascular risk category. Methods: In this cross-sectional study, one eye per subject was evaluated (N = 73). The study cohort was divided into three groups according to the clinical criteria established by the European Guidelines for Arterial Hypertension: 26 controls, 24 patients with low cardiovascular risk, and 23 patients with very high cardiovascular risk. All patients were examined using RS-3000 Advance optical coherence tomography angiography to analyze macular and peripapillary perfusion density. Results: There were no differences among the three risk groups by sex or age. Decreased macular perfusion density was found at the level of the superficial and deep plexuses (p ⩽ 0.047). No differences were observed in peripapillary perfusion density (p = 0.18). Conclusion: Optical coherence tomography angiography can detect changes in macular perfusion density in patients with hypertension and high cardiovascular risk and might represent a supportive imaging method in the evaluation of the cardiovascular risk in hypertensive patients.
Integrating mental health and disaster preparedness in intervention: a randomized controlled trial with earthquake and flood-affected communities in Haiti

Abstract Background Given the frequency of natural hazards in Haiti, disaster risk reduction is crucial. However, evidence suggests that many people exposed to prior disasters do not engage in disaster preparedness, even when they receive training and have adequate resources. This may be partially explained by a link between mental health symptoms and preparedness; however, these components are typically not integrated in intervention. Methods The current study assesses effectiveness of an integrated mental health and disaster preparedness intervention. This group-based model was tested in three earthquake-exposed and flood-prone communities (N = 480), across three time points, using a randomized controlled trial design. The 3-day community-based intervention was culturally-adapted, facilitated by trained Haitian lay mental health workers, and focused on enhancing disaster preparedness, reducing mental health symptoms, and fostering community cohesion. Results Consistent with hypotheses, the intervention increased disaster preparedness, reduced symptoms associated with depression, post-traumatic stress disorder, anxiety, and functional impairment, and increased peer-based help-giving and help-seeking. Mediation models indicated support for the underlying theoretical model, such that the effect of the intervention on preparedness was mediated by mental health, and that effects on mental health were likewise mediated by preparedness. Conclusions The community-based mental health-integrated disaster preparedness intervention is effective in improving mental health and preparedness among community members in Haiti vulnerable to natural hazards. This brief intervention has the potential to be scaled up for use with other communities vulnerable to earthquakes, seasonal flooding, and other natural hazards.
Impact of a Usual Serving Size of Flavanol-Rich Cocoa Powder Ingested with a Diabetic-Suitable Meal on Postprandial Cardiometabolic Parameters in Type 2 Diabetics—A Randomized, Placebo-Controlled, Double-Blind Crossover Study

Randomized controlled trials indicate that flavanol-rich cocoa intake may improve postprandial glucose and lipid metabolism in patients with type 2 diabetes (T2D), based on studies with meals that impose a strong metabolic load. Hence, the aim of the present study was to investigate whether flavanol-rich cocoa powder ingested as part of a diabetic-suitable meal may beneficially affect glucose, lipid metabolism, and blood pressure (BP) in patients with T2D. Twelve adults with T2D, overweight/obesity, and hypertension ingested capsules with 2.5 g of flavanol-rich cocoa or microcrystalline cellulose with a diabetic-suitable breakfast in a randomized, placebo-controlled, double-blind crossover study. BP was measured and blood samples were taken before, 2 and 4 h after breakfast and capsule intake. Cocoa treatment did not affect glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-IR), triglycerides, total cholesterol, low density lipoprotein-cholesterol, high density lipoprotein-cholesterol, and BP. For glucose, insulin and HOMA-IR, only effects by time were observed after both treatments. Thus, 2.5 g of flavanol-rich cocoa powder ingested as part of a diabetic-suitable meal does not seem to affect postprandial glucose and lipid metabolism and BP in stably-treated diabetics. Nevertheless, future studies with close-meshed investigations are desirable, providing realistic amounts of cocoa together with realistic meals rich in carbohydrates to subjects with T2D or metabolic syndrome, which do not afford pharmacological treatment.
U2AF65 enhances milk synthesis and growth of bovine mammary epithelial cells by positively regulating the mTOR‐SREBP‐1c signalling pathway

U2 snRNP auxiliary factor 65 kDa (U2AF65) is a splicing factor that promotes prespliceosome assembly. The function of U2AF65 in alternative splicing has been identified; however, the essential physiological role of U2AF65 remains poorly understood. In this study, we investigated the regulatory role of U2AF65 in milk synthesis and growth of bovine mammary epithelial cells (BMECs). Our results showed that U2AF65 localizes in the nucleus. Treatment with amino acids (Met and Leu) and hormones (prolactin and β‐estradiol) upregulated the expression of U2AF65 in these cells. U2AF65 overexpression increased the synthesis of β‐casein, triglycerides, and lactose; increased cell viability; and promoted proliferation of BMECs. Furthermore, our results showed that U2AF65 positively regulated mTOR phosphorylation and expression of mature mRNA of mTOR and SREBP‐1c. Collectively, our findings demonstrate that U2AF65 regulates the mRNA expression of signalling molecules (mTOR and SREBP‐1c) involved in milk synthesis and growth of BMECs, possibly via controlling the splicing and maturation of these mRNAs. U2 snRNP auxiliary factor 65 kDa (U2AF65) is a splicing factor that promotes prespliceosome assembly. The essential physiological role of U2AF65 remains poorly understood. In the present study, we confirmed that U2AF65 functions as a positive regulator of milk synthesis in and proliferation of bovine mammary epithelial cells via the mTOR‐SREBP‐1c signalling pathway. Therefore, our study uncovers the regulatory role of U2AF65 in milk synthesis and cell proliferation.
Differences in Clinical Manifestations, Antimicrobial Susceptibility Patterns, and Mutations of Fluoroquinolone Target Genes between Chryseobacterium gleum and Chryseobacterium indologenes

Chryseobacterium infections are uncommon, and previous studies have revealed that Chryseobacterium gleum is frequently misidentified as Chryseobacterium indologenes. We aimed to explore the differences in clinical manifestations and antimicrobial susceptibility patterns between C. gleum and C. indologenes. ABSTRACT Chryseobacterium infections are uncommon, and previous studies have revealed that Chryseobacterium gleum is frequently misidentified as Chryseobacterium indologenes. We aimed to explore the differences in clinical manifestations and antimicrobial susceptibility patterns between C. gleum and C. indologenes. The database of a clinical microbiology laboratory was searched to identify patients with Chryseobacterium infections between 2005 and 2017. Species were reidentified using 16S rRNA gene sequencing, and patients with C. gleum and C. indologenes infections were included in the study. A total of 42 C. gleum and 84 C. indologenes isolates were collected from consecutive patients. A significant increase in C. indologenes incidence was observed. C. gleum was significantly more associated with bacteremia than C. indologenes. Patients with C. gleum infections had more comorbidities of malignancy and liver cirrhosis than those with C. indologenes infections. The overall case fatality rate was 19.8%. Independent risk factors for mortality were female sex and C. indologenes infection. These isolates were most susceptible to minocycline (73%), followed by trimethoprim-sulfamethoxazole (47.6%), tigecycline (34.1%), and levofloxacin (32.5%). C. gleum exhibited a significantly higher rate of susceptibility than C. indologenes to piperacillin, piperacillin-tazobactam, ceftazidime, tigecycline, and levofloxacin. Alterations in DNA gyrase subunit A were identiﬁed to be associated with fluoroquinolone resistance in C. indologenes. No nonsynonymous substitutions were observed in the quinolone resistance-determining regions (QRDRs) of C. gleum. Differences in epidemiology, clinical manifestations, and antimicrobial susceptibility patterns exist between C. gleum and C. indologenes. Additional investigations are needed to explore the significance of these differences.
Cumulative Toxicity in Targeted Therapies: What to Expect at the Recommended Phase II Dose.

BACKGROUND In the era of molecularly targeted agents (MTAs), it is recommended to account for toxicity over several cycles to identify the recommended phase II dose (RP2D). We investigated the relationship between the risk of toxicity at cycle 1 and the cumulative incidence of toxicity over subsequent cycles in trials of single MTAs. METHODS On individual patient data from 26 phase I clinical trials of single MTAs provided by the National Cancer Institute, we estimated the probability of first-severe toxicity per treatment cycle as well as the cumulative incidence at, below and above the maximum tolerated dose (MTD). Toxicity was further sub-classified into non-hematologic and hematologic. A prediction table was developed to estimate the cumulative incidence up to six cycles based on the toxicity rate observed in the first cycle. RESULTS Overall, 942 patients were included. For patients treated at the MTD, the probability of first-severe toxicity decreased from 24.8% (95% prediction interval [PI]: 20.3% to 32.9%) to 2.2% (95% PI: 0.1% to 7.7%) from cycle 1 to 6, whereas the cumulative incidence of toxicity reached 51.7% (95% PI: 40.5% to 66.3%) and after six cycles. Toxicity rates ranging from 20.0% to 30.0% in the first cycle were associated with 46.8% (95% PI: 39.5% to 54.2%) and 65.8% (95% PI: 57.7% to 73.1%) cumulative incidence after six cycles. CONCLUSION This study examined the risk of severe toxicity over time of single MTAs. The cumulative incidence of toxicity at the MTD was higher than the usually accepted toxicity targets, challenging the definition of the RP2D of MTAs. The prediction table may help calibrating the target rate at the RP2D.
Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds

Renal impairment (RI) is a highly prevalent disease which can alter the pharmacokinetics (PK) of xenobiotics, including those that are predominately metabolized. The expression and activity of drug metabolizing enzymes (DMEs) and protein binding of compounds has been demonstrated to be affected in RI. A simulation based approach allows for the characterization of the impact of changes in these factors on the PK of compounds which are highly metabolized and allows for improved prediction of PK in RI. Simulations with physiologically based pharmacokinetic (PBPK) modeling was utilized to define the impact of these factors in PK in RI for a model substrate, nifedipine. Changes in fraction unbound and DME expression/activity had profound effects on PK in RI. Increasing fraction unbound and DME expression resulted in a reduction in exposure of nifedipine, while the reduction of DME activity resulted in an increase in exposure. In vitro and preclinical data were utilized to inform simulations for nifedipine, sildenafil and zidovudine. Increasing fraction unbound and changes in the expression/activity of DMEs led to improved predictions of PK. Further characterization of the impact of RI on these factors is warranted in order to better inform a priori predictions of PK in RI.
Development of aggressive-victims from childhood through adolescence: Associations with emotion dysregulation, withdrawn behaviors, moral disengagement, peer rejection, and friendships

Abstract At multiple developmental periods spanning from middle childhood through adolescence, we investigated the development of aggressive-victims. Multiple-informant data collected across four grade levels (1, 5, 8, and 11; N = 482; 50% females) was used to perform person-centered analyses including latent profile and latent transition analyses in order to examine the co-occurring development of multiple forms (i.e., physical, verbal, and relational) of aggression and peer victimization. Results indicated that there were two distinct subgroups of aggressive-victims, one of which was more relational in form (i.e., relational aggressive-victims), and children in these two subgroups were distinguishable with respect to their individual characteristics (emotion dysregulation, withdrawn behaviors, and moral disengagement) and relational experiences (peer rejection and friendships). Furthermore, the findings elucidated the mechanisms by which developmental continuity and change (i.e., transitions) among the subgroups occurred across childhood and adolescence.
Overexpression of a Laccase with Dye Decolorization Activity from Bacillus sp. Induced in Escherichia coli

Laccases from bacteria have been widely studied in the past 2 decades due to the higher growth rate of bacteria and their excellent thermal and alkaline pH stability. In this study, a novel laccase gene was cloned from Bacillus sp. , analyzed, and functionally expressed in Escherichia coli. The laccase was highly induced in the E. coli expression system with a maximum intracellular activity of 16 U mg-1 protein. The optimal temperature and pH of the purified laccase were 40°C and 4.6, respectively, when ABTS (2,2'-azino-bis[3-ethylbenzothiazoline-6-sulfonate]) was used as the substrate. The purified laccase showed high stability in the pH range of 3.0-9.0, and retained more than 70% of its activity after 24 h of incubation at 40°C with a pH value of 9.0. Furthermore, the enzyme exhibited extremely high temperature and ion metal tolerance. The half-life of the purified laccase at 70°C was 15.9 h. The purified laccase could efficiently decolorize 3 chemical dyes, especially in the presence of ABTS as a mediator. The high production of this laccase in E. coli and exceptional characteristics of the recombinant enzyme protein make it a promising candidate for industrial applications.