Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.
A Historic Perspective and Overview of H-Ras Structure, Oncogenicity, and Targeting

H-Ras is a unique isoform of the Ras GTPase family, one of the most prominently mutated oncogene families across the cancer landscape. Relative to other isoforms, though, mutations of H-Ras account for the smallest proportion of mutant Ras cancers. Yet, in recent years, there have been renewed efforts to study this isoform, especially as certain H-Ras–driven cancers, like those of the head and neck, have become more prominent. Important advances have therefore been made not only in the understanding of H-Ras structural biology but also in approaches designed to inhibit and impair its signaling activity. In this review, we outline historic and present initiatives to elucidate the mechanisms of H-Ras–dependent tumorigenesis as well as highlight ongoing developments in the quest to target this critical oncogene.
Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer

Background The expression of programmed cell death ligand 1(PD-L1) is related to the efficacy of immune checkpoint inhibitors on patients with non-small cell lung cancer (NSCLC), but tumor tissue (TT) samples are difficult to obtain, and initial TT samples are difficult to reflect the spatial-temporal heterogeneity. Therefore, we explored the feasibility of separating circulating tumor cells (CTCs) and detecting PD-L1 expression on CTCs. Patients and Methods Peripheral blood specimens were sampled from 66 NSCLC patients, and CTCs were separated by membrane filtration based on size. For 59 patients with paired TT specimens, the expression of PD-L1 in their CTCs and TTs was determined using the immunohistochemistry and immunocytochemistry based on 28–8 antibody, respectively. The PD-L1 expression in TTs was set as a gold standard for calculation of sensitivity, specificity, consistency, positive predictive value (PPV), and negative predictive value (NPV), and the Cohen kappa coefficient for CTCs and paired TTs was calculated. In addition, the T-test, Chi-square test, and Mann–Whitney U-test were adopted to analyze the correlation of clinical pathological features and prognosis with PD-L1 expression. Results Sensitivity, specificity, concordance, PPV and NPV of detecting PD-L1 in CTCs of the 41 initial treated patients were 88.89%, 73.91%, 80%, 72.73% and 89.47%, respectively, and the Cohen kappa coefficient of CTC and paired TTs was 0.613. The univariate analysis of survival showed that the progression-free survival time of initial treated patients with positive PD-L1 expression was shorter than that of those with negative PD-L1 expression in CTCs or TTs (P>0.05), and the positive PD-L1 expression in CTCs or TTs had nothing to do with age, sex, smoking status, histological type, and stage (P > 0.05). Conclusion The study confirms the feasibility of CTC PD-L1 detection in peripheral blood and lays a foundation for exploring real-time and individualized immunotherapy molecular biomarkers.
Exposure to Auditory Feedback Delay while Speaking Induces Perceptual Habituation but does not Mitigate the Disruptive Effect of Delay on Speech Auditory-motor Learning

Perceiving the sensory consequences of our own actions with a delay alters the interpretation of these afferent signals and impacts motor learning. For reaching movements, delayed visual feedback of hand position reduces the rate and extent of visuomotor adaptation, but substantial adaptation still occurs. Moreover, the detrimental effect of visual feedback delay on reach motor learning—in particular its explicit component—can be mitigated by prior habituation to the delay. Auditory-motor learning for speech has been reported to be more sensitive to feedback delay, and it remains unknown whether prior habituation to auditory delay reduces its negative impact on learning. We investigated whether 30 minutes of exposure to auditory feedback delay during speaking (a) affects the subjective perception of this delay, and (b) mitigates its disruptive effect on speech auditory-motor learning. During a speech adaptation task with real-time perturbation of vowel spectral properties, participants heard this frequency-shifted auditory feedback with either no delay, 75 ms delay, or 115 ms delay. In the delay groups, half of the participants had been exposed to the delay throughout a preceding 30-minute block of speaking whereas the remaining participants completed this initial block without delay. Even though habituation reduced the subjective perception of delay, no improvement in adaptation to the spectral perturbation was observed as compared with non-habituated participants. Thus, short-term habituation to auditory feedback delays is not effective in reducing the negative impact of delay on speech auditory-motor adaptation, suggesting the involvement of predominantly implicit learning mechanisms in this form of sensorimotor learning. HIGHLIGHTS Speech auditory-motor adaptation to a spectral perturbation was substantially reduced when feedback was delayed by 75 or 115 ms. Thirty minutes of prior exposure to the delay without perturbation was effective in reducing participants’ subjective perception of the delay. However, perceptual habituation was ineffective in remediating the detrimental effect of the delay on speech auditory-motor adaptation. The dissociation of perceptual experience and auditory-motor learning suggests that this form of adaptation is predominantly implicit.
Event-related potentials reflect prediction errors and pop-out during comprehension of degraded speech

Comprehension of degraded speech requires higher-order expectations informed by prior-knowledge. Accurate top-down expectations of incoming degraded speech cause a subjective semantic “pop-out” or conscious breakthrough experience. Indeed, the same stimulus can be perceived as meaningless when no expectations are made in advance. We investigated the ERP correlates of these top-down expectations, their error signals, and the subjective pop-out experience in healthy participants. We manipulated expectations in a word-pair priming noise-vocoded speech task and investigated the role of top-down expectation with a between-groups attention manipulation. Consistent with the role of expectations in comprehension, repetition priming significantly enhanced perceptual intelligibility of the noise-vocoded degraded targets for attentive participants. An early ERP was larger for mismatched (i.e. unexpected) targets than matched targets, indicative of an initial error signal not reliant on top-down expectations. Subsequently, a P3a-like ERP was larger to matched targets than mismatched targets only for attending participants - i.e. a pop-out effect. Rather than relying on complex post hoc interactions between prediction error and precision to explain this apredictive pattern, we consider our data to be consistent with prediction error minimisation accounts for early stages of processing followed by Global Neuronal Workspace-like breakthrough and processing in service of task goals.
Promotion of miR-221-5p on the Sensitivity of Gastric Cancer Cells to Cisplatin and Its Effects on Cell Proliferation and Apoptosis by Regulating DDR1

Purpose This research aimed to explore the role of miR-221-5p on the sensitivity of gastric cancer cells to cisplatin, and the proliferation and invasion of gastric cancer cells by regulating DDR1. Patients and Methods Altogether 69 patients who treated with radical gastrectomy from January 2014 to January 2016 were collected. With the agree of the patients, 69 gastric carcinoma and 69 adjacent tissues were taken, respectively, during the operation, and gastric carcinoma and human gastric mucosa cells were purchased. RT-PCR was used for detection of the expression level of miR-221-5p and DDR1. Wound healing assay and CCK-8 assay were used for exploration of the cell migration and viability. Western blot and double luciferase reporter gene were performed to determine the target gene of miR-221-5p. Results It was showed that miR-221-5p expression was decreased in GC tissues and cell lines. The high expression of miR-221-5p reduced the resistance of GC cells to cisplatin and inhibited the proliferation and migration of gastric cancer cells. The high expression of miR-221-5p promoted the proliferation, invasion and migration of GC cells. In addition, we found that DDR1 was a direct target gene of miR-221-5p in GC cells. We found that DDR1 expression increased in gastric carcinoma. Moreover, there was a negative correlation of DDR1 with the expression level of miR-221-5p. The increase of miR-221-5p increased the chemosensitivity of GC cells to cisplatin, and inhibited the proliferation, invasion, migration and EMT of GC cells by targeting DDR1. Conclusion The above research indicated that miR-221-5p may be a target for enhancing cisplatin chemotherapy sensitivity in gastric cancer patients.
Pathogenesis and Prevention of Worsening Axial Elongation in Pathological Myopia

Purpose This review discusses the etiology and pathogenesis of myopia, prevention of disease progression and worsening axial elongation, and emerging myopia treatment modalities. Introduction Pediatric myopia is a public health concern that impacts young children worldwide and is associated with numerous future ocular diseases such as cataract, glaucoma, retinal detachment and other chorioretinal abnormalities. While the exact mechanism of myopia of the human eye remains obscure, several studies have reported on the role of environmental and genetic factors in the disease development. Methods A review of literature was conducted. PubMed and Medline were searched for combinations and derivatives of the keywords including, but not limited to, “pediatric myopia”, “axial elongation”, “scleral remodeling” or “atropine. ” The PubMed and Medline database search were performed for randomized control trials, systematic reviews and meta-analyses using the same keyword combinations. Results Studies have reported that detection of genetic correlations and modification of environmental influences may have a significant impact in myopia progression, axial elongation and future myopic ocular complications. The conventional pharmacotherapy of pediatric myopia addresses the improvement in visual acuity and prevention of amblyopia but does not affect axial elongation or myopia progression. Several studies have published varying treatments, including optical, pharmacological and surgical management, which show great promise for a more precise control of myopia and preservation of ocular health. Discussion Understanding the role of factors influencing the onset and progression of pediatric myopia will facilitate the development of successful treatments, reduction of disease burden, arrest of progression and improvement in future of the management of myopia.
Light and Temperature Synchronizes Locomotor Activity in the Linden Bug, Pyrrhocoris apterus

Circadian clocks are synchronized with the external environment by light and temperature. The effect of these cues on behavior is well-characterized in Drosophila, however, little is known about synchronization in non-model insect species. Therefore, we explored entrainment of locomotor activity by light and temperature in the linden bug Pyrrhocoris apterus (Heteroptera), an insect species with a strong seasonal response (reproductive diapause), which is triggered by both photoperiod and thermoperiod. Our results show that either light or temperature cycles are strong factors entraining P. apterus locomotor activity. Pyrrhocoris is able to be partially synchronized by cycles with temperature amplitude as small as 3°C and more than 50% of bugs is synchronized by 5°C steps. If conflicting zeitgebers are provided, light is the stronger signal. Linden bugs lack light-sensitive (Drosophila-like) cryptochrome. Notably, a high percentage of bugs is rhythmic even in constant light (LL) at intensity ∼400 lux, a condition which induces 100% arrhythmicity in Drosophila. However, the rhythmicity of bugs is still reduced in LL conditions, whereas rhythmicity remains unaffected in constant dark (DD). Interestingly, a similar phenomenon is observed after temperature cycles entrainment. Bugs released to constant thermophase and DD display weak rhythmicity, whereas strong rhythmicity is observed in bugs released to constant cryophase and DD. Our study describes the daily and circadian behavior of the linden bug as a response to photoperiodic and thermoperiodic entraining cues. Although the molecular mechanism of the circadian clock entrainment in the linden bug is virtually unknown, our study contributes to the knowledge of the insect circadian clock features beyond Drosophila research.
Anticipatory responses along motion trajectories in awake monkey area V1

What are the neural mechanisms underlying motion integration of translating objects? Visual motion integration is generally conceived of as a feedforward, hierarchical, information processing. However, feedforward models fail to account for many contextual effects revealed using natural moving stimuli. In particular, a translating object evokes a sequence of transient feedforward responses in the primary visual cortex but also propagations of activity through horizontal and feedback pathways. We investigated how these pathways shape the representation of a translating bar in monkey V1. We show that, for long trajectories, spiking activity builds-up hundreds of milliseconds before the bar enters the neurons’ receptive fields. Using VSDI and LFP recordings guided by a phenomenological model of propagation dynamics, we demonstrate that this anticipatory response arises from the interplay between horizontal and feedback networks driving V1 neurons well ahead of their feedforward inputs. This mechanism could subtend several perceptual contextual effects observed with translating objects. Highlights Our hypothesis is that lateral propagation of activity in V1 contributes to the integration of translating stimuli Consistent with this hypothesis, we find that a translating bar induces anticipatory spiking activity in V1 neurons. A V1 model describes how this anticipation can arise from inter and intra-cortical lateral propagation of activity. The dynamic of VSDi and LFP signals in V1 is consistent with the predictions made by the model. The intra-cortical origin is further confirmed by the fact that a bar moving from the ipsilateral hemifield does not evoke anticipation. Horizontal and feedback input are not only modulatory but can also drive spiking responses in specific contexts.
Morbidity Profile Of Out-Patients Attending A Primary Health Centre In Rural Puducherry, South India -

Author’s Affiliation: 1Senior Resident, Dept of Community and Family Medicine, AIIMS, Bhopal; 2Asst Prof, Dept of Community Medicine, Madha Medical College & Research Institute, Kovur; 3Junior Resident, Centre for Community Medicine, AIIMS, New Delhi; 4Asst Prof , Dept of Community medicine, Velammal Medial College and Research Institute, Madhurai; 5Senior Resident, Dept of Community medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi; 6Asst Prof , Dept of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry
Potentially Inappropriate Prescriptions in Ambulatory Elderly Patients Living in Rural Areas of Romania Using STOPP/START (Version 2) Criteria

Background Rational use of medications and monitoring of prescriptions in elderly patients is important to decrease the number and duration of hospitalizations, emergency medical consultations, mortality, as well as medical costs. Purpose To identify potentially inappropriate medications (PIMs) and potential prescription omissions (PPOs), and determine their prevalence based on the Screening Tool of Older Persons’ potentially inappropriate Prescriptions (STOPP) v2 criteria and Screening Tool to Alert doctors to Right Treatment (START) v2 criteria for patients aged >65 years. Methods This cross-sectional study was conducted in two rural counties in Romania based on electronic prescriptions for chronic conditions (EPCCs) issued from 30 days to 90 days by a specialist or general practitioner. Collected EPCCs were evaluated by an interdisciplinary team of specialists based on 26 STOPP v2 criteria and 10 START v2 criteria. Results PIM prevalence was 25.80% and PPO prevalence was 41.72% for 646 EPCCs. The mean age of patients was 75 years and the mean number of drugs per EPCC was four. The most frequently identified PIMs were treatment duration (6.65%), theophylline administration (5.72%), drug indication (4.64%), cyclo-oxygenase-2 non-steroidal anti-inflammatory drugs (1.39%), and zopiclone prescription (0.77%). Statins (24.76%), beta-blockers (8.04%), and beta-2 agonist/antimuscarinic bronchodilators (5.88%) were the most frequently identified PPOs. Conclusion PPOs were more prevalent than PIMs for elderly populations living in the two rural counties in Romania we studied. Health practitioners (family physicians, specialists, and pharmacists) should focus on prophylactic and curative considerations when prescribing agents to decrease the morbidity and mortality of elderly rural Romanian patients.
Albumin-to-Alkaline Phosphatase Ratio Associates with Good Prognosis of Hepatitis B Virus-Positive HCC Patients

Purpose The aim of this study was to investigate the prognostic significance of preoperative AAPR in hepatitis B virus-related hepatocellular carcinoma patients after curative hepatectomy. Patients and Methods A total of 221 patients with hepatitis B virus-related HCC patients who received curative liver resection were included. After propensity matching analysis, 188 patients were enrolled in the final analysis. COX regression analyses were used to analyze the prognosis value of AAPR and other prognostic factors. The overall survival (OS) and recurrence-free survival (RFS) curves were constructed and compared between different groups. Results The optimal cutoff of AAPR was defined as 0.40 with X-tile software. According to cutoff value, patients were divided into low-AAPR group (≤0.40) and high-AAPR group (>0.40). The cumulative 1-, 3-, and 5-year OS rates were 97.1%, 78.2%, and 67.3% in patients with AAPR>0.40 group, respectively, which were significantly higher than those in the AAPR≤0.40 group (80.2%, 54.4%, and 40.1%, respectively) (P <0.001). In the multivariate COX regression analysis, AAPR, tumor number, ascites, and portal vein tumor thrombus (PVTT) were independent risk factors for OS and RFS. Conclusion AAPR shows promise as a reliable prognostic factor in patients with hepatitis B virus-related HCC after curative hepatectomy, which could be used as a routine inspection of HCC patients before surgery.
Antioxidant and Anti-Inflammatory Properties of Melatonin in Patients with Type 2 Diabetes Mellitus with Periodontal Disease Under Non-Surgical Periodontal Therapy: A Double-Blind, Placebo-Controlled Trial

Background and Aim The imbalance between pro-oxidant and antioxidant systems often leads to further oxidative damage in the pathogenesis of both diabetes and periodontal disease. This study aimed to investigate the antioxidant and anti-inflammatory properties of melatonin in type 2 diabetes mellitus (T2DM) patients with periodontal disease (PD) under non-surgical periodontal therapy (NSPT). Materials and Methods In this double-blind clinical trial study, 50 T2DM patients with PD were randomly allocated to intervention and control groups and received 250 mg/day (2 tablets) either melatonin or placebo 1 h before bedtime for 8 weeks. The NSPT was performed for all patients in both groups at the beginning of the study. The serum levels of interleukin-1b (IL-1b), malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were measured pre- and post-intervention. Results Supplementation with melatonin in adjunct to NSPT significantly increased the serum levels of TAC, SOD, CAT, and GPx in the intervention group (P = 0.02, 0.008, 0.004 and 0.004, respectively). The mean changes of SOD, CAT, and GPx were significantly (P = 0.02, 0.04 and 0.04, respectively) greater in the intervention group compared with the control group. Also, after adjusting for confounding factors, the results did not change in terms of significance (P < 0.05). After the intervention, serum levels of MDA and IL-1b were significantly reduced in the intervention group (P < 0.001 and P = 0.008, respectively). The intervention group exhibited lower mean changes of MDA compared with the control group, and these changes were statistically significant (P = 0.008). In addition, after adjusting for confounding factors, the results did not change in terms of significance. Conclusion The adjunctive effects of melatonin and NSPT may improve inflammatory and antioxidant parameters in T2DM patients with PD.
Poly(N-Isopropyl-Acrylamide)/Poly(γ-Glutamic Acid) Thermo-Sensitive Hydrogels Loaded with Superoxide Dismutase for Wound Dressing Application

Introduction Chronic trauma repair is an important issue affecting people’s healthy lives. Thermo-sensitive hydrogel is injectable in situ and can be used to treat large-area wounds. In addition, antioxidants play important roles in promoting wound repair. Methods The purpose of this research was to prepare a novel thermo-sensitive hydrogel-poly(N-isopropyl-acrylamide)/poly(γ-glutamic acid) (PP) loaded with superoxide dismutase (SOD) to improve the effect for trauma treatment. The micromorphology of the hydrogel was observed by scanning electron microscope and the physical properties were measured. The biocompatibility of hydrogel was evaluated by MTT experiment, and the effect of hydrogel on skin wound healing was evaluated by in vivo histological staining. Results Gelling behavior and differential scanning calorimeter outcomes showed that the PP hydrogels possessed thermo-sensitivity at physiological temperature and the phase transformation temperature was 28.2°C. The high swelling rate and good water retention were conducive to wound healing. The activity of SOD in vitro was up to 85% at 10 h, which was advantageous to eliminate the superoxide anion. MTT assay revealed that this hydrogel possessed good biocompatibility. Dressings of PP loaded with SOD (SOD-PP) had a higher wound closure rate than other treatments in vivo in diabetic rat model. Discussion The SOD-PP thermo-sensitive hydrogels can effectively promote wound healing and have good application prospects for wound repair.