Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of a novel compound that simultaneously impairs the ubiquitin-proteasome system and autophagy

ABSTRACT The ubiquitin-proteasome system (UPS) and macroautophagy/autophagy are the main proteolytic systems in eukaryotic cells for preserving protein homeostasis, i.e., proteostasis. By facilitating the timely destruction of aberrant proteins, these complementary pathways keep the intracellular environment free of inherently toxic protein aggregates. Chemical interference with the UPS or autophagy has emerged as a viable strategy for therapeutically targeting malignant cells which, owing to their hyperactive state, heavily rely on the sanitizing activity of these proteolytic systems. Here, we report on the discovery of CBK79, a novel compound that impairs both protein degradation by the UPS and autophagy. While CBK79 was identified in a high-content screen for drug-like molecules that inhibit the UPS, subsequent analysis revealed that this compound also compromises autophagic degradation of long-lived proteins. We show that CBK79 induces non-canonical lipidation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) that requires ATG16L1 but is independent of the ULK1 (unc-51 like autophagy activating kinase 1) and class III phosphatidylinositol 3-kinase (PtdIns3K) complexes. Thermal preconditioning of cells prevented CBK79-induced UPS impairment but failed to restore autophagy, indicating that activation of stress responses does not allow cells to bypass the inhibitory effect of CBK79 on autophagy. The identification of a small molecule that simultaneously impairs the two main proteolytic systems for protein quality control provides a starting point for the development of a novel class of proteostasis-targeting drugs.
Effect of increasing dose level of a novel consensus bacterial 6-phytase variant on phytate degradation in broilers fed diets containing varied phytate levels

ABSTRACT 1. The effect of increasing the dose level of a novel consensus bacterial 6-phytase variant on apparent ileal digestibility (AID) of phosphorus (P), phytic acid (inositol hexa-phosphate, IP6) and ileal IP6 degradation profile was studied in diets containing varying phytate-P (PP) levels. 2. Ross 308, one-day-old males (n = 1,800) were allocated to cages (20 birds/cage, six cages/treatment) in a completely randomised design employing a 3 × 5 factorial arrangement (three PP levels: 2.45 (low) 2.95 (medium) and 3.45 g/kg (high); five dose levels of phytase (PhyG): 0, 500, 1,000, 2,000 and 4,000 FTU/kg). Phased diets were based on wheat, corn, soybean meal, rapeseed meal and rice bran (d 0 to 10; 2.60 g/kg digestible P, 7.6 g/kg calcium (Ca); d 11 to 21; 2.10 g/kg digestible P, 6.4 g/kg Ca). Ileal digesta was collected on d 21 for determination of P, IP6 and IP-esters content. Data were analysed by factorial ANOVA; means separation was achieved using Tukey’s HSD test. 3. Increasing PP reduced AID of IP6 and sum of IP3-6 (%) (P < 0.05) but absolute P-release (g/kg diet) above NC was increased (P < 0.05) at high vs. low PP. Increasing phytase dose exponentially increased (P < 0.001) AID IP6, sum of IP3-6 (%) and digestible IP3-6-P g/kg diet (P < 0.001). AID P was increased but there was an interaction with PP level (P < 0.001). Ileal accumulation of IP5-3-P was universally low with PhyG at ≥1,000 FTU/kg (<0.06 g/100 g DM). At 2,000 and 4,000 FTU/kg, AID IP6 was 97.2, 92.7, 92.6% and 100, 97.2, 97.1%, respectively, at low, medium and high PP. At 2,000 FTU/kg, phytate-P release estimated as the increase (above NC) in ileal digestible sum of IP3-6-P in the diet was 2.26, 2.59 and 3.10 g/kg in low, medium and high PP, respectively. 4. The data demonstrated that the novel phytase was effective in breaking down phytate to low IP-esters in diets with varied PP content but the optimal dose level for maximising P-release may differ in diets with varying PP content.
Loss of Long Noncoding RNA NXTAR in Prostate Cancer Augments Androgen Receptor Expression and Enzalutamide Resistance

This study identifies NXTAR as a tumor suppressive lncRNA that can epigenetically downregulate AR/AR-V7 expression and provides a therapeutic strategy to reinstate NXTAR expression for treating recurrent CRPC. Androgen receptor (AR) signaling continues to play a dominant role in all stages of prostate cancer, including castration-resistant prostate cancers (CRPC) that have developed resistance to second generation AR antagonists such as enzalutamide. In this study, we identified a long noncoding RNA (lncRNA), NXTAR (LOC105373241) that is located convergent with the AR gene and is repressed in human prostate tumors and cell lines. NXTAR bound upstream of the AR promoter and promoted EZH2 recruitment, causing significant loss of AR (and AR-V7) expression. Paradoxically, AR bound the NXTAR promoter, and inhibition of AR by the ACK1/TNK2 small molecule inhibitor (R)-9b excluded AR from the NXTAR promoter. The histone acetyltransferase GCN5 bound and deposited H3K14 acetylation marks, enhancing NXTAR expression. Application of an oligonucleotide derived from NXTAR exon 5 (NXTAR-N5) suppressed AR/AR-V7 expression and prostate cancer cell proliferation, indicating the translational relevance of the negative regulation of AR. In addition, pharmacologic restoration of NXTAR using (R)-9b abrogated enzalutamide-resistant prostate xenograft tumor growth. Overall, this study uncovers a positive feedback loop, wherein NXTAR acts as a novel prostate tumor-suppressing lncRNA by inhibiting AR/AR-V7 expression, which in turn upregulates NXTAR levels, compromising enzalutamide-resistant prostate cancer. The restoration of NXTAR could serve as a new therapeutic modality for patients who have acquired resistance to second generation AR antagonists. Significance: This study identifies NXTAR as a tumor suppressive lncRNA that can epigenetically downregulate AR/AR-V7 expression and provides a therapeutic strategy to reinstate NXTAR expression for treating recurrent CRPC. Graphical Abstract
Cardiovascular involvement in patients affected by multiple myeloma: a comprehensive review of recent advances

ABSTRACT Introduction Multiple Myeloma (MM) is hematological neoplasia originating from plasma cells, which accounts for almost 1% of all oncologic malignancies. The median age of patients at diagnosis is about 65 years old and over. In this age group, cardiovascular (CV) diseases often co-exist, increasing the risk of adverse events related to MM treatment. A comprehensive search on the main educational platforms was performed and high-quality original articles and reviews were included. Areas Covered Patients affected by MM are at risk for heart failure, uncontrolled systemic hypertension, accelerated ischemic heart disease, arterial/venous thromboembolism, and arrhythmias. These complications may be due to the effects of chemotherapy on the CV system, which may play on preexisting risk factors, and amyloid deposition at cardiac level. Expert Opinion This review provides an updated overview of the spectrum of CV diseases that may affect MM patients, highlighting possible treatment strategies according to the latest recommendations. Cooperation between onco-hematologist and cardiologist is crucial in managing this population, in particular for adequate risk assessment, early diagnosis of CV complications, and proper treatment.
Weight Change, Lifestyle and Mortality in Patients with Type 2 Diabetes.

OBJECTIVE To examine the association between weight change and mortality among participants with incident type 2 diabetes (T2D) and evaluate the impact of adopting a healthy lifestyle on this association. RESEARCH DESIGN AND METHODS This prospective analysis included 11,262 incident T2D patients from the Nurses' Health Study and Health Professionals Follow-up Study. We assessed weight change bracketing T2D diagnosis in relation to mortality. We also examined potential effect modification by a healthy lifestyle consisting of high-quality diet, regular physical activity, non-smoking status and moderate alcohol consumption. RESULTS On average, T2D patients lost 2.3 kg during a two-year time-window spanning the T2D diagnosis, and body weight increased afterwards following a trajectory similar to that of non-diabetics. Compared with patients with a stable weight, T2D patients who lost ≥10% body weight had a 21% (95% CI: 9%, 35%) increased all-cause mortality. Lifestyle significantly modified these associations: the hazard ratios (95% CIs) of all-cause mortality comparing ≥10% weight loss with stable weight were 1.63 (1.26, 2.09) among participants with a deteriorated lifestyle, 1.27 (1.11, 1.46) for a stable lifestyle, and 1.02 (0.81, 1.27) for an improved lifestyle (Pinteraction <0.001). Major weight loss was associated with increased cause-specific mortality and similar effect modifications by lifestyle were also observed. CONCLUSIONS Significant weight loss upon T2D incidence was associated with increased mortality, although improved lifestyle quality abolished these associations. These results highlight the role of adopting a healthy lifestyle for newly diagnosed T2D patients, especially among those who might lose weight unintentionally, and improving long-term survival.
Fusibacter ferrireducens sp. nov., an anaerobic, Fe(Ⅲ)- and sulphur-reducing bacterium isolated from mangrove sediment.

An anaerobic, alkaliphilic, halotolerant, Gram-stain-positive and rod-shaped bacterium, designated Q10-2T, was isolated from mangrove sediment sampled at the Jiulong river estuary, PR China. The cells of strain Q10-2T were motile and 0.5×2-4 µm in size. Strain Q10-2T grew at 8-45 °C (optimum, 32 °C), at pH 7.0-10.5 (optimum, pH 8.5) and in the presence of 0-6 % (w/v) NaCl (optimum, 3 %). It could use complex organic compounds and carbohydrates including d-fructose, d-galactose, d-glucose, d-mannitol, d-xylose, trehalose, lactose, maltose, sucrose and starch as carbon sources and electron donors. It could reduce sulphate, thiosulphate and elemental sulphur to sulphide, but not sulphite. Fe (Ⅲ) citrate, ferrihydrite, haematite and goethite in the presence of glucose as the electron donor were also reduced. Acetate, butyrate, ethanol, CO2 and H2 were end products of glucose fermentation. The predominant cellular fatty acids were composed of C14 : 0, C16 : 0 and summed features containing C16 : 1 ω7c and/or iso-C15 : 0 2-OH and iso-C17 : 1 and/or anteiso-C17 : 1 B. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the novel strain was most closely related to Fusibacter paucivorans DSM 12116T (95.5 % sequence similarity). The genome size of strain Q10-2T was 5.0 Mb, with a G+C content of 37.4 mol%. The average nucleotide identity and digital DNA-DNA hybridization values between strain Q10-2T and F. paucivorans DSM 12116T were 69.1 and 21.8 %, respectively. The combined genotypic and phenotypic data showed that strain Q10-2T represents a novel species of the genus Fusibacter, for which the name Fusibacter ferrireducens sp. nov. is proposed. The type strain is Q10-2T (=MCCC 1A16257T=KCTC 15906T).
Identification and functional study of FOXC1 variants in Chinese families with glaucoma

This study aimed to identify the disease‐causing gene of three Chinese families with glaucoma. Whole exome sequencing was performed on the probands and detected three different variants (c.405C>A (p.Cys135Ter), c.851G>T (p.Ser284Ile), and c.392C>T (p.Ser131Leu)) in FOXC1 as a causative gene of glaucoma, and Sanger sequencing was performed for verification and cosegregation analysis. Three in silico tools all predicted these two missense variants to be probably disease‐causing. Western blot analysis, immunofluorescence, and dual‐luciferase assay were further used to evaluate the effect of FOXC1 missense variants, and demonstrated that the two variants resulted in decreased transactivation activity of FOXC1 although the variants had no effect on the protein amount and the nucleus subcellar localization of FOXC1 compared with the wild type, which implies that both of two variants may be probably pathogenic. In this study, we reported two novel FOXC1 variants as well as a reported variant and the phenotypes associated to these variants, which expands the spectrum and relevant phenotypes of FOXC1 variants. Additionally, the functional analysis of FOXC1 variants provides further insight into the possible pathogenesis of anterior segment anomaly related to FOXC1.
COVID-19 serological evaluation in a cohort of Vaccinated healthcare workers

Introduction: Severe Acquired Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) infection represents an unprecedented public health problem and, at present, vaccination is the only weapon available to combat the infection. The simplest and most immediate method to quantify the response of the subject’s immune system to vaccination and / or infection is the serological assessment of the antibody titer. The objective of our study was 1) to evaluate the presence of antibody responses in a sample of healthcare workers subjected to a complete vaccination course as per ministerial provisions (double dose for negatives and single dose for ex-SARS-CoV subjects -2 positive) with Comirnaty vaccine (Pfizer / BioNTech) 2) evaluate the presence of statistically significant associations for sex, age and previous positive swab. Materials and methods: the antibody levels of both nucleocapsid antibodies and anti-Sars-CoV2 Spike antibodies of the study subjects were examined with the electrochemiluminescent immunoassay (ECLIA) method developed by Roche®. The cut-off value, as suggested by the manufacturer, for anti-nucleocapsid antibodies was 1 COI, while the Ig Spike value was 0.8 I / mL. The study sample was stratified by age (≤45 years, 46-55, ≥56 years old), previous positive molecular swab, gender and IgG S1 / S2 values at the completed vaccination course (≤200, ≥200 AU / mL ). Statistical analyzes were carried out with the R software. Results: almost all of the sample (89.45%) showed IgG Spike values> 200 AU / mL with statistically significant associations in relation to sex (greater in females, p≤0.05), to previous swab positivity in the presence of a vaccine dose (n = 44; p <0.001) and at age (with greater antibody response in subjects under 45; p <0.001). Discussion and conclusions: The current study confirms what is reported in the literature. In the light of the results obtained, it could be interesting to promote studies that evaluate the antibody titers trend over time a) in women of childbearing age and postmenopausal age b) in particular categories of subjects with chronic degenerative diseases to assess the actual need for doses booster, it being understood that the immune system response is guaranteed by both cellular and humoral immunity and that the antibody titer does not faithfully reflect the protection obtained. (www.actabiomedica.it)
Topical Administration of ACE Inhibitor Interrupts the Progression of Cataract in Two Kidney One Clip Induced Hypertensive Cataract Model

ABSTRACT Purpose Previously, we assessed that hypertension increases cataractogenesis. In the present study, we evaluated the effect of oral and topical administration of enalapril on two kidney one clip (2K1C)-induced hypertensive cataract model by evaluating the biochemical alteration of lenticular antioxidants, ionic content, ATPase activity, protein content and careful examination of the lenticular opacity. Materials and Method Animals were divided into normal and hypertensive animals. Hypertensive animals were divided into hypertensive control group (0.3% CMC), enalapril (oral) treatment group (20 mg/kg/day; p.o), and enalapril (topical) treatment group (0.1% w/v on the eye cornea) for a period of twelve weeks. During experimental study blood pressure, heart rate and morphology of the eyes were monitored biweekly. After twelve weeks, lenses were photographed and various catractogenic biochemical parameters were assessed. Results Enalapril (oral) treatment conserved the blood pressure (systolic and diastolic), restored the level of antioxidants, restored the lipid peroxidation marker, nitrite content, ionic content, ATPase function, protein content, and thus delayed the cataract formation. While, enalapril (topical) treatment exhibited anti-cataract effect without affecting the systolic and diastolic blood pressure that could be by restoring the antioxidant level, maintaining the ionic balance, balancing the protein levels, and by inhibiting the upregulated ocular renin angiotensin system. The overall results suggest that enalapril (topical) treatment showed conspicuous effect than enalapril (oral) treatment in adjourning the cataract formation. Conclusion Based on the results, it may be concluded that upregulated ocular RAS by increasing oxidative stress and by misbalancing the lenticular ionic and protein content may lead to cataract formation in hypertensive condition.
Effect of non‐alcoholic beer containing matured hop bitter acids on mood states in healthy adults: A single‐arm pilot study

Abstract This study aimed to investigate the effect of non‐alcoholic beer containing matured hop bitter acids on mood states among healthy adults older than 20 years. This study was an open‐label longitudinal intervention design in which each participant served as their control. For 3 weeks, we evaluated the effect of non‐alcoholic beer containing 35 mg of matured hop bitter acids on mood, sleep quality, and work performance. The data of 97 participants (age range: 23–72 years, median age: 42) were analyzed. After the intervention, we found that matured hop bitter acids significantly improved total mood state, including anxiety, depression, fatigue, and vigor, compared with the baseline. Furthermore, sleep quality and absolute presenteeism were significantly improved after the intervention compared with the baseline. The present exploratory study suggested that 3‐week supplementation with matured hop bitter acids improved mood and peripheral symptoms in persons of a wide range of ages. Although further investigation is needed, the findings suggested that non‐alcoholic beer in daily life might become a choice for maintaining mood states.
Nonlinear all-optical phase and power-controlled switch by using the spatial soliton interaction

We propose a novel nonlinear all-optical switch by using the phase and power modulation of spatial solitons. The proposed waveguide structure is composed of a straight nonlinear signal waveguide, a nonlinear delay branch, a nonlinear control waveguide, and three nonlinear output guides. By properly launching the control power and varying the length of the delay branch, this nonlinear waveguide structure could really function as an all-optical switch. It could be a potential key component in the application of integrated-optics circuits.
Implement of Lamb Wave Using PZT Phased Arrays for Structural Health Monitoring

Phased array theory is analyzed. The PZT phased array is applied in SHM for the Al plate to identify the hole in the structure. The Lamb wave beam steering is controlled by adding the time delay to the signals. The structure can be scanned in half plane by using the phased array theory to control the Lamb wave beam steering. The damage in the structure can be recognized and localized by the phased array method. The identification result is shown on mapped image. The phased array damage localization method is verified by the experiment and the result shows that the method is effective to recognize the hole damage in the structure.
Influence of CO 2 concentration on the performance of MgO cement mixes 1 2 3

15 16 This paper investigated the influence of different CO2 concentrations on the microstructural 17 and mechanical development of reactive MgO cement (RMC) concrete. Combination of 18 various analyses revealed the enhancement of hydrated magnesium carbonate (HMC) phases 19 with relatively superior micro-mechanical properties as the CO2 concentration increased from 20 ambient (~0.04%) to accelerated (5-20%) levels. The higher CO2 diffusion within samples 21 cured under 5-20% CO2 increased the compressive strength by ~5 times. While samples cured 22 under 20% CO2 revealed high early strengths, the formation of a dense HMC layer on the 23 sample exterior led to limitations on further CO2 diffusion. Use of 5% CO2 produced 24 comparable strengths as 20% CO2 at 28 days, highlighting the potential of using lower 25 concentrations. Samples cured under 10% CO2 revealed the best performance at 28 days, 26 thereby defining this environment as the most favorable condition for the development of 27 microstructural and mechanical properties of RMC concrete. 28 29 30
Partial Discharge Signal Denoising using Adaptive Translation Invariant Wavelet Transform-Online Measurement

Partial discharge (PD) measurements have emerged as a dominant investigative tool for condition monitoring of insulation in high voltage equipment. But the major problem behind them the PD signal is severely polluted by several noises like White noise, Random noise, Discrete Spectral Interferences (DSI) and the challenge lies with removing these noise from the onsite PD data effectively which leads to preserving the signal for feature extraction. Accordingly the paper is mainly classified into two parts. In first part the PD signal is artificially simulated and mixed with white noise. In second part the PD is measured then it is subjected to the proposed denoising techniques namely Translation Invariant Wavelet Transform (TIWT). The proposed TIWT method remains the edge of the original signal efficiently. Additionally TIWT based denoising is used to suppress Pseudo Gibbs phenomenon. In this paper an attempt has been made to review the methodology of denoising the PD signals and shows that the proposed denoising method results are better when compared to other wavelet-based approaches like Fast Fourier Transform (FFT), Discrete Wavelet Transform (DWT), by evaluating five different parameters like, Signal to noise ratio, Cross-correlation coefficient, Pulse amplitude distortion, Mean square error, Reduction in noise level.
Prototype System of Knowledge Management Based on Data Mining

Knowledge is a very crucial resource to promote economic development and society progress which includes facts, information, descriptions, or skills acquired through experience or education. With knowledge has being increasingly prominent, knowledge management has become important measure for the core competences promotion of a corporation. The paper begins with knowledge managements definition, and studies the process of knowledge discovery from databases (KDD),data mining techniques and SECI(Socialization, Externalization, Combination, Internalization) model of knowledge dimensions. Finally, a simple knowledge management prototype system was proposed which based on the KDD and data mining.
Detection of tool wear using multisensor readings defused by artificial neural network

Real-time tool wear sensing is essential for machining process optimization and implementation of untended manufacturing systems. This paper proposes a tool wear model based on an artificial neural network (ANN), used as a pattern associator, that is trained using experimental data which consists of tool wear measurement and corresponding readings of a variety of sensors. During operation, the network is fed only with the sensors'' readings; it fuses this data and, according to the `model'' established during the training, provides an estimation for the tool wear. Discussion and experimental results are provided. © (1991) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.