Miracle-dz/UniFAR-FTUs huggingface dataset:
A dual druggable genome-wide siRNA and compound library screening approach identifies modulators of parkin recruitment to mitochondria

Genetic and biochemical evidence points to an association between mitochondrial dysfunction and Parkinson's disease (PD). PD-associated mutations in several genes have been identified and include those encoding PTEN-induced putative kinase 1 (PINK1) and parkin. To identify genes, pathways, and pharmacological targets that modulate the clearance of damaged or old mitochondria (mitophagy), here we developed a high-content imaging-based assay of parkin recruitment to mitochondria and screened both a druggable genome-wide siRNA library and a small neuroactive compound library. We used a multiparameter principal component analysis and an unbiased parameter-agnostic machine-learning approach to analyze the siRNA-based screening data. The hits identified in this analysis included specific genes of the ubiquitin proteasome system, and inhibition of ubiquitin-conjugating enzyme 2 N (UBE2N) with a specific antagonist, Bay 11-7082, indicated that UBE2N modulates parkin recruitment and downstream events in the mitophagy pathway. Screening of the compound library identified kenpaullone, an inhibitor of cyclin-dependent kinases and glycogen synthase kinase 3, as a modulator of parkin recruitment. Validation studies revealed that kenpaullone augments the mitochondrial network and protects against the complex I inhibitor MPP+. Finally, we used a microfluidics platform to assess the timing of parkin recruitment to depolarized mitochondria and its modulation by kenpaullone in real time and with single-cell resolution. We demonstrate that the high-content imaging-based assay presented here is suitable for both genetic and pharmacological screening approaches, and we also provide evidence that pharmacological compounds modulate PINK1-dependent parkin recruitment.
Regrets of family caregivers in Israel about the end of life of deceased relatives

Abstract Objective: We aimed to clarify the content of different types of regrets or lack of regret, and the frequency of feeling regret among family caregivers who assisted their relatives during their end of life stage. Method: Seventy primary informal caregivers in Israel were interviewed (17 spouses, 52 children, and 1 cousin) concerning their regret about the end of life of their deceased relative, including a general question about regret and questions about regret concerning life-sustaining treatments. After calculating the frequency of regrets and lack of regret, we conducted a qualitative analysis, using a thematic approach to identify themes and interpret data. Results: A majority of caregivers (63%) expressed regret and about 20% expressed ambivalence involving both regret and denial of regret. Regrets pertained to care given, suffering experienced, and the caregiver's behavior towards, and relationship with the deceased, including missing opportunities to express love and caring toward relatives. Caregivers viewed almost 30% of 75 administered life-sustaining procedures as misguided. Most regrets involved inaction, such as not communicating sufficiently, or not fighting for better care. Conclusion: This article provides a comprehensive description of EoL regrets, and helps clarify the complexity of regrets, lack of regrets, and ambivalence concerning regrets, though the study is limited to one country. Analysis suggests the need for public education concerning the EoL process, and for changes within the health care system to improve communication, to improve understanding of the needs of the terminally ill, and to provide more instruction to family caregivers to help them understand EoL.
Knowledge, attitudes, and practices of influenza and pneumococcal vaccines among agricultural workers: results of an Italian a cross-sectional study

Background: Working age is increasing across Europe. Seasonal influenza (SID) and pneumococcal disease (PND) immunization programmes might be successfully implemented at the workplace. We conducted a cross-sectional survey among to assess SID and PND vaccine status, as well as knowledge, attitudes and practices (KAP) in a representative sample of agricultural workers (AWs) aged ≥55 years in North-Eastern Italy. Methods: A structured questionnaire was administered in person by trained personnel. Bivariate and multivariate logistic regression analyses were carried out to identify behavioral and work-related factors associated with SID and PND vaccine uptake. Results: Among 707 participants, 238 were aged 55 years or more (33.7% of total). Of them, 39.1% had an up-to-date immunization status towards influenza, and 17.6% towards pneumococcus. Factors associated with inadequate immunization were doubts about influenza vaccine safety (40.0%) and the confidence in natural immunity towards pneumococcus (30.8%). Attitude towards vaccinations was somehow favorable in 44.5% of participants for SID, and 37.8% for PND. Overall, 37.4% and 21.8% workers were aware of national recommendations on SID and PND immunization, respectively. This factor was characterized as a significant predictor for SID vaccination (multivariated Odds Ratio, OR 32.688 95%CI 12.015-88.930), as well as the perception of SID as a severe disease (OR 7.539 95%CI 3.312-17.164), and the perceived value of preventing new infections (OR 3.215 95%CI 1.205-8.578). A somehow favorable attitude towards vaccinations was the main predictor (OR 39.214 95%CI 10.179-151.1) for PND vaccination. Conclusions: Our study indicates that older workers lack appropriate knowledge of national recommendations and correct risk perception of SID and PND infections, but also vaccines’ side effects. As the latter has been recognized as predictive factor for SID vaccination, our results stress the importance for tailored informative interventions in the workplaces aimed to increase risk perception and vaccine acceptance. (www.actabiomedica.it)
Hypertension prevalence and control in Ulaanbaatar, Mongolia

This study examines the prevalence, awareness, treatment, and control of hypertension in Ulaanbaatar, Mongolia, using both the American Heart Association and conventional thresholds (130/80 and 140/90 mm Hg, respectively). In this randomized cross‐sectional study, two‐stage cluster sampling was used to obtain a sample of 4515 individuals aged ≥20 years. Hypertension was defined by the use of antihypertensives in the last 2 weeks or a blood pressure at or above the thresholds of 140/90 and 130/80 mm Hg. The mean age of the participants was 41.1 ± 14.0 years and 54.5% were women. Hypertension prevalence was 25.6% (using 140/90 mm Hg) and 46.5% (using 130/80 mm Hg). Prevalence increased with age and below 50 years men were consistently more likely to be hypertensive. Among hypertensive participants, the rates of awareness, treatment, and control were 69.7%, 46.8%, and 24.0% (using 140/90 mm Hg) and 49.1%, 25.8%, and 6.4% (using 130/80 mm Hg, respectively). Men had lower rates of awareness, treatment, and control compared with women, with the most pronounced differences at younger ages. This study shows that awareness, treatment, and control rates in Ulaanbaatar are better than in most low‐ and middle‐income countries but are still suboptimal. The largest “care gap” was in young men where a regulatory requirement for annual workplace blood pressure screening has the potential to enhance care. A major hypertension control program has just been initiated in Ulaanbaatar.
Effects of CK2β subunit down-regulation on Akt signalling in HK-2 renal cells

The PI3K/Akt pathway is interconnected to protein kinase CK2, which directly phosphorylates Akt1 at S129. We have previously found that, in HK-2 renal cells, downregulation of the CK2 regulatory subunit β (shCK2β cells) reduces S129 Akt phosphorylation. Here, we investigated in more details how the different CK2 isoforms impact on Akt and other signaling pathways. We found that all CK2 isoforms phosphorylate S129 in vitro, independently of CK2β. However, in HK-2 cells the dependence on CK2β was confirmed by rescue experiments (CK2β re-expression in shCK2β HK-2 cells), suggesting the presence of additional components that drive Akt recognition by CK2 in cells. We also found that CK2β downregulation altered the phosphorylation ratio between the two canonical Akt activation sites (pT308 strongly reduced, pS473 slightly increased) in HK-2 cells. Similar results were found in other cell lines where CK2β was stably knocked out by CRISPR-Cas9 technology. The phosphorylation of rpS6 S235/S236, a downstream effector of Akt, was strongly reduced in shCK2β HK-2 cells, while the phosphorylation of two Akt direct targets, PRAS40 T246 and GSK3β S9, was increased. Differently to what observed in response to CK2β down-regulation, the chemical inhibition of CK2 activity by cell treatment with the specific inhibitor CX-4945 reduced both the Akt canonical sites, pT308 and pS473. In CX-4945-treated cells, the changes in rpS6 pS235/S236 and GSK3β pS9 mirrored those induced by CK2β knock-down (reduction and slight increase, respectively); on the contrary, the effect on PRAS40 pT246 phosphorylation was sharply different, being strongly reduced by CK2 inhibition; this suggests that this Akt target might be dependent on Akt pS473 status in HK-2 cells. Since PI3K/Akt and ERK1/2/p90rsk pathways are known to be interconnected and both modulated by CK2, with GSK3β pS9 representing a convergent point, we investigated if ERK1/2/p90rsk signaling was affected by CK2β knock-down and CX-4945 treatment in HK-2 cells. We found that p90rsk was insensitive to any kind of CK2 targeting; therefore, the observation that, similarly, GSK3β pS9 was not reduced by CK2 blockade suggests that GSK3β phosphorylation is mainly under the control of p90rsk in these cells. However, we found that the PI3K inhibitor LY294002 reduced GSK3β pS9, and concomitantly decreased Snail1 levels (a GSK3β target and Epithelial-to-Mesenchymal transition marker). The effects of LY294002 were observed also in CK2β-downregulated cells, suggesting that reducing GSK3β pS9 could be a strategy to control Snail1 levels in any situation where CK2β is defective, as possibly occurring in cancer cells.
BiORSEO: a bi-objective method to predict RNA secondary structures with pseudoknots using RNA 3D modules

MOTIVATION RNA loops have been modelled and clustered from solved 3D structures into ordered collections of recurrent non-canonical interactions called" RNA modules", available in databases. This work explores what information from such modules can be used to improve secondary structure prediction. We propose a bi-objective method for predicting RNA secondary structures by minimizing both an energy-based and a knowledge-based potential. The tool, called BiORSEO, outputs secondary structures corresponding to the optimal solutions from the Pareto set. RESULTS We compare several approaches to predict secondary structures using inserted RNA modules information: two module data sources, Rna3Dmotif and The RNA 3D Motif Atlas, and different ways to score the module insertions: module size, module complexity, or module probability according to models like JAR3D and BayesPairing. We benchmark them against a large set of known secondary structures, including some state-of-the-art tools, and comment on the usefulness of the half physics-based, half data-based approach. AVAILABILITY The software is available for download on the EvryRNA website, as well as the datasets. SUPPLEMENTARY INFORMATION Supplementary sections are available at Bioinformatics online.
Inferior vena cava revisited – Real‐time flow MRI of respiratory maneuvers

Recent MRI studies of blood flow in the inferior vena cava (IVC) resulted in findings which are inconsistent with earlier observations by invasive procedures – most likely because ECG‐gated MRI techniques are unable to resolve dynamic adjustments due to respiration. The purpose of this work was to apply real‐time phase‐contrast MRI at 50 ms resolution to re‐evaluate IVC flow in response to normal and deep breathing as well as breath holding and Valsalva maneuver (11 young healthy subjects). Real‐time flow MRI relied on highly undersampled radial gradient‐echo sequences and a model‐based nonlinear inverse reconstruction. A frequency analysis of the predominant pulsatility classified IVC flow in individual subjects as “cardiac”, “respiratory” or “mixed” type. Peak flow velocities during free breathing ranged from 30 to 58 cm s−1, while flow rates varied from 15 to 37 ml s−1. The subject‐specific IVC flow pattern persists during deep breathing although the enhanced respiratory influence may shift subjects form “cardiac” to “mixed” or from “mixed” to “respiratory” type. Peak velocities increased relative to normal breathing but led to similar flow rates of 16 to 34 ml s−1. Inspiration during deep breathing elicited brief periods of flow reversal in all subjects with mean peak velocities of −21 cm s−1. The observation of only mildly flattened parabolic velocity distributions within the IVC indicated mostly laminar flow. Breath holding reduced blood flow velocities and rates by more than 40% on average, while Valsalva maneuvers completely abolished venous return. In conclusion, IVC blood flow is dominated by the acquired respiratory behavior of individual subjects and its pressure‐induced alterations relative to cardiac pulsation. The responses to breath holding and Valsalva maneuver are in full agreement with previous invasive observations of reduced or even ceased flow, respectively.
Safe eradication of large established tumors using neovasculature‐targeted tumor necrosis factor‐based therapies

Systemic toxicities have severely limited the clinical application of tumor necrosis factor (TNF) as an anticancer agent. Activity‐on‐Target cytokines (AcTakines) are a novel class of immunocytokines with improved therapeutic index. A TNF‐based AcTakine targeted to CD13 enables selective activation of the tumor neovasculature without any detectable toxicity in vivo. Upregulation of adhesion markers supports enhanced T‐cell infiltration leading to control or elimination of solid tumors by, respectively, CAR T cells or a combination therapy with CD8‐targeted type I interferon AcTakine. Co‐treatment with a CD13‐targeted type II interferon AcTakine leads to very rapid destruction of the tumor neovasculature and complete regression of large, established tumors. As no tumor markers are needed, safe and efficacious elimination of a broad range of tumor types becomes feasible.
Microbial reconstitution reverses early female puberty induced by maternal high-fat diet during lactation.

Recent work shows that gut microbial dysbiosis contributes to the risk of obesity in children whose mothers consume a high-fat diet (HFD) during both gestation and lactation or during gestation alone. Obesity predisposes children to developing precocious puberty. However, to date, no study has examined how maternal high-fat diet (MHFD) during lactation regulates the gut microbiota (GM), pubertal timing, and fertility of offspring. Here, we found that MHFD during lactation markedly altered the GM of offspring. The pups developed juvenile obesity, early puberty, irregular estrous cycles, and signs of disrupted glucose metabolism. Remarkably, permitting coprophagia between MHFD and maternal normal chow offspring successfully reversed the GM changes as well as early puberty and insulin insensitivity. Our data suggest that microbial reconstitution may prevent or treat early puberty associated with insulin resistance.
Recent advances in allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

PURPOSE OF REVIEW Allogeneic hematopoietic cell transplantation (HCT), with associated graft-versus-leukemia effects, remains the best postremission strategy for patients with intermediate or high-risk acute myeloid leukemia (AML), with a curative potential. Here, we highlight recent advances in allogeneic HCT that broadened access, refined prognostication, and improved outcomes of AML patients undergoing this procedure. RECENT FINDINGS Eligibility for allogeneic HCT continued to expand to AML patients older than 60 years, as well as to patients lacking human leukocyte antigen (HLA)-matched donors with the advent of alternative donor sources, such as umbilical cord blood and HLA-haploidentical transplantation. Molecular profiling of AML has redefined prognostication for patients in specific AML genomic subgroups undergoing allogeneic HCT and has served as a new strategy for measuring minimal residual disease before and after allogeneic HCT. Using high intensity conditioning regimens has emerged as a potential strategy to reduce risk of relapse and improve overall survival, especially in patients with minimal residual disease prior to allogeneic HCT. SUMMARY As access to allogeneic HCT continues to improve, also, with more refined prognostic strategies, the field continues to move to optimize transplantation approaches by decreasing the risk of relapse and minimizing transplant-related complications.
EVALUATION OF TAPM USING THE INDIANAPOLIS (URBAN) AND KWINANA (COASTAL) FIELD DATA SETS

The Air Pollution Model (TAPM) is evaluated using the 1985 Indianapolis (USA) and the 1995 Kwinana (Australia) point-source dispersion data sets, both taken in relatively flat terrain. The first represents urban dispersion, while the Kwinana data set represents coastal dispersion (including fumigation). The model is run with multi-level nesting, both with and without wind data assimilation. Various statistical measures are used to evaluate model performance. Comparison with (published) results obtained from other commonly used models, namely ADMS3, AERMOD and ISCST3, that have been applied to the Indianapolis data set with the observed meteorology, indicates that TAPM performs as well as, if not better than, the best of these models. Comparison with the Kwinana data shows that TAPM performs well in simulating coastal effects, such as sea breezes, fumigation and wind direction shear.
Magnetic resonance imaging noise filtering using adaptive polynomial-fit non-local means

Abstract— Every image, whether it is a Magnetic Resonance (MR) image or a gray scale image, usually contains noise, which negatively affects image processing and analysis outcomes. For MR images, noise can be induced by environmental, equipment, and human factors. Rician noise obeys a Rician distribution. It degrades the quality of an image and makes it blurry. Rician noise is signal-dependent. Thus, it is a difficult task to separate signals from noise. In order to reduce Rician noise in MR images, noise-removing techniques are necessary to be applied before the image undergoes further processing. In this paper, a noiseremoving technique is developed by cascading a new noise estimation method known as Nonlinear Spatial Mean Absolute Deviation (NSMAD) with a new noise filter known as Adaptive Polynomial-Fit Non-Local Means (Adaptive_PFNLM) filter. The NSMAD method is used to estimate the level of noise standard deviation in MR images. Then, the value of noise standard deviation is passed to the Adaptive_PFNLM filter to remove noise. The NSMAD method is compared with three existing estimation methods, namely Brummer’s method, Maximum Likelihood (ML) method, and Local Mean method. The Adaptive_PFNLM filter is also compared with three existing filters, namely Non-Local Means (NLM) filter, Linear Minimum Mean Square Error (LMMSE) filter, and Polynomial-Fit NonLocal Means (PFNLM) filter. The comparison is evaluated by using the mean absolute error (MAE), signal-to-noise ratio (SNR), mean square error (MSE), peak signal-to-noise ratio (PSNR), structure similarity (SSIM) and quality index (Q). The results indicate that NSMAD and Adaptive_PFNLM perform better than the existing noise estimation methods and noise filters.
Working Paper 2/2015 The importance of effective economic regulation and coordinated institutions for inclusive growth: Lessons from South Africa’s renewable energy programmes in the Electricity Supply Industry

Economic regulation, including competition policy, is not an end in itself but a means to an end, and must ultimately have a positive impact on the economy as a whole. However, this positive impact needs to be broad-based or inclusive, particularly in the context of South Africa given its legacy of non-inclusive growth and persistent inequality. An area where increased participation is important in achieving more inclusive growth in a developing country context is in the procurement of large-scale infrastructure. The South African experience with procuring large-scale renewable energy-based electricity generation capacity carries interesting lessons in this respect. The paper reviews the development of South Africa’s large-scale renewable energy sector from an economic regulation and inclusive growth lens. The regulatory framework governing the sector is examined, looking at both the policy and institutional environment, and their role in contributing to inclusive growth objectives. As such, the paper investigates the role that economic regulation can play in stimulating inclusive growth, through the promotion of both competitive and socio-economic outcomes. The paper also looks at the importance of factoring vested interests in order to maximise inclusive growth outcomes through economic regulation.
BOLETIM DO INSTITUTO DE PESCA

3Universidade Federal do Vale do São Francisco, Departamento de Zootecnia, Campus Ciências Agrárias Rodovia BR 407 Km 12 Lote 543 Projeto de Irrigação Nilo Coelho –Petrolina – PE 56300000, Brazil. E-mail: melojfb@yahoo.com. br (corresponding author) ABSTRACT This study aimed to analyze the effect of mango meal, a non-starch polysaccharide, as a carbohydrate source on the metabolism plasticity and performance indicators for hybrid surubim (Pseudoplatystoma fasciatum x P. corruscans), a tropical carnivorous fish. Juveniles (±14.5g initial weight) were fed 3% of total biomass for 60 days in four experimental diets replacing 0, 33, 66 and 100% of the cornmeal. Growth by final weight was evaluated, but statistical differences (p<0.05) were not observed among the treatments. The activity of total alkaline protease was statistically lower in the fish group fed 100% cornmeal substitution. However, trypsin levels also decreased when 100% of the cornmeal was replaced by mango meal, but without statistical significance. Zymograms showed bands of protease and amylase activities for all treatments. Cholesterol (0%141.83±46.10; 100%71.36±14.40 mg.dL-1) and total protein (0%3.98±0.94; 100%1.70±1.03 mg.dL-1) in the plasma decreased as mango meal levels increased in the feed. On the other hand, glucose (0%105.08±31.24; 100%128.11±24.51 mg.dL-1) and free amino acids (0%24.51±2.62; 100%38.13±8.94 nmoles.ml-1) in the plasma increased. Although growth was not affected, the carbohydrate source affected fish metabolism, which showed metabolic adaptation by the species. The result suggests that mango meal can replace up to 33% of the cornmeal in diets for Pseudoplatystoma sp.