Miracle-dz/UniFAR-FTUs huggingface dataset:
Eyes are mirror of the brain: comparison of multiple sclerosis patients and healthy controls using OCT

Abstract Objective: To evaluate the thickness of choroid and retinal nerve fiber layer (RNFL) in multiple sclerosis (MS) patients with and without optic neuritis using enhanced depth imaging optical coherence tomography (EDI-OCT). Methods: In this cross-sectional study, both eyes of 52 MS patients [n = 104 eyes; 62 eyes of MS patients without optic neuritis (MS-NON) and 42 eyes of MS patients with optic neuritis (MS-ON)] and only one eye of 36 healthy control subjects (n = 36 eyes) were evaluated. Complete ophthalmologic examination and EDI-OCT scanning were completed for all participants. Choroidal thickness measurements were executed at three different points. Results: Choroidal thickness measurements were similar between MS patients and healthy control subjects. However, the mean subfoveal choroidal thickness was increased significantly in MS-ON group (399.13 ± 82.91 μm) compared to MS-NON group (342.71 ± 82.46 μm; p = 0.004). Mean RNFL thickness was significantly reduced in MS patients (90.42 ± 13.31 μm) compared to healthy controls (101.18 ± 10.75 μm; p < 0.001). Moreover, temporal RNFL thickness was significantly thinner in MS-ON group (54 ± 14.50 μm) than MS-NON group (62.15 ± 15.88 μm; p = 0.01). In MS patients, temporal RNFL thickness was correlated with both Expanded Disability Status Score (r = 0.383; p < 0.001) and longer disease duration (r=–0.202; p = 0.04). Conclusion: The results of the present study suggest that RNFL thickness can be used as an important parameter while following up with MS patients. However, more studies using EDI-OCT are required with larger MS patient groups and automated method.
Using supervised learning to select audit targets in performance-based financing in health: An example from Zambia

Independent verification is a critical component of performance-based financing (PBF) in health care, in which facilities are offered incentives to increase the volume of specific services but the same incentives may lead them to over-report. We examine alternative strategies for targeted sampling of health clinics for independent verification. Specifically, we empirically compare several methods of random sampling and predictive modeling on data from a Zambian PBF pilot that contains reported and verified performance for quantity indicators of 140 clinics. Our results indicate that machine learning methods, particularly Random Forest, outperform other approaches and can increase the cost-effectiveness of verification activities.
PDZ Domains Across the Microbial World: Molecular Link to the Proteases, Stress Response, and Protein Synthesis

Abstract The PSD-95/Dlg-A/ZO-1 (PDZ) domain is highly expanded, diversified, and well distributed across metazoa where it assembles diverse signaling components by virtue of interactions with other proteins in a sequence-specific manner. In contrast, in the microbial world they are reported to be involved in protein quality control during stress response. The distribution, functions, and origins of PDZ domain-containing proteins in the prokaryotic organisms remain largely unexplored. We analyzed 7,852 PDZ domain-containing proteins in 1,474 microbial genomes in this context. PDZ domain-containing proteins from planctomycetes, myxobacteria, and other eubacteria occupying terrestrial and aquatic niches are found to be in multiple copies within their genomes. Over 93% of the 7,852 PDZ domain-containing proteins were classified into 12 families including six novel families based on additional structural and functional domains present in these proteins. The higher PDZ domain encoding capacity of the investigated organisms was observed to be associated with adaptation to the ecological niche where multicellular life might have originated and flourished. Predicted subcellular localization of PDZ domain-containing proteins and their genomic context argue in favor of crucial roles in translation and membrane remodeling during stress response. Based on rigorous sequence, structure, and phylogenetic analyses, we propose that the highly diverse PDZ domain of the uncharacterized Fe–S oxidoreductase superfamily, exclusively found in gladobacteria and several anaerobes and acetogens, might represent the most ancient form among all the existing PDZ domains.
Prediction model for hepatocellular carcinoma risk in treatment-naive chronic hepatitis B patients receiving entecavir/tenofovir

Supplemental Digital Content is available in the text. Background/aim Accurate assessment of hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients receiving entecavir (ETV)/tenofovir disoproxil fumarate (TDF) is likely to play a pivotal role in post-treatment follow-up strategy. We aimed to develop a simple and reliable predictive model for HCC risk in these patients. Patients and methods A database of 1242 consecutive treatment-naive CHB patients who initially underwent ETV/TDF between February 2007 and January 2017 at four referral hospitals in South Korea was analyzed. The HCC risk model was constructed on the basis of a multivariable Cox proportional hazards model in the derivation dataset (n=944) and was validated using Harrell’s C-statistic in a validation dataset (n=298). Results The 3/5-year cumulative incidence rates of HCC were 3.9/6.5 and 4.2/11.6% in the derivation and the validation dataset, respectively (P=0.08). In the derivation dataset, we identified four factors associated with HCC, namely, age, albumin, sex, and liver cirrhosis. The AASL (age, albumin, sex, liver cirrhosis)-HCC scoring system was developed on the basis of these factors, and simplified to an integer scoring system. AASL-HCC scores were found to have high discriminating performance for the prediction of HCC development at 5 years in the derivation (C-statistics=0.802, 95% confidence interval: 0.716–0.888) and validation dataset (C-statistics=0.805, 95% confidence interval: 0.671–0.939). When AASL-HCC scores were classified as 5 or less, 6–19, and at least 20 (low-risk, intermediate-risk, and high-risk groups, respectively), the 5-year cumulative incidence rates of HCC were 0, 4.2, and 17.6%, respectively, in the derivation dataset. Conclusions The AASL-HCC model was simple and reliable for HCC risk prediction in treatment-naive CHB patients receiving ETV/TDF, and is easily applicable in the clinical setting.
miR‐545 promoted enterovirus 71 replication via directly targeting phosphatase and tensin homolog and tumor necrosis factor receptor‐associated factor 6

Enterovirus 71 (EV71) is a small, nonenveloped icosahedral RNA virus and is the predominant causative pathogen of hand‐foot‐and‐mouth disease. Recently, microRNAs (miRNAs) are reported to play important roles in the pathogenesis of EV71 replication. This study investigated the role of miR‐545 in the EV71 replication and explored the underlying molecular mechanisms. We showed that miR‐545 was upregulated in the EV71‐infected human embryonic kidney (HEK) 293 cells and rhabdomyosarcoma (RD) cells. Overexpression of miR‐545 promoted the viral replication of EV71 and attenuated the inhibitory effects of EV71 on cell viability in HEK293 and RD cells; while knockdown of miR‐545 significantly suppressed the EV71 replication in these two cell lines. Bioinformatics analysis and luciferase reporter assay showed that miR‐545 directly targeted the 3′untranslated region of phosphatase and tensin homolog (PTEN) and tumor necrosis factor receptor‐associated factor 6 (TRAF6) in HEK293 cells. Furthermore, miR‐545 negatively regulated the messenger RNA (mRNA) and protein expression of PTEN and TRAF6. The mRNA and protein expression of PTEN and TRAF6 was also suppressed by EV71 infection, which was attenuated by miR‐545 knockdown in HEK293 cells. Overexpression of PTEN and TRAF6 both suppressed the EV71 replication in HKE293 cells, and also attenuated the enhanced effects of miR‐545 overexpression on the EV71 replication in HEK293 cells. Collectively, our study for the first time showed that miR‐545 had an enhanced effect on the EV71 replication in HEK293 and RD cells. Further mechanistic results indicated that miR‐545 promoted EV71 replication at least partly via targeting PTEN and TRAF6.
CRISPR/Cas9 technology as a potent molecular tool for gene therapy

Clustered regularly interspaced short palindromic repeats/CRISPR‐associated nuclease 9 (CRISPR‐Cas9) is an RNA‐guided gene editing tool which offers several advantageous characteristics in comparison with the conventional methods (e.g., zinc finger nucleases and transcription activator‐like effector nucleases) such as cost‐effectiveness, flexibility, and being easy‐to‐use. Despite some limitations such as efficient delivery and safety, CRISPR‐Cas9 is still the most convenient tool for gene editing purposes. Due to the potential capability of the CRISPR‐Cas9 system in genome editing and correction of casual mutations, it can be considered as a possible therapeutic system in the treatment of disorders associated with the genome mutations and in particular cancer treatment. In this review, we will discuss CRISPR‐Cas‐based gene editing along with its classifications and mechanism of action. Furthermore, the therapeutic application of the CRISPR‐Cas9 system in mutational disorders, delivery systems, as well as its advantages and limitations with a special emphasis on cancer treatment will be discussed.
Long‐term outcomes of endoscopic submucosal dissection versus surgery in early gastric cancer: a systematic review and meta-analysis

Endoscopic submucosal dissection (ESD) and gastrectomy with lymph node dissection are considered acceptable treatment modalities for early gastric cancer (EGC). In the last decade, ESD has become more favorable than surgery as it offers faster recovery, lower costs, and a superior quality of life when compared to gastrectomy. The aim of this study is to compare the long-term outcome of ESD versus surgery in EGC. We performed a systematic and comprehensive search of major reference databases (Medline, Embase, CINHAL) for all studies that compared the outcome of EGC for patients underwent ESD or surgery in the same cohort. A systematic review was conducted through November 2017, using pooled analysis to calculate 5-year overall survival (OS) rate, disease-specific survival (DSS) rate, disease-free survival (DFS) rate, and recurrence-free survival (RFS) rate of ESD versus gastrectomy. Five-year OS and DSS were similar between ESD and gastrectomy groups 96 versus 96% and 99.4 versus 99.2%, respectively. Likewise, DFS was similar in both groups 95.9 versus 98.5% odds ratio 1.86 (0.57–6.0) P=0.3. However, ESD had a lower RFS compared to surgery 92.4 versus 98.3% odds ratio 0.17 (0.1–4.9) P=0.001. Overall, there was a higher recurrence rate in patients who underwent ESD compared to surgery [40/2943 (1.4%) vs. 12/3116 (0.4) risk ratio (RR) 2.5 (1.3–4.8) P=0.005]. Moreover, synchronous and metachronous cancers were more prevalent in the ESD group compared to the surgery group [1.5 vs. 0.1% RR 5.7 (1.5–21.9) P=0.01] [16/1082 (1.5%) vs. 1/1485 (0.1%) RR 10.1 (5.9–17.1) P=0.0001]. Five-year OS, DSS and DFS were similar between ESD and surgery groups. However, recurrent, synchronous and metachronous cancers were more prevalent in patients treated by ESD compared to patients treated by surgery, resulting in a lower RFS. Adequate surveillance with upper endoscopy is crucial after ESD to detect early recurrence and metachronous lesions.
Mechanisms of Strain Diversity of Disease-Associated in-Register Parallel β-Sheet Amyloids and Implications About Prion Strains

The mechanism of strain diversity of prions still remains unsolved, because the investigation of inheritance and diversification of the protein-based pathogenic information demands identification of the detailed structures of abnormal isoform of prion protein (PrPSc), while it is difficult to purify for analysis without affecting the infectious nature. On the other hand, the similar prion-like properties are recognized also in other disease-associated in-register parallel β-sheet amyloids including Tau and α-synuclein (αSyn) amyloids. Investigations into structures of those amyloids by solid-state nuclear magnetic resonance spectroscopy and cryo-electron microscopy recently made remarkable advances, because of their relatively small sizes and lack of post-translational modifications. We review the advances on those pathogenic amyloids, particularly Tau and αSyn, and discuss their implications about strain diversity mechanisms of prion/PrPSc from the viewpoint that PrPSc is an in-register parallel β-sheet amyloid. We also present our recent data of molecular dynamics simulations of αSyn amyloid, which suggest significance of compatibility between β-sheet propensities of the substrate and local structures of the template for stability of the amyloid structures. Detailed structures of the αSyn and Tau amyloids are good surrogate models of pathogenic amyloids including PrPSc to elucidate not only the strain diversity but also their pathogenic mechanisms.
Blood Flow Restriction Only Increases Myofibrillar Protein Synthesis with Exercise

Purpose Combining blood flow restriction (BFR) with exercise can stimulate skeletal muscle hypertrophy. Recent observations in an animal model suggest that BFR performed without exercise can also induce anabolic effects. We assessed the effect of BFR performed both with and without low-load resistance-type exercise (LLRE) on in vivo myofibrillar protein synthesis rates in young men. Methods Twenty healthy young men (age = 24 ± 1 yr, body mass index = 22.9 ± 0.6 kg·m−2) were randomly assigned to remain in resting condition (REST ± BFR; n = 10) or to perform LLRE (LLRE ± BFR at 20% one-repetition maximum; n = 10), combined with two 5-min cycles of single leg BFR. Myofibrillar protein synthesis rates were assessed during a 5-h post-BFR period by combining a primed continuous L-[ring-13C6]phenylalanine infusion with the collection of blood samples, and muscle biopsies from the BFR leg and the contralateral control leg. The phosphorylation status of anabolic signaling (mammalian target of rapamycin pathway) and metabolic stress (acetyl-CoA carboxylase)–related proteins, as well as the mRNA expression of genes associated with skeletal muscle mass regulation, was assessed in the collected muscle samples. Results Under resting conditions, no differences in anabolic signaling or myofibrillar protein synthesis rates were observed between REST + BFR and REST (0.044% ± 0.004% vs 0.043% ± 0.004% per hour, respectively; P = 0.683). By contrast, LLRE + BFR increased myofibrillar protein synthesis rates by 10% ± 5% compared with LLRE (0.048% ± 0.005% vs 0.043% ± 0.004% per hour, respectively; P = 0.042). Furthermore, compared with LLRE, LLRE + BFR showed higher phosphorylation status of acetyl-CoA carboxylase and 4E-BP1 as well as the elevated mRNA expression of MuRF1 (all P < 0.05). Conclusion BFR does not increase myofibrillar protein synthesis rates in healthy young men under resting conditions. When combined with LLRE, BFR increases postexercise myofibrillar protein synthesis rates in vivo in humans.
Exercise-mediated improvement of depression in patients with gastro-esophageal junction cancer is linked to kynurenine metabolism

Abstract Background: Exercise may improve depression in cancer patients, yet the molecular mechanism behind this protection is poorly understood. Here, we aimed to explore the link between exercise and regulation of kynurenine (Kyn) metabolism and inflammation in patients with operable gastro-esophageal junction (GEJ) cancer patients, who improved significantly in depression score with exercise training. Material and Methods: Fifty GEJ cancer patients were allocated to 12 weeks of supervised training twice weekly including interval-based aerobic exercise and resistance training, or standard care. Depression score was evaluated by HADS, and blood samples and muscle biopsies were collected for determination of Kyn metabolism and inflammation across the intervention. Results: Depression scores decreased by −1.3 points in the exercise group (p < 0.01), whereas no changes were observed in the control group. Plasma 3-hydroxykynurenine (HK), a Kyn metabolite giving rise to other neurotoxic metabolites, increased by 48% (p <0.001) in the control group, while exercise training attenuated this accumulation. The production of HK is induced by inflammation, and while we observed no differences in systemic pro-inflammatory cytokines, exercise training ameliorated the treatment-induced intramuscular inflammation. Moreover, exercise has been suggested to convert Kyn to the neuroprotective metabolite, kynurenic acid (KA), but despite marked functional and muscular exercise-mediated adaptations, we did not observe any enhancement of KA production and related enzyme expression in the muscles of GEJ cancer patients. Conclusion: Exercise training reduced symptoms of depression in patients with GEJ cancer, and this effect was associated with an exercise-dependent attenuation of the inflammation-induced conversion of Kyn to neurotoxic metabolites.
Differences in Engineered Nanoparticle Surface Physicochemistry Revealed by Investigation of Changes in Copper Bioavailability During Sorption to Nanoparticles in the Aqueous Phase

Sorption of chemical substances to nanoparticles (NPs) in the aqueous phase strongly influences NP physicochemisty, and investigations of these complex interactions can provide important insights into the environmental fate of NPs. The objective of the present study was to use differences in copper (Cu) bioavailability to investigate aqueous‐phase sorption with NPs that had different physicochemical characteristics (silicon [Si], perovskite, and titanium dioxide NPs [TiO2 NPs]). Sorption of Cu with NPs was assessed by the presence of adsorbent in water and onto the NP surface after ultracentrifugation, and by changes in Cu bioavailability under static conditions during exposure of larval zebrafish, as well as under conditions of continuous agitation during exposure of the alga Chlorella vulgaris. The presence of TiO2 NPs reduced total Cu in the water column and Cu bioavailability (measured by growth inhibition, mortality, and metallothionein 2 gene expression), confirming Cu sorption to TiO2 NPs. Nanoparticle surface area was the most important factor that affected Cu sorption, as indicated by less bioavailable Cu in the presence of smaller TiO2 NPs. The surface area effect was consistent regardless of exposure conditions (alga, continuous agitation; zebrafish, static water) and was further supported by the fact that the lowest total Cu concentration in the water column was found in the presence of the smallest NP. The results differed with other NP types, for example, silicon NPs, in which Cu sorption was indicated by analytical chemistry, but sorption was not sufficient to significantly alter Cu bioavailability. The bioavailability tests did not indicate Cu sorption with perovskite NPs. The results demonstrate that surface area critically influences sorption, that Cu sorption as measured by bioavailability is not affected by agitation or static conditions, and that Cu sorption differs among types of NPs, indicating differences in their surface physicochemistry. Environ Toxicol Chem 2019;9999:1–11. © 2019 SETAC
Derivatives of Piperazines as Potential Therapeutic Agents for Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder that is the major cause of dementia in the elderly. There is no cure against AD. We have recently discovered a novel transient receptor potential canonical 6 (TRPC6)–mediated intracellular signaling pathway that regulates the stability of dendritic spines and plays a role in memory formation. We have previously shown that TRPC6 agonists exert beneficial effects in models of AD and may serve as lead compounds for development of AD therapeutic agents. In the current study, we used the Clarivate Analytics Integrity database to search for additional TRPC6 agonists. We selected four compounds to study as potential neuroprotective agents. We applied bioinformatics analyses to test the basic pharmacological properties of the selected compounds. We performed in vitro screening of these compounds to validate their ability to protect mushroom spines from amyloid toxicity and determined that two of these compounds exert neuroprotective effects in the nanomolar concentration range. We have chosen one of these compounds [piperazine (PPZ)] for further testing. In agreement with previously published data, we have shown that PPZ potentiates TRPC6 channels. We demonstrated that the neuroprotective mechanism of the investigated PPZ is based on activation of neuronal store-operated calcium entry in spines. We have shown that PPZ restores long-term potentiation induction in 6-month-old 5xFAD mouse hippocampal slices. The obtained results suggest that PPZ and its derivatives are potential lead molecules for development of AD therapeutic agents.
Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

*Correspondence to Dr. Paul S. de Vries, HumanGenetics Center, Department of Epidemiology, HumanGenetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, 1200 Pressler Street, Suite E-429, Houston, TX 77030 (e-mail: paul.s.devries@uth.tmc.edu); Dr. Dabeeru C. Rao, Division of Biostatistics, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8067, St. Louis, MO 63110 (e-mail: rao@wustl.edu); or Dr. Alanna C. Morrison, HumanGenetics Center, Department of Epidemiology, HumanGenetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, 1200 Pressler Street, Suite E-447, Houston, TX 77030 (e-mail: alanna.c.morrison@uth.tmc.edu). ‡ For the complete author list, please see the Acknowledgments.
Lead in piscivorous raptors during breeding season in the Chesapeake Bay region of Maryland and Virginia, USA

Sources of lead exposure of many bird species are poorly understood. We analyzed blood lead concentrations from osprey (n = 244; Pandion haliaetus) and bald eagles (n = 68; Haliaeetus leucocephalus) and documented potential sources of lead they may encounter. Adult bald eagles had higher blood lead concentrations than did adult osprey. However, blood lead concentrations of nestlings were similar for both species. Although 62% of osprey had detectable lead concentrations ( x¯ = 1.99 ± 4.02 μg/dL, mean ± standard deviation [SD]), there was no difference in the detection frequency or lead concentrations between osprey adults and nestlings. Likewise, we found no differences in the detection frequency or lead concentrations in osprey adults and nestlings from high‐ and low‐salinity areas. Of the bald eagle samples tested, 55% had detectable lead levels ( x¯ = 6.23 ± 10.74 μg/dL). Adult bald eagles had more detectable and higher lead concentrations than did nestlings or pre‐adults. Among environmental samples, paint had the highest lead concentrations, followed by sediment, blue catfish (Ictalurus furcatus), and gizzard shad (Dorosoma cepedianum). There was no correlation between blood lead concentrations of osprey adults and their offspring. Our results indicate that, in the Chesapeake Bay region of Maryland and Virginia (USA), there are multiple sources by which piscivorous raptors may be exposed to lead. Environ Toxicol Chem 2019;38:862–871. © Published 2019 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.