Miracle-dz/UniFAR-FTUs huggingface dataset:
Cholesterol-rich naked mole-rat brain lipid membranes are susceptible to amyloid beta-induced damage in vitro

Naked mole-rats are extraordinarily long-lived rodents that offer unique opportunities to study the molecular origins of age-related neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentrations of amyloid beta (Aβ) peptide from a young age. Therefore, they represent a particularly favourable organism to study the mechanisms of resistance against Aβ neurotoxicity. Here we examine the composition, phase behaviour, and Aβ interactions of naked mole-rat brain lipids. Relative to mouse, naked mole-rat brain lipids are rich in cholesterol and contain sphingomyelin in lower amounts and of shorter chain lengths. Proteins associated with the metabolism of ceramides, sphingomyelins and sphingosine-1-phosphate receptor 1 were also found to be decreased in naked mole-rat brain lysates. Correspondingly, we find that naked mole-rat brain lipid membranes exhibit a high degree of phase separation, with the liquid ordered phase extending to 80% of the supported lipid bilayer. These observations are consistent with the ‘membrane pacemaker’ hypothesis of ageing, according to which long-living species have lipid membranes particularly resistant to oxidative damage. We also found that exposure to Aβ disrupts naked mole-rat brain lipid membranes significantly, breaking the membrane into pieces while mouse brain derived lipids remain largely intact upon Aβ exposure.
Clinical correlates of serum 25-hydroxyvitamin D in Parkinson’s disease

ABSTRACT Background Parkinson’s disease (PD) patients have lower levels of serum 25-hydroxyvitamin D (25(OH)D) than the general population. Previous studies have suggested a negative association between 25(OH)D and clinical features of PD, but the data are inconsistent. Materials and Methods We conducted a cross-sectional, observational study. Serum 25(OH)D, disease (Hoehn-Yahr stage [HY]) and clinical symptom (Unified Parkinson Disease Rating Scale [UPDRS]) severity and global cognitive functions (Mini-Mental State Examination [MMSE]) were studied in 500 consecutive PD patients not using vitamin D supplements. Information on sunlight exposure and dietary intakes (using a 66-item food frequency questionnaire) were also collected. A convenient sample of age and sex-matched community healthy controls (N = 100) was included as a control group. Results PD patients had lower 25(OH)D serum levels than controls. Deficiency status (<20 ng/mL) was found in 65.6% of patients. 25(OH)D levels were independently correlated to sunlight exposure (P = .002) and vitamin D intake (P = .009). In multivariate models, using a Mendelian randomization approach, lower serum 25(OH)D was associated with more severe disease (HY, P = .035), worse clinical symptoms (UPDRS Part-III total score [P = .006] and dopaminergic [P = .033] and non-dopaminergic subscores [P = .001]) and greater global cognitive function impairment (P = .041). Neither cognitive functions nor clinical features were associated with reduced intake of vitamin D and sunlight exposure. Conclusion : Serum 25(OH)D was negatively correlated with disease and symptoms severity, as well as with global cognitive functions. Our study adds to the evidence that low 25(OH)D may affect the progression of PD negatively. Intervention studies in this area are required.
Age- and gender-specific characteristics of the resting-state brain activity: a magnetoencephalography study

Aging and gender influence regional brain activities. Although these biases should be considered during the clinical examinations using magnetoencephalography, they have yet to be standardized. In the present study, resting-state magnetoencephalography data were recorded from 54 healthy females and 48 males aged 22 to 75 years, who were controlled for cognitive performance. The regional oscillatory power was estimated for each frequency band (delta, theta, alpha, beta, low-gamma, and high-gamma) using the sLORETA-like algorithm and the biases of age and gender were evaluated, respectively. The results showed that faster oscillatory powers increased with age in the rostral regions and decreased in the caudal regions, while few slower oscillatory powers changed with age. Gender differences in oscillatory powers were found in a broad frequency range, mostly in the caudal brain regions. The present study characterized the effects of healthy aging and gender asymmetricity on the regional resting-state brain activity, with the aim to facilitate the accurate and efficient use of magnetoencephalography in clinical practice.
Frontotemporal dementia‐linked P112H mutation of TDP‐43 induces protein structural change and impairs its RNA binding function

TDP‐43 forms the primary constituents of the cytoplasmic inclusions contributing to various neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). Over 60 TDP‐43 mutations have been identified in patients suffering from these two diseases, but most variations are located in the protein's disordered C‐terminal glycine‐rich region. P112H mutation of TDP‐43 has been uniquely linked to FTD, and is located in the first RNA recognition motif (RRM1). This mutation is thought to be pathogenic, but its impact on TDP‐43 at the protein level remains unclear. Here, we compare the biochemical and biophysical properties of TDP‐43 truncated proteins with or without P112H mutation. We show that P112H‐mutated TDP‐43 proteins exhibit higher thermal stability, impaired RNA‐binding activity, and a reduced tendency to aggregate relative to wild‐type proteins. Near‐UV CD, 2D‐nuclear‐magnetic resonance, and intrinsic fluorescence spectrometry further reveal that the P112H mutation in RRM1 generates local conformational changes surrounding the mutational site that disrupt the stacking interactions of the W113 side chain with nucleic acids. Together, these results support the notion that P112H mutation of TDP‐43 contributes to FTD through functional impairment of RNA metabolism and/or structural changes that curtail protein clearance.
Substrate specificity of bacterial endoribonuclease toxins

Bacterial endoribonuclease toxins belong to a protein family that inhibits bacterial growth by degrading mRNA or rRNA sequences. The toxin genes are organized in pairs with its cognate antitoxins in the chromosome and thus the activities of the toxins are antagonized by antitoxin proteins or RNAs during active translation. In response to a variety of cellular stresses, the endoribonuclease toxins appear to be released from antitoxin molecules via proteolytic cleavage of antitoxin proteins or preferential degradation of antitoxin RNAs and cleave a diverse range of mRNA or rRNA sequences in a sequence-specific or codon-specific manner, resulting in various biological phenomena such as antibiotic tolerance and persister cell formation. Given that substrate specificity of each endoribonuclease toxin is determined by its structure and the composition of active site residues, we summarize the biology, structure, and substrate specificity of the updated bacterial endoribonuclease toxins.
Adaptions to the National Diabetes Prevention Programme lifestyle change curriculum by Hawai‘i Federally Qualified Health Centers: a qualitative descriptive study

Objective The objective of this qualitative study was to describe the community-appropriate and culturally appropriate adaptations made by lifestyle change programme (LCP) coaches to the National Diabetes Prevention Programme curriculum for Federally Qualified Health Center (FQHC) patients in Hawaiʻi, an ethnically diverse state with a high proportion of Native Hawaiians and Pacific Islanders (NHPI). Research design and methods We used a qualitative descriptive approach. First, we conducted a document review of existing programmatic notes and materials followed by video interview calls with 13 lifestyle coaches at 7 FQHCs implementing in-person LCPs. Lifestyle coaches catalogued, described and explained the rationale for adaptations. The research team counted adaptations if they met a specific adaptation definition derived from several sources. Community and cultural relevancy of adaptations were analysed using an existing framework for weight loss and diabetes prevention for NHPIs. Results The average number of adaptations per FQHC was 8.61 (range: 4–16). Adaptations fell into 11 broad categories such as off-site community field trips, food-related and nutrition-related activities, and physical activity opportunities. Novel adaptations included goal setting with motivational interviewing and dyadic recruitment. Field trips and in-class food demonstrations addressed the most constructs related to weight loss and diabetes prevention for NHPI, including social and community barriers, familial barriers and barriers to self-efficacy. Conclusions Lifestyle coaches were culturally attuned to the needs of LCP participants, particularly from NHPI communities. Policy-makers should recognise the extra work that LCP coaches do in order to increase enrollment and retention in these types of programmes.
DNA methylation in blood—Potential to provide new insights into cell biology

Epigenetics plays a fundamental role in cellular development and differentiation; epigenetic mechanisms, such as DNA methylation, are involved in gene regulation and the exquisite nuance of expression changes seen in the journey from pluripotency to final differentiation. Thus, DNA methylation as a marker of cell identify has the potential to reveal new insights into cell biology. We mined publicly available DNA methylation data with a machine-learning approach to identify differentially methylated loci between different white blood cell types. We then interrogated the DNA methylation and mRNA expression of candidate loci in CD4+, CD8+, CD14+, CD19+ and CD56+ fractions from 12 additional, independent healthy individuals (6 male, 6 female). ‘Classic’ immune cell markers such as CD8 and CD19 showed expected methylation/expression associations fitting with established dogma that hypermethylation is associated with the repression of gene expression. We also observed large differential methylation at loci which are not established immune cell markers; some of these loci showed inverse correlations between methylation and mRNA expression (such as PARK2, DCP2). Furthermore, we validated these observations further in publicly available DNA methylation and RNA sequencing datasets. Our results highlight the value of mining publicly available data, the utility of DNA methylation as a discriminatory marker and the potential value of DNA methylation to provide additional insights into cell biology and developmental processes.
Polyvalent transition-state analogues of sialyl substrates strongly inhibit bacterial sialidases.

Bacterial sialidases (SA) are validated drug targets expressed by common human pathogens such as Streptococcus pneumoniae, Vibrio cholerae or Clostridium perfringens. Non-covalent inhibitors of bacterial SA capable of reaching the submicromolar level are rarely reported. We developed multi- and polyvalent compounds based on the transition state analogue 2-deoxy-2,3-didehydro-N-acetylneuraminic (DANA). Poly-DANA inhibits the catalytic activity of SA from S. pneumoniae (NanA) and the symbiotic microorganism B. thetaiotaomicron (BtSA) at the picomolar and low nanomolar levels when expressed in moles of molecules and of DANA, respectively. Each DANA grafted to the polymer surpasses the inhibitory potential of the monovalent analogue by more than four orders of magnitude, which represents the highest multivalent effect reported so far for an enzyme inhibition. The synergistic interaction was shown to operate in the catalytic domain exclusively, and not in the flanked carbohydrate-binding module (CBM). These results offers interesting perspectives for the multivalent inhibition of other SA families lacking a CBM, such as viral, parasitic or human SA.
Reelin Mediates Hippocampal Cajal-Retzius Cell Positioning and Infrapyramidal Blade Morphogenesis

We have previously described hypomorphic reelin (Reln) mutant mice, RelnCTRdel, in which the morphology of the dentate gyrus is distinct from that seen in reeler mice. In the RelnCTRdel mutant the infrapyramidal blade of the dentate gyrus fails to extend, while the suprapyramidal blade forms with a relatively compact granule neuron layer. The distribution of Cajal-Retzius cells in the dentate gyrus was aberrant; Cajal-Retzius neurons were increased in the suprapyramidal blade, but were greatly reduced along the subpial surface of the prospective infrapyramidal blade. We also observed multiple abnormalities of the fimbriodentate junction. Firstly, progenitor cells were distributed abnormally; the “neurogenic cluster” at the fimbriodentate junction was absent, lacking the normal accumulation of Tbr2-positive intermediate progenitors. However, the number of dividing cells in the dentate gyrus was not generally decreased. Secondly, a defect of secondary glial scaffold formation, limited to the infrapyramidal blade, was observed. The densely radiating glial fibers characteristic of the normal fimbriodentate junction were absent in mutants. These fibers might be required for migration of progenitors, which may account for the failure of neurogenic cluster formation. These findings suggest the importance of the secondary scaffold and neurogenic cluster of the fimbriodentate junction in morphogenesis of the mammalian dentate gyrus. Our study provides direct genetic evidence showing that normal RELN function is required for Cajal-Retzius cell positioning in the dentate gyrus, and for formation of the fimbriodentate junction to promote infrapyramidal blade extension.
Metal Accumulation Using a Bacterium (K-142) Identified from Environmental Microorganisms by the Screening of Au Nanoparticles Synthesis

The use of technology that uses organisms to synthesize metal nanoparticles is necessary to maintain a sustainable society. In this study, we investigated and screened the microorganisms isolated from environmental water by quantifying the reproducibility of synthetic Au nanoparticles and the ability of large amount synthesis. The microorganism (K-142) of the Bacillus genus showed the best activity in the investigation. K-142 can also synthesize Ag, CdS and PbS nanoparticles, and the deposition efficiency of Ag, Al, Cd, Cu, and Pb was about 64.8–99.2%. According to the observation results under the microscope after fluorescent staining, K-142 could survive after being treated with 0.5 mM metal solution for 24 h. Therefore, it is expected that K-142, which is easy to cultivate, would also have a high ability to reduce and deposit metal substances. K-142 can be applied to the concentration and recovery of heavy metals in environmental water, thereby opening up channels for biological water purification.
Patients’ perspectives on three-monthly administration of antipsychotic treatment with paliperidone palmitate – a qualitative interview study

Abstract Introduction Three-monthly dosage of paliperidone palmitate entails longer time to relapse after discontinuation, is similarly tolerable and safe compared to monthly injections of paliperidone palmitate and is beneficial for the caregivers. However, few studies have so far explored in depth the patients’ experiences with paliperidone palmitate medication every three months, or with switching from monthly to three-monthly injections of paliperidone palmitate. Material and methods A qualitative study based on individual interviews with persons with schizophrenia who receive three-monthly paliperidone palmitate in Norway, Sweden and Denmark. Data was analysed according to qualitative content analysis. Results Twenty-four patients, 16 men and 8 women, took part in individual interviews. The patients’ mental health care professionals mainly recommended the switch to three-monthly paliperidone palmitate, and few or no disadvantages were described. According to the patients, three-monthly paliperidone palmitate had several advantages, such as less frequent injections, less administration and planning and less focus on the illness. In addition, the participants described feeling more stability, being more physically and socially active, and that improvement processes were supported. For some, the use involved practical and economic challenges, and some worried whether the medicine ‘wore off’ before the next injection. According to the patients, switching to three-monthly paliperidone palmitate did not influence the frequency or content of patients’ interaction with health care professionals. Conclusion Switching from monthly to three-monthly injections with paliperidone palmitate seems to be experienced as advantageous for patients with schizophrenia.
Reliability and Validity of Turkish Version of The Brief-BESTest in Stroke Patients

ABSTRACT Background The Brief-BESTest is the short version of the BESTest used to evaluate balance and fall risk in a multiple disease populations. The clinicians need practical, short application scales to evaluate the risk of falling, balance and rehabilitation results. Objective This study aims to investigate the validity and reliability of the Turkish version of the Brief-BESTest (Brief-BESTest–T) in stroke patients. Methods This study included a total of 40 subacute and chronic stroke patients (mean age of 60.28 ± 9.96 years). The Brief-BESTest, Berg Balance Scale (BBS), Timed Up and Go Test (TUG), Functional Reach Test (FRT), Falls Efficacy Scale (FES) and 10 m walking test were applied to the patients. Results A strong correlation was observed between the1st and 2nd evaluation Brief-BESTest–T total scores (r = 0.933). Cronbach’s alpha coefficient was excellent. According to the correlation analysis performed to test the inter-rater reliability, a very high correlation (r = 0.906) was observed between the Brief-BESTest–T total scores. A high correlation was found between the Brief-BESTest–T and BBS and TUG, while a moderate correlation was found between the FRT, FES, and 10 m walking test. The clinical cut-off point for the Brief-BESTest – T was determined to be 9 points with an AUC of 0.872. There were no floor and ceiling effects found. Conclusions This study showed that the Brief-BESTest-T had excellent internal consistency, intra-rater, and inter-rater reliability. Its concurrent, discriminant, and known-groups validity were also good and had no substantial floor and ceiling effects.
Incidence, Risk Factors, and Clinical Consequence of Enteral Feeding Intolerance in the Mechanically Ventilated Critically Ill: An Analysis of a Multicenter, Multiyear Database

Supplemental Digital Content is available in the text. OBJECTIVES: To determine the incidence of enteral feed intolerance, identify factors associated with enteral feed intolerance, and assess the relationship between enteral feed intolerance and key nutritional and clinical outcomes in critically ill patients. DESIGN: Analysis of International Nutrition Survey database collected prospectively from 2007 to 2014. SETTING: Seven-hundred eighty-five ICUs from around the world. PATIENTS: Mechanically ventilated adults with ICU stay greater than or equal to 72 hours and received enteral nutrition during the first 12 ICU days. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: We defined enteral feed intolerance as interrupted feeding due to one of the following reasons: high gastric residual volumes, increased abdominal girth, distension, subjective discomfort, emesis, or diarrhea. The current analysis included 15,918 patients. Of these, 4,036 (24%) had at least one episode of enteral feed intolerance. The enteral feed intolerance rate increased from 1% on day 1 to 6% on days 4 and 5 and declined daily thereafter. After controlling for site and patient covariates, burn (odds ratio 1.46; 95% CIs, 1.07–1.99), gastrointestinal (odds ratio 1.45; 95% CI, 1.27–1.66), and sepsis (odds ratio 1.34; 95% CI, 1.17–1.54) admission diagnoses were more likely to develop enteral feed intolerance, as compared to patients with respiratory-related admission diagnosis. enteral feed intolerance patients received about 10% less enteral nutrition intake, as compared to patients without enteral feed intolerance after controlling for important covariates including severity of illness. Enteral feed intolerance patients had fewer ventilator-free days and longer ICU length of stay time to discharge alive (all p < 0.0001). The daily mortality hazard rate increased by a factor of 1.5 (1.4–1.6; p < 0.0001) once enteral feed intolerance occurred. CONCLUSIONS: Enteral feed intolerance occurs frequently during enteral nutrition delivery in the critically ill. Burn and gastrointestinal patients had the highest risk of developing enteral feed intolerance. Enteral feed intolerance is associated with lower enteral nutrition delivery and worse clinical outcomes. Identification, prevention, and optimal management of enteral feed intolerance may improve nutrition delivery and clinical outcomes in important “at risk” populations.
PIPAC-OX: A Phase I Study of Oxaliplatin-Based Pressurized Intraperitoneal Aerosol Chemotherapy in Patients with Peritoneal Metastases

Purpose: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m2. We conducted a phase I study to establish safety and tolerability. Patients and Methods: We used a 3+3 dose-escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90, and 120 mg/m2. Results: This study included 16 patients with 24 PIPAC procedures (8 gastric; 5 colorectal; and 1 gallbladder, pancreas, and appendix cancer each). Median age and peritoneal cancer index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/m2. There were no other dose-limiting toxicities, and the highest-dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2 = 0.95) and AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two PIPAC procedures, with improvement of median PCI and peritoneal regression grade score from 15 to 12 and 2.5 to 2.0, respectively. Conclusions: The recommended phase II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases. See related commentary by de Jong et al., p. 1830
Effects of fosinopril and valsartan on expressions of ICAM-1 and NO in human umbilical vein endothelial cells

ObjectiveTo investigate the effects of fosinopril and valsartan on the expression of intercellular adhesion molecule-1 (ICAM-1) and nitric oxide (NO) induced by oxidizlls. MethodsThe levels of NO, ICAM-1, and nitric oxide synthase (NOS) were determined using the nitrate reductase method, ELISA, immunohistochemical and image analyses.ResultsThe ox-LDL can significantly increase the expression of ICAM-1 and inhibit theexpression of NO and NOS in a dose-dependent manner. Fosinopril and valsartancan significantly inhibit these roles of ox-LDL. The roles of fosinopril and valsartan were not significantly different. ConclusionFosinopril and valsartan inhibit oxidized LDL-induced expression of ICAM-1and increase the expression of NO in human umbilical vein endothelial cells, which is one of the mechanisms of antiatherosclerosis.