Miracle-dz/UniFAR-FTUs huggingface dataset:
Endometriotic Mesenchymal Stem Cells Epigenetic Pathogenesis: Deregulation of miR-200b, miR-145, and let7b in A Functional Imbalanced Epigenetic Disease

Objective Stem cell issue is a strong theory in endometriosis pathogenesis. It seems that endometriotic mesenchymal stem cells (MSCs) show different characteristics compared to the normal MSCs. Determined high proliferation and low differentiation/ decidualization potential of endometriotic MSCs could be accompanied by their microRNAs deregulation influencing their fate and function. In this study for the first time, we evaluated the expression of miR-200b, miR-145, and let7b in endometriotic compared to non-endometriotic MSCs. These microRNAs are involved in biological pathways related to proliferation and differentiation of stem cells. Their aberrant expressions can disturb the proliferation/ differentiation balance in stem cells, altering their function and causing various diseases, like endometriosis. Materials and Methods In this experimental study, MSCs were isolated from three endometriotic and three non- endometriotic eutopic endometrium, followed by their characterization and culture. Expression of miR-200b, miR-145, and let-7b was ultimately analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results We found that the expression of miR-200b was up-regulated (P<0/0001) whereas the expression of miR- 145 and let-7b was down-regulated (P<0.0001) in endometriotic MSCs in comparison with non-endometriotic normal controls. Conclusion Proliferation and differentiation are important dynamic balanced biological processes, while in equillibrium, they determine a healthy stem cell fate. It seems that they are deregulated in endometriotic MSCs and change their function. miR-200b, miR-145, and let7b are deregulated during endometriosis and they have pivotal roles in the modulating proliferation and differentiation of stem cells. We found up-regulation of miR-200b and down-regulation of miR-145 and let-7b in endometriotic MSCs. These changes can increase self-renewal and migration, while decreasing differentiation of endometriotic MSCs. Our achievements emphasize previous findings on the importance of proliferation/ differentiation balance in MSCs and clarify the role of microRNAs as main players in faulty endometriotic stem cells development.
Regulation of Iron Uptake by Fine-Tuning the Iron Responsiveness of the Iron Sensor Fur

Iron is a fundamental metal ion for living organisms as it facilitates various biological processes. The ferric uptake regulator (Fur) protein controls iron homeostasis in various bacterial species. It is believed that Fur’s iron-dependent regulatory action is sufficient for it to function as an iron sensor. However, we now establish that the bacterial pathogen Salmonella enables Fur to properly reflect changes in surrounding iron availability by fine-tuning its responsiveness to iron. This process requires a protein that hampers Fur DNA binding at low iron concentrations. In this way, Salmonella broadens the range of iron concentrations that Fur responds to. Our findings reveal a potentially widespread control mechanism of bacterial iron homeostasis. ABSTRACT Iron is one of most abundant environmental metal ions but is highly limited in organisms. It is an important metal ion as it facilitates various biological processes, including catalysis of metabolic enzymes and DNA biogenesis. In bacteria, the ferric uptake regulator (Fur) protein controls iron uptake by regulating genes coding for iron transporters in response to iron concentration. This iron response is ascribed to Fur’s intrinsic affinity for iron because its binding to iron dictates its regulatory function. However, we now report that the pathogen Salmonella achieves a proper response of Fur to changes in environmental iron concentrations via EIIANtr (a nitrogen metabolic phosphotransferase system component). We establish that EIIANtr increases expression of iron transporter-coding genes under low-iron conditions (i.e., nanomolar ranges) in a Fur-dependent manner, which promotes Salmonella growth under such conditions. EIIANtr directly hampers Fur binding to DNA, thereby inducing expression of those genes. This regulation allows Salmonella to express Fur-regulated genes under low-iron conditions. Our findings reveal a potentially widespread control mechanism of bacterial iron uptake systems operating in response to iron availability. IMPORTANCE Iron is a fundamental metal ion for living organisms as it facilitates various biological processes. The ferric uptake regulator (Fur) protein controls iron homeostasis in various bacterial species. It is believed that Fur’s iron-dependent regulatory action is sufficient for it to function as an iron sensor. However, we now establish that the bacterial pathogen Salmonella enables Fur to properly reflect changes in surrounding iron availability by fine-tuning its responsiveness to iron. This process requires a protein that hampers Fur DNA binding at low iron concentrations. In this way, Salmonella broadens the range of iron concentrations that Fur responds to. Our findings reveal a potentially widespread control mechanism of bacterial iron homeostasis.
Assembly and cryo-EM structures of RNA-specific measles virus nucleocapsids provide mechanistic insight into paramyxoviral replication

Significance Measles virus is a highly contagious virus, with recent resurgence posing serious problems for human health. Replication of paramyxoviral RNA genomes involves assembly into helical nucleocapsids that protect the genome from the host immune system. Genome encapsidation is essential to the viral cycle and represents a powerful and largely unexplored target for viral treatment. To understand genome protection, we determined the near-atomic resolution structures of nucleocapsid particles assembled on specific RNA sequences using cryoelectron microscopy. The 3′ end of the RNA genome is found to be accessible to the viral polymerase, possibly enabling efficient RNA processing. We identify an amino acid that stabilizes the RNA within the binding cleft that is shown to be essential for encapsidation. Assembly of paramyxoviral nucleocapsids on the RNA genome is an essential step in the viral cycle. The structural basis of this process has remained obscure due to the inability to control encapsidation. We used a recently developed approach to assemble measles virus nucleocapsid-like particles on specific sequences of RNA hexamers (poly-Adenine and viral genomic 5′) in vitro, and determined their cryoelectron microscopy maps to 3.3-Å resolution. The structures unambiguously determine 5′ and 3′ binding sites and thereby the binding-register of viral genomic RNA within nucleocapsids. This observation reveals that the 3′ end of the genome is largely exposed in fully assembled measles nucleocapsids. In particular, the final three nucleotides of the genome are rendered accessible to the RNA-dependent RNA polymerase complex, possibly enabling efficient RNA processing. The structures also reveal local and global conformational changes in the nucleoprotein upon assembly, in particular involving helix α6 and helix α13 that form edges of the RNA binding groove. Disorder is observed in the bound RNA, localized at one of the two backbone conformational switch sites. The high-resolution structure allowed us to identify putative nucleobase interaction sites in the RNA-binding groove, whose impact on assembly kinetics was measured using real-time NMR. Mutation of one of these sites, R195, whose sidechain stabilizes both backbone and base of a bound nucleic acid, is thereby shown to be essential for nucleocapsid-like particle assembly.
Efficacy and safety of adalimumab in Japanese patients with psoriatic arthritis and inadequate response to non-steroidal anti-inflammatory drugs (NSAIDs): A prospective, observational study

Abstract Objectives: To evaluate the efficacy and safety of adalimumab in psoriatic arthritis (PsA) patients in Japan. Methods: In this open-label, single-arm study conducted at six sites from October 2014 to June 2016 (UMIN000016543), PsA patients (≥20 years old) with inadequate response to nonsteroidal anti-inflammatory drugs received adalimumab subcutaneously (80 mg initially, then 40 mg every other week; 24 weeks total). Primary endpoint was American College of Rheumatology 20% improvement (ACR20) response rate at week 12. Results: Of 42 enrolled patients, 37 were treated (mean (SD) age, 56.2 (13.0) years; male, 27 (73.0%)). ACR20, ACR50, and ACR70 response rates were 40.5%, 24.3%, and 16.2% at week 12 and increased to 45.9%, 37.8%, and 21.6% at week 24, respectively. Psoriasis Area and Severity Index (PASI) 50 response rates were unchanged at weeks 12 and 24 (73%), but PASI75 and PASI90 increased from 40.5% and 21.6% to 59.5% and 40.5%, respectively. Other indices such as Physician’s Global Assessment score, C-reactive protein-based disease activity score in 28 joints, Bath Ankylosing Spondylitis Disease Activity Index, and serum biomarker levels were significantly improved. No unexpected adverse events were reported. Conclusion: Similar to the global population, adalimumab was efficacious and well tolerated in Japanese treatment-experienced PsA patients.
Fine-Needle Aspiration with Immunohistochemistry Using a Modified Scrape Cell Block Technique for the Diagnosis of Thyroid and Parathyroid Nodules

Objective: To evaluate the diagnostic accuracy of a modified scrape cell block (SCB) technique in a large series of patients. The technique was especially developed and tested for fine-needle aspiration of thyroid and parathyroid nodules. Study Design: Eighty-two ultrasound-guided fine-needle aspiration specimens with the sonographic aspect of a thyroid (n = 33) or a possible parathyroid nodule (n = 49) were studied. Immunohistochemistry (IHC) was used on cell blocks containing plasma, thromboplastin, and selected 3-dimensional cell aggregates scraped off Papanicolaou-stained smears. Antibodies for chromogranin A, thyroglobulin, parathyroid hormone, calcitonin, and carcinoembryonic antibody (CEA) were used. In cases of reduced immunosensitivity or suspected metastases or rare primary tumors, additional IHC markers were employed. Results: Chromogranin A was expressed in all 28 parathyroid adenomas (PA), in 7 of 8 hyperplastic parathyroid glands, and in 13 of 14 medullary thyroid carcinomas (MTC). When combining positivity for chromogranin A and calcitonin/CEA, the specificity for the detection of MTC was 100%. Parathyroid hormone was expressed in 26 of 36 parathyroid nodules (72.2%). When combining follicular microarchitecture and expression of chromogranin A, the specificity for the detection of parathyroid tissue was 97%. Conclusion: With the modified SCB technique, accurate cytological diagnoses were obtained in 97.6% of 82 patients.
TMEM30A deficiency in endothelial cells impairs cell proliferation and angiogenesis

ABSTRACT Phosphatidylserine (PS) asymmetry in the eukaryotic cell membrane is maintained by a group of proteins belonging to the P4-ATPase family, namely, PS flippases. The folding and transporting of P4-ATPases to their cellular destination requires a β-subunit member of the TMEM30 protein family. Loss of Tmem30a has been shown to cause multiple disease conditions. However, its roles in vascular development have not been elucidated. Here, we show that TMEM30A plays critical roles in retinal vascular angiogenesis, which is a fundamental process in vascular development. Our data indicate that knockdown of TMEM30A in primary human retinal endothelial cells led to reduced tube formation. In mice, endothelial cell (EC)-specific deletion of Tmem30a led to retarded retinal vascular development with a hyperpruned vascular network as well as blunted-end, aneurysm-like tip ECs with fewer filopodia at the vascular front and a reduced number of tip cells. Deletion of Tmem30a also impaired vessel barrier integrity. Mechanistically, deletion of TMEM30A caused reduced EC proliferation by inhibiting VEGF-induced signaling. Our findings reveal essential roles of TMEM30A in angiogenesis, providing a potential therapeutic target. Summary: Deletion of TMEM30A in endothelial cells causes impaired cell proliferation, reduced tip cells and delayed vascular development toward the deep layers in the retina.
Sarcopenia Prevalence and Risk Factors among Japanese Community Dwelling Older Adults Living in a Snow-Covered City According to EWGSOP2

Sarcopenia is a common problem among the elderly worldwide. Muscle mass can decrease with aging and decreased physical activity may occur. However, the sarcopenia prevalence among community dwelling older adults living in snow-covered cities remains largely unknown. Therefore, we evaluated the prevalence of and risk factors for sarcopenia in this population aged 65 years or older according to the definitions and diagnoses of the European Working Group on Sarcopenia in Older People-2 from two welfare centers in Sapporo, Hokkaido, Japan. The demographic characteristics, nutrition, and depression status of 310 participants were assessed using a standardized questionnaire. All participants were assessed for grip strength. Skeletal muscle index, body mass index (BMI), and total body water (TBW) were measured using bioelectrical impedance analysis. The overall sarcopenia prevalence in the study population was 8.1%. Multivariate analysis revealed that diabetes and taking more than four drugs per day were independently associated with sarcopenia (adjusted odds ratio (OR) = 3.66, 95% confidence interval (CI) = 1.06–12.61; OR = 2.66, CI = 1.05–6.77, respectively). BMI and TBW were negatively associated with sarcopenia. Sarcopenia prevalence was low in community dwelling older adults living in the snow-covered city. It is indicated that welfare center exercise may be a good intervention for the prevention of sarcopenia. Moreover, the management of diabetes, medication, and nutrition is necessary for sarcopenia prevention in community dwelling older adults.
Modelling Impulse Response Function of Functional Infrared Imaging for General Linear Model Analysis of Autonomic Activity

Functional infrared imaging (fIRI) is a validated procedure to infer autonomic arousal. Currently, fIRI signals are analysed through descriptive metrics, such as average temperature changes in a region of interest (ROI). However, the employment of mathematical models could provide a powerful tool for the accurate identification of autonomic activity and investigation of the mechanisms underlying autonomic arousal. A linear temporal statistical model such as the general linear model (GLM) is particularly suited for its simplicity and direct interpretation. In order to apply the GLM, the thermal response linearity and time-invariance of fIRI have to be demonstrated, and the thermal impulse response (TIR) needs to be characterized. In this study, the linearity and time-invariance of the thermal response to sympathetic activating stimulation were demonstrated, and the TIR for employment of the GLM was characterized. The performance of the GLM-fIRI was evaluated by comparison with the GLM applied on synchronous measurements of the skin conductance response (SCR). In fact, the GLM-SCR is a validated procedure to estimate autonomic arousal. Assuming the GLM-SCR as the gold standard approach, a GLM-fIRI sensitivity and specificity of 86.4% and 75.9% were obtained. The GLM-fIRI may allow increased performances in the evaluation of autonomic activity and a broader range of application of fIRI in both research and clinical settings for the assessment of psychophysiological and psychopathological states.
The common cavity vs incomplete partition type I conundrum: Decision making and management with the cochlear implant form electrode

It has been seen that 20% of children with deafness have inner ear malformations. Studies demonstrate that Cerebrospinal Fluid (CSF) leakage occurs in 40–50% of patients with inner ear malformations. Differentiating between the various malformations pre-operatively allows the cochlear implant surgeon to plan and prepare for various difficulties associated with the management of such cases. In case of a CSF gusher, a choice of an electrode with a stopper helps in effectively closing off the cochleostomy, thus reducing the chances of post-operative infections. Case description: SM, a 10-year-old girl with the diagnosis of bilateral progressive profound hearing loss showed cochlear malformations on high resolution computed tomography (HRCT) scans of the temporal bones. A detailed study and discussion with the neuro-radiologist helped in identifying the cochleo-vestibular malformations (CVM) on both sides, thus making the choice of the better ear for electrode insertion and the type of electrode. She was subjected to left ear cochlear implantation using a lateral canal labyrinthotomy approach and a Form electrode (Med El®) with a special conical stopper was used to effectively seal the labyrinthostomy. Conclusion: Common cavity (CC) and Incomplete Partition (IP) Type I present as diagnostic challenges. Getting to the right diagnosis is of paramount importance as it helps in deciding the correct ear, choosing the correct electrode, and preparing for the surgical situations the surgeon might encounter. The Form electrode shows promise due to its unique conical seal which helps in preventing CSF leakage, thus reducing the chances of post-operative infections in cases of deformed cochlea.
The c.1-260C>T Promoter Variant of CD14 but Not the c.896A>G (p.D299G) Variant of Toll-Like Receptor 4 (TLR4) Genes Is Associated with Inflammatory Bowel Disease

Background: Inflammatory bowel disease (IBD) results from an aberrant immune response to the indigenous intestinal flora in genetically susceptible hosts. Therefore, the study of candidate genes involved in host pathogen interactions is of key interest. Methods: In this two-center, retrospective German and Hungarian cohort study, patients with Crohn’s disease (CD) (n = 379; German n = 235, Hungarian n = 144) and ulcerative colitis (UC) (n = 263; German n = 145, Hungarian n = 118) and healthy controls (n = 605; German n = 403, Hungarian n = 202) were genotyped for the presence of the CD14 c.1-260C>T promoter variant and the TLR4 c.896A>G (p.D299G) variant by melting curve analysis using fluorescence resonance energy transfer probes. Data were stratified according to the presence of NOD2 (CARD15) mutations and a detailed genotype-phenotype analysis was performed. Results: In the German cohort the CD14 single-nucleotide polymorphism was associated with UC, but not CD (UC p = 0.016 vs. CD p = 0.190), while the opposite was found in the Hungarian cohort (UC p = 0.083 vs. CD p = 0.019). No association of IBD with the TLR4 single-nucleotide polymorphism was found in either cohort (UC p = 0.430, CD p = 0.783 vs. UC p = 0.745, CD p = 0.383). Conclusion: IBD appears to be associated with the CD14 c.1-260C>T promoter variant in Germans and Hungarians, but not with the TLR4 c.896A>G (p.D299G) variant.
Nanoscale reference materials for environmental, health and safety measurements: needs, gaps and opportunities

Abstract The authors critically reviewed published lists of nano-objects and their physico-chemical properties deemed important for risk assessment and discussed metrological challenges associated with the development of nanoscale reference materials (RMs). Five lists were identified that contained 25 (classes of) nano-objects; only four (gold, silicon dioxide, silver, titanium dioxide) appeared on all lists. Twenty-three properties were identified for characterisation; only (specific) surface area appeared on all lists. The key themes that emerged from this review were: 1) various groups have prioritised nano-objects for development as “candidate RMs” with limited consensus; 2) a lack of harmonised terminology hinders accurate description of many nano-object properties; 3) many properties identified for characterisation are ill-defined or qualitative and hence are not metrologically traceable; 4) standardised protocols are critically needed for characterisation of nano-objects as delivered in relevant media and as administered to toxicological models; 5) the measurement processes being used to characterise a nano-object must be understood because instruments may measure a given sample in a different way; 6) appropriate RMs should be used for both accurate instrument calibration and for more general testing purposes (e.g., protocol validation); 7) there is a need to clarify that where RMs are not available, if “(representative) test materials” that lack reference or certified values may be useful for toxicology testing and 8) there is a need for consensus building within the nanotechnology and environmental, health and safety communities to prioritise RM needs and better define the required properties and (physical or chemical) forms of the candidate materials.
Overexpression of BHLHE41, correlated with DNA hypomethylation in 3′UTR region, promotes the growth of human clear cell renal cell carcinoma

Basic helix-loop-helix family member e41 (BHLHE41) serves an important role in regulating cell differentiation, circadian rhythms and the response to hypoxia. However, the roles of BHLHE41 in clear cell renal cell carcinoma (ccRCC) remain unclear. The aim of the present study was to analyze the expression of BHLHE41 in ccRCC and investigate the effect of downregulated BHLHE41 on the growth and migration of ccRCC cells. The expression of BHLHE41 in ccRCC was demonstrated to be significantly increased in gene expression microarray datasets and RNA sequencing data. Reverse transcription-quantitative polymerase chain reaction and western blot analysis demonstrated that BHLHE41 expression in fresh ccRCC tissues was increased, compared with than their adjacent non-tumorous controls. BHLHE41 knockdown significantly reduced cell proliferation and migration of A498 and CAKI-1 cells. For the investigation of the molecules mediated by BHLHE41, immunoblotting analyses revealed that phosphorylation of p70S6K and protein levels of E-cadherin were reduced. Additionally, a lower frequency methylation was determined in the BHLHE41 3′-untranslated region through The Cancer Genome Atlas dataset analysis for the first time. These observations demonstrated that BHLHE41 could be a biomarker and an oncogene for ccRCC.
Interleukin-22 regulates the homeostasis of the intestinal epithelium during inflammation

Interleukin-22 (IL-22) has both pro-inflammatory and anti-inflammatory properties in a number tissues depending on the environment. Epithelial cells usually have a rapid turnover and are fueled by tissue stem cells. However, the question of whether IL-22 regulates tissue homeostasis through the modulation of stem cells remains unanswered. In this study, we investigated the role of IL-22 in the homeostasis of intestinal epithelial cells (IECs) during inflammation through a 3D organoid culture system. qPCR was performed to detect the changes in important gene transcriptions, and immunohistochemistry and western blot analysis were carried out to determine protein expression. As a result, we found that the expression of IL-22 was synchronously altered with the damage of the intestine. IL-22 treatment promoted cell proliferation and suppressed the cell differentiation of intestinal organoids. Surprisingly, IL-22 also led to self-renewal defects of intestinal stem cells (ISCs), thereby eventually resulting in the death of organoids. In examining the underlying mechanisms, we found that IL-22 activated signal transducer and activator of transcription 3 (Stat3) phosphorylation and suppressed the Wnt and Notch signaling pathways. Importantly, Wnt3a treatment attenuated the organoid defects caused by IL-22, which consolidated the importance of Wnt pathway at the downstream of IL-22. Collectively, the findings of this study indicate that IL-22 regulates the homeostasis of the intestinal epithelium and is critical for the regeneration of the intestine during inflammation. Thus, the data of this study may provide a potential strategy and a basis for the treatment of diseases of intestinal inflammation in clinical practice.