Miracle-dz/UniFAR-FTUs huggingface dataset:
Cyclosporin A Impairs the Secretion and Activity of ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin Type 1 Repeat)*

Background: Immunosuppressive drug cyclosporin A (CsA) is a potent inhibitor of cyclophilin B (CypB) function. Results: CsA treatment leading to reduction in CypB levels is associated with decreased secretion of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat). Conclusion: CypB function and levels affect the secretion of ADAMTS13. Significance: A novel mechanistic explanation for CsA-induced thrombotic thrombocytopenic purpura in transplant patients is suggested. The protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat) cleaves multimers of von Willebrand factor, thus regulating platelet aggregation. ADAMTS13 deficiency leads to the fatal disorder thrombotic thrombocytopenic purpura (TTP). It has been observed that cyclosporin A (CsA) treatment, particularly in transplant patients, may sometimes be linked to the development of TTP. Until now, the reason for such a link was unclear. Here we provide evidence demonstrating that cyclophilin B (CypB) activity plays an important role in the secretion of active ADAMTS13. We found that CsA, an inhibitor of CypB, reduces the secretion of ADAMTS13 and leads to conformational changes in the protein resulting in diminished ADAMTS13 proteolytic activity. A direct, functional interaction between CypB (which possesses peptidyl-prolyl cis-trans isomerase (PPIase) and chaperone functions) and ADAMTS13 is demonstrated using immunoprecipitation and siRNA knockdown of CypB. Finally, CypB knock-out mice were found to have reduced ADAMTS13 levels. Taken together, our findings indicate that cyclophilin-mediated activity is an important factor affecting secretion and activity of ADAMTS13. The large number of proline residues in ADAMTS13 is consistent with the important role of cis-trans isomerization in the proper folding of this protein. These results altogether provide a novel mechanistic explanation for CsA-induced TTP in transplant patients.
Öğretim Elemanlarının Teknopedagojik Eğitim Yeterliliklerinin Çeşitli Değişkenler Açısından İncelenmesi

Egitim teknolojilerinin derse entegrasyonu ile ilgili arastirmalarin bircogu ogretmen ya da ogretmen adaylari ile ilgilidir; bununla birlikte ogretmen yetistiren kurumlardaki ogretim elemanlarinin bu konudaki gorusleri ya da yeterlik duzeyleri arastirilmasi gereken onemli bir durumdur Bu calismanin amaci ogretim elemanlarinin teknopedagojik egitim yeterliliklerinin incelenmesidir Calisma betimsel tarama yontemi ile Turkiye’de bir devlet universitesinin egitim fakultesinde 2012 2013 egitim ogretim yilinin guz doneminde gorev yapan 132 ogretim elemaniyla yurutulmustur Veri toplama araci olarak Kabakci Yurdakul vd 2012 tarafindan gelistirilen Teknopedagojik Egitim Yeterlik TPACK deep Olcegi kullanilmistir Bu olcme araci ile ogretim elemanlarinin cinsiyetlerine yas gruplarina bolumlerine ve unvanlarina gore teknolojik pedagojik icerik bilgisi TPIB egitim yeterlilik puan ortalamalari arasinda istatistiksel olarak anlamli fark olup olmadigi 05 onem denetiminde incelenmistir Verilerin cozumlenmesi icin bagimsiz orneklemler icin t testi bagimsiz gruplar icin tek yonlu varyans analizi yapilmistir Arastirma sonuclarina gore ogretim elemanlarinin TPIB egitim yeterlik duzeylerinin ileri duzeyde oldugu cinsiyetlerine bolumlerine ve unvanlarina gore puan ortalamalari arasinda anlamli bir fark olmadigi gorulmustur Yas gruplari bakimindan TPIB puan ortalamalari arasinda istatistiksel olarak 31 40 ile 50 ve ustu yas gruplari arasinda 31 40 yas grubu lehine orta etki buyuklugunde anlamli fark bulunmustur
Children Sleep Habits Questionnaire (CSHQ): Psychometric validation in Indian school children

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Abstract Objective: Validity studies on scales of sleep-related habits and problems for pediatric population are few, and cross-validation with Indian population has not been reported. This study was designed to assess the psychometric properties of a parent-rated measure of sleep habits i.e. Children Sleep Habits Questionnaire (CSHQ) in Indian school going children Methods: Cross-sectional data were examined for 371 primary school going children from Pre Nursery to 3rd class. Reliability testing and psychometric validation using principal component analysis was carried out. Results: Our study cohort achieved a mean score of 49.35 (S.D. 7.6). Though CSHQ scale items had a good overall internal consistency (Cronbach’s alpha 0.77), its subscales had poor reliability. Data analysis conducted by excluding the youngest school children (class Pre-Nursery) significantly improved the internal consistency alphas of the various subscales, indicating better reliability of CSHQ subscales in the older age groups in our setting. On comparison with Visual Analogue Scale (VAS) for global sleep rating, CSHQ showed good concurrent validity. Construct validity of CSHQ was evaluated by principal factor analysis which extracted 8 underlying latent factors (with eigen value >1) matching original CSHQ domains. However, these latent factors explained only 48.2% of total variance in the data. Principal Component Analysis (PCA) of CSHQ in our study cohort also favors shortening of original 33-item scale to a shorter 23-item scale with better acceptability for parents. Conclusions: The CSHQ is a reliable and internally consistent scale, and it is useful optional tool for assessing sleep problems in Indian school children.
Lin‐Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders

We report two patients with sagittal craniosynostosis, hypoplastic male genitalia, agenesis of the corpus callosum, thyroid abnormalities, and dysmorphic features which include short palpebral fissures and retrognathia. The clinical presentation of both patients was initially thought to be suggestive of Lin‐Gettig syndrome (LGS), a multiple malformation syndrome associated with craniosynostosis that was initially reported in two brothers in 1990, with a third patient reported in 2003. Our first patient was subsequently found through exome sequencing to have a de novo mutation in KAT6B, c.4572dupT, p.(Thr1525Tyrfs*16). The second patient was ascertained as possible LGS, but KAT6B mutation testing was pursued clinically after the identification of the KAT6B mutation in Patient 1, and identified a de novo mutation, c. 4205_4206delCT, p.(Ser1402Cysfs*5). The phenotypic spectrum of KAT6B mutations has been expanding since identification of KAT6B mutations in genitopatellar syndrome (GPS) and Say Barber Biesecker Young Simpson (SBBYS) syndrome patients. We show that craniosynostosis, which has not been previously reported in association with KAT6B mutations, may be part of the genitopatellar/Say Barber Biesecker Young Simpson spectrum. These two patients also further demonstrate the overlapping phenotypes of genitopatellar and SBBYS syndromes recently observed by others. Furthermore, we propose that it is possible that one or more of the previous cases of LGS may have also been due to mutation in KAT6B, and that LGS may actually be a variant within the KAT6B spectrum and not a distinct clinical entity.
Sleep spindles are related to schizotypal personality traits and thalamic glutamine/glutamate in healthy subjects.

BACKGROUND Schizophrenia is a severe mental disorder affecting approximately 1% of the worldwide population. Yet, schizophrenia-like experiences (schizotypy) are very common in the healthy population, indicating a continuum between normal mental functioning and the psychosis found in schizophrenic patients. A continuum between schizotypy and schizophrenia would be supported if they share the same neurobiological origin. Two such neurobiological markers of schizophrenia are: (1) a reduction of sleep spindles (12-15 Hz oscillations during nonrapid eye movement sleep), likely reflecting deficits in thalamo-cortical circuits and (2) increased glutamine and glutamate (Glx) levels in the thalamus. Thus, this study aimed to investigate whether sleep spindles and Glx levels are related to schizotypal personality traits in healthy subjects. METHODS Twenty young male subjects underwent 2 all-night sleep electroencephalography recordings (128 electrodes). Sleep spindles were detected automatically. After those 2 nights, thalamic Glx levels were measured by magnetic resonance spectroscopy. Subjects completed a magical ideation scale to assess schizotypy. RESULTS Sleep spindle density was negatively correlated with magical ideation (r = -.64, P < .01) and thalamic Glx levels (r = -.70, P < .005). No correlation was found between Glx levels in the thalamus and magical ideation (r = .12, P > .1). CONCLUSIONS The common relationship of sleep spindle density with schizotypy and thalamic Glx levels indicates a neurobiological overlap between nonclinical schizotypy and schizophrenia. Thus, sleep spindle density and magical ideation may reflect the anatomy and efficiency of the thalamo-cortical system that shows pronounced impairment in patients with schizophrenia.
Glycodelin-A Stimulates Interleukin-6 Secretion by Human Monocytes and Macrophages through L-selectin and the Extracellular Signal-regulated Kinase Pathway*

Background: Decidual glycodelin-A (GdA) is a regulator of immune cells. Results: GdA binds to L-selectin and induces IL-6 expression in monocytes/macrophages, which suppress the Th-1 response of T-cells. Conclusion: GdA has regulatory roles in monocytes/macrophages, which may contribute to the Th-1/Th-2 shift in early pregnancy. Significance: The results increase our knowledge of the regulation of monocyte/macrophage functions and may provide insights into the pathology of complicated pregnancy. Macrophages represent the second major type of decidual leukocytes at the fetomaternal interface. Changes in macrophage number and activity are associated with fetal loss and pregnancy complications. Glycodelin-A (GdA) is an abundant glycoprotein in the first-trimester decidua. It is involved in fetomaternal defense and early placental development through its regulatory activities in various immune cells. The N-glycosylation of GdA mediates the binding and therefore the activities of the molecule. In this study, we studied the biological activities of GdA in the functions of human monocytes/macrophages. GdA was purified from amniotic fluid by affinity chromatography. GdA treatment did not affect the viability, cell death, or phagocytic activity of the monocytes/macrophages. GdA, but not recombinant glycodelin without glycosylation, induced IL-6 production as demonstrated by cytokine array, intracellular staining, and ELISA. GdA also induced phosphorylation of ERK in monocytes/macrophages. The involvement of ERKs in IL-6 induction was confirmed using pharmacological inhibitors. Co-immunoprecipitation showed that L-selectin on the monocytes/macrophages was the binding protein of GdA. Treatment with anti-L-selectin antibody reduced GdA binding and GdA-induced IL-6 production. GdA-treated macrophages suppressed IFN-γ expression by co-cultured T-helper cells in an IL-6-dependent manner. These results show that GdA interacts with L-selectin to induce IL-6 production in monocytes/macrophages by activating the ERK signaling pathway. In turn, the increased IL-6 production suppresses IFN-γ expression in T-helper cells, which may play an important role in inducing a Th-2-polarized cytokine environment that flavors the immunotolerance of the fetoplacental unit.
Disruption of Ionic Interactions between the Nucleotide Binding Domain 1 (NBD1) and Middle (M) Domain in Hsp100 Disaggregase Unleashes Toxic Hyperactivity and Partial Independence from Hsp70*

Background: Hsp100 chaperones cooperate with Hsp70 chaperones to disaggregate and reactivate heat-denatured proteins. Results: Mutations in the interface region between NBD1 and M domains of Hsp100 result in a hyperactive protein toxic to the cell. Conclusion: The interaction between M and NBD1 domains is crucial for regulation of Hsp100 activity. Significance: A novel important aspect of the Hsp100 mechanism of action is described. Hsp100 chaperones cooperate with the Hsp70 chaperone system to disaggregate and reactivate heat-denatured aggregated proteins to promote cell survival after heat stress. The homology models of Hsp100 disaggregases suggest the presence of a conserved network of ionic interactions between the first nucleotide binding domain (NBD1) and the coiled-coil middle subdomain, the signature domain of disaggregating chaperones. Mutations intended to disrupt the putative ionic interactions in yeast Hsp104 and bacterial ClpB disaggregases resulted in remarkable changes of their biochemical properties. These included an increase in ATPase activity, a significant increase in the rate of in vitro substrate renaturation, and partial independence from the Hsp70 chaperone in disaggregation. Paradoxically, the increased activities resulted in serious growth impediments in yeast and bacterial cells instead of improvement of their thermotolerance. Our results suggest that this toxic activity is due to the ability of the mutated disaggregases to unfold independently from Hsp70, native folded proteins. Complementary changes that restore particular salt bridges within the suggested network suppressed the toxic effects. We propose a novel structural aspect of Hsp100 chaperones crucial for specificity and efficiency of the disaggregation reaction.
Effect of radioprotective agents in sporulation medium on Bacillus subtilis spore resistance to hydrogen peroxide, wet heat and germicidal and environmentally relevant UV radiation

Aims: To determine the effects of cysteine, cystine, proline and thioproline as sporulation medium supplements on Bacillus subtilis spore resistance to hydrogen peroxide (H2O2), wet heat, and germicidal 254 nm and simulated environmental UV radiation.
The TG-interacting Factor TGIF1 Regulates Stress-induced Proinflammatory Phenotype of Endothelial Cells*

Background: TG-interacting factor 1 plays a role in radiation-induced injury. Results: In vitro, TGIF1 overexpression increases stress-induced cytokine expression whereas TGIF1 knockdown limits it. Conclusion: TGIF1 regulates radiation and TNF-α-induced inflammation in endothelial cells. Significance: TGIF1 could be a molecular target to limit radiation or TNF-α-induced proinflammatory phenotype in endothelium. The endothelium contributes to the control of the tissue inflammatory response following stress and in particular after exposure to ionizing radiation. We previously showed that the TG-interacting factor 1 (TGIF1) plays a role in radiation-induced normal tissue injury. In this study we hypothesized that this protein could play a role in inflammation. The role of TGIF1 in the stress-induced proinflammatory phenotype was investigated in human endothelial cells. In HUVECs ionizing radiation induces TGIF1 expression as well as a proinflammatory phenotype associated with up-regulation of IL-6, IL-8, CXCL1, MIP-2, and MCP-1. TGIF1 overexpression enhances the radiation-induced proinflammatory phenotype whereas TGIF1 silencing limits both the TNF-α- and radiation-induced overexpression of proinflammatory cytokines. Interestingly, in vivo, in radiation-induced intestinal inflammation in mice, TGIF1 genetic deficiency is associated with a reduced radiation-induced overexpression of proinflammatory molecules. In HUVECs, TNF-α- and radiation-induced NF-κB pathway activation is not influenced by TGIF1 expression, whereas TGIF1 knockdown inhibits both TNF-α- and radiation-induced p38 MAPK pathway activation. This study demonstrates that TGIF1 plays a role in TNF-α- and radiation-induced inflammation and suggests that it could be a target in limiting this event in the vascular compartment.
The use of psychotropic medication in people with learning disability: Towards rational prescribing

Between 20 per cent to 50 per cent of institutionalized people with a learning disability receive psychotropic medication. A similar or a slightly lower proportion of those who live in the community also receive these drugs. There is a decreasing rate of use of these drugs with the increasing age. The rate of psychotropic drug use seems to have declined in the last decade among the community‐based population. The two main reasons for the use of these drugs are psychiatric illness and behaviour disorder. These drugs cause unacceptable side‐effects in a proportion of patients. Recent double‐blind studies lend some support to the efficacy of zuclopenthixol in the treatment of behaviour disorder. Some drugs have been use on an experimental basis to treat behavioural problems with equivocal results. These include lithium carbonate, carbamazepine, sodium valproate, fluoxetine, buspirone, naloxone, naltrxone, dextroamphetamine, methylphenidate, fenfluramine, propranolol, nadolol, amantadine and midazolam. Non‐durg dietary regimes, such as folic acid, vitamin B6, magnesium, and specific amino‐acid rich diets have also been applied in the treatment of behavioural problems. Guidelines have been proposed for a common‐sense rational approach to the use of psychotropic drugs in people with a learning disability.
Epidermal Growth Factor (EGF) Regulates α5β1 Integrin Activation State in Human Cancer Cell Lines through the p90RSK-dependent Phosphorylation of Filamin A*

Background: Regulation of integrin activation has important implications for tumor cell invasion and metastasis. Results: EGF activates ERK/p90RSK and Rho/Rho kinase signaling in A431 and DiFi colon cancer cells, leading to phosphorylation of filamin A (FLNa) and inactivation of the α5β1 integrin receptor. Conclusion: EGF promotes α5β1 inactivation through the p90RSK-dependent phosphorylation of FLNa. Significance: We have identified a novel EGF-dependent mechanism controlling the α5β1 integrin activation state. Cell adhesion, motility, and invasion are regulated by the ligand-binding activity of integrin receptors, transmembrane proteins that bind to the extracellular matrix. Integrins whose conformation allows for ligand binding and appropriate functional activity are said to be in an active state. Integrin activation and subsequent ligand binding are dynamically regulated by the association of cytoplasmic proteins with integrin intracellular domains. In this study, we evaluated the role of EGF in the regulation of the activation state of the α5β1 integrin receptor for fibronectin. The addition of EGF to either A431 squamous carcinoma cells or DiFi colon cancer cells resulted in loss of α5β1-dependent adhesion to fibronectin but no loss of integrin from the cell surface. EGF activated the EGF receptor/ERK/p90RSK and Rho/Rho kinase signaling pathways. Blocking either pathway inhibited EGF-mediated loss of adhesion, suggesting that they work in parallel to regulate integrin function. EGF treatment also resulted in phosphorylation of filamin A (FLNa), which binds and inactivates β1 integrins. EGF-mediated FLNa phosphorylation was completely blocked by an inhibitor of p90RSK and partially attenuated by an inhibitor of Rho kinase, suggesting that both pathways converge on FLNa to regulate integrin function. A431 clonal cell lines expressing non-phosphorylated dominant-negative FLNa were resistant to the inhibitory effects of EGF on integrin function, whereas clonal cell lines overexpressing wild-type FLNa were more sensitive to the inhibitory effect of EGF. These data suggest that EGF-dependent inactivation of α5β1 integrin is regulated through FLNa phosphorylation and cellular contractility.
Age of Onset and Lifetime Projected Risk of Psychotic Experiences: Cross-National Data From the World Mental Health Survey.

BACKGROUND Given the early age of onset (AOO) of psychotic disorders, it has been assumed that psychotic experiences (PEs) would have a similar early AOO. The aims of this study were to describe (a) the AOO distribution of PEs, (b) the projected lifetime risk of PEs, and (c) the associations of PE AOO with selected PE features. METHODS Data came from the WHO World Mental Health (WMH) surveys. A total of 31 261 adult respondents across 18 countries were assessed for lifetime prevalence of PE. Projected lifetime risk (at age 75 years) was estimated using a 2-part actuarial method. AOO distributions were described for the observed and projected estimates. We examined associations of AOO with PE type metric and annualized PE frequency. RESULTS Projected lifetime risk for PEs was 7.8% (SE = 0.3), slightly higher than lifetime prevalence (5.8%, SE = 0.2). The median (interquartile range; IQR) AOO based on projected lifetime estimates was 26 (17-41) years, indicating that PEs commence across a wide age range. The AOO distributions for PEs did not differ by sex. Early AOO was positively associated with number of PE types (F = 14.1, P < .001) but negatively associated with annualized PE frequency rates (F = 8.0, P < .001). DISCUSSION While most people with lifetime PEs have first onsets in adolescence or young adulthood, projected estimates indicate that nearly a quarter of first onsets occur after age 40 years. The extent to which late onset PEs are associated with (a) late onset mental disorders or (b) declining cognitive and/or sensory function need further research.
The relationship between airway bacterial load and airways inflammation in stable non-cystic fibrosis bronchiectasis

Objective: To investigate the relationship between airway bacterial load and markers of airways inflammation in stable patients with bronchiectasis. Methods: 302 patients with non-CF bronchiectasis confirmed by HRCT were enrolled. At 6 monthly review, spontaneous sputum samples were processed to determine bacterial load, expressed as log 10 colony forming units/ml (cfu/ml). Sputum sol was analysed for myeloperoxidase (MPO) and neutrophil elastase elastase activity. Interleukin-8 (IL-8), Interleukin 1-beta (IL-1β) and tumour necrosis factor alpha (TNF-α) were measured by ELISA. Results: 67 patients (22.1%) of patients grew no pathogens. Pathogenic micro-organisms were obtained in 77.9% of patients, most frequently Haemophilus influenzae (37.4% of isolates), Pseudomonas aeruginosa (20.4%), Staphylococcus aureus (13.2%), Streptococcus pneumoniae (11.9%) and Moraxella catarrhalis (10.6%). Airway inflammation increased progressively with increasing bacterial load. Statistically significant differences were observed, when compared to patients with no pathogens, at bacterial loads above 1×10 6 cfu/ml for MPO (p=0.01), neutrophil elastase activity (p=0.006) and IL-8 (p=0.02), and above 1×10 7 for TNF-α (p=0.04) and above 1×10 5 for IL-1β (p=0.003). Conclusion: There is a direct relationship between airway bacterial load and the degree of airway inflammation in stable bronchiectasis.