Miracle-dz/UniFAR-FTUs huggingface dataset:
Lipid Binding Requirements for Oxysterol-binding Protein Kes1 Inhibition of Autophagy and Endosome-trans-Golgi Trafficking Pathways*

The Saccharomyces cerevisiae protein Kes1/Osh4 is a member of the enigmatic family of oxysterol-binding proteins found throughout Eukarya united by a β-barrel structure that binds sterols and oxysterols. In this study, we determined that phosphoinositides are the major determinant in membranes that facilitate Kes1 association both in vitro and in cells. Increased expression of Kes1 in yeast cells decreased the levels of both phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 3-phosphate (PI3P). Phosphoinositide and sterol bindings by Kes1 were necessary for Kes1 to decrease the level of PI4P but not PI3P. Kes1 inhibited vesicular trafficking between the trans-Golgi and plasma membrane as evidenced by accumulation of the vacuolar soluble NSF attachment protein receptors Snc1 in the cytoplasmic vesicles. Sterol and phosphoinositide binding by Kes1 both contributed to its regulation of Snc1 trafficking. This study also describes a previously unknown role for Kes1 in the regulation of the autophagy/cytoplasm to the vacuole trafficking pathway. The Kes1-mediated regulation of the autophagy/cytoplasm to the vacuole trafficking pathway was prevented by increasing expression of the PI3K Vps34, suggesting that it is the Kes1-mediated decrease in PI3P level that contributes to this regulation.
Flow cytometric detection and quantification of CD56 (neural cell adhesion molecule, NCAM) expression in diffuse large B cell lymphomas and review of the literature

Stacchini A, Barreca A, Demurtas A, Aliberti S, di Celle P F & Novero D (2012) Histopathology 60, 452–459 Flow cytometric detection and quantification of CD56 (neural cell adhesion molecule, NCAM) expression in diffuse large B cell lymphomas and review of the literature
Distribution of aldehyde dehydrogenase 1‐positive stem cells in benign mammary tissue from women with and without breast cancer

Isfoss B L, Holmqvist B, Alm P & Olsson H (2012) Histopathology 60, 617–633 Distribution of aldehyde dehydrogenase 1‐positive stem cells in benign mammary tissue from women with and without breast cancer
Calmodulin Regulates Ca2+-sensing Receptor-mediated Ca2+ Signaling and Its Cell Surface Expression*

The Ca2+-sensing receptor (CaSR) is a member of family C of the GPCRs responsible for sensing extracellular Ca2+ ([Ca2+]o) levels, maintaining extracellular Ca2+ homeostasis, and transducing Ca2+ signaling from the extracellular milieu to the intracellular environment. In the present study, we have demonstrated a Ca2+-dependent, stoichiometric interaction between CaM and a CaM-binding domain (CaMBD) located within the C terminus of CaSR (residues 871–898). Our studies suggest a wrapping around 1–14-like mode of interaction that involves global conformational changes in both lobes of CaM with concomitant formation of a helical structure in the CaMBD. More importantly, the Ca2+-dependent association between CaM and the C terminus of CaSR is critical for maintaining proper responsiveness of intracellular Ca2+ responses to changes in extracellular Ca2+ and regulating cell surface expression of the receptor.
Natural selection In Utero: Evidence from the great East Japan earthquake

Controversy remains over whether declines in male births reported after population stressors result from either or both reduced conception of males or increased selection in utero against male fetuses. We use monthly birth cohorts to determine if Japanese male births following the Great East Japan Earthquake of 2011 fell below levels expected from female births and from history (i.e., autocorrelation) among cohorts exposed to the Earthquake at or after conception.
Peroxisome Proliferator-activated Receptor γ Negatively Regulates IFN-β Production in Toll-like Receptor (TLR) 3- and TLR4-stimulated Macrophages by Preventing Interferon Regulatory Factor 3 Binding to the IFN-β Promoter*

Toll-like receptors 3 and 4 utilize adaptor TRIF to activate interferon regulatory factor 3 (IRF3), resulting in IFN-β production to mediate anti-viral and bacterial infection. Peroxisome proliferator-activated receptor (PPAR)-γ is a ligand-activated transcription factor expressed in various immune cells and acts as a transcriptional repressor to inhibit the transcription of many proinflammatory cytokines. But, the function of PPAR-γ in TLR3- and -4-mediated IFN-β production is not well elucidated. Here, we have analyzed the effect of the PPAR-γ agonists on IFN-β production in peritoneal primary macrophages in response to LPS and poly(I:C). PPAR-γ agonists inhibited LPS and poly(I:C)-induced IFN-β transcription and secretion. siRNA knockdown of PPAR-γ expression and transfection of PPAR-γ expression plasmid demonstrated that PPAR-γ agonist inhibits IFN-β production in a PPAR-γ-dependent manner. The ability of the PPAR-γ agonist to inhibit IFN-β production was confirmed in vivo as mice treated with troglitazone exhibited decreased levels of IFN-β upon LPS and poly(I:C) challenge. Chromatin immunoprecipitation (CHIP) assay and electrophoretic mobility shift assay (EMSA) demonstrated that troglitazone treatment impaired IRF3 binding to the IFN-β promoter. Furthermore, troglitazone could inhibit LPS and poly(I:C)-induced STAT1 phosphorylation and subsequent ISRE activation. These results demonstrate that PPAR-γ negatively regulates IFN-β production in TLR3- and 4-stimulated macrophages by preventing IRF3 binding to the IFN-β promoter.
High level of Ets‐related gene expression has high specificity for prostate cancer: a tissue microarray study of 11 483 cancers

Minner S, Luebke A M, Kluth M, Bokemeyer C, Jänicke F, Izbicki J, Schlomm T, Sauter G & Wilczak W (2012) Histopathology 61, 445–453
HLA-DR4, DR13(6) and the ancestral haplotype A1B8DR3 are associated with ANCA-associated vasculitis and Wegener's granulomatosis.

OBJECTIVES As the HLA system is involved in recognition of self and non-self, an association with the development of ANCA-associated vasculitis (AAV) seems probable. In this study, the relation between HLA antigens and AAV and it's severity were investigated. METHODS Consecutive patients diagnosed with AAV at our centre, who were followed for at least 2 years, were included. The frequency of HLA antigens of AAV and WG patients was compared with 5872 healthy blood donors from the same region and with 4000 healthy Dutch controls originating from a Eurotransplant database. RESULTS From 304 AAV patients, sufficient data were available. We found DR13(6) to be less prevalent and both DR4 and the ancestral haplotype A1B8DR3 more prevalent in patients with AAV compared with controls, particularly in patients with WG. In addition, DR1 was less prevalent in patients with WG in comparison with controls. Further, DR8 was more prevalent in patients with CSS compared with other forms of vasculitis and controls. There were no associations between HLA antigens and disease characteristics or course of AAV or WG. CONCLUSIONS AAV is associated with increased prevalence of DR4 and the ancestral haplotype A1B8DR3 and with decreased prevalence of DR13(6), particularly in patients with WG. In patients with WG, prevalence of DR1 was decreased, whereas in patients with CSS DR8 was increased. No associations between HLA antigens and disease characteristics or course of AAV were found.
Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M (2012) Histopathology 61, 562–575
RET/PTC rearrangement is prevalent in follicular Hürthle cell carcinomas

de Vries M M, Celestino R, Castro P, Eloy C, Máximo V, van der Wal J E, Plukker J T M, Links T P, Hofstra R M W, Sobrinho‐Simões M & Soares P (2012) Histopathology 61, 833–843
Urinary FOXP3 mRNA in patients with lupus nephritis--relation with disease activity and treatment response.

OBJECTIVE Regulatory T lymphocytes (Tregs) probably play an important role in the pathogenesis of SLE. METHODS We quantified messenger RNA (mRNA) expression of FOXP3, a critical regulator for the development and function of Tregs, in the urinary sediment of 25 subjects with active lupus nephritis (LN), 17 with inactive lupus and 7 healthy subjects. RESULTS We found that the expression level of FOXP3 was significantly higher in urine from patients with active LN than from subjects with inactive lupus and healthy controls (24.5 +/- 45.8 vs 0.8 +/- 1.0 vs 0.6 +/- 0.8 copy; P < 0.001). In the active group, urinary FOXP3 mRNA expression level was higher in patients with proliferative LN than non-proliferative nephritis (34.6 +/- 56.3 vs 2.7 +/- 2.1 copy; P = 0.019). Urinary FOXP3 mRNA level significantly correlated with SLEDAI (r = 0.668; P < 0.001) and proteinuria (r = 0.414; P = 0.006). In the active group, urinary FOXP3 mRNA level also significantly correlated with histological activity index (r = 0.541; P = 0.009) and marginally with intra-renal FOXP3 mRNA level (r = 0.360; P = 0.08). Urinary FOXP3 mRNA in patients with no response to therapy was higher than those with partial response or complete response (57.6 +/- 69.8 vs 2.4 +/- 1.9 copies; P = 0.02). CONCLUSION We concluded that urinary FOXP3 mRNA is markedly up-regulated in patients with active LN, and the level of expression is closely correlated with the clinical and histological disease activity. A high urinary FOXP3 mRNA in LN predicts a poor therapeutic response. Measurement of FOXP3 mRNA in urine sediment may be a non-invasive biomarker for assessing the severity and risk stratification in LN.
Physical activity, cardiorespiratory fitness, and clustered cardiometabolic risk in 10‐ to 12‐year‐old school children: The REACH Y6 study

(1) Investigate whether clustered cardiometabolic risk score, cardiorespiratory fitness (CRF), sedentary time (ST), and body mass index Z‐scores (BMI Z‐scores), differed between participants that met and did not achieve ≥60 min of daily moderate to vigorous intensity physical activity (MVPA). (2) Compare clustered cardiometabolic risk score, BMI Z‐score, ST, and MVPA by CRF status.
No clear association between female hormonal aspects and osteoarthritis of the hand, hip and knee: a systematic review.

OBJECTIVE Incidence of OA rises steeply in women of age >50 years; the climacteric period for women. The simultaneous occurrence of these events suggests an association between OA and changes in female hormonal aspects. This systematic review studies the assumed association between OA and aspects concerning the fertile period (duration, endogenous hormones, age at menarche/menopause) and the menopause [menopausal status, years since menopause (YSM) and surgical menopause]. METHODS Medline and EMBASE were searched for articles assessing associations between hand/hip/knee OA and female hormonal aspects. Methodological quality was assessed systematically, and results were summarized in a best-evidence synthesis. RESULTS Sixteen studies were included in the present study. For most hormonal aspects no association was found. Conflicting evidence was found for an association of age at menarche with Herberden's nodes (HNs) and hand ROA, YSM with knee ROA and ovariectomy with hip OA. An increased risk was seen for low estradiol serum levels in the early follicular phase with incident knee ROA, age at menarche being < or =11 years old with total hip replacement, being post-menopausal and YSM with the presence of HN. A protective effect was seen for age at menopause being > or =52 years with total knee replacement. Evidence level was limited for all. CONCLUSIONS The assumed relationship between the female hormonal aspects and OA was not clearly observed in this review. The relationship is perhaps too complex, or other aspects, yet to be determined, play a role in the increased incidence in women aged >50 years.
ICT Knowledge and Skills Among Students of Library and Information Science in Umaru Musa Yar’adu University, Nigeria

The aim of the study is to investigate Information and Communication Technology (ICT) knowledge and skills amongst the students of library and information science in Umaru Musa Yar’adua University, Katsina, whether the courses taught in the department were adequate enough to provide students with ICT knowledge and skills, whether there were adequate ICT infrastructures needed for students training and whether the students had adequate knowledge and skills on ICT. Survey technique was adopted for the study and questionnaire was the main instrument used for data collection. Descriptive statistics using simple percentage was used in analyzing the data collected. The results of the study showed that the department had adequate courses with ICT components and also had adequate ICT infrastructures. The study further revealed that students of the department did not have significant knowledge and skills on search engines, computer applications, using and cataloguing e-resources as well as media resources. Recommendations for improving the students’ ICT knowledge and skills include making the department’s information technology and audio visual laboratories more functional by providing laboratory attendants and practical hours in the departmental lecture time table. The department curriculum should be reviewed to include more ICT related core courses.
Lysyl Oxidase-like-2 (LOXL2) Is a Major Isoform in Chondrocytes and Is Critically Required for Differentiation*

The lysyl oxidase family is made up of five members: lysyl oxidase (LOX) and lysyl oxidase-like 1–4 (LOXL1-LOXL4). All members share conserved C-terminal catalytic domains that provide for lysyl oxidase or lysyl oxidase-like enzyme activity; and more divergent propeptide regions. LOX family enzyme activities catalyze the final enzymatic conversion required for the formation of normal biosynthetic collagen and elastin cross-links. The importance of lysyl oxidase enzyme activity to normal bone development has long been appreciated, but regulation and roles for specific LOX isoforms in bone formation in vivo is largely unexplored. Fracture healing recapitulates aspects of endochondral bone development. The present study first investigated the expression of all LOX isoforms in fracture healing. A remarkable coincidence of LOXL2 expression with the chondrogenic phase of fracture healing was found, prompting more detailed analyses of LOXL2 expression in normal growth plates, and LOXL2 expression and function in developing ATDC5 chondrogenic cells. Data show that LOXL2 is expressed by pre-hypertrophic and hypertrophic chondrocytes in vivo, and that LOXL2 expression is regulated in vitro as a function of chondrocyte differentiation. Moreover, LOXL2 knockdown studies in vitro show that LOXL2 expression is required for ATDC5 chondrocyte cell line differentiation through regulation of SNAIL and SOX9, important transcription factors that control chondrocyte differentiation. Taken together, data provide evidence that LOXL2, like LOX, is a multifunctional protein. LOXL2 promotes chondrocyte differentiation by mechanisms that are likely to include roles as both a regulator and an effector of chondrocyte differentiation.
CT60 and +49 polymorphisms of CTLA 4 are associated with ANCA-positive small vessel vasculitis.

OBJECTIVE To investigate whether single nucleotide polymorphisms (SNPs) within cytotoxic T-lymphocyte antigen-4 (CTLA-4) are associated with ANCA-associated small vessel vasculitis (SVV). METHODS The CTLA-4 CT60 (exon 4), +49 (exon 1) and -318 (promoter region) genotypes were determined by PCR and restriction fragment length polymorphism (RFLP) in 222 white Caucasians of UK origin with SVV and 670 ethnically matched controls. RESULTS The CTLA-4 exon 1 (+49) and 4 (CT60) polymorphisms are associated with SVV (+49: chi(2) = 10.965, P = 0.004; CT60: chi(2) = 12.017, P = 0.002). Both disease-susceptible and disease-protective haplotypes have been identified in this cohort, and their frequencies are similar in the subtypes of WG and microscopic polyangiitis. CONCLUSION This study provides further evidence that CTLA-4, a susceptibility locus for a number of common autoimmune diseases, may also be involved in the development of ANCA-associated SVV.
Sorting out subacute encephalopathy

INTRODUCTION Chronic encephalopathies lead to dementia syndromes that develop over months or years in a setting of clear consciousness (Neary & Snowden 2002). By contrast, acute encephalopathies are neurological and neurosurgical emergencies associated with rapid and severe disturbance of consciousness over hours or days, causing delirium, stupor and ultimately coma (Bateman 2001). Subacute encephalopathies are in between – impaired consciousness develops insidiously over weeks or months. The term ‘confusional state’ is applicable to subacute encephalopathies. However, the clinician may also be confused. For example, patients with chronic dementia are sometimes inappropriately described as ‘confused’, while patients who are in a genuine confusional state may not be recognized as such. Diagnostic mistakes are particularly likely in older people who are sometimes thought, even nowadays, to be inherently senile and demented. Moreover, the situation is complicated by the fact that people who do have dementia may develop transient confusional states following acute perturbations
Geographic variation in nasal cavity form among three human groups from the Japanese Archipelago: Ecogeographic and functional implications

Geographic variation in human nasal form has often been interpreted as a climatic adaptation, owing to the nasal air‐conditioning function. The aim of this study was to further address morphofunctional issues of the nasal cavity, using three human groups from subarctic, temperate, and subtropical regions of the Japanese Archipelago: prehistoric Okhotsk, early‐modern Honshu and Okinawa groups.
Anti tumour necrosis‐α therapy increases the number of FOXP3+ regulatory T cells in children affected by Crohn’s disease

Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Its pathogenesis is not completely understood, though the prevailing model is that the intestinal flora drives a strong intestinal T helper 1 (Th1)/Th17 type immune response and inflammation in the genetically susceptible host. This leads to overly aggressive T‐cell responses to normal bacteria causing tissue damage. Intestinal homeostasis and maintenance of tolerance to harmless antigens in the intestine has been shown to be maintained by CD4+ CD25+ T regulatory cells (Treg) in animal models of inflammatory bowel diseases. Here we investigated whether Infliximab, a chimeric monoclonal antibody directed against tumour necrosis factor (TNF)‐α shown to be highly effective in the treatment of CD, has any effect on mucosal CD4+ CD25+ (FOXP3+) Tregs. Colonic mucosal biopsies from children with active Crohn’s disease treated in vivo with Infliximab and controls were analysed to determine FOXP3 expression by immunofluorescence and reverse transcription–polymerase chain reaction. We observed that FOXP3+ T cells were significantly reduced in mucosa of CD patients with active disease compared with controls and restored to normal following Infliximab treatment. The frequency of FOXP3+ cells and mRNA expression was significantly increased in CD mucosa from patients treated in vivo with Infliximab compared with CD patients treated with conventional therapies. In conclusion, we show that Infliximab treatment does not solely neutralize soluble TNF‐α, but also affects activation and possibly expansion of mucosal regulatory T cells. We suggest that anti TNF‐α immunotherapy can also restore mucosal homeostasis in Crohn’s disease.
Assessment of cardiovascular disease risk factors in a genetically homogenous population of Parsi Zoroastrians in the United States: A pilot study

Genetically isolated and homogenous populations are ideal for detecting genes underlying common complex diseases. The use of isolated populations with reduced disease heterogeneity has led to significant gene discoveries in the past. The aim of this pilot study was to assess the prevalence of cardiovascular disease (CVD) risk phenotypes in a genetically homogenous population of Parsi Zoroastrians in the United States.
Reciprocal Regulation of Notch and Nuclear Factor of Activated T-cells (NFAT) c1 Transactivation in Osteoblasts*

Notch are transmembrane receptors involved in the determination of cell fate. Nuclear factor of activated T-cells (NFAT)c are transcription factors that control cell differentiation and function. We tested whether Notch and NFAT signaling pathways interacted in osteoblastic cells. Notch signaling was induced in ST-2 cells using vectors expressing Notch1 intracellular domain (NICD), and in RosaNotch osteoblastic cells by Cre recombinase-mediated excision of a loxP-flanked STOP cassette cloned between the Rosa26 promoter and NICD. NFATc1 was induced in RosaNotch osteoblastic cells by transducing an adenoviral vector expressing constitutively active NFATc1. Notch inhibited NFAT transactivation and NFATc1 transcription. In ST-2 cells, suppression of NFAT transactivation by Notch was reversed by constitutively active cGMP-dependent protein kinase type II. NFATc1 inhibited the transactivation of Notch target genes, and competed for binding to DNA with the Notch interacting protein Epstein-Barr virus latency C promoter binding factor-1, suppressor of hairless, Lag-1 (CSL). Co-immunoprecipitation and confocal microscopy demonstrated that NFATc1 and CSL interacted. Studies on the effects of NICD and NFATc1 on the differentiation and function of osteoblastic cells demonstrated that NICD and NFATc1 inhibited expression of osteoblast gene markers in RosaNotch osteoblasts, but only NICD suppressed the commitment of bone marrow stromal cells to the osteoblastic lineage. In conclusion, NICD and NFATc1 reciprocally inhibit their signaling pathways, and form a regulatory network to control their activity in osteoblasts.
Anti‐inflammatory effects of tumour necrosis factor (TNF)‐α are mediated via TNF‐R2 (p75) in tolerogenic transforming growth factor‐β‐treated antigen‐presenting cells

Exposure of macrophages to transforming growth factor (TGF)‐β is known to alter their functional phenotype such that antigen presentation by these cells leads to tolerance rather than an inflammatory immune response. Typically, eye‐derived antigen‐presenting cells (APCs) exposed to TGF‐β in the local environment are known to induce a form of peripheral tolerance and protect the eye from inflammatory immune effector‐mediated damage. In response to TGF‐β, APCs increase their expression of tumour necrosis factor (TNF)‐α and TNF receptor 2 (TNF‐R2). Although TNF‐α has been implicated in tolerance and the associated regulation of the inflammatory immune response, its source and the receptors involved remain unclear. In this report we determined the contribution of TNF‐α and TNF‐R2 expressed by TGF‐β‐treated APCs to their anti‐inflammatory tolerogenic effect. Our results indicate that APC‐derived TNF‐α is essential for the ability of APCs to regulate the immune response and their IL‐12 secretion. Moreover, in the absence of TNF‐R2, APCs exposed to TGF‐β failed to induce tolerance or regulatory cells known to participate in this tolerance. Also, blocking of TNF‐R1 signalling enhanced the ability of the APCs to secrete increased TGF‐β in response to TGF‐β exposure. Together our results support an anti‐inflammatory role of TNF‐α in regulation of an immune response by TGF‐β‐treated APCs and suggest that TNF‐R2 contributes significantly to this role.