Miracle-dz/UniFAR-FTUs huggingface dataset:
Syk Activation of Phosphatidylinositol 3-Kinase/Akt Prevents HtrA2-dependent Loss of X-linked Inhibitor of Apoptosis Protein (XIAP) to Promote Survival of Epstein-Barr Virus+ (EBV+) B Cell Lymphomas*

Background: Syk activation is required for B cell survival. EBV can induce B cell lymphomas. Results: Syk, PI3K/Akt inhibition induces apoptosis of EBV+ B cell lymphomas. Syk PI3K/Akt inhibition results in HtrA2-dependent loss of XIAP protein. Conclusion: Syk activates PI3K/Akt to promote survival by preventing HtrA2-dependent loss of XIAP. Significance: Syk, PI3K/Akt, and XIAP are new therapeutic targets for EBV+ B cell lymphomas. B cell lymphoma survival requires tonic or ligand-independent signals through activation of Syk by the B cell receptor. The Epstein-Barr virus (EBV) protein latent membrane 2a (LMP2a), a mimic of the B cell receptor, provides constitutive survival signals for latently infected cells through Syk activation; however, the precise downstream mechanisms coordinating this survival response in EBV+ B cell lymphomas remain to be elucidated. Herein, we assess the mechanism of Syk survival signaling in EBV+ B cell lymphomas from post-transplant lymphoproliferative disorder (PTLD) to discover virally controlled therapeutic targets involved in lymphomagenesis and tumor progression. Using small molecule inhibition and siRNA strategies, we show that Syk inhibition reduces proliferation and induces apoptosis of PTLD-derived EBV+ B cell lines. Syk inhibition also reduces autocrine IL-10 production. Although Syk inhibition attenuates signaling through both the PI3K/Akt and Erk pathways, only PI3K/Akt inhibition causes apoptosis of PTLD-derived cell lines. Loss of the endogenous caspase inhibitor XIAP is observed after Syk or PI3K/Akt inhibition. The loss of XIAP and apoptosis that results from Syk or PI3K/Akt inhibition is reversed by inhibition of the mitochondrial protease HtrA2. Thus, Syk drives EBV+ B cell lymphoma survival through PI3K/Akt activation, which prevents the HtrA2-dependent loss of XIAP. Syk, Akt, and XIAP antagonists may present potential new therapeutic strategies for PTLD through targeting of EBV-driven survival signals.
Addressing the health needs of south Asians: The community perspective

Community based organizations play a vital role in the health of communities in the United States, particularly among immigrant and minority populations. Yet the gap between the needs of the community and the health issues that are being addressed remains quite large. This qualitative assessment provides a brief summary of community-based organizations in the US that focus on health issues specifically addressing the needs of South Asian Americans. In addition, this assessment explores the health needs of the South Asian American community living in the Washington DC metropolitan region, the fifth largest densely populated city in the US of South Asian Americans. While the report provides an array of organizations serving this population, the question of how effective can community-based organizations be if they can not prioritize their needs based on the community’s needs still remains.
PIM‐1 kinase expression in adipocytic neoplasms: diagnostic and biological implications

The differential diagnosis of soft tissue tumours poses a considerable challenge for pathologists, especially adipocytic tumours, as these may show considerable overlap in clinical presentation and morphological features with many other mesenchymal neoplasms. Hence, a specific and reliable marker that identifies adipocytic differentiation is much sought. We investigated the immunohistochemical expression of PIM‐1 kinase in 35 samples of soft tissue tumours using tissue microarray technology and 49 full sections of adipocytic (n = 26) and non‐adipocytic tumours (n = 23). Benign and malignant adipocytic tumours showed strong expression of PIM‐1 while the non‐adipocytic tumours were either negative or showed only weak staining for the protein. In myxoid liposarcomas, PIM‐1 showed a distinct, unique vacuolar staining pattern, clearly outlining fine cytoplasmic lipid vacuoles. By contrast, non‐adipocytic myxoid tumours (myxoma, chordoma and myxoid chondrosarcoma) did not show this vacuolar pattern of PIM‐1 staining, although vacuolated cells were present on H&E. This differential expression was confirmed at a gene expression level in selected cases. Our results indicate that the expression of PIM‐1 in adipose tissue may be a useful marker of adipocytic differentiation, in particular if the staining is both of high intensity and present in a unique, vacuolar pattern.
Oligomerization of MDC1 Protein Is Important for Proper DNA Damage Response*

Mediator of DNA damage checkpoint 1 (MDC1) plays an important role in the DNA damage response (DDR). MDC1 functions as a mediator protein and binds multiple proteins involved in different aspects of the DDR. However, little is know about the organization of MDC1 complexes. Here we show that ataxia telangiectasia, mutated (ATM) phosphorylates MDC1 at Thr-98 following DNA damage, which promotes its oligomerization. Oligomerization of MDC1 is important for the accumulation of MDC1 complex at the sites of DNA damage. Mutation of Thr-98 (T98A) would abolish its oligomerization and result in a defect in DNA damage checkpoint activation and increased sensitivity to irradiation. Taken together, these results suggest that the oligomerization of MDC1 plays an important role in DDR and help understand the formation of proteins complexes at the sites of DNA damage.
Antibody formation and immunomodulation in experimental allergic encephalomyelitis and multiple sclerosis

textabstractMultiple sclerosis (MS) is a chronic demyelinating disease characterized by perivascular accumulation of infiammatory cells, resulting in numerous (multiple) plaques (sclerosis), in the central nervous system (CNS). Despite ample research efforts both etiology and pathogenicity of the disease remain largely unknown. Due to the complexity of clinical manifestations the unequivocal diagnosis of MS is difficult to make. It is generally accepted that the effector phase of the disease depends on an autoimmune reaction. Notwithstanding the fact that oligoclonal antibodies can be found in the cerebrospinal fluid during disease, the role of antibodies in MS is still unclear. In order to investigate the involvement of autoantigen specific antibodies in the pathology of MS, we performed a study to detect antigen specific B-cells (AFCs) in CNS tissues of MS patients. Using a new immunohistochemical technique we have revealed that a significant part of the AFCs localized in MS brain is specific for myelin basic protein (MBP). This provides further evidence for the local involvement of anti-MBP antibodies in the pathogenesis of MS. Production of antibodies by B-cells is critically dependent on T-cell help. It has been shown that interactions between the gp39 T-cell marker and its CD40 ligand on B-cells are essential for B-cell activation. In our experiments we have revealed gp39 positive T-cells in the same affected eNS tissue areas (plaques) in which we have detected the MBP specific AFe. The presence of both gp39t Th-cells and MBP specific B-cells in plaques of MS patients CNS tissues indicates that autoantigen specific B-cells can be activated directly within the CNS.
Sirtuin 1 (SIRT1) Deacetylase Activity Is Not Required for Mitochondrial Biogenesis or Peroxisome Proliferator-activated Receptor-γ Coactivator-1α (PGC-1α) Deacetylation following Endurance Exercise*

The protein deacetylase, sirtuin 1 (SIRT1), is a proposed master regulator of exercise-induced mitochondrial biogenesis in skeletal muscle, primarily via its ability to deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). To investigate regulation of mitochondrial biogenesis by SIRT1 in vivo, we generated mice lacking SIRT1 deacetylase activity in skeletal muscle (mKO). We hypothesized that deacetylation of PGC-1α and mitochondrial biogenesis in sedentary mice and after endurance exercise would be impaired in mKO mice. Skeletal muscle contractile characteristics were determined in extensor digitorum longus muscle ex vivo. Mitochondrial biogenesis was assessed after 20 days of voluntary wheel running by measuring electron transport chain protein content, enzyme activity, and mitochondrial DNA expression. PGC-1α expression, nuclear localization, acetylation, and interacting protein association were determined following an acute bout of treadmill exercise (AEX) using co-immunoprecipitation and immunoblotting. Contrary to our hypothesis, skeletal muscle endurance, electron transport chain activity, and voluntary wheel running-induced mitochondrial biogenesis were not impaired in mKO versus wild-type (WT) mice. Moreover, PGC-1α expression, nuclear translocation, activity, and deacetylation after AEX were similar in mKO versus WT mice. Alternatively, we made the novel observation that deacetylation of PGC-1α after AEX occurs in parallel with reduced nuclear abundance of the acetyltransferase, general control of amino-acid synthesis 5 (GCN5), as well as reduced association between GCN5 and nuclear PGC-1α. These findings demonstrate that SIRT1 deacetylase activity is not required for exercise-induced deacetylation of PGC-1α or mitochondrial biogenesis in skeletal muscle and suggest that changes in GCN5 acetyltransferase activity may be an important regulator of PGC-1α activity after exercise.
TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis1

Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-β1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-β1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-β1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-β1 variants or haplotypes. The −509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the −509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the −509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the −509C and codon 10T, implicated in lower levels of TGF-β1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-β1, although future studies will be needed to correlate TGF-β1 protein levels with known TGF-β1 genotypes and assess whether there is a shared mechanisms for TGF-β1 in these two granulomatous diseases.
Myocarditis: A Rheumatologic Perspective

Myocarditis is an uncommon complication in patients with autoimmune rheumatic diseases. The majority of cases refer to postmortem findings. The mechanism of myocardial damage in Connective Tissue Diseases (CTDs) depends on the pathophysiology of underlying disease. Systemic inflammation, impaired microvascular circulation and vasculitis affect myocardial remodeling process, cause repeated focal ischemia resulting in hypertrophy, fibrosis of myocardium, conductive system and thus reduced contractility. Additionally, immunological abnormalities, coexisting myositis and the degree of disease activity are predictors of myocarditis progression. Clinical manifestations range from subclinical to severe forms. Early recognition is important for institution of appropriate immunomodulatory therapy.
Ligand-switchable Substrates for a Ubiquitin-Proteasome System*

Cellular maintenance of protein homeostasis is essential for normal cellular function. The ubiquitin-proteasome system (UPS) plays a central role in processing cellular proteins destined for degradation, but little is currently known about how misfolded cytosolic proteins are recognized by protein quality control machinery and targeted to the UPS for degradation in mammalian cells. Destabilizing domains (DDs) are small protein domains that are unstable and degraded in the absence of ligand, but whose stability is rescued by binding to a high affinity cell-permeable ligand. In the work presented here, we investigate the biophysical properties and cellular fates of a panel of FKBP12 mutants displaying a range of stabilities when expressed in mammalian cells. Our findings correlate observed cellular instability to both the propensity of the protein domain to unfold in vitro and the extent of ubiquitination of the protein in the non-permissive (ligand-free) state. We propose a model in which removal of stabilizing ligand causes the DD to unfold and be rapidly ubiquitinated by the UPS for degradation at the proteasome. The conditional nature of DD stability allows a rapid and non-perturbing switch from stable protein to unstable UPS substrate unlike other methods currently used to interrogate protein quality control, providing tunable control of degradation rates.
Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism*

Post-transcriptional mechanisms play an important role in the control of inflammatory gene expression. The heterogeneous nuclear ribonucleoprotein K homology (KH)-type splicing regulatory protein (KSRP) triggers rapid degradation of mRNAs for various cytokines, chemokines, and other inflammation-related proteins by interacting with AU-rich elements (AREs) in the 3′-untranslated mRNA regions. In addition to destabilizing mRNAs, AU-rich elements can restrict their translation. Evidence that KSRP also participates in translational silencing was obtained in a screen comparing the polysome profiles of cells with siRNA-mediated depletion of KSRP with that of control cells. Among the group of mRNAs showing increased polysome association upon KSRP depletion are those of interleukin (IL)-6 and IL-1α as well as other ARE-containing transcripts. Redistribution of IL-6 mRNA to polysomes was associated with increased IL-6 protein secretion by the KSRP-depleted cells. Silencing of IL-6 and IL-1α mRNAs depended on their 3′-untranslated regions. The sequence essential for translational control of IL-6 mRNA and its interaction with KSRP was located to an ARE. KSRP-dependent silencing was reversed by IL-1, a strong inducer of IL-6 mRNA and protein expression. The results identify KSRP as a protein involved in ARE-mediated translational silencing. They suggest that KSRP restricts inflammatory gene expression not only by enhancing degradation of mRNAs but also by inhibiting translation, both functions that are counteracted by the proinflammatory cytokine IL-1.
Sucking habits in childhood and the effects on the primary dentition: findings of the Avon Longitudinal Study of Pregnancy and Childhood.

INTRODUCTION Most previous research on non-nutritive sucking habits has been cross-sectional in nature. This study determined the prevalence of non-nutritive sucking habits and the effects on the developing dentition within a longitudinal observational cohort. METHODS The Children in Focus group of the Avon Longitudinal Study of Pregnancy and Childhood study was studied. Questionnaire data on non-nutritive sucking habits were collected on the children at 15 months, 24 months, and 36 months of age. Dental examinations were performed on the same children at 31 months, 43 months, and 61 months of age. RESULTS At 15 months, 63.2% of children had a sucking habit, 37.6% used just a dummy, and 22.8% used a digit. By 36 months, sucking had reduced to 40%, with similar prevalence of dummy and digit sucking. Both habits had effects on the developing dentition, most notably in upper labial segment alignment and the development of anterior open bites and posterior crossbites. CONCLUSIONS The majority of children had non-nutritive sucking habits up until 24 months of age. Both digit and dummy sucking were associated with observed anomalies in the developing dentition, but dummy-sucking habits had the most profound influence on the anterior and posterior occlusions of the children.
Bleeding and stent thrombosis with P2Y12-inhibitors: a collaborative analysis on the role of platelet reactivity for risk stratification after PCI

Aims: Balancing bleeding events and thrombotic complications are crucial in patients undergoing PCI and receiving dual antiplatelet therapy. The potential role of platelet function testing in risk stratification after PCI is unknown. We sought to determine the prognostic value of low (LPR), optimal (OPR), or high platelet reactivity (HPR) during P2Y12-inhibitor treatment by applying standardised cutoff criteria for recommended platelet function assays (VerifyNOW, Multiplate and VASP) in patients undergoing PCI. Methods and results: Authors of studies published before December 2014, reporting associations between platelet reactivity, ST and major bleeding were contacted for a collaborative analysis using a priori defined, uniform cutoff values for standardised platelet function assays. Based on recommendations of prior consensus documents and the best evidence available (exploratory studies), LPR-OPR-HPR categories were defined as 208 PRU for VerifyNow, 46 U for the Multiplate analyser and 50% for VASP assay, respectively. Seventeen studies including 20,841 patients were pooled for the analysis; 97% were treated with clopidogrel and 3% with prasugrel. Patients with HPR had a significantly higher risk for ST (RR: 2.73, 95% CI: 2.03-3.69, p<0.00001) yet a slightly lower risk for bleeding (RR: 0.84, 95% CI: 0.71-0.99, p=0.04) compared to those with OPR. In contrast, patients with LPR had a significantly higher risk for bleeding (RR: 1.74, 95% CI: 1.47-2.06, p<0.0001), but identical risk for ST (RR: 1.06 95% CI: 0.68-1.05, p=0.85) as those with OPR. Mortality was significantly higher in patients with HPR (RR: 1.54 95% CI: 1.22-1.94, p<0.0002), but was similar between LPR and OPR patients (RR: 1.03 95% CI: 0.76-1.40 p=0.85). Validation cohorts confirmed the results suggested by exploratory studies. Conclusions: Assessing platelet reactivity during P2Y12-inhibitor treatment with the herein-validated cutoff values may help stratifying PCI-treated patients to higher risk for mortality and ST (HPR) or an elevated risk for bleeding (LPR).
Approach to hydatid cyst rupture patient who administered with anaphylactic shock

Hydatid cyst is a parasitic disease, which can involve liver, lungs, spleen, kidneys, orbita, heart, brain and bone. In case of rupture it can cause anaphylactic reactions, shock and cardiovascular collapse. Cyst hydatid is a very common health problem in our country among 30-50 year-old males therefore it is essential to include it in differential diagnosis idiopathic anaphylactic shock
Peer teaching pilot programme for caries prevention in underprivileged and migrant populations.

BACKGROUND Focused caries prevention programmes for migrant children often fail because there is an important barrier of linguistic and cultural diversity. AIM The aim of this study was to evaluate whether a tailored peer teaching approach can improve oral health behaviours of underprivileged and/or multinational migrant first graders. DESIGN Two fourth grade classes (30 children, mean age 9.6) and two first grade classes (38 children, mean age 6.6) with high migrant background participated. The fourth graders took part in a preparatory course of oral health and developed a concept for tutoring first graders in oral health concepts as well as the Fones toothbrushing method. Later then, the fourth graders instructed the first graders during two lessons. Toothbrushing of each first grader was filmed before and 7 days after instruction. Toothbrushing time, method, and systematic were evaluated. RESULTS After instruction, circular toothbrushing movements and systematic toothbrushing were observed significantly more often (P = 0.0001); toothbrushing time did not change. CONCLUSIONS This pilot study shows that tutoring by older peers of similar origin resulted in significant changes towards better oral health in underprivileged and/or multinational migrant first graders. Authentic role models could be provided, and communication and cultural barriers circumvented.
Suppression of 5′-Nucleotidase Enzymes Promotes AMP-activated Protein Kinase (AMPK) Phosphorylation and Metabolism in Human and Mouse Skeletal Muscle*

Background: The 5′-nucleotidase (NT5) family of enzymes dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Results: NT5 silencing increases the intracellular availability of AMP/ATP and invokes AMP-activated protein kinase (AMPK) activation, glucose uptake, and lipid oxidation. Conclusion: NT5C enzymes inhibit basal lipid oxidation and glucose transport in skeletal muscle. Significance: Suppression of cytosolic NT5C expression or activity may bypass metabolic inflexibility in type 2 diabetes. The 5′-nucleotidase (NT5) family of enzyme dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. We hypothesized that gene silencing of NT5 enzymes to increase the intracellular availability of AMP would increase AMP-activated protein kinase (AMPK) activity and metabolism. We determined the role of cytosolic NT5 in metabolic responses linked to the development of insulin resistance in obesity and type 2 diabetes. Using siRNA to silence NT5C2 expression in cultured human myotubes, we observed a 2-fold increase in the AMP/ATP ratio, a 2.4-fold increase in AMPK phosphorylation (Thr172), and a 2.8-fold increase in acetyl-CoA carboxylase phosphorylation (Ser79) (p < 0.05). siRNA silencing of NT5C2 expression increased palmitate oxidation by 2-fold in the absence and by 8-fold in the presence of 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside. This was paralleled by an increase in glucose transport and a decrease in glucose oxidation, incorporation into glycogen, and lactate release from NT5C2-depleted myotubes. Gene silencing of NT5C1A by shRNA injection and electroporation in mouse tibialis anterior muscle reduced protein content (60%; p < 0.05) and increased phosphorylation of AMPK (60%; p < 0.05) and acetyl-CoA carboxylase (50%; p < 0.05) and glucose uptake (20%; p < 0.05). Endogenous expression of NT5C enzymes inhibited basal lipid oxidation and glucose transport in skeletal muscle. Reduction of 5′-nucleotidase expression or activity may promote metabolic flexibility in type 2 diabetes.