Miracle-dz/UniFAR-FTUs huggingface dataset:
MicroRNA-15b Modulates Cellular ATP Levels and Degenerates Mitochondria via Arl2 in Neonatal Rat Cardiac Myocytes*

MicroRNAs (miRNAs or miRs) are small, non-coding RNAs that modulate mRNA stability and post-transcriptional translation. A growing body of evidence indicates that specific miRNAs can affect the cellular function of cardiomyocytes. In the present study, miRNAs that are highly expressed in the heart were overexpressed in neonatal rat ventricular myocytes, and cellular ATP levels were assessed. As a result, miR-15b, -16, -195, and -424, which have the same seed sequence, the most critical determinant of miRNA targeting, decreased cellular ATP levels. These results suggest that these miRNAs could specifically down-regulate the same target genes and consequently decrease cellular ATP levels. Through a bioinformatics approach, ADP-ribosylation factor-like 2 (Arl2) was identified as a potential target of miR-15b. It has already been shown that Arl2 localizes to adenine nucleotide transporter 1, the exchanger of ADP/ATP in mitochondria. Overexpression of miR-15b, -16, -195, and -424 suppressed the activity of a luciferase reporter construct fused with the 3′-untranslated region of Arl2. In addition, miR-15b overexpression decreased Arl2 mRNA and protein expression levels. The effects of Arl2 siRNA on cellular ATP levels were the same as those of miR-15b, and the expression of Arl2 could restore ATP levels reduced by miR-15b. A loss-of-function study of miR-15b resulted in increased Arl2 protein and cellular ATP levels. Electron microscopic analysis revealed that mitochondria became degenerated in cardiomyocytes that had been transduced with miR-15b and Arl2 siRNA. The present results suggest that miR-15b may decrease mitochondrial integrity by targeting Arl2 in the heart.
Autoimmune diseases and myelodysplastic syndromes

Immune dysregulation and altered T‐cell hemostasis play important roles in the pathogenesis of myelodysplastic syndromes (MDS). Recent studies suggest an increased risk of MDS among patients with autoimmune diseases. Here, we investigated the prevalence of autoimmune diseases among MDS patients, comparing characteristics and outcomes in those with and without autoimmune diseases. From our study group of 1408 MDS patients, 391 (28%) had autoimmune disease, with hypothyroidism being the most common type, accounting for 44% (n = 171) of patients (12% among all MDS patients analyzed). Other autoimmune diseases with ≥5% prevalence included idiopathic thrombocytopenic purpura in 12% (n = 46), rheumatoid arthritis in 10% (n = 41), and psoriasis in 7% (n = 28) of patients. Autoimmune diseases were more common in female MDS patients, those with RA or RCMD WHO subtype, and those who were less dependent on red blood cell transfusion. Median overall survival (OS) was 60 months (95% CI, 50–70) for patients with autoimmune diseases versus 45 months (95% CI, 40–49) for those without (log‐rank test, P = 0.006). By multivariate analysis adjusting for revised IPSS and age >60 years, autoimmune diseases were a statistically significant independent factor for OS (HR 0.78; 95% CI, 0.66–0.92; P = 0.004). The rate of acute myeloid leukemia (AML) transformation was 23% (n = 89) in MDS patients with autoimmune disease versus 30% (n = 301) in those without (P = 0.011). Patient groups did not differ in response to azacitidine or lenalidomide treatment. Autoimmune diseases are prevalent among MDS patients. MDS patients with autoimmune diseases have better OS and less AML transformation. Am. J. Hematol. 91:E280–E283, 2016. © 2016 Wiley Periodicals, Inc.
Loss of Dact1 Disrupts Planar Cell Polarity Signaling by Altering Dishevelled Activity and Leads to Posterior Malformation in Mice*

Wnt signaling plays a key role in embryogenesis and cancer development. Dvl (Dishevelled) is a central mediator for both the canonical and noncanonical Wnt pathways. Dact1 (Dapper1, Dpr1), a Dvl interactor, has been shown to negatively modulate Wnt signaling by promoting lysosomal degradation of Dvl. Here we report that Dact1-deficient mice have multiple physiological defects that resemble the human neonate disease congenital caudal regression syndrome, including caudal vertebrae agenesis, anorectal malformation, renal agenesis/dysplasia, fused kidneys, and loss of bladder. These urogenital defects can be traced to impaired hindgut formation starting at embryonic day 8.25. Examination of morphological changes and Wnt target gene expression revealed that the planar cell polarity (PCP) signaling is deregulated, whereas the canonical Wnt/β-catenin pathway is largely unaffected in mutant embryos. Consistently, the activity of the PCP signal mediators Rho GTPase and c-Jun N-terminal kinase is altered in Dact1−/− mouse embryonic fibroblasts. We further observed alterations in the protein level and the cellular distribution of Dvl in the primitive streak of mutant embryos. An increased amount of Dvl2 tends to be accumulated in the cortical regions of the cells, especially at the primitive streak ectoderm close to the posterior endoderm that lately forms the hindgut diverticulum. Together, these data suggest that Dact1 may regulate vertebrate PCP by controlling the level and the cellular localization of Dvl protein.
The long pentraxin PTX-3 in prevalent hemodialysis patients: associations with comorbidities and mortality.

BACKGROUND Pentraxin (PTX)-3, a new candidate marker for inflammation is expressed in a variety of cell types. Recently, we have shown that increase in PTX-3 level is associated with clinical outcome in incident CKD stage 5 patients at start of renal replacement therapy. However, no data are available on PTX-3 and its relationship with clinical outcome in prevalent dialysis patients. METHODS We analyzed plasma PTX-3 concentrations in relation to comorbidities (Davies score), protein-energy wasting (PEW) and inflammation markers in 200 prevalent hemodialysis (HD) patients, aged 64 +/- 14 years, who had been on HD treatment for a median period of 36 months. Survival (42 months) was analyzed in relation to PTX-3 levels (high PTX-3 tertile vs. low two tertiles). RESULTS Plasma PTX-3 correlated positively with C-reactive protein and interleukin-6, and negatively with s-albumin and fetuin-A. Patients with cardiovascular disease (CVD) and PEW had higher levels of PTX-3 than their counterparts and PTX-3 was associated with comorbidity score. In multiple logistic regression analysis, the high comorbidity score and PEW were the significant predictive variables of high PTX-3. In unadjusted analysis high PTX-3 was significantly associated with all-cause mortality. After adjustment for sex, age, dialysis vintage, comorbidity score, PEW and CRP using the multivariate Cox regression analysis, death rate was still significantly higher in patients with high PTX-3 (HR 1.7; CI 1.1-2.7, P = 0.03). CONCLUSION Markedly increased levels of PTX-3 were found in HD patients with signs of CVD and PEW. In addition, the concentration of PTX-3 was associated with inflammation markers and comorbidity score. Our data also shows that high PTX-3 level was independently associated with all-cause mortality.
Outcomes of elderly patients aged 80 and over with symptomatic, severe aortic stenosis: impact of patient's choice of refusing aortic valve replacement on survival.

BACKGROUND Aortic valve replacement (AVR) can be performed safely in selected elderly patients with aortic stenosis (AS). However, the survival benefits of AVR over conservative treatment have not been convincingly demonstrated in AS patients aged above 80. AIM To investigate the outcomes of patients aged 80 and over with symptomatic, severe AS and by analyzing the effects of patient's choice in either agreeing or refusing to undergo AVR, determine the survival benefits afforded by AVR. DESIGN Cohort study. METHODS Subjects aged 80 and over with severe symptomatic AS, diagnosed between 2001 and 2006 were segregated into three groups: subjects who underwent AVR (Group A); patients who were fit for AVR but declined surgery due to personal choice (Group B) and those who were not fit for surgery and were managed conservatively (Group C). Follow-up was conducted by out-patient attendances, review of medical records and telephone interviews. The primary endpoint was all-cause mortality. RESULTS A total of 103 patients (86.0 +/- 4.2 years, 41% male) were identified and no patient was lost during follow-up. In Group A (n = 17), all 15 patients who underwent AVR were alive after 3.6 +/- 1.4 years follow-up and 2 died whilst awaiting AVR. Seventy-four percent of Group B (n = 24) and 76% of Group C (n = 62) died during follow-up. Group A had significantly better survival than B and C. (P < 0.01) Amongst patients fit for AVR with similar operative risks (Groups A and B), refusal to undergo surgery (hazard ratio 12.61, P = 0.001) was the only predictor of mortality in a multivariate model. CONCLUSION For elderly AS patients fit for surgery, the patient's decision to refuse AVR is associated with a >12-fold increase in mortality risk. These findings have significant implications for informed decision-making when managing the fit, elderly patient with AS.
METABOLISM OF UNDERNOURISHED CHILDREN

INTRODUCTION The work reported in this and subsequent papers was undertaken at the request of the trustees of the Elizabeth McCormick Memorial Fund of Chicago. This organization has been interested for a number of years in the practical task of attempting to overcome, by the organization of nutrition classes and by work in the home, undernutrition in children of school age. The work has, in general, been successful, but a small proportion of the children who have come under observation could not be made to gain, in spite of the fact that no evident cause of the undernourished state could be detected. It was to determine the metabolic abnormality, if any actually existed, of such "refractory" children that the Nelson Morris Institute was asked to investigate the subject at the suggestion of Dr. I. A. Abt, consulting pediatrician of the fund. In outlining the work to be undertaken, it was
Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

Although generally considered a clinically indolent neoplasm, CLL/SLL may undergo transformation to a clinically aggressive lymphoma. The most common form of transformation, to DLBCL, is also known as Richter syndrome. Transformation determines the course of the disease and is associated with unfavorable patient outcome. Precise detection of transformation and identification of predictive biomarkers and specific molecular pathways implicated in the pathobiology of transformation in CLL/SLL will enable personalized therapeutic approach and provide potential avenues for improving the clinical outcome of patients. In this review, we present an overview of the pathologic features, risk factors, and pathogenic mechanisms of CLL/SLL transformation. Am. J. Hematol. 91:1036–1043, 2016. © 2016 Wiley Periodicals, Inc.
Hereditary Sensory Neuropathy Type 1 Is Caused by the Accumulation of Two Neurotoxic Sphingolipids*♦

HSAN1 is an inherited neuropathy found to be associated with several missense mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT). SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial step in the de novo synthesis of sphingolipids. Here we show that the HSAN1 mutations induce a shift in the substrate specificity of SPT, which leads to the formation of the two atypical deoxy-sphingoid bases (DSBs) 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine. Both metabolites lack the C1 hydroxyl group of sphinganine and can therefore neither be converted to complex sphingolipids nor degraded. Consequently, they accumulate in the cell, as demonstrated in HEK293 cells overexpressing mutant SPTLC1 and lymphoblasts of HSAN1 patients. Elevated DSB levels were also found in the plasma of HSAN1 patients and confirmed in three groups of HSAN1 patients with different SPTLC1mutations. The DSBs show pronounced neurotoxic effects on neurite formation in cultured sensory neurons. The neurotoxicity co-occurs with a disturbed neurofilament structure in neurites when cultured in the presence of DSBs. Based on these observations, we conclude that HSAN1 is caused by a gain of function mutation, which results in the formation of two atypical and neurotoxic sphingolipid metabolites.
Dimeric Arrangement of the Parathyroid Hormone Receptor and a Structural Mechanism for Ligand-induced Dissociation*

The parathyroid hormone receptor (PTH1R) is a class B G protein-coupled receptor that is activated by parathyroid hormone (PTH) and PTH-related protein (PTHrP). Little is known about the oligomeric state of the receptor and its regulation by hormone. The crystal structure of the ligand-free PTH1R extracellular domain (ECD) reveals an unexpected dimer in which the C-terminal segment of both ECD protomers forms an α-helix that mimics PTH/PTHrP by occupying the peptide binding groove of the opposing protomer. ECD-mediated oligomerization of intact PTH1R was confirmed in living cells by bioluminescence and fluorescence resonance energy transfer experiments. As predicted by the structure, PTH binding disrupted receptor oligomerization. A receptor rendered monomeric by mutations in the ECD retained wild-type PTH binding and cAMP signaling ability. Our results are consistent with the hypothesis that PTH1R forms constitutive dimers that are dissociated by ligand binding and that monomeric PTH1R is capable of activating G protein.
Prevalence and Antibiotic Resistance Patterns of Salmonella Isolates from Lactating Cows andIn-contact Humans in Dairy Farms, Northwest Ethiopia -

Background: Salmonellosis is an infectious disease of humans and animals caused by species of Salmonella. Salmonella are widespread in the environment and commonly found in farm effluents and sewage. Epidemiological information on the prevalence of salmmonelosis is a prerequisite to develop appropriate control strategies. Objective: To assess the prevalence and antibiotic resistance patterns of Salmonella isolates. Methods: A cross-sectional study was conducted. A total of 152 cows and 14 humans were included in the study. Milk, fecal sample and human stool were collected. Samples were pre-enriched with buffered peptone water and transferred to selenite cysteine broth and rappaport-vassilidis broth. Isolation was made by plating on to xylose lysine deoxycholate agar and brilliant green agar. Biochemical, antibiotic susceptibility testing and serotyping were done. Data were entered and analyzed using SPSS version 20 software. Binary logistic regression was applied and p-values of less than 0.05 were considered statistically significant. Results: Of the total 21 Salmonella isolates identified, 19(90.5%) and 2(9.5%) isolates were from lactating cows and in-contact individuals, respectively. Salmonella bredeney was the most common (85.7%). Drinking water source had statistically significant (P=0.027) association. All isolates were resistant at least to one of the antibiotics tested with 100% to ampicillin. All isolates were sensitive to ciprofloxacin and amoxacilin/clavulanic acid. Conclusion: Large percentage of Salmonella isolates were resistant at least to one of the antibiotics tested. Salmonellosis treatment could be difficult in the future unless wise use of antibiotics is practiced.
Advances in Water Resources River networks as ecological corridors: A coherent ecohydrological perspective

This paper draws together several lines of argument to suggest that an ecohydrological framework, i.e. la- boratory, ﬁ eld and theoretical approaches focused on hydrologic controls on biota, has contributed substantially to our understanding of the function of river networks as ecological corridors. Such function proves relevant to: the spatial ecology of species; population dynamics and biological invasions; the spread of waterborne disease. As examples, we describe metacommunity predictions of ﬁ sh diversity patterns in the Mississippi – Missouri basin, geomorphic controls imposed by the ﬂ uvial landscape on elevational gradients of species ’ richness, the zebra mussel invasion of the same Mississippi – Missouri river system, and the spread of proliferative kidney disease in salmonid ﬁ sh. We conclude that spatial descriptions of ecological processes in the ﬂ uvial landscape, constrained by their speci ﬁ c hydrologic and ecological dynamics and by the ecosystem matrix for interactions, i.e. the directional dispersal embedded in ﬂ uvial and host/pathogen mobility networks, have already produced a remarkably broad range of signi ﬁ cant results. Notable scienti ﬁ c and practical perspectives are thus open, in the authors ’ view, to future developments in ecohydrologic research.
Age, alcohol and liver transplantation.

Sir, Two recent cases of young men with severe alcoholic hepatitis, who were not offered a transplant, have highlighted some of the difficult decisions that have to be made in the field of liver transplantation.1,2 Although not all relevant medical information was available in the public domain, these two cases generated considerable and sometimes ill-informed public debate about the issues surrounding organ allocation and withholding of life-saving treatment from young men. In the UK, criteria for patient selection and organ allocation are developed within national health service (NHS) Blood and Transplant (NHSBT) by clinicians in consultation with patients and other health care professionals; and, as donated organs are considered a national resource, protocols are applied nationally to ensure the optimal balance of utility and equity. Cirrhosis, secondary to alcohol, raises controversies not seen with other indications because it is construed to be self-inflicted despite the existence of strong genetic and environmental factors. Indeed, patient outcome is better than some other indications, such as hepatitis C and hepatocellular carcinoma,3 and there are no significant differences in compliance or levels of re-employment in comparison to patients grafted for other conditions.3 Understandable concerns do remain about relapse in these patients; although …
Immunohistochemical Expression of Sialyl Lewisa in Salivary Gland Tumors

Sialyl Lewisa (CA19-9 antigen), a high molecular weight glycoprotein, was originally described as a gastrointestinal tract- and pancreas-specific tumor marker. However, the diagnostic usefulness of sialyl Lewisa expression in salivary gland tumors is not well established. Therefore, we examined the diagnostic significance of sialyl Lewisa (CA19-9 antigen) expression in salivary gland tumors. Surgical materials, consisting of 30 benign (20 pleomorphic adenomas, 5 basal cell adenomas, 5 myoepitheliomas) and 30 malignant (13 mucoepidermoid carcinomas, 13 adenoid cystic carcinomas, 4 salivary duct carcinomas) salivary gland tumors, were subjected to examination in this study. To measure expression of sialyl Lewisa in these tumors, a streptavidin-biotinyl immunoperoxidase method was performed using anti-human CA19-9 antibody. There was a tendency for malignant salivary gland tumors, to express sialyl Lewisa more intensely than benign tumor (P<0.05). As the expression pattern is generally characterized by localization in relatively highly differentiated malignant cells such as mucous-producing cells and atypical luminal duct cells, poorly differentiated tumors such as adenoid cystic carcinoma solid type and salivary duct carcinoma are consistently shown to express sialyl Lewisa less frequently. Five (tubular type 2 and cribriform type 3) of 13 (38.5%) cases were stroma positive for sialyl Lewisa in the adenoid cystic carcinoma. Sialyl Lewisa expression appears to be increased by the malignant transformation of salivary gland tumors. The clinical applications of sialyl Lewisa in patients with salivary gland tumors may be worth examining more closely in the future.
Impact of achievement of complete cytogenetic response on outcome in patients with myelodysplastic syndromes treated with hypomethylating agents

Two hundred and sixteen consecutive patients with MDS and abnormal karyotype treated with hypomethylating agents between 4/04 and 10/12 were reviewed. Median follow‐up was 17 months. Using IWG criteria, best responses were complete response (CR) in 79 patients (37%), partial response (PR) in 4 (2%), and hematologic improvement (HI) in 10 (5%). Cytogenetic response (CyR) was achieved in 78 patients (36%): complete (CCyR) in 62 (29%) and partial in 16 (7%). CyR was achieved in 48 of 79 patients (61%) with CR, 1 of 14 (7%) with PR/HI, and in 29 of the 123 (24%) with no morphologic response. Median overall survival (OS) and leukemia‐free survival (LFS) for patients with and without CCyR were 21 and 13 months (P = .007), and 16 and 9 months (P = .001), respectively. By multivariate analysis, the achievement of CCyR was predictive for better OS (HR = 2.1; P < .001). In conclusion, CyR occurs at a rate of 36% (complete in 29%) in patients with MDS treated with HMA and is not always associated with morphological response. The achievement of CCyR is associated with survival improvement and constitutes a major predictive factor for outcome particularly in patients without morphologic response. Therefore, the achievement of CCyR should be considered a milestone in the management of patients with MDS.
Concomitant monitoring of WT1 and FLT3‐ITD expression in FLT3‐ITD acute myeloid leukemia patients: which should we trust as a minimal residual disease marker?

rs766432 and who use HU had greater increases in HbF expression and corresponding improvement in hematological parameters. The results of a study with polymorphisms in BCL11A and OR51B5/6, and HBS1L-MYB in 622 Brazilian sickle cell disease patients including patients with HbSC disease and SCA who were not taking HU were similar to the present study. A study of Tanzanian SCA found SNPs in HBS1L-MYB and BCL11A associated with HbF. The multivariate model shows that HBS1L-MYB, sex, HU treatment, and HbS gene haplotype modulated HbF expression. This was a crosssectional study and a determination of the change in HbF in response to HU according to SNP genotype requires prospective studies.
Perturbation of 60 S Ribosomal Biogenesis Results in Ribosomal Protein L5- and L11-dependent p53 Activation*

Ribosomal proteins play an important role in p53 activation in response to nucleolar stress. Multiple ribosomal proteins, including L5, L11, L23, and S7, have been shown to bind to and inhibit MDM2, leading to p53 activation. However, it is not clear whether ribosomal protein regulation of MDM2 is specific to some, but not all ribosomal proteins. Here we show that L29 and L30, two ribosomal proteins from the 60 S ribosomal subunit, do not bind to MDM2 and do not inhibit MDM2-mediated p53 suppression, indicating that the ribosomal protein regulation of the MDM2-p53 feedback loop is specific. Interestingly, direct perturbation of the 60 S ribosomal biogenesis by knocking down either L29 or L30 drastically induced the level and activity of p53, leading to p53-depedent cell cycle arrest. This p53 activation was drastically inhibited by knockdown of L11 or L5. Consistently, knockdown of L29 or L30 enhanced the interaction of MDM2 with L11 and L5 and markedly inhibited MDM2-mediated p53 ubiquitination, suggesting that direct perturbation of 60 S ribosomal biogenesis activates p53 via L11- and L5-mediated MDM2 suppression. Mechanistically, knockdown of L30 or L29 significantly increased the NEDDylation and nuclear retention of L11. Knocking down endogenous NEDD8 suppressed p53 activation induced by knockdown of L30. These results demonstrate that NEDDylation of L11 plays a critical role in mediating p53 activation in response to perturbation of ribosomal biogenesis.