Miracle-dz/UniFAR-FTUs huggingface dataset:
The Nonconserved Hydrophilic Loop Domain of Presenilin (PS) Is Not Required for PS Endoproteolysis or Enhanced Aβ42 Production Mediated by Familial Early Onset Alzheimer's Disease-linked PS Variants*

Presenilin 1 (PS1) and presenilin 2 (PS2) are polytopic membrane proteins that are mutated in the majority of early onset familial Alzheimer's disease (FAD) cases. Two lines of evidence establish a critical role for PS in the production of β-amyloid peptides (Aβ). FAD-linked PS mutations elevate the levels of highly amyloidogenic Aβ ending at residue 42 (Aβ42), and cells with ablated PS1 alleles secrete low levels of Aβ. Several recent reports have shown that the hydrophilic loop (HL) domain, located between transmembrane domains 6 and 7, contains sites for phosphorylation, caspase cleavage, and sequences that bind several PS-interacting proteins. In the present report, we examined the metabolism of PS polypeptides lacking the HL domain and the influence of these molecules on Aβ production. We report that the deletion of the HL domain does not have a deleterious effect on the regulated endoproteolysis of PS, saturable accumulation of PS fragments, or the self-association of PS fragments. Aβ production was not significantly altered in cells expressing HL-deleted PS polypeptides compared with cells expressing full-length PS. Importantly, deletion of the HL domain did not affect FAD mutation-mediated elevation in the production of Aβ42. Furthermore, the deletion of the HL domain did not impair the role of PS1 or PS2 in facilitating Notch processing. Thus, our results argue against a biologically or pathologically relevant role for the HL domain phosphorylation and caspase cleavage and the association of PS HL domain-interacting proteins, in amyloid precursor protein metabolism and Aβ production or Notch cleavage.
Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion

Background Split-hand/foot malformation (SHFM)—also known as ectrodactyly—is a congenital disorder characterised by severe malformations of the distal limbs affecting the central rays of hands and/or feet. A distinct entity termed SHFLD presents with SHFM and long bone deficiency. Mouse models suggest that a defect of the central apical ectodermal ridge leads to the phenotype. Although six different loci/mutations (SHFM1–6) have been associated with SHFM, the underlying cause in a large number of cases is still unresolved. Methods High resolution array comparative genomic hybridisation (CGH) was performed in patients with SHFLD to detect copy number changes. Candidate genes were further evaluated for expression and function during limb development by whole mount in situ hybridisation and morpholino knock-down experiments. Results Array CGH showed microduplications on chromosome 17p13.3, a locus previously associated with SHFLD. Detailed analysis of 17 families revealed that this copy number variation serves as a susceptibility factor for a highly variable phenotype with reduced penetrance, particularly in females. Compared to other known causes for SHFLD 17p duplications appear to be the most frequent cause of SHFLD. A ∼11.8 kb minimal critical region was identified encompassing a single gene, BHLHA9, a putative basic loop helix transcription factor. Whole mount in situ hybridisation showed expression restricted to the limb bud mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos. Knock down of bhlha9 in zebrafish resulted in shortening of the pectoral fins. Conclusions Genomic duplications encompassing BHLHA9 are associated with SHFLD and non-Mendelian inheritance characterised by a high degree of non-penetrance with sex bias. Knock-down of bhlha9 in zebrafish causes severe reduction defects of the pectoral fin, indicating a role for this gene in limb development.
Endothelial inflammatory transcriptional responses to an altered plasma exposome following inhalation of diesel emissions

Abstract Background: Air pollution, especially emissions derived from traffic sources, is associated with adverse cardiovascular outcomes. However, it remains unclear how inhaled factors drive extrapulmonary pathology. Objectives: Previously, we found that canonical inflammatory response transcripts were elevated in cultured endothelial cells treated with plasma obtained after exposure compared with pre-exposure samples or filtered air (sham) exposures. While the findings confirmed the presence of bioactive factor(s) in the plasma after diesel inhalation, we wanted to better examine the complete genomic response to investigate (1) major responsive transcripts and (2) collected response pathways and ontogeny that may help to refine this method and inform the pathogenesis. Methods: We assayed endothelial RNA with gene expression microarrays, examining the responses of cultured endothelial cells to plasma obtained from six healthy human subjects exposed to 100 μg/m3 diesel exhaust or filtered air for 2 h on separate occasions. In addition to pre-exposure baseline samples, we investigated samples obtained immediately-post and 24 h-post exposure. Results: Microarray analysis of the coronary artery endothelial cells challenged with plasma identified 855 probes that changed over time following diesel exhaust exposure. Over-representation analysis identified inflammatory cytokine pathways were upregulated both at the 2 and 24 h conditions. Novel pathways related to FOXO transcription factors and secreted extracellular factors were also identified in the microarray analysis. Conclusions: These outcomes are consistent with our recent findings that plasma contains bioactive and inflammatory factors following pollutant inhalation and provide a novel pathway to explain the well-reported extrapulmonary toxicity of ambient air pollutants.
Resampling the N9741 trial to compare tumor dynamic versus conventional end points in randomized phase II trials.

PURPOSE The optimal end point for randomized phase II trials of anticancer therapies remains controversial. We simulated phase II trials by resampling patients from N9741, a randomized phase III trial of chemotherapy regimens for metastatic colorectal cancer, and compared the power of various end points to detect the superior therapy (FOLFOX [infusional fluorouracil, leucovorin, and oxaliplatin] had longer overall survival than both IROX [irinotecan plus oxaliplatin] and IFL [irinotecan and bolus fluorouracil plus leucovorin]). METHODS Tumor measurements and progression-free survival (PFS) data were obtained for 1,471 patients; 1,002 had consistently measured tumors and were resampled (5,000 replicates) to simulate two-arm, randomized phase II trials with α = 0.10 (one sided) and 20 to 80 patients per arm. End points included log ratio of tumor size at 6, 12, and 18 weeks relative to baseline; time to tumor growth (TTG), estimated using a nonlinear mixed-effects model; and PFS. Arms were compared using rank sum tests for log ratio and TTG and a log-rank test for PFS. RESULTS For FOLFOX versus IFL, TTG and PFS had similar power, with both exceeding the power of log ratio at 18 weeks; for FOLFOX versus IROX, TTG and log ratio at 18 weeks had similar power, with both exceeding the power of PFS. The best end points exhibited > 80% power with 60 to 80 patients per arm. CONCLUSION TTG is a powerful end point for randomized phase II trials of cytotoxic therapies in metastatic colorectal cancer; it was either comparable or superior to PFS and log ratio at 18 weeks. Additional studies will be needed to clarify the potential of TTG as a phase II end point.
Viroids with Hammerhead Ribozymes: Some Unique Structural and Functional Aspects with Respect to Other Members of the Group

Abstract Viroids, subviral pathogens of plants, are composed of a single-stranded circular RNA of 246–399 nucleotides. Within the 27 viroids sequenced, avocado sunblotch, peach latent mosaic and chrysanthemum chlorotic mottle viroids (ASBVd, PLMVd and CChMVd, respectively) can form hammerhead structures in both of their polarity strands. These ribozymes mediate self-cleavage of the oligomeric RNAs generated in the replication through a rolling circle mechanism, whose two other steps are catalyzed by an RNA polymerase and an RNA ligase. ASBVd, and presumably PLMVd and CChMVd, replicate and accumulate in the chloroplast, whereas typical viroids replicate and accumulate in the nucleus. PLMVd and CChMVd do not adopt a rod-like or quasi rod-like secondary structure as typical viroids do but have a highly branched conformation. A pathogenicity determinant has been mapped in a defined region of the CChMVd molecule.
Stock Return Predictability: Using the Cyclical Component of the Price Ratio

Abstract We examine whether the cyclical component of the log dividend-price and price-earnings ratios contain forecast power for stock returns. While the levels of these series contain slow moving information for predicting long horizon returns, they typically provide poor short horizon forecasts. Using three approaches to extract the ratios cyclical component, we conduct several in- and out-of-sample tests. In-sample estimation using the cyclical component leads to economically sensible values, as well as an improved fit compared to the ratio level results. Out-of-sample evidence reveals forecast improvement over a historical mean model, although this varies according to the metric used. The historical mean model is preferred using mean absolute and squared error measures, but the predictive models perform better using Mincer-Zarnowitz and encompassing regressions. Using economic based forecast evaluation, the predictive models are clearly preferred, with a stronger ability to predict the future direction of return movements and with higher trading returns. A further examination of the results reveal that this greater performance largely arises from a superior ability to predict future negative returns.
The columnar-lined (Barrett's) oesophagus in black patients.

OBJECTIVE To determine the prevalence of a columnar-lined Barrett's oesophagus in black patients. DESIGN In the present study we retrospectively reviewed the records of all black patients with Barrett's oesophagus. SETTING Johannesburg Hospital's referral-based oesophageal clinic. SUBJECTS Eleven black patients with Barrett's oesophagus from a series of 216 consecutive patients with Barrett's oesophagus who were referred to the oesophageal clinic from 1970 to 1993. MAIN OUTCOME MEASURES Prevalence, demographics and characteristics of black patients with a columnar-lined Barrett's oesophagus. RESULTS Only 5% of the total series of Barrett's patients were black. Because the ratio of black to white in Johannesburg is about 5:1, the comparative prevalence of Barrett's oesophagus in blacks is extremely low when compared with that of whites. Although the number of patients is small, this series demonstrates that a columnar-lined oesophagus does occur in blacks. When compared with Caucasians, blacks had far fewer associated hiatus hernias (33%). The presentation of blacks is also different in that a greater proportion presented with adenocarcinoma (36%). CONCLUSIONS Gastro-oesophageal reflux and related conditions such as a columnar-lined oesophagus are uncommon conditions in African blacks. This series demonstrates however that a columnar-lined oesophagus does occur in black patients. It is possible that in black patients an inherent defect of the lower oesophageal sphincter rather than a hiatus hernias is the cause of the reflux. A greater proportion of this small group of patients presented with adenocarcinoma than would have been expected. The reasons for the low prevalence of Barrett's oesophagus in black South Africans are unknown.
Carbon Dioxide Emissions and Crop Production: Finding A Sustainable Balance

Amidst fears of food insecurity in Africa and climate change challenges to economic growth, the study observes the trend of carbon dioxide emissions and crop production with an objective to contribute to the body of knowledge, the empirical investigation of the nature of relationship existing between them. The fully modified ordinary least squares (FMOLS) method (with some pre-estimation and post-estimation tests) was adopted given the order of stationarity integration of the variables in the model. The result showed that there exists a positive significant long-run relationship between the two variables. This implies that carbon dioxideemissions and crop production over time associated with crop productivity and further contributes to the achievement of the goal two of the sustainable development goals (SDGs) 2, 3, 7 and 9.
Liver‐targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis

CD4+CD25high regulatory T cells (Tregs) play a critical role in self‐tolerance, as seen in murine autoimmunity. Studies on Tregs in human autoimmunity have focused primarily on peripheral blood samples. A study targeting diseased tissue should identify direct relationships between Tregs and autoimmunity. Peripheral blood samples were collected from 91 patients with primary biliary cirrhosis (PBC), 28 immediate relatives, and 41 healthy controls, and Treg frequencies were determined as a percentage of CD4+CD25high T cells in CD4+TCR‐αβ+ T cells. A tissue‐targeted determination of frequency and distribution of FoxP3+ Tregs was also performed on 90 different liver tissue specimens exhibiting PBC (n = 52), chronic hepatitis C (CHC) (n = 30), and autoimmune hepatitis (AIH) (n = 8). Treg suppression studies were performed on 50 PBC patients and 27 controls. Patients with PBC demonstrated a relative reduction of Tregs compared with controls (P < .0002). Interestingly, a deficiency in CD4+CD25+ Tregs was also found in the daughters and sisters of PBC patients compared with controls (P < .0007). However, functional studies did not reveal a global PBC Treg defect. The level of FoxP3‐expressing Tregs was markedly lower in affected PBC portal tracts compared with CHC and AIH (P < .001). In addition, the CD8+T cell/FoxP3+ Treg ratio was significantly higher in livers of late‐stage PBC compared with those of CHC (P < .001) and early‐stage AIH (P < .001). In conclusion, these data provide support for a genetic modulation of Treg frequency and illustrate the role Tregs play in the loss of tolerance in PBC. (HEPATOLOGY 2006;43:729–737.)
Characterization of diaper dermatitis in the United States.

BACKGROUND Diaper dermatitis is the most common dermatologic disorder of infancy. This study evaluates the frequency of outpatient visits resulting in this diagnosis, specialties of physicians providing services, demographics of patients, and leading agents used in treatment. DESIGN Records of 272,841 encounters from the National Ambulatory Medical Care Survey (1990-1997) were examined for visits in which diaper dermatitis was diagnosed in children. The likelihood of diagnosis in the general pediatric population was calculated and the leading treatment agents were ranked. RESULTS There were approximately 8.2 million visits in which diaper dermatitis was diagnosed. For the pediatric population in the at-risk age range, there was a 1 in 4 likelihood of being diagnosed with the skin disorder. Pediatricians provided 75% of services for the treatment of diaper dermatitis; the demographics of patients were similar to those of comparably aged individuals in the general population. Nystatin was the leading treatment agent prescribed (27% of visits), followed by clotrimazole (16%), a combination product of nystatin and triamcinolone (16%), hydrocortisone (8%), and a combination product of clotrimazole and betamethasone dipropionate (6%). CONCLUSIONS Visits for diaper dermatitis are frequent, and pediatricians are the physicians most often called on to provide treatment. No portion of the pediatric population is disproportionately diagnosed. The frequent use of potent corticosteroids contained in combination agents is a potential target for improving the management of diaper dermatitis.
A matter of control or identity? Family firms' environmental reporting decisions along the corporate life cycle

Building on the socioemotional wealth (SEW) perspective, this study explores environmental disclosure (ED) practices in family firms and investigates whether the firm's life cycle stage plays a moderating role in these practices. We focus on two dimensions of the SEW: family control and influence and family identity. To the extent that different types of family‐controlled firms have different reporting behaviors based on their primary SEW dimension, they will undertake the ED strategies that allow them to preserve their SEW. Using a sample of listed firms from the Milan Stock Exchange, we show that family firms for which the family control and influence SEW dimension is most salient provide less environmental information than non‐family firms and that this effect is weakened along the family firm's life cycle. Our findings also indicate that middle‐aged family firms, where the family identity dimension prevails, provide more ED than do non‐family firms. Our study contributes to knowledge about how the socioemotional endowment affects family firms' reporting behavior.
Clinical manifestations and treatment outcomes in HIV-1-infected children receiving antiretroviral therapy in Karachi, Pakistan.

INTRODUCTION The impact of antiretroviral (ARV) therapy on immunological and growth parameters in HIV-positive children in Pakistan has not been reported to date. METHODOLOGY A retrospective chart review of children diagnosed with HIV at the Sindh AIDS Control Proigramme (SACP) and registered at the Aga Khan University, Karachi, between January 2005 and 2013 was conducted, evaluating clinical and laboratory profiles of HIV+ ARV+ children for ARV impact (serial height and weight CD4 and viral counts). RESULTS Twenty-four children were diagnosed and registered as HIV positive over five years, and 20 were started on ARV. Six were excluded from analysis (ARV duration < 6 months). Nine (64.3%) of 14 fulfilled WHO criteria for treatment failure at a median duration of 25 weeks (IQR 18-32) on ARV and underwent resistance genotyping. All nine had NNRTI resistance, two had high-grade NRTI resistance (≥ 4 thymidine analog mutations). Median age at start of ARV was 71.5 weeks (IQR 37.5-119). Median baseline weight for age (WAZ) and height for age (HAZ) z-scores changed from -1.94 to 1.69 and -1.99 to -1.59, respectively, after six months of therapy. Median CD4 percentage and viral load at baseline changed from 13.8 to 17.8, while viral load changed from 285 × 104 copies to zero at six months. CONCLUSIONS ARV improved absolute CD4 and viral counts. Weight and height did not improve significantly, highlighting the need for aggressive nutritional rehabilitation. Early development of ARV resistance in these children requires formal assessment.
Randomized double-blind study of remifentanil and dexmedetomidine for flexible bronchoscopy.

BACKGROUND The safety profiles and efficacies of remifentanil and dexmedetomidine (a sedative-analgesic without respiratory depression) for sedation during flexible bronchoscopy were investigated. METHODS Seventy-two patients undergoing elective flexible bronchoscopy were randomly assigned to a propofol-remifentanil group (Group PR, n=36) or a propofol-dexmedetomidine group (Group PD, n=36). The primary outcome was the incidence of oxygen desaturation. Haemodynamic variables, adverse events, need of oral cavity suction, cough scores, satisfaction scores of patients and bronchoscopists, levels of sedation, and recovery times were also compared. RESULTS The incidence of oxygen desaturation was significantly lower in the PD group than in the PR group (P=0.01). There were no significant differences between groups in terms of level of sedation, oxygen saturation, mean arterial pressure, heart rate over time, cough scores, or patient satisfaction scores (P>0.05). However, cough scores and bronchoscopist satisfaction scores (P<0.01) were lower in the PD group. In addition, topical anaesthesia (P<0.01) was required more frequently and recovery time (P=0.00) was significantly longer in the PD group. However, oral suction (P=0.03) was required less frequently in the PD group. CONCLUSIONS Dexmedetomidine was associated with fewer incidents of oxygen desaturation and a reduced need for oral cavity suction than remifentanil during flexible bronchoscopy. However, dexmedetomidine was associated with a longer recovery time and poorer bronchoscopist satisfaction score.
Does nocturnal blood pressure fall in people of African and South Asian descent differ from that in European white populations? A systematic review and meta-analysis

Objective To assess whether nocturnal blood pressure fall in people of African (Black) and South Asian descent differs from that of the European origin white populations (White). Methods A systematic literature review was carried out using Medline 1966–2003 and Embase 1980–2003, and citations from references. The meta-analysis was performed using Cochrane review manager software (RevMan version 4.2; The Cochrane Collaboration, Oxford, UK). Results Seventeen studies were identified; 11 studies from the USA, one from the USA and Canada, and six studies from the United Kingdom. The mean percentage systolic blood pressure (SBP) nocturnal fall was below 10% (non-dipping) in 10 of 17 studies (59%) and the diastolic blood pressure (DBP) nocturnal fall was below 10% in four of 16 studies (25%) in Blacks compared with four of 17 studies (24%) in SBP and none in DBP nocturnal falls in Whites. Compared with Whites, Blacks had a significantly lower mean percentage nocturnal fall; the overall weighted mean difference in SBP was −3.07 (95% confidence interval, −3.81, −2.33; P < 0.00001) and in DBP was −2.98 (95% confidence interval, −3.97, −2.00; P < 0.00001). Two studies on South Asians showed a higher SBP but a similar mean DBP nocturnal fall compared with Whites. Conclusion Smaller nocturnal blood pressure falls and a higher prevalence of non-dipping may contribute to the higher levels of hypertension complications seen in Black people. No such phenomenon was seen in South Asians but more research is needed to explore their higher stroke mortality.