Miracle-dz/UniFAR-FTUs huggingface dataset:
Single base‐pair substitutions in exon–intron junctions of human genes: nature, distribution, and consequences for mRNA splicing

Although single base‐pair substitutions in splice junctions constitute at least 10% of all mutations causing human inherited disease, the factors that determine their phenotypic consequences at the RNA level remain to be fully elucidated. Employing a neural network for splice‐site recognition, we performed a meta‐analysis of 478 disease‐associated splicing mutations, in 38 different genes, for which detailed laboratory‐based mRNA phenotype assessment had been performed. Inspection of the ±50‐bp DNA sequence context of the mutations revealed that exon skipping was the preferred phenotype when the immediate vicinity of the affected exon–intron junctions was devoid of alternative splice‐sites. By contrast, in the presence of at least one such motif, cryptic splice‐site utilization, became more prevalent. This association was, however, confined to donor splice‐sites. Outside the obligate dinucleotide, the spatial distribution of pathological mutations was found to differ significantly from that of SNPs. Whereas disease‐associated lesions clustered at positions –1 and +3 to +6 for donor sites and –3 for acceptor sites, SNPs were found to be almost evenly distributed over all sequence positions considered. When all putative missense mutations in the vicinity of splice‐sites were extracted from the Human Gene Mutation Database for the 38 studied genes, a significantly higher proportion of changes at donor sites (37/152; 24.3%) than at acceptor splice‐sites (1/142; 0.7%) was found to reduce the neural network signal emitted by the respective splice‐site. Based upon these findings, we estimate that some 1.6% of disease‐causing missense substitutions in human genes are likely to affect the mRNA splicing phenotype. Taken together, our results are consistent with correct donor splice‐site recognition being a key step in exon recognition. Hum Mutat 28(2), 150–158, 2007. © 2006 Wiley‐Liss, Inc.
High-dose intravenous immunoglobulin (IVIG) adjuvant therapy for cell-mediated pancreas transplant rejection.

1. Heidt DG, Burant C, Simeone DM. Total pancreatectomy: indications, operative technique, and postoperative sequelae. J Gastrointest Surg 2007; 11: 209. 2. Balcom JHT, Rattner DW, Warshaw AL, et al. Ten-year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization. Arch Surg 2001; 136: 391. 3. Bramis K, Gordon-Weeks AN, Friend PJ, et al. Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Br J Surg 2012; 99: 761. 4. Muchova L, Vanova K, Zelenka J, et al. Bile acids decrease intracellular bilirubin levels in the cholestatic liver: implications for bile acid-mediated oxidative stress. J Cell Mol Med 2011; 15: 1156. 5. Drews G, Krippeit-Drews P, Dufer M. Oxidative stress and beta-cell dysfunction. Pflugers Arch 2010; 460: 703. 6. Acharya JD, Ghaskadbi SS. Islets and their antioxidant defense. Islets 2010; 2: 225. 7. Perez MJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol 2009; 15: 1677.
Carbon monoxide has direct toxicity on the myocardium distinct from effects of hypoxia in an ex vivo rat heart model.

OBJECTIVES Carbon monoxide (CO) toxicity causes significant central nervous system and cardiac injury. Although the neurological damage caused by CO toxicity is extensively described, the mechanisms underlying myocardial insult are unclear. The authors used an externally perfused isolated rat heart model to examine the effects of a physiological saline solution (Krebs Henseleit HEPES, KHH) aerated with CO on cardiac function. METHODS Fifteen rats were equally divided into three groups: the control group (KHH + 100% O(2)), the nitrogen control group (KHH + 70% O(2), 30% N(2)), and the CO group (KHH + 70% oxygen, 30% CO). Left ventricular peak systolic pressure (LVPsP), end diastolic pressure (LVEdP), and coronary perfusion pressure were measured while the isolated heart was paced and perfused on a modified Langendorf apparatus. RESULTS Left ventricular generated pressure (LVGP = LVPsP - LVEdP) decreased in the nitrogen control and CO groups compared to the control group. There was higher LVGP in the recovery phase between the nitrogen control group compared to the CO group. Both groups had increased lactic acid levels in the experimental phase. CONCLUSIONS Carbon monoxide with hypoxia and hypoxemic hypoxia both result in similar depression of cardiac function. Hearts poisoned with CO with hypoxia do not recover function to the extent that hearts rendered hypoxic with nitrogen do when perfused with 100% oxygen after the insult. This suggests that CO causes direct myocardial toxicity distinct from the effects of hypoxia.
Plasmin accelerates platelet‐dependent prothrombinase formation without activating the platelets

Patients with acute myocardial infarction who undergo thrombolytic therapy may shortly thereafter present evidence for increased platelet activation and thrombin activity, and recurrent thrombosis. This study investigated whether plasmin activates platelets and prothrombin in recalcified platelet‐rich plasma (RPRP) to cause (at least in part) these side‐effects of thrombolytic therapy. Plasmin (0.1 and 1.0 CU/ml) addition to RPRP with 1 μM r‐tick anticoagulant peptide (the latter a factor Xa inhibitor which abrogates prothrombin activation by prothrombinase at the concentration used) resulted in no change in the concentration of prothrombin fragment 1 + 2, or in the expression of GMP‐140, the resting and activated GP IIb–IIIa conformers, and GPIb on platelets. Thus, plasmin neither activates platelets nor prothrombin in RPRP. However, plasmin accelerated platelet activation and secretion, and prothrombin fragment 1 + 2 production in RPRP. When combined with 1 μM r‐tick anticoagulant peptide and 1 or 10 nMα‐thrombin to RPRP, plasmin also increased the number of GMP‐140 molecules expressed/platelet without enhancing α‐thrombin binding to the platelets. Additionally, plasmin accelerated prothrombin activation when it was added to washed platelets resuspended in factor V depleted plasma simultaneously with 10 mM CaCl2, 10 nMα‐thrombin for 10 s (to activate platelets and platelet factor V), followed by 4 μM hirudin and 1 nM factor Xa. Thus, plasmin potentiates the platelet release reaction in response to α‐thrombin (probably by increasing the availability of factor V on the platelets) to enhance prothrombin activation in RPRP. These actions of plasmin may contribute to the increased platelet activation and thrombotic side‐effects that can occur after thrombolytic therapy.
Liver Transplantation for Children With Primary Sclerosing Cholangitis and Autoimmune Hepatitis: UNOS Database Analysis

Objectives: Autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are progressive immune-mediated inflammatory diseases that may require liver transplant (LT). Outcomes in children undergoing LT for these diseases are poorly studied in the pediatric end-stage liver disease era. We aimed to characterize the outcome of LT in children with AIH and PSC. Methods: Children 18 years or younger with PSC or AIH who had a first, isolated LT from 2002 to 2012 were identified from the United Network for Organ Sharing database. Graft and patient outcomes were studied. Results: A total of 174 children with AIH and 113 with PSC were transplanted in the study period. One-year patient survival was 95.4% for AIH and 97.3% for PSC. Five-year patient survival was 91.4% for AIH and 92.9% for PSC. Patient survival was not significantly different between the 2 groups. Forty-four (25.2%) children with AIH were listed as status 1 for transplant (fulminant hepatic failure at presentation or acute-on-chronic disease). Patients transplanted as status 1 had significantly lower patient survival compared with patients transplanted with AIH and end-stage liver disease. The one- and five-year graft survival rates were not significantly different between patients with AIH and PSC. Conclusion: Children with AIH transplanted as status 1 had significantly lower patient survival rates but similar graft survival rates to children with chronic AIH. Children transplanted for AIH versus PSC showed no significant differences in patient or graft survival at both 1 and 5 years.
Effects of different control strategies of distributed generation on the equivalent output impedance of the grid-connected inverter

This paper focuses on the effects of different control strategies of the distributed generations (DG) on the equivalent output impedance of the grid-connected inverter under different operating conditions of microgrid. For grid-connected inverter with LCL filter, two equivalent impedance models using PQ and V/f control were deduced in detail respectively, meanwhile the spectrum response curves of these two kinds of impedance under typical parameters were drawn. The different characteristics of the inverter output impedances between PQ control mode and V/f control mode were compared and analyzed. Finally, under the situation of grid-connected and islanded operation of microgrid, simulation researches of DG equivalent impedance with and without consideration of the inverter control mode on the current harmonic characteristics of each node were carried out, and the validity of the proposed method was verified.
Acetylcholine Liberation from Cerebral Cortex during Paradoxical (REM) Sleep

The rate of liberation of free acetylcholine from the surface of prostigmin-treated cerebral cortex in the freely moving cat has been determined in states of slow wave sleep, paradoxical or activated sleep, and waking. The average rate during slow wave sleep (1.2 nanograms per minute per square centimeter of cortical surface) increased during paradoxical sleep (2.2 nanograms per minute) and during waking (2.1 nanograms per minute). The rate of acetylcholine release is thus related to the electroencephalogram pattern of desynchronized activatin of the cortex rahter than to the behavioral responsiveness of the animals.
Design and Performance of a High Temperature Superconducting Axial Flux Generator

In this paper, a high temperature axial flux (HTSAF) generator is presented. In this generator the excitation of the generator is obtained by using some high temperature superconducting magnets. In order to reduce the negative effects of vibrations, the excitation is located on the stationary part of the generator. Starting, running and endurance tests of the machine are presented.
The security, privacy, and ethical implications of social networking sites

The chapter investigates the security and ethical issues relating to privacy and security. This chapter also examines the ethical issues of new forms of bullying that are being played out weekly in the media: cyber bulling, specifically on SNS such as Facebook. The traditional and direct forms of bullying are being replaced by consistent abuse via SNS due to the ease and accessibility of these new forms of communications.
Predischarge occupational therapy home assessment visits: towards an evidence base.

BACKGROUND/AIM Predischarge home assessment visits are a commonly accepted, but little researched, aspect of occupational therapy practice. The aim of this research was to systematically investigate current predischarge occupational therapy home assessment visit practices in a rehabilitation ward of a regional Australian hospital. METHODS A retrospective chart audit was conducted over a 7-month time period and included 227 patients discharged from the inpatient rehabilitation ward at the study hospital. RESULTS Fifty-five per cent of patients in the study sample received home assessment visits. At least one recommendation for change was made as a result of the visit for 99% of those patients receiving visits. A total of 139 visits were completed and resulted in 1179 recommendations for change. The median number of recommendations made for the home assessment visits was 10 (range 0-33). The most common types of recommendations, timing of visits, persons present during the visit and documentation of visits were also investigated. CONCLUSION Although occupational therapy home assessment visits are routinely completed, there is limited research available to provide evidence-based guidelines relating to predischarge occupational therapy home assessment visit practices. Recommendations for future practice and areas for further research into occupational therapy home assessment visits are discussed.
Writing Therapy for Posttraumatic Stress: A Meta-Analysis

Background: Face-to-face psychological treatments have difficulty meeting today’s growing mental health needs. For the highly prevalent posttraumatic stress (PTS) conditions, accumulating evidence suggests that writing therapy may constitute an efficient treatment modality, especially when administered through the Internet. We therefore conducted a meta-analysis to investigate the efficacy of writing therapies for PTS and comorbid depressive symptoms. Methods: The literature was searched using several structured and unstructured strategies, including key word searches of the PubMed, Web of Science, PsycINFO, and PILOTS databases. Six studies met eligibility criteria and were included in the analyses. These studies included a total of 633 participants, of which 304 were assigned to writing therapy. Results: Across 5 direct comparisons of writing therapy to waiting-list control, writing therapy resulted in significant and substantial short-term reductions in PTS and comorbid depressive symptoms. There was no difference in efficacy between writing therapy and trauma-focused cognitive behavioral therapy, but we caution that this finding was based on only 2 direct comparisons. Conclusions: Writing therapy is an evidence-based treatment for PTS, and constitutes a useful treatment alternative for patients who do not respond to other evidence-based treatments. Internet adaptations of writing therapy for PTS may be especially useful for reaching trauma survivors in need of evidence-based mental health care who live in remote areas or who prefer to retain their anonymity.
Biological Actions of Leukotrienes: State of the Art Lecture

Leukotrienes are novel mediators derived from arachidonic acid through the 5-lipoxygenase enzyme system. Leukotriene B4 has potent effects on leukocyte function and in vivo induces leukocyte accumulation and changes in vascular permeability and modulates pain responses. Peptidolipid leukotrienes are potent smooth muscle-contracting agents. They may have important cardiovascular actions through mechanisms involving either vasoconstriction or indirect vasodilatation. Evidence for leukotriene production has been found in subjects with allergic conditions and psoriasis, indicating a putative role for these substances in human disease.
The research on the comprehensive model of the evolving trade network

Based on the results of the fact — finding visit, this paper established a comprehensive directed weighted evolving network model that integrated fitness-based preferential attachment, node deletion, link establishment and link deletion, and performed analytical deductions. Then the in-strength distribution index is taken as the main object of study, this paper validated the model respectively when the node fitness is homogenesis, when the node fitness is chosen from the [0, 1] uniform distribution, and when the node fitness is chosen from the exponential distribution. Finally, this paper analyzed the influence of different mechanism of evolution to the power law index, and validated the model with numerical simulations.
Molecular correlates of gefitinib responsiveness in human bladder cancer cells

We characterized the effects of the small molecule epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839, Iressa) on cell proliferation in a panel of 17 human bladder cancer cell lines. Gefitinib inhibited DNA synthesis in a concentration-dependent fashion in 6 of 17 lines. Growth inhibition was associated with p27Kip1 accumulation and decreased cyclin-dependent kinase 2 activity. Gefitinib also inhibited baseline EGFR, AKT, and extracellular signal-regulated kinase (ERK) phosphorylation in the EGFR-dependent cells maintained in serum-free medium, whereas it had no effect on baseline EGFR or ERK phosphorylation in the EGFR-independent cells. Analyses of candidate markers of EGFR dependency revealed that the gefitinib-sensitive cells expressed higher surface EGFR levels than the gefitinib-resistant lines. Gefitinib-sensitive cells generally expressed higher levels of E-cadherin and lower levels of vimentin than the gefitinib-resistant cells, but these correlations were not perfect, suggesting that these markers of epithelial-mesenchymal transition cannot be used by themselves to prospectively predict EGFR-dependent growth. Together, our results show that bladder cancer cells are markedly heterogeneous with respect to their sensitivity to EGFR antagonists. Although surface EGFR levels and epithelial-mesenchymal transition status seem to roughly correlate with responsiveness, they cannot be used by themselves to identify bladder tumors that will be sensitive to EGFR-directed therapy. However, comparing levels of p27Kip1 or DNA synthesis before and after gefitinib exposure does identify the drug-sensitive cells. [Mol Cancer Ther 2007;6(1):277–85]
The Effect of Spillover on Volatility Forecasting: An Empirical Study in Indian Stock Market

In this article, we have investigated whether the precision of one-step-ahead forecast of the market volatility can be improved by incorporating the spillover effect of other markets. For this, we have used the MGARCH model and shown empirically that if the group of markets is chosen judiciously so as to avoid multicollinearity, then it is indeed possible to obtain better forecasts. For this purpose, we have employed a BEKK parameterization of MGARCH models on the daily data of 10 sectors of the Bombay Stock Exchange (BSE).
Cells Comprising the Prostate Cancer Microenvironment Lack Recurrent Clonal Somatic Genomic Aberrations

Prostate cancer–associated stroma (CAS) plays an active role in malignant transformation, tumor progression, and metastasis. Molecular analyses of CAS have demonstrated significant changes in gene expression; however, conflicting evidence exists on whether genomic alterations in benign cells comprising the tumor microenvironment (TME) underlie gene expression changes and oncogenic phenotypes. This study evaluates the nuclear and mitochondrial DNA integrity of prostate carcinoma cells, CAS, matched benign epithelium and benign epithelium–associated stroma by whole-genome copy-number analyses, targeted sequencing of TP53, and FISH. Array comparative genomic hybridization (aCGH) of CAS revealed a copy-neutral diploid genome with only rare and small somatic copy-number aberrations (SCNA). In contrast, several expected recurrent SCNAs were evident in the adjacent prostate carcinoma cells, including gains at 3q, 7p, and 8q, and losses at 8p and 10q. No somatic TP53 mutations were observed in CAS. Mitochondrial DNA (mtDNA) extracted from carcinoma cells and stroma identified 23 somatic mtDNA mutations in neoplastic epithelial cells, but only one mutation in stroma. Finally, genomic analyses identified no SCNAs, LOH, or copy-neutral LOH in cultured cancer-associated fibroblasts, which are known to promote prostate cancer progression in vivo. Implications: The gene expression changes observed in prostate cancer–adjacent stroma and the attendant contribution of the stroma to the development and progression of prostate cancer are not due to frequent or recurrent genomic alterations in the TME. Mol Cancer Res; 14(4); 374–84. ©2016 AACR.
Delay in Sexual Maturity of the Follicle-Stimulating Hormone Receptor Knockout Male Mouse1

Abstract In the highly organized and complex process of mammalian spermatogenesis, the development of an undifferentiated diploid germ cell into a fully differentiated and mature spermatozoon is orchestrated in a time frame unique for each species including man. If the various hormonal signals including environmental cues that play a critical part in initiating these events are not properly executed, various deficiencies including delay in sexual maturity or puberty are likely. In this study we have followed testicular development and spermatogenesis in the FSH receptor knockout (FORKO) mice from Day 7 onward by using histology and quantitative DNA flow cytometry. The drastic reduction in testicular weight and shrinkage of seminiferous tubules that occurred at this early age persisted into the adult stage in the FORKOs, suggesting inhibition of the initial developmental processes. The round spermatids that were clearly abundant on Day 21 in the wild-type and heterozygous males were few and present only in some tubules of the FORKOs. There were no elongated spermatids in FORKO males on Day 35. The sperm produced by Day 49 FORKOs were already aberrant, a feature that persisted into adulthood in these animals. As all these changes occurred in a background of normal circulating testosterone levels, we may conclude that the delay in testicular development is a consequence of the loss of FSH-receptor signaling. The delay in sexual maturity of FORKOs was accompanied by reduction in fertility as evidenced by mating studies. Based on these data we suggest that the FORKO mouse might be a useful experimental model to define the molecular mechanisms that underlie the delay in puberty.
Comparison of the effect of coagulation and platelet function impairments on various mouse bleeding models

Summary Haemostatic impairments are studied in vivo using one of several murine bleeding models. However it is not known whether these models are equally appropriate for assessing coagulation or platelet function defects. It was our study objective to assess the performance of arterial, venous and combined arterial and venous murine bleeding models towards impaired coagulation or platelet function. Unfractionated heparin (UFH) or αIIbβ3 inhibitory antibody (Leo.H4) were administered to mice, and their effects on bleeding in saphenous vein, artery, and tail tip transection models were quantified and correlated with their effects on plasma clotting and ADP-induced platelet aggregation, respectively. All models exhibited similar sensitivity with UFH (EC50 dose = 0.19, 0.13 and 0.07 U/g, respectively) (95% CI = 0.14 – 0.27, 0.08 – 0.20, and 0.03 – 0.16 U/g, respectively). Maximal inhibition of ex vivo plasma clotting could be achieved with UFH doses as low as 0.03 U/g. In contrast, the saphenous vein bleeding model was less sensitive to αIIbβ3 inhibition (EC50 = 6.9 µg/ml) than tail transection or saphenous artery bleeding models (EC50 = 0.12 and 0.37 µg/ml, respectively) (95% CI = 2.4 – 20, 0.05 – 0.33, and 0.06 – 2.2 µg/ml, respectively). The EC50 of Leo.H4 for ADP-induced platelet aggregation in vitro (8.0 µg/ml) was at least 20-fold higher than that of the tail and arterial, but not the venous bleeding model. In conclusion, venous, arterial and tail bleeding models are similarly affected by impaired coagulation, while platelet function defects have a greater influence in models incorporating arterial injury.