Miracle-dz/UniFAR-FTUs huggingface dataset:
Arg260‐Cys mutation in severe factor XIII deficiency: conformational change of the A subunit is predicted by molecular modelling and mechanics

To explore the implications of the structure/function relationships in factor XIII, a patient with severe A subunit deficiency was examined at the DNA and RNA levels. Nucleotide sequence analysis of the patient's DNA amplified by PCR revealed that the patient had a replacement of C by T in the codon for Arg260. RT‐PCR analysis demonstrated that only one kind of mRNA coding for the Arg260‐Cys mutation was expressed in the patient at a normal level. Another possible defective allele of the A subunit gene with a G‐A polymorphism was not expressed (null allele). The substitution of Arg260 by Cys located on the interface of two A subunits would preclude the reciprocal ionic interaction (salt bridge) between Arg260 and Asp404. Molecular modelling and, for the first time, molecular mechanics calculated that Cys260 changed the local conformation of the A subunit and reduced the electrostatic interaction between two monomers, suggesting destabilization of the molecule's dimer.
Functional properties of the ryanodine receptor type 3 (RyR3) Ca2+ release channel

Single‐channel analysis of sarcoplasmic reticulum vesicles prepared from diaphragm muscle, which contains both RyR1 and RyR3 isoforms, revealed the presence of two functionally distinct ryanodine receptor calcium release channels. In addition to channels with properties typical of RyR1 channels, a second population of ryanodine‐sensitive channels with properties distinct from those of RyR1 channels was observed. The novel channels displayed close‐to‐zero open‐probability at nanomolar Ca2+ concentrations in the presence of 1 mM ATP, but were shifted to the open conformation by increasing Ca2+ to micromolar levels and were not inhibited at higher Ca2+ concentrations. These novel channels were sensitive to the stimulatory effects of cyclic adenosine 5′‐diphosphoribose (cADPR). Detection of this second population of RyR channels in lipid bilayers was always associated with the presence of the RyR3 isoform in muscle preparations used for single‐channel measurements and was abrogated by the knockout of the RyR3 gene in mice. Based on the above, we associated the novel population of channels with the RyR3 isoform of Ca2+ release channels. The functional properties of the RyR3 channels are in agreement with a potential qualitative contribution of this channel to Ca2+ release in skeletal muscle and in other tissues.
Decoding the Molecular Evolution of Human Cognition Using Comparative Genomics

Identification of genetic and molecular factors responsible for the specialized cognitive abilities of humans is expected to provide important insights into the mechanisms responsible for disorders of cognition such as autism, schizophrenia and Alzheimer's disease. Here, we discuss the use of comparative genomics for identifying salient genes and gene networks that may underlie cognition. We focus on the comparison of human and non-human primate brain gene expression and the utility of building gene coexpression networks for prioritizing hundreds of genes that differ in expression among the species queried. We also discuss the importance of and methods for functional studies of the individual genes identified. Together, this integration of comparative genomics with cellular and animal models should provide improved systems for developing effective therapeutics for disorders of cognition.
Activation of the platelet‐derived growth factor receptor by the bovine papillomavirus E5 transforming protein.

The bovine papillomavirus E5 gene encodes a 44 amino acid membrane‐associated protein that can induce tumorigenic transformation of rodent fibroblast cell lines. Genetic studies suggest that the E5 protein may transform cells by influencing the activity of cellular proteins involved in growth regulation. We report here that the endogenous cellular beta type receptor for the platelet‐derived growth factor (PDGF) is constitutively activated in C127 and FR3T3 cells stably transformed by the E5 protein, but not in these cell types transformed by a variety of other oncogenes. In C127 cells, a metabolic precursor as well as the mature form of the receptor is activated by E5 transformation. Activation of the receptor also occurs upon acute E5‐mediated transformation of these cells and precedes mitogenic stimulation in this system. Moreover, activation of the receptor by addition of PDGF or the v‐sis gene to untransformed cells is sufficient to induce DNA synthesis and stable growth transformation. We propose that the PDGF receptor is an important cellular intermediate in the transforming activity of the bovine papillomavirus E5 protein. There is a short region of sequence similarity between the fibropapillomavirus E5 proteins and PDGF, suggesting that the E5 proteins may activate the PDGF receptor by binding directly to it.
Efficacy of Caspofungin Addition to Trimethoprim-Sulfamethoxazole Treatment for Severe Pneumocystis Pneumonia in Solid Organ Transplant Recipients

Background. Pneumocystis jiroveci pneumonia may be a life-threatening opportunistic infection in immunosuppressed solid organ transplant recipients. Despite effective treatment with high-dose trimethoprim-sulfamethoxazole and steroids, morbidity is often severe and lethality remains high. New therapeutic approaches are therefore warranted. Caspofungin, a beta-1,3-glucan synthesis inhibitor, has shown activity against the cyst forms of P. jiroveci in experimental animal models. We here report our preliminary clinical experience with caspofungin as an additional drug to the standard trimethoprim-sulfamethoxazole regimen. Methods. Four solid organ transplant patients with severe hypoxemic P. jiroveci pneumonia were treated with the combination of trimethoprim-sulfametoxazole and caspofungin. In two cases, caspofungin was added as salvage treatment due to failure of trimethoprim-sulfametoxazole monotherapy. Results. In these four patients, the use of caspofungin as an additional drug to the standard trimethoprim-sulfamethoxazole regimen led to a rapid improvement and a complete cure of pneumonia. No side effects or drug interactions were observed. Discussion. This preliminary clinical experience suggests that the addition of caspofungin to trimethoprim-sulfamethoxazole, which is active against trophic forms, may provide a synergistic activity against P. jiroveci by fully inhibiting the organism life cycle.
Discrimination of prostate cancer from normal peripheral zone and central gland tissue by using dynamic contrast-enhanced MR imaging.

PURPOSE To evaluate which parameters of dynamic magnetic resonance (MR) imaging and T2 relaxation rate would result in optimal discrimination of prostatic carcinoma from normal peripheral zone (PZ) and central gland (CG) tissues and to correlate these parameters with tumor stage, Gleason score, patient age, and tumor markers. MATERIALS AND METHODS Of 58 patients with prostatic carcinoma, 36 were included for analysis. Patients underwent MR imaging at 1.5 T with an endorectal-pelvic phased-array coil and subsequently underwent prostatectomy. A T2-weighted turbo spin-echo sequence, an intermediate-weighted sequence, and a fast T1-weighted gradient-echo sequence (seven sections in 2.03 seconds) during bolus injection of 0.1 mmol gadopentetate dimeglumine per kilogram of body weight were performed. Contrast agent concentration-time curves were obtained for prostatic carcinoma and normal PZ and CG tissue by using whole-mount sections to guide placement of regions of interest. Onset time, time to peak, peak enhancement, relative peak enhancement, washout, and T2 relaxation rates were calculated. Multivariate receiver operating characteristic analysis was performed with and without relative peak enhancement. RESULTS Results of multivariate receiver operating characteristic analysis showed that relative peak enhancement demonstrated the highest area under the receiver operating characteristic curve (AUC) in the PZ and the CG (AUC = 0.93, 0.82). Results of multivariate analysis without relative peak enhancement showed that relative peak enhancement in the PZ and washout in the CG demonstrated the highest AUC (AUC = 0.9, 0.81). Pearson correlation coefficients between the dynamic parameters or T2 relaxation rates in carcinoma and the tumor stage, Gleason score, patient age, and tumor markers ranged between 0.02 and 0.44. CONCLUSION The optimal parameter for discrimination of prostatic carcinoma in the PZ and CG was relative peak enhancement. If relative peak enhancement was not used, then peak enhancement was optimal in the PZ, and washout was optimal in the CG. Poor-to-moderate correlation was present between the dynamic parameters or T2 relaxation rate in carcinoma and the tumor stage, Gleason score, patient age, tumor volume, and prostate-specific antigen.
Association of Higher Plasma Vitamin D Binding Protein and Lower Free Calcitriol Levels with Tenofovir Disoproxil Fumarate Use and Plasma and Intracellular Tenofovir Pharmacokinetics: Cause of a Functional Vitamin D Deficiency?

ABSTRACT Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. IMPORTANCE (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.)
Absence of Sterol Regulatory Element-binding Protein-1 (SREBP-1) Ameliorates Fatty Livers but Not Obesity or Insulin Resistance inLep ob /Lep ob Mice*

Obesity is a common nutritional problem often associated with diabetes, insulin resistance, and fatty liver (excess fat deposition in liver). Leptin-deficientLep ob /Lep ob mice develop obesity and those obesity-related syndromes. Increased lipogenesis in both liver and adipose tissue of these mice has been suggested. We have previously shown that the transcription factor sterol regulatory element-binding protein-1 (SREBP-1) plays a crucial role in the regulation of lipogenesis in vivo. To explore the possible involvement of SREBP-1 in the pathogenesis of obesity and its related syndromes, we generated mice deficient in both leptin and SREBP-1. In doubly mutant Lep ob/ob × Srebp-1 −/− mice, fatty livers were markedly attenuated, but obesity and insulin resistance remained persistent. The mRNA levels of lipogenic enzymes such as fatty acid synthase were proportional to triglyceride accumulation in liver. In contrast, the mRNA abundance of SREBP-1 and lipogenic enzymes in the adipose tissue ofLep ob /Lep ob mice was profoundly decreased despite sustained fat, which could explain why the SREBP-1 disruption had little effect on obesity. In conclusion, SREBP-1 regulation of lipogenesis is highly involved in the development of fatty livers but does not seem to be a determinant of obesity inLep ob /Lep ob mice.
How Important are Firms in Explaining Wage Changes During a Recession?

During the Great Recession, many Irish workers experienced nominal earnings reductions, with about 50% of private sector employees receiving pay cuts at the height of the crisis. However, at the same time, a substantial minority of workers continued to receive pay increases. In this paper we use a unique dataset containing earnings on every worker in Ireland to examine the relative roles of worker and firm characteristics in explaining this heterogeneity in earnings dynamics. Our results show that between&#8208;firm effects play a small role in determining pay changes in Ireland. Although between&#8208;firm effects became more important in the peak year of the economic crisis, the vast majority of earnings changes continued to be driven by within&#8208;firm forces. These findings raise a number of important questions about the role of morale and fairness in the wage&#8208;setting process.
A Construct Validity Study of Commitment and Perceived Support Variables

Social exchange theory suggests that employees feel commitment toward both their employing organizations and their work teams, while also experiencing varying levels of support from these same entities. Unfortunately, previous work has neither fully explored this possibility nor tested the capacity of currently available instruments to adequately measure the distinctiveness of the associated constructs. To address this need, we collected data from 902 employees in four diverse organizations. As predicted, respondents distinguished among organizational commitment, team commitment, organizational support, and team support. Furthermore, as predicted, perceived support from an entity predicted commitment to that same entity.
NF2 gene expression in sporadic meningiomas: Relation to grades or histotypes real time‐PCR study

One of the most common regions involved in the meningiomas tumorigenesis is chromosome 22q where the NF2 gene resides. The deficiency or loss of the NF2 gene product, merlin/schwannomin, plays a role in tumor development and metastatization. Conflicting results have been reported on the prognostic value of merlin in meningiomas. Several studies have indicated NF2 gene inactivation as an early tumorigenic event unrelated to the histological grade or clinical behavior. On the contrary, the NF2 gene alteration rate differs between the different histotypes. A pathogenesis independent from the NF2 gene has been suggested in meningothelial meningiomas. In the present work, we studied the NF2 gene expression through real time‐PCR (RT‐PCR) in 30 meningiomas. The average of the NF2 gene expression of all meningiomas was considered as reference value. The average of expression of WHO grade I and II meningiomas was higher than the average of all meningiomas, whereas that of WHO grade III meningiomas was lower. When we compared the NF2 gene expression in the different meningioma grades we did not note a significant difference (P = 0.698) despite the tendency to decrease from grade I to grade III. The average expression of meningothelial meningiomas was higher than the reference value, and that of non‐meningothelial meningiomas was lower. The difference in NF2 gene expression between meningothelial and non‐meningothelial meningiomas was statistically significant (P = 0.013). Our data supports the finding that alterations in NF2 gene alteration are histotype related but not grade related.
International spillover effects of U.S. tax reforms: evidence from Germany

This paper explores the international transmission of U.S. tax shocks and provides evidence for the German economy. Using structural vector autoregressions, we find that after a U.S. tax cut, German GDP increases moderately. While higher U.S. demand stimulates German exports, a deterioration of price competitiveness lowers this positive growth impulse. The current account increases significantly. Surprisingly, German prices fall as domestic companies reduce unit labor costs. The resulting increase of the real interest rate dampens domestic demand. German tax policy shows an opposite reaction to U.S. tax policy. The latter result, however, is driven by the decade of the 1970s. We find that significant changes in the transmission channels arise by distinguishing between different types of U.S. tax reforms. In particular, in contrast to U.S. personal income tax reforms, changes in the corporate income tax cause a depreciation of the German real effective exchange rate.
Atrial flutter in a patient with glioblastoma multiforme: problems in treating thromboembolic complications

A 55-year-old gentleman with a left-sided glioblastoma multiforme (GBM) presented with palpitations which were shown to be atrial flutter (AFL) on ECG. Approximately 6 h later, he developed ataxia and expressive dysphasia. A brain CT scan showed no acute haemorrhage and no progression of the brain tumour. Ischaemic stroke was the top differential diagnosis. However, the authors could not perform thrombolysis due to the risk of intratumour haemorrhage. The AFL reverted to sinus rhythm with metoprolol and digoxin after 3 days. His neurological signs resolved within 24 h, and a diagnosis of transient ischaemic attack secondary to AFL was made. This case highlights the challenge of managing thrombo-embolic complications of arrhythmias in cancer patients.
Distribution of Tn551 insertion sites responsible for auxotrophy on the Staphylococcus aureus chromosome

A method was devised to efficiently select isolates of Staphylococcus aureus 8325 in which Tn551, a transposon originating on the pI258 plasmid responsible for erythromycin resistance (Emr), had translocated to the host chromosome. This method consisted of selecting for Emr at 43 degrees C with a strain in which the pI258 plasmid was unable to replicate at 43 degrees C because of a temperature-sensitive plasmid mutation. By selecting isolates that were Emr at 43 degrees C and auxotrophic for nutrients not required by the parent strain. Tn551-induced auxotrophic mutants were readily isolated. The incidence of auxotrophic classes was not random; 80% of the isolates in one experiment were Trp-, whereas only a single example of each of some of the other classes was isolated. Among the Trp- mutants, the distribution of trp genes affected and the frequency of precise excision of Tn551 from individual sites varied. When analyzed by transformation, the Tn551-induced ala, his, ilv, lys, rib, thrA, thrB, and trp mutations were shown to occupy sites previously defined by nitrosoguanidine-induced mutations. Tn551-induced mutagenesis provided three previously unrecognized classes of auxotrophs (tyr, met, and thrC), and the Tn551 integration sites resulting in these mutations have been identified. In addition, a chromosomal region (uraB) was identified by Tn551 mutagenesis that is distinct from uraA (previously defined by chemical mutagenesis). Some Tn551-induced mutations (most notably pur) could not be linked to the known linkage groups of the chromosome by transformation. With the exception of two pur mutations, all of the Tn551-induced auxotrophic mutational sites cotransformed at unity with Tn551 and, in cases in which they were selected, prototrophic transformants were always Ems. Thus, the Tn551 and auxotrophic sites are identical.
Multiplex PCR and Microarray for Detection of Swine Respiratory Pathogens

Summary Porcine respiratory disease complex (PRDC) is one of the most important health concerns for pig producers and can involve multiple viral and bacterial pathogens. No simple, single‐reaction diagnostic test currently exists for the simultaneous detection of major pathogens commonly associated with PRDC. Furthermore, the detection of most of the bacterial pathogens implicated in PRDC currently requires time‐consuming culture‐based methods that can take several days to obtain results. In this study, a novel prototype automated microarray that integrates and automates all steps of post‐PCR microarray processing for the simultaneous detection and typing of eight bacteria and viruses commonly associated with PRDC is described along with associated multiplex reverse transcriptase PCR. The user‐friendly assay detected and differentiated between four viruses [porcine reproductive and respiratory syndrome virus (PRRSV), influenza A virus, porcine circovirus type 2, porcine respiratory corona virus], four bacteria (Mycoplasma hyopneumoniae, Pasteurella multocida, Salmonella enterica serovar Choleraesuis, Streptococcus suis), and further differentiated between type 1 and type 2 PRRSV as well as toxigenic and non‐toxigenic P. multocida. The assay accurately identified and typed a panel of 34 strains representing the eight targeted pathogens and was negative when tested with 34 relevant and/or closely related non‐target bacterial and viral species. All targets were also identified singly or in combination in a panel of clinical lung samples and/or experimentally inoculated biological material.
Adhesions and pain in women with first diagnosis of endometriosis: results from a cross-sectional study.

OBJECTIVE To analyze the relationship between pain and presence, site, and type of adhesions in women with endometriosis. METHODS This was a multicenter, observational cross-sectional study. Eligible for the study were women with endometriosis and pelvic pain, consecutively observed during the study period at the collaborating centers. A total of 574 women entered the study. RESULTS Adhesions were observed in 81.9% of cases (470 women). The frequency was lower in women with endometriosis at stage I-II (65%) and higher in women with stage III-IV (88%); this difference was statistically significant (p < .01). The frequency of adhesions was lower in women with ovarian endometriosis (74%) and higher in those with ovarian and peritoneal endometriosis (87%) or other sites (96%) (p < .01). The presence of adhesions was associated with higher mean visual analog scale (VAS) scores and median multidimensional scale ratings in women with ovarian disease and with stage I-II disease. Women with ovarian adhesions reported higher VAS and multidimensional scale scores (p < .05) than women with peritoneal adhesions or adhesions in other sites. CONCLUSIONS The results of this study suggest that there is no overall association between the presence of adhesions and the degree of pain in women with endometriosis. The data suggests that there may be an association between adhesions and pain in women with ovarian and Type I-II endometriosis. However, these associations were no longer significant after correction for multiple comparisons. Further research is indicated to test these associations.