Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular determinants of cadherin ideal bond formation: Conformation-dependent unbinding on a multidimensional landscape

Significance Multicellular assemblies rely on the robust binding of classical cadherin cell–cell adhesion proteins to maintain their integrity and withstand mechanical stress. Cadherins can form adhesive interactions that are insensitive to tugging forces; however, the biophysical mechanism for cadherin force insensitivity is unknown. Here, we integrate single-molecule biophysical measurements with computer simulations to show that cadherins, which are known to bind in two distinct conformations, adopt an intermediate structure as they transition between their alternate conformations. When this intermediate structure is pulled, it unbinds along a force-independent pathway that makes it insensitive to tugging forces. Force-independent unbinding is blocked when cadherins associate laterally, suggesting a physical mechanism by which mechanical force enhances cadherin clustering on the cell surface. Classical cadherin cell–cell adhesion proteins are essential for the formation and maintenance of tissue structures; their primary function is to physically couple neighboring cells and withstand mechanical force. Cadherins from opposing cells bind in two distinct trans conformations: strand-swap dimers and X-dimers. As cadherins convert between these conformations, they form ideal bonds (i.e., adhesive interactions that are insensitive to force). However, the biophysical mechanism for ideal bond formation is unknown. Here, we integrate single-molecule force measurements with coarse-grained and atomistic simulations to resolve the mechanistic basis for cadherin ideal bond formation. Using simulations, we predict the energy landscape for cadherin adhesion, the transition pathways for interconversion between X-dimers and strand-swap dimers, and the cadherin structures that form ideal bonds. Based on these predictions, we engineer cadherin mutants that promote or inhibit ideal bond formation and measure their force-dependent kinetics using single-molecule force-clamp measurements with an atomic force microscope. Our data establish that cadherins adopt an intermediate conformation as they shuttle between X-dimers and strand-swap dimers; pulling on this conformation induces a torsional motion perpendicular to the pulling direction that unbinds the proteins and forms force-independent ideal bonds. Torsional motion is blocked when cadherins associate laterally in a cis orientation, suggesting that ideal bonds may play a role in mechanically regulating cadherin clustering on cell surfaces.
Regulation of Salmonella typhimurium lipopolysaccharide O antigen chain length is required for virulence; identification of FepE as a second Wzz

Wzz proteins regulate the degree of polymerization of the O antigen (Oag) subunits in lipopolysaccharide (LPS) biosynthesis. Although the pathogenic relevance of Oag is well recognized, the significance of Oag chain length regulation is not well defined. In this report, Salmonella typhimurium was shown to possess two functional wzz genes resulting in a bimodal Oag length distribution. In addition to the previously described wzzST that results in long (L) modal length LPS with 16–35 Oag repeat units (RUs), we now report that wzzfepE, a homologue of Escherichia coli fepE, is responsible for the production of very long (VL) modal length LPS Oag, estimated to contain> 100 Oag RUs. Analysis of a series of isogenic S. typhimurium C5 mutants found that the presence of either wzz gene (and hence either modal length) was sufficient for complement resistance and virulence in the mouse model of infection, suggesting a degree of redundancy in the role of these two wzz genes and their respective Oag modal lengths. In contrast, the wzzST/wzzfepE double mutant, with relatively short, random‐length Oag, displayed enhanced susceptibility to complement and was highly attenuated in the mouse. This clearly demonstrates the molecular genetic basis for the longer LPS Oag chains previously identified as the basis of complement resistance in Salmonella. The presence of wzzfepE homologues in the genomic sequences of strains of Escherichia coli, Shigella flexneri and multiple serovars of Salmonella suggests that bimodality of LPS Oag is a common phenomenon in the Enterobacteriaceae.
Interleukin‐12 and the host response to parasitic helminths; the paradoxical effect on protective immunity and immunopathology

In general, helminth infections are associated with the development of dominant Th2‐mediated immune responses which may be host protective but can also be the cause of immunopathology. Interleukin 12 (IL‐12) is known to be a potent inhibitor of Th2 immune responses and as such it might be expected to have an important modulatory role in helminth‐induced immune responses. In this review, we discuss the effect of IL‐12 on susceptibility to infection, protective immunity and immunopathology, in the context of exposure to a range of helminths including intestinal nematodes, filariae and schistosomes. It is apparent that the effects of IL‐12 are complex and can be beneficial as well as detrimental for the host. The precise role of IL‐12 depends upon a number of factors including the type of helminth and the specific tissue involved in the inflammatory response.
Myocardial Strain and Strain Rate in Kawasaki Disease: Range, Recovery, and Relationship to Systemic Inflammation/Coronary Artery Dilation

Background Kawasaki Disease (KD), a systemic vasculitis of medium sized vessels, is the most common cause of acquired heart disease among children in the developed world. Some KD patients demonstrate echocardiographic evidence of depressed myocardial mechanics. However, the incidence, etiology, and reversibility of abnormal mechanics in KD patients remain undefined. Methods and results We retrospectively studied 41 KD patients and measured myocardial strain and strain rate by velocity vector imaging from pre-treatment and convalescent echocardiograms. Pre-treatment procalcitonin, C-reactive protein (CRP), and coronary artery z-scores were obtained in all patients and compared between the groups with preserved versus depressed acute phase mechanics. The change in mechanics between the acute and convalescent phases was also assessed. Patients with initially low longitudinal strain improved by the convalescent period (mean difference - 4.0%; p<0.005) with the greatest improvement occurring in patients with the lowest initial strain (−7.3%; p<0.05). Patients with higher initial strain did not change significantly by the convalescent period. Patients with lower longitudinal and circumferential strain demonstrated higher median procalcitonin levels (1.2 vs. 0.3 ng/mL; p<0.05 and 1.8 vs. 0.4 ng/mL; p<0.05 respectively) and a trend towards higher CRP, but no difference in coronary artery z-scores. Strain rate was not associated with inflammatory markers or coronary artery z-scores. Conclusions The range of strain found in our cohort was large. Improvement in mean strain was driven primarily by patients with lower initial strain. Lower strain was associated with increased markers of systemic inflammation, but not proximal coronary artery changes.
Exploring the Employability of African-American Male Ex-Offenders in Local Government

Exploring the Employability of African-American Male Ex-Offenders in Local Government by Chandra LaTrelle Porter MS, Walden University, 2012 MS, Webster University, 2002 BBA, Georgia Southern University, 1997 BBA, Savannah State College, 1993 Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Management
N-acetylated metabolites in urine: proton nuclear magnetic resonance spectroscopic study on patients with inborn errors of metabolism.

BACKGROUND There is no comprehensive analytical technique to analyze N-acetylated metabolites in urine. Many of these compounds are involved in inborn errors of metabolism. In the present study, we examined the potential of proton nuclear magnetic resonance ((1)H-NMR) spectroscopy as a tool to identify and quantify N-acetylated metabolites in urine of patients with various inborn errors of metabolism. METHODS We performed (1)H-NMR spectroscopy on a 500 MHz spectrometer. Using a combination of one- and two-dimensional correlation spectroscopy (COSY) (1)H-NMR spectra, we were able to assign and quantify resonances of characteristic N-acetylated compounds products in urine of patients with 13 inborn errors of metabolism. RESULTS The disease-specific N-acetylated metabolites were excreted at concentrations >100 micromol/mmol of creatinine in the patients' urine. In control urine samples, the concentration of individual N-acetyl-containing compounds was <40 micromol/mmol of creatinine. The combination of one- and two-dimensional COSY NMR spectroscopy led to the correct diagnosis of nine different inborn errors of metabolism. No abnormalities were observed in the spectra of urine from patients with G(M1)- or G(M2)-gangliosidosis. We also determined the (1)H-NMR characteristics of N-acetylated metabolites that may be relevant to human metabolism. CONCLUSION (1)H-NMR spectroscopy may be used to identify and quantify N-acetylated metabolites of diagnostic importance for the field of inborn errors of metabolism.
What is the Effect of Pseudoexfoliation Syndrome on Renal Function in Patients without Glaucoma?

Abstract Purpose: To evaluate renal function in patients with pseudoexfoliation syndrome. Materials and Methods: This prospective, cross-sectional, case-control study involved 49 patients with pseudoexfoliation syndrome (PEX) and 42 control subjects. Renal function was examined by biochemical parameters and Doppler ultrasonography. Serum creatinine, blood urea nitrogen, urea levels, urine microalbumin level and creatinine clearance were measured. Renal volume, resistive index and pulsatility index were calculated using Doppler ultrasonography. Results: The mean laboratory values for both groups were as follows: Creatinine, PEX: 0.81 ± 0.28 mg/dL – Control: 0.79 ± 0.22 mg/dL; urea, PEX: 31.6 ± 9.7 mg/dL – Control: 32.2 ± 8.4 mg/dL; blood urea nitrogen, PEX: 14.8 ± 4.6 mg/dL – Control: 15.1 ± 4.0 mg/dL; creatinine clearance, PEX: 89.1 ± 35.6 mL/min – Control: 99.0 ± 47.2 mL/min; microalbumin, PEX: 5.8 ± 22.7 mg/dL – Control: 2.7 ± 6.0 mg/dL. The differences between groups were not significant (p > 0.300). Renal volume, resistive index and pulsatility index values were similar in both groups (p > 0.200). Conclusions: This study showed that pseudoexfoliation syndrome does not affect biochemical and ultrasonographic parameters associated with renal function.
Persepsi Wajib Pajak Mengenai Pengaruh Keadilan, Sistem Perpajakan dan Sanksi Perpajakan terhadap Penggelapan Pajak (Survey terhadap UMKM di Bekasi)

This study aimed to determine of tax payers perception about the effect of justice, tax system, and tax sanctions to the tax evasion (surveys to Small Medium Entities in Bekasi). Purposive sampling is used, and result 90 SME’s as the respondents. Linear regression is used as the analysis data technique. The results show that justice did not effect to tax evasion, but tax system and tax sanction have negatively significant impact to tax evasion. Keywords: Tax payers perception, tax justice, tax system, tax sanction, tax evasion.
The effects of audit quality on the value relevance of other comprehensive incomes

Stockholders claim deals with handling crucial role to investors while another ac-counting measurement has not yet been paid attention by the investors and analysts. Beside, another comprehensive income despite of its equal role to net income also re-quires a deep concern. This research uses financial industry data in Indonesia Capital Market for 2011-2012 under panel method and also cross-section method as the addi-tional analysis. This research assesses the effect of audit quality on value relevance of other comprehensive income regarding subjectivity embedded in other comprehensive income components. These components are determined through fair value aspects, which eventually lead to management discretion in measuring other comprehensive income components. Subjective components of other comprehensive incomes consist of foreign exchange translation (forex), revaluation in fixed assets (rev), minimum pension liability adjustment (pen), and available-for-sale securities adjustment (sec). The audit quality is believed as a mechanism which can increase the value relevance of subjective of other comprehensive income components. On the other hand, when as-sessing the value relevance of other comprehensive income components both indivi-dually and in aggregate, it is encouraged by inconsistency of previous research results.
Spatio-temporal population structuring and genetic diversity retention in depleted Atlantic Bluefin tuna of the Mediterranean Sea

Fishery genetics have greatly changed our understanding of population dynamics and structuring in marine fish. In this study, we show that the Atlantic Bluefin tuna (ABFT, Thunnus thynnus), an oceanic predatory species exhibiting highly migratory behavior, large population size, and high potential for dispersal during early life stages, displays significant genetic differences over space and time, both at the fine and large scales of variation. We compared microsatellite variation of contemporary (n = 256) and historical (n = 99) biological samples of ABFTs of the central-western Mediterranean Sea, the latter dating back to the early 20th century. Measures of genetic differentiation and a general heterozygote deficit suggest that differences exist among population samples, both now and 96–80 years ago. Thus, ABFTs do not represent a single panmictic population in the Mediterranean Sea. Statistics designed to infer changes in population size, both from current and past genetic variation, suggest that some Mediterranean ABFT populations, although still not severely reduced in their genetic potential, might have suffered from demographic declines. The short-term estimates of effective population size are straddled on the minimum threshold (effective population size = 500) indicated to maintain genetic diversity and evolutionary potential across several generations in natural populations.
Do Multi‐Plant Firms Reduce Misallocation? Evidence from Canadian Manufacturing

Using Canadian plant-level data, this paper shows that, depending on the industry, the differences in the average plant-level productivity and cross-plant allocation of resources between multi-plant and single-plant firms account for 1 to 15 per cent of the industry-level TFP. A large part of this contribution stems from more efficient cross-plant allocation of resources, measured by the covariance between plant size and productivity, in the pool of plants in multi-plant firms compared to the pool of plants in single-plant firms. There is less dispersion in the marginal products of the inputs, and thus less misallocation, in industries in which multi-plant firms account for a larger share of output. The patterns found in the cross-plant distribution of productivity and size are also consistent with better allocative efficiency among plants in multi-plant firms than among plants in single-plant firms.
Haplotype-Based Case-Control Study of the Human CYP4F2 Gene and Essential Hypertension in Japanese Subjects

CYP4F2 acts primarily as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the regulation of blood pressure in humans. The aim of the present study was to assess the association between the human CYP4F2 gene and essential hypertension (EH) using a haplotype-based case-control study that included separate analysis of the two gender groups. The 249 EH patients and 238 age-matched controls were genotyped for 5 single-nucleotide polymorphisms (SNPs) of the human CYP4F2 gene (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). Data were analyzed for 3 separate groups: all subjects, and men and women separately. For the total population and for male subjects, the distribution of the dominant model of rs1558139 (CC vs. CT+TT) differed significantly between the EH patients and control subjects (p=0.037 and p=0.005, respectively), with a higher percentage of EH patients showing the CC genotype. Logistic regression showed that, for men, the CC genotype of rs1558139 was more prevalent in the EH patients than in the control subjects (p=0.026), while, for the total population, the difference disappeared (p=0.247). For men, the overall distribution of the haplotypes was significantly different between the EH patients and the control subjects (p=0.042), and the frequency of the T-T-G haplotype was also significantly lower for EH patients than for control subjects (p=0.009). In conclusion, the present results indicate that rs1558139 might be a genetic marker for EH and the T-T-G haplotype might be a protective genetic marker for EH in Japanese men.
Is Early Reperfusion a Good Thing? Optimal Timing of CABG Surgery Postacute Myocardial Infarction

Objectives The optimal timing of coronary artery bypass grafting (CABG) following an acute myocardial infarction (AMI) is a topic of debate. The present study was designed to evaluate patients undergoing CABG both early (<5 days) and late (>5 days) after AMI in the era of percutaneous coronary intervention. Methods The medical records at our institution from 2008 through 2012 were reviewed. A total of 128 patients underwent CABG after AMI during this time period and fulfilled criteria for the study. Death, stroke, renal failure, need for intraaortic balloon pump, postoperative ventilator days, and length of stay were examined. Results Patients undergoing early CABG had an increased need for an intraaortic balloon pump. There were no other correlations that we could discern between early and late CABG. Conclusions Our data demonstrate no statistical difference in mortality or in the factors of morbidity studied between either early or late CABG after AMI.
Deficits in transcriptional regulators of cortical parvalbumin neurons in schizophrenia.

OBJECTIVE In schizophrenia, alterations within the prefrontal cortical GABA system appear to be most prominent in neurons that contain parvalbumin or somatostatin but not calretinin. The transcription factors Lhx6 and Sox6 play critical roles in the specification, migration, and maturation of parvalbumin and somatostatin neurons, but not calretinin neurons, and continue to be strongly expressed in this cell type-specific manner in the prefrontal cortex of adult humans. The authors investigated whether Lhx6 and/or Sox6 mRNA levels are deficient in schizophrenia, which may contribute to cell type-specific disturbances in cortical parvalbumin and somatostatin neurons. METHOD The authors used quantitative PCR and in situ hybridization with film and grain counting analyses to quantify mRNA levels in postmortem samples of prefrontal cortex area 9 of 42 schizophrenia subjects and 42 comparison subjects who had no psychiatric diagnoses in life, as well as antipsychotic-exposed monkeys. RESULTS In schizophrenia subjects, the authors observed lower mRNA levels for Lhx6, parvalbumin, somatostatin, and glutamate decarboxylase (GAD67; the principal enzyme in GABA synthesis), but not Sox6 or calretinin. Cluster analysis revealed that a subset of schizophrenia subjects consistently showed the most severe deficits in the affected transcripts. Grain counting analyses revealed that some neurons that normally express Lhx6 were not detectable in schizophrenia subjects. Finally, lower Lhx6 mRNA levels were not attributable to psychotropic medications or illness chronicity. CONCLUSIONS These data suggest that in a subset of individuals with schizophrenia, Lhx6 deficits may contribute to a failure of some cortical parvalbumin and somatostatin neurons to successfully migrate or develop a detectable GABA-ergic phenotype.
Role of the N‐terminus in permeability of chicken connexin45.6 gap junctional channels

Previous studies have shown that gap junctional channels formed from the lens connexins Cx50 (or its chicken orthologue, Cx45.6) and Cx43 exhibit marked differences in transjunctional voltage gating and unitary conductance. In the present study, we used the negatively charged dye, Lucifer Yellow (LY), to examine and compare quantitative differences in dye transfer between pairs of HeLa cells stably transfected with Cx45.6 or Cx43. Our results show that Cx45.6 gap junctional channels are three times less permeable to LY than Cx43 channels. Replacement of the N‐terminus of Cx45.6 with the corresponding domain of Cx43 increased LY permeability, reduced the transjunctional voltage (Vj) gating sensitivity, and reduced the unitary conductance of Cx45.6–43N gap junctional channels. Further experiments, using a series of Alexa probes that had similar net charge but varied in size showed that the Cx45.6–43N had a significantly higher permeability for the two largest Alexa dyes than Cx45.6. These data suggest that the N‐terminus plays a critical role in determining many of biophysical properties of Cx45.6 gap junctional channels, including molecular permeability and voltage gating.
Therapeutic options in post-transplant lymphoproliferative disorders

Post-transplantation lymphoproliferative disorders (PTLD) are the second most frequent malignancies after solid organ transplantation and cover a wide spectrum ranging from polyclonal early lesions to monomorphic lymphoma. Available treatment modalities include immunosuppression reduction, immunotherapy with anti-B-cell monoclonal antibodies, chemotherapy, antiviral therapy, cytotoxic T-cell therapy as well as surgery and irradiation. Owing to the small number of cases and the heterogeneity of PTLD, current treatment strategies are mostly based on case reports and small, often retrospective studies. Moreover, many studies on the treatment of PTLD have involved a combination of different treatment options, complicating the evaluation of individual treatment components. However, there has been significant progress over the last few years. Three prospective phase II trials on the efficacy of rituximab monotherapy have shown significant complete remission rates without any relevant toxicity. A prospective, multicenter, international phase II trial evaluating sequential treatment with rituximab and CHOP-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) is ongoing and preliminary results have been promising. Cytotoxic T-cell therapy targeting Epstein–Barr virus (EBV)-infected B cells has shown low toxicity and high efficacy in a phase II trial and will be a future therapeutic option at specialized centers. Here, we review the currently available data on the different treatment modalities with a focus on PTLD following solid organ transplantation in adult patients.