Miracle-dz/UniFAR-FTUs huggingface dataset:
Biochemical analysis of the interactions of IQGAP1 C-terminal domain with CDC42.

AIM To understand the interaction of human IQGAP1 and CDC42, especially the effects of phosphorylation and a cancer-associated mutation. METHODS Recombinant CDC42 and a novel C-terminal fragment of IQGAP1 were expressed in, and purified from, Escherichia coli. Site directed mutagenesis was used to create coding sequences for three phosphomimicking variants (S1441E, S1443D and S1441E/S1443D) and to recapitulate a cancer-associated mutation (M1231I). These variant proteins were also expressed and purified. Protein-protein crosslinking using 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide was used to investigate interactions between the C-terminal fragment and CDC42. These interactions were quantified using surface plasmon resonance measurements. Molecular modelling was employed to make predictions about changes to the structure and flexibility of the protein which occur in the cancer-associated variant. RESULTS The novel, C-terminal region of human IQGAP1 (residues 877-1558) is soluble following expression and purification. It is also capable of binding to CDC42, as judged by crosslinking experiments. Interaction appears to be strongest in the presence of added GTP. The three phosphomimicking mutants had different affinities for CDC42. S1441E had an approximately 200-fold reduction in affinity compared to wild type. This was caused largely by a dramatic reduction in the association rate constant. In contrast, both S1443D and the double variant S1441E/S1443D had similar affinities to the wild type. The cancer-associated variant, M1231I, also had a similar affinity to wild type. However, in the case of this variant, both the association and dissociation rate constants were reduced approximately 10-fold. Molecular modelling of the M1231I variant, based on the published crystal structure of part of the C-terminal region, revealed no gross structural changes compared to wild type (root mean square deviation of 0.564 Å over 5556 equivalent atoms). However, predictions of the flexibility of the polypeptide backbone suggested that some regions of the variant protein had greatly increased rigidity compared to wild type. One such region is a loop linking the proposed CDC42 binding site with the helix containing the altered residue. It is suggested that this increase in rigidity is responsible for the observed changes in association and dissociation rate constants. CONCLUSION The consequences of introducing negative charge at Ser-1441 or Ser-1443 in IQGAP1 are different. The cancer-associated variant M1231I exerts its effects partly by rigidifying the protein.
Estrogen and progesterone receptors in non-small cell lung cancer in 248 consecutive patients who underwent surgical resection.

CONTEXT Different authors have reported estrogen receptor (ER) expression between 0% and 96.8% and progesterone receptor (PR) expression between 21.8% and 34.7%. OBJECTIVE To examine the discrepancies in the literature regarding the expression of ERs and PRs in non-small cell lung cancer. DESIGN Retrospective analysis. SETTING A referral tertiary care center. PATIENTS We reviewed 248 consecutive cases of stage I and II non-small cell lung cancers. METHODS AND RESULTS Sections of formalin-fixed and paraffin-embedded tumor tissue were stained with ER and PR monoclonal antibodies using the avidin-biotin complex detection system with antigen retrieval. Men represented 66.1% of the patients, and women represented 33.9%. Large cell (undifferentiated) carcinoma constituted 10.4% of the entire population; squamous cell carcinoma, 39.1%; adenocarcinoma, 33.0%; and bronchoalveolar carcinoma, 17.3%. Patients with stage I disease represented 77.0% of the population. In this patient population, we found no nuclear or cytoplasmic expression of either ERs or PRs (95% confidence interval, 0%-1.2%). CONCLUSIONS The absence of expression of ERs and PRs differs from previous articles, which use a variety of techniques, impairing a meaningful comparison of data. In addition, the presence of ER and PR expression in a lung carcinoma is supportive of a nonpulmonary primary tumor metastatic to the lung. The absence of their expression in non-small cell lung cancer does not support a role of these transcription factors in initiating and maintaining this neoplastic process.
A novel seven transmembrane receptor induced during the early steps of astrocyte differentiation identified by differential expression

The rat glial progenitor cell line CG‐4 can be induced to differentiate into either oligodendrocytes or type‐2 astrocytes. In order to identify genes whose expression varies coincident with such phenotypic differentiation, we employed representational difference analysis (RDA) of mRNA. Here, we report 38 cDNAs induced in type‐2 astrocytes, oligodendrocytes, or both differentiated states. Among these were known transcription factors, membrane receptors, extracellular matrix proteins, secreted signaling modulators, chromatin regulators and myelin sheath components. In addition several novel genes were identified; among these was a gene induced during the very early stages of astrocyte differentiation that we have named Ieda (induced early in differentiating astrocytes). Several Ieda transcripts were detected by RT‐PCR, and appeared to be produced by alternative splicing and promoter usage. The protein deduced from the longest Ieda mRNA exhibited sequence features characteristic of G‐protein coupled receptors, including seven putative transmembrane domains, while the shorter Ieda transcripts encoded proteins that lacked several transmembrane segments. In the adult rat, Ieda transcripts were found exclusively in brain and testis. In the developing rat brain, Ieda expression was first detected at embryonic day 16, that is two days before the first appearance of mature astrocytes. Thus, this approach has yielded a potential source of markers for differentiation states of these two cellular types as well as genes predicted to be functionally involved in the differentiation process itself.
Comparison of QLF and DIAGNOdent for Quantification of Smooth Surface Caries

The aim was to compare the detection and quantification of smooth surface caries by KaVo DIAGNOdent and quantitative laser/light–induced fluorescence (QLF) using a laser and a lamp as two different light sources. On 40 premolar teeth extracted from adolescents, 71 non–cavitated approximal surfaces were assessed. For QLF, both mean and maximum fluorescence losses were registered. To provide a gold standard for verification, the teeth were then sectioned and lesion depth, stratified on a five–point scale, was determined by histopathology and microradiography. The correlation between the gold standard and the two methods was assessed by Spearman’s rank correlation coefficient. The sensitivity and specificity of the methods for detection of smooth surface caries at D3 level were also assessed. For lesion depth, correlation with the gold standard was similar for QLF and DIAGNOdent: about 0.85. With respect to dentinal caries detection, sensitivity for DIAGNOdent was 0.75 and specificity 0.96, with a cut–off point of 9. The corresponding values for QLF were 0.94 and 1, with a cut–off value of 20% of fluorescence loss. Spearman’s rank correlation coefficients for enamel mineral loss and QLF and DIAGNOdent, respectively, were 0.76 and 0.67. It was concluded that for quantification of smooth surface caries, the methods are of equal merit, but for scientific purposes, QLF offers the advantage of closer correlation with changes in mineral content.
Dopamine D2-like receptor agonist bromocriptine protects against ischemia/reperfusion injury in rat kidney.

BACKGROUND Dopamine, via activation of D1-like and D2-like receptors, plays an important role in the regulation of renal sodium excretion. Recently, we demonstrated that dopamine D2-like receptor agonist (bromocriptine) stimulates p44/42 mitogen-activated protein kinases (MAPKs) and Na+,K(+)ATPase (NKA) activity in proximal tubular epithelial cells. Since both these parameters are compromised in ischemia/reperfusion (I/R) injury to the kidney, we investigated whether bromocriptine protects against the injury. METHODS In this study we used unilateral rat model of renal I/R injury. The Sprague-Dawley rats were divided into vehicle and bromocriptine groups. The vehicle and bromocriptine group was treated with vehicle and bromocriptine (500 microg/kg intravenously), respectively, 15 minutes before the induction of unilateral ischemia followed by 24- or 48-hour reperfusion. At the end of 24 or 48 hours the animals were sacrificed to collect control and ischemic kidney cortices, in which necrosis, apoptosis, NKA activity, NKA alpha1 subunit expression, and p44/42 MAPK phosphorylation were measured. RESULTS We found extensive necrosis, apoptosis, and decreased NKA activity (with no change in alpha1 subunit) in the ischemic kidney cortex compared to the nonischemic cortex from the vehicle-treated rats as early as 24 hours post-reperfusion. In contrast, I/R injury-induced necrotic, apoptotic, and decrease in NKA activity were absent in the outer cortex of bromocriptine-treated rats after 24 or 48 hours. Interestingly, we detected significantly higher phosphorylation of p44/42 MAPKs in control and ischemic kidneys of bromocriptine-treated rats compared to those of vehicle-treated rats. CONCLUSION Therefore, bromocriptine, a D1-like receptor agonist, may protect against I/R injury to proximal tubules of the kidney, via p44/42 MAPK activation.
Political Corruption and Auditor Behavior: Evidence from US Firms

Abstract This paper investigates the impact of political corruption on auditor behavior in the United States. We find that US firms headquartered in more corrupt regions pay higher audit fees, have longer audit report lags, and are more likely to receive a going concern audit opinion. Political corruption is a manifestation of a weak institutional environment and, as such, weakens the rule of law. In addition, political corruption erodes the public’s belief in a political system and reduces interpersonal trust. Our results suggest that auditors assess the risk and trustworthiness of their clients based on where firms are headquartered. The results are robust to using a 2SLS regression analysis and a propensity-score-matched sample. This study extends the prior research on political corruption and the client risk management strategies used by external auditors. Moreover, the current study will be helpful to regulators considering the more explicit role of external auditors in corruption risk assessment.
The psychosocial impact of the implantable cardioverter defibrillator: a meta-analytic review.

OBJECTIVE The implantable cardioverter defibrillator (ICD) has become the treatment of choice for ventricular arrhythmia (VA; abnormal heart rhythms) and the prevention of sudden cardiac death (SCD). Recent clinical trials have shown the ICD to be superior to anti-arrhythmic medication in reducing mortality; however, research has suggested that ICD recipients experience poor psychosocial adjustment following implantation of the device. This aim of this study was to identify the key psychological characteristics associated with ICD implantation and to establish whether poor psychosocial outcome can be attributed directly to the device and its therapy. METHOD Studies which reported valid and reliable measures of psychological functioning in ICD patients and appropriate comparison groups were considered for inclusion in a meta-analytic review. A systematic search of electronic databases and reference lists identified 20 studies which fulfilled the inclusion criteria. RESULTS There were no significant differences in psychosocial outcome between ICD patients and drug-maintained VA patients or between pre- and post-implant ICD patients. However, ICD patients reported significantly worse psychological functioning and physical functioning than other cardiac controls. CONCLUSION These findings suggest that poor psychosocial outcome in ICD patients may occur as a result of variables associated with the underlying VA condition, rather than as a direct response to implantation of the device and its therapy. This holds important implications for the development and implementation of psychological interventions for patients experiencing VA, in preference to ICD-specific programmes.
Three dimensional numerical prediction of epoxy flow during the underfill process in flip chip packaging

In the present paper, a 3D numerical prediction has been made to study the flip chip underfill process using the epoxy molding compound (EMC). The prediction considered the EMC filling behavior for the flow induced between the tiny gap of silicon die and substrate. Three different arrangements of the solder bump have been tested in this work. The EMC is treated as a generalized Newtonian fluid (GNF). The developed methodology combines the Kawamura and Kawahara technique, and the melt front volume tracking method to solve the two-phase flow field around the solder bumps. The Castro-Macosko rheology model with Arrhenius temperature dependence is adopted in the viscosity model. The predictions are made to investigate the filling patterns at several time intervals. The results show that the underfill process for solder bump with Type A gives minimum filling time and better filling yield. The effect of gap height between the plate and substrate on the underfill process also has been considered. The close agreement between prediction and experimental results from the previous work illustrates the applicability of the present numerical model.
Renewable Energy Integration in Zonal Markets

In this paper, we investigate the impact of zonal network management in the operation of power systems with significant levels of renewable energy integration. Our study is inspired by the current state of the European energy market, and we focus on a case study of the Central Western European (CWE) system. First, we present a hierarchy of models that account for unit commitment, the separation of energy and reserves, and the simplified representation of transmission constraints in a zonal market, in order to examine the impact of these factors on efficiency in a regime of large-scale renewable energy integration. Second, we simulate operations of the CWE system under the zonal market design using a detailed instance that consists of 656 thermal generators, 679 nodes, and 1073 lines, with multiarea renewable energy production and 15-minute time resolution. Zonal market operations are compared against deterministic and stochastic unit commitment using high-performance computing in order to tackle the scale of the resulting models. We find that market design can have an influence on cost efficiency which far exceeds the benefits of stochastic unit commitment relative to deterministic unit commitment. We conduct a detailed analysis of the numerical results in order to explain the relative performance of the different models.
On the ability of New Zealand actively managed funds to generate outperformance in their domestic equity allocations

Purpose This paper aims to assess the ability of New Zealand (NZ) actively managed funds to generate risk-adjusted outperformance using portfolio holdings data. Focusing on domestic equity allocations addresses the benchmark selection issue, particularly for funds with national and international exposures. Design/methodology/approach The authors assess performance using several asset pricing models including the CAPM, three-factor and four-factor models. The authors also assess performance across funds with different characteristics such as fund size, size of local holdings, type of fund provider, past returns and fees. The authors further examine whether funds engage in any stock-picking or market timing by considering the active share and tracking error. Findings The returns on NZ equity holdings of NZ actively managed funds from 2010 to 2017 provide little evidence of risk-adjusted outperformance and stock-picking skill. These exposures yield pre-cost returns that have a nearly perfect correlation with the market index and an insignificant alpha. Funds show little tendency to bet on any of the main characteristics known to predict stock returns, such as size, book-to-market and momentum. In addition, the authors show that the average active shares and tracking errors are low, suggesting that the majority of funds hold NZ equity portfolios that closely mimic the market index. Originality/value Existing studies rely on returns data which aggregate performance across all asset classes with varying exposures. This may lead to benchmark selection issues (particularly for funds with international exposures) which may obscure the fund manager’s true stock-picking skills. Assessment using holdings data would enable suitable performance measurement by researchers and industry analysts.
A novel combination of mild electrical stimulation and hyperthermia: General concepts and applications

This review discusses the basic concepts, effects and applications of hyperthermia and mild electrical stimulation (MES) using low-intensity direct current. It also proposes a novel combinatorial use of MES and hyperthermia, and briefly outlines the rationale and the effects of MES and hyperthermia combination treatment on certain diseases (diabetes, hepatic ischaemia/reperfusion injury and gastric ulcer). The integrated modalities of MES and hyperthermia might find therapeutic applications to stress-induced diseases and intractable diseases of dysregulated signalling pathways.
p53 protein expression in chronic lymphocytic leukemia

Abstract Alterations in the function of the p53 pathway are frequently described in chronic lymphocytic leukemia (CLL), mostly associated with deletion of 17p13 and/or mutations of the TP53 gene. In the present study, we investigated 103 CLLs for the impact of protein expression of full-length p53 and its isoforms β and γ. A strong correlation between deletions of 17p13 and an accumulation of full-length p53 protein was found and was associated with a worse outcome compared to CLL with normal p53 (treatment-free survival p < 0.001, overall survival p = 0.04). Interestingly, the relative expression levels between full-length p53 protein and its isoforms β and γ were significantly altered in CLL even without deletions of 17p13, compared to normal B-cells (p = 0.005). Furthermore, CLLs with higher p53 protein ratios showed worse clinical courses compared to CLLs with lower p53 protein ratios. Taken together, the differential expression of p53 isoforms could disrupt the p53 response and contribute to CLL pathogenesis.
Anthocyanins from Purple Corn Ameliorated Tumor Necrosis Factor-α-Induced Inflammation and Insulin Resistance in 3T3-L1 Adipocytes via Activation of Insulin Signaling and Enhanced GLUT4 Translocation.

SCOPE The aim was to compare the effect of an anthocyanin-rich extract from purple corn pericarp (PCW) and pure anthocyanins on adipogenesis, inflammation, and insulin resistance in 3T3-L1 adipocytes on basal and inflammatory conditions. METHODS AND RESULTS Preadipocytes (3T3-L1) were treated during differentiation with or without PCW. Differentiated adipocytes were treated either individually or in combination with tumor necrosis factor α (TNF-α) and PCW, or pure C3G, Pr3G, P3G. PCW reduced preadipocyte differentiation (IC50 = 0.4 mg/mL). PCW and pure anthocyanins including C3G reduced fatty acid synthase enzymatic activity. PCW reduced TNF-α-dependent inflammatory status increasing adiponectin (39%), and decreasing leptin (-79%). PCW and C3G increased glucose uptake and reduced reactive oxygen species generation in insulin resistant adipocytes. An increase in phosphorylation was observed in AKT, IKK, and MEK, and a decrease in IRS and mTOR activating the insulin receptor-associated pathway. PCW (7.5-fold) and C3G (6.3-fold) enhanced GLUT4 membrane translocation compared to insulin resistant adipocytes. CONCLUSION Anthocyanins from colored corn prevented adipocyte differentiation, lipid accumulation, and reduced PPAR-γ transcriptional activity on adipocytes in basal conditions. Ameliorated TNF-α-induced inflammation and insulin resistance in adipocytes via activation of insulin signaling and enhanced GLUT4 translocation suggesting a reduced hyperglycemia associated with the metabolic syndrome.
Asymmetry in corticomotor facilitation revealed in right-handers in the context of haptic discrimination

In this study we asked whether asymmetries related to handedness in right-handers (n=10) and left-handers (n=10) could influence hemispheric motor facilitation when the preferred or less-preferred hand is engaged in haptic sensing. Transcranial magnetic stimulation (TMS) was used to assess corticomotor excitability when young participants performed a precision grip under two conditions, i.e., with or without a haptic sensing component. In the grip condition participants were required to grasp a 5-mm thick plate between thumb and index fingers, whereas in the haptic condition they performed the same action but were also required to make judgements about the plate's thickness, i.e., either thin (5 mm) or thick (10 mm). Analysis of task-related variations in motor evoked potentials (MEP) amplitude recorded in hand muscles revealed a significant task×hand/hemisphere interaction only in the group of right-handers when the left hand/right hemisphere was engaged in haptic sensing as opposed to simply gripping. Collectively, these results are congruent with other TMS reports describing a greater degree of hemispheric asymmetry in right-handers, who are typically more strongly lateralised than left-handers. Our results with regard to a rightward hemispheric asymmetry for MEP facilitation with haptic sensing are also congruent with the predominant role ascribed to the right sensorimotor cortex in the processing of proprioceptive information.
Continuous terbutaline infusion in severe asthma in adults: a retrospective study of long-term efficacy and safety

Abstract Background: Long-term subcutaneous or intravenous infusion of terbutaline has been used to stabilize asthma in patients enduring frequent hospital admissions due to severe asthma despite maximum therapy. However, this treatment is not supported by significant body of evidence. Aim: To study long-term efficacy and safety of using continuous infusions of terbutaline in unstable severe asthma. Methods: The available medical records of all patients received terbutaline infusions at a severe asthma unit between 1982 and 2008 were retrospectively studied. We retrieved data on treatment indication, asthma subtype, patient demographics, pre-treatment terbutaline trial outcome, duration of treatment, effect on lung function, hospital admissions, oral corticosteroids (OCSs) requirement, safety and side effects. Results: Forty-two patients with adequate medical information were studied (31 females, mean age 43.6 years, 88% had type 1 brittle asthma and 12% had other severe asthma). This group of patients had a mean body mass index of 30.8 kg/m2, mean oral prednisolone or equivalent of 26.6 mg and mean predicted FEV1 of 66.8%. The mean treatment duration was 86.7 months (range 7–216). Long-term continuous terbutaline infusion significantly reduced hospital admissions (mean pre-treatment = 6.7 (95% CI 0.96–12.4) per annum, and mean annualized on-treatment admission = 3.3 (95% CI 0.63–6.9, p = 0.045). We observed overall reduction in OCSs use in 59% of patients with available data, but there was no significant change in lung function. Side effects related to terbutaline or the method of its infusion were common and some were serious especially when central venous access device were used. Conclusion: Continuous terbutaline infusion could be a treatment option for severe unstable asthma and may reduce hospital admissions. However, the treatment was associated with significant side effects and its use should be limited to centers possessing necessary expertise.