Miracle-dz/UniFAR-FTUs huggingface dataset:
No correlation between clinical response to CTLA-4 blockade and presence of NY-ESO-1 antibody in patients with metastatic melanoma.

To the Editor: A recent study by Yuan et al suggested that the blockade of inhibitory cytotoxic T-lymphocyte antigen-4 (CTLA-4) signaling enhanced NY-ESO1 antigen-specific responses in patients with responding or stable disease. Five of 8 patients experiencing ‘‘clinical benefit’’ from anti CTLA-4 antibody (ipilimumab) administration had increased serum levels of anti NY-ESO1 antibody compared with no antibody detected in 7 clinical nonresponders. We thus conducted an analysis of this association in patients treated in the Surgery Branch, National Cancer Institute (NCI). Twenty-three objective responders (partial response or complete response by RECIST criteria) were identified from 2 clinical trials performed in the Surgery Branch, NCI. Nonresponding patients were selected to match age, HLA-A2 status, and protocol assignment. In Trial 1, 29 HLA-A*0201 patients received anti CTLA-4 antibody (ipilimumab, Bristol-Myers Squibb/ Medarex Inc, Laurenceville and Princeton, NJ) every 3 weeks at 3mg/kg intravenously over 90 minutes in conjunction with the subcutaneous injection of 1mg of gp100:209-217(210M) peptide (IMDQVPFSV) emulsified in Montanide ISA-51 in 1 extremity and 1mg of gp100:280-288(288V) peptide (YLEPGPVTV) similarly emulsified, in another extremity. An additional 27 HLA-A*0201 patients in a second cohort of Trial 1 received an initial dose of 3mg/kg ipilimumab, followed by subsequent doses every 3 weeks of 1mg/kg. Ipilimumab was supplied by the manufacturer; peptides and Montanide ISA-51 were supplied by the Cancer Therapy Evaluation Program, NCI Trial 2 was designed as an intrapatient dose-escalation study, and HLA-A*0201-positive patients were randomized to receive ipilimumab every 3 weeks, alone or in conjunction with gp100:209-217(210M) and gp100:280288(288V) peptides emulsified in Montanide ISA-51. HLA-A*0201-negative patients received ipilimumab alone. Ipilimumab treatment was started at 3 or 5mg/kg. If after 1 course (2 treatments), patients did not achieve an objective response or a dose-limiting toxicity, the dose was increased to 5 or 9mg/kg. After another 2 treatments, patients could then be escalated to 9mg/kg/dose. Sera collected before the therapy and at a point >6 weeks from first dose of therapy were analyzed when
Glutaredoxins Grx4 and Grx3 of Saccharomyces cerevisiae Play a Role in Actin Dynamics through Their Trx Domains, Which Contributes to Oxidative Stress Resistance

ABSTRACT Grx3 and Grx4 are two monothiol glutaredoxins of Saccharomyces cerevisiae that have previously been characterized as regulators of Aft1 localization and therefore of iron homeostasis. In this study, we present data showing that both Grx3 and Grx4 have new roles in actin cytoskeleton remodeling and in cellular defenses against oxidative stress caused by reactive oxygen species (ROS) accumulation. The Grx4 protein plays a unique role in the maintenance of actin cable integrity, which is independent of its role in the transcriptional regulation of Aft1. Grx3 plays an additive and redundant role, in combination with Grx4, in the organization of the actin cytoskeleton, both under normal conditions and in response to external oxidative stress. Each Grx3 and Grx4 protein contains a thioredoxin domain sequence (Trx), followed by a glutaredoxin domain (Grx). We performed functional analyses of each of the two domains and characterized different functions for them. Each of the two Grx domains plays a role in ROS detoxification and cell viability. However, the Trx domain of each Grx4 and Grx3 protein acts independently of its respective Grx domain in a novel function that involves the polarization of the actin cytoskeleton, which also determines cell resistance against oxidative conditions. Finally, we present experimental evidence demonstrating that Grx4 behaves as an antioxidant protein increasing cell survival under conditions of oxidative stress.
Bullying Victimization (Being Bullied) among Adolescents Referred for Urgent Psychiatric Consultation: Prevalence and Association with Suicidality

Objective: To examine the prevalence of bullying victimization among adolescents referred for urgent psychiatric consultation, to study the association between bullying victimization and suicidality, and to examine the relation between different types of bullying and suicidality. Method: A retrospective chart review was conducted for all adolescents referred to a hospital-based urgent consultation clinic. Our study sample consisted of adolescents with a history of bullying victimization. The Research Ethics Board of Queen's University provided approval. Data analysis was conducted using SPSS (IBM SPSS Inc, Armonk, NY). Chi-square tests were used for sex, suicidal ideation, history of physical and sexual abuse, and time and type of bullying, and an independent sample t test was used for age. Results: The prevalence of bullying victimization was 48.5% (182 of 375). There was a significant association between being bullied and suicidal ideation (P = 0.01), and between sex and suicidal ideation (P = 0.001). Victims of cyberbullying reported more suicidal ideation than those who experienced physical or verbal bullying (P = 0.04). Conclusions: Bullying victimization, especially cyberbullying, is associated with increased risk of suicidal ideation among adolescents referred for psychiatric risk assessment. The detailed history of the type and duration of bullying experienced by the victims should be considered when conducting a psychiatric risk assessment.
Modulation of the Transforming Growth Factor-β Signal Transduction Pathway by Hepatitis C Virus Nonstructural 5A Protein*

Transforming growth factor-β (TGF-β) is implicated in the pathogenesis of liver disease. TGF-β is involved both in liver regeneration and in the fibrotic and cirrhotic transformation with hepatitis viral infection. Hepatitis C virus (HCV) infection often leads to cirrhosis and hepatocellular carcinoma. HCV nonstructural 5A (NS5A) protein is a multifunctional protein that modulates cytokine-mediated signal transduction pathways. To elucidate the molecular mechanism of HCV pathogenesis, we examined the effect of NS5A protein on TGF-β-stimulated signaling cascades. We show that NS5A protein inhibited the TGF-β-mediated signaling pathway in hepatoma cell lines as determined by reporter gene assay. To further investigate the role of NS5A, we examined the protein/protein interaction between NS5A and TGF-β signal transducers. Both in vitro and in vivo binding data showed that NS5A protein directly interacted with TGF-β receptor I (TβR-I) in hepatoma cell lines. This interaction was mapped to amino acids 148-238 of NS5A. We also found that NS5A protein co-localized with TβR-I in the cytoplasm of Huh7 cells and inhibited TGF-β-mediated nuclear translocation of Smad2. Furthermore, we demonstrate that NS5A protein abrogated the phosphorylation of Smad2 and the heterodimerization of Smad3 and Smad4. To further explore the relevance to viral infection, we examined the effect of the HCV subgenomic replicon on the TGF-β signaling pathway. We show that the HCV subgenomic replicon also inhibited TGF-β-induced signaling cascades. These results indicate that HCV NS5A modulates TGF-β signaling through interaction with TβR-I and that NS5A may be an important risk factor in HCV-associated liver pathogenesis.
Higher risk behaviour and rates of sexually transmitted diseases in Mwanza compared to Uganda may help explain HIV prevention trial outcomes

Objective: To determine to what extent the higher impact of treatment for sexually transmitted diseases (STD) on HIV incidence in Mwanza, Tanzania than in Rakai and Masaka, Uganda might be explained by baseline differences between the trial populations. Design: A re-analysis of baseline data from the three trial populations comparing demography, sexual risk behaviour and HIV/STD epidemiology. Methods: Data were compared after age-standardization and adjustments for sample selection where necessary. STD rates were also adjusted for the sensitivities and specificities of the diagnostic techniques used. Results: Demographic patterns were similar across populations, apart from effects of AIDS on fertility and mortality (including widowhood) in Uganda. Higher sexual risk behaviours, including younger age of sexual debut, higher numbers of recent partners and lower frequency of condom use, were apparent in Mwanza compared to Masaka and Rakai. High-titre serological syphilis, gonorrhoea, chlamydia infection and trichomoniasis were all more prevalent in Mwanza, except for chlamydia infection in males. There was little difference between sites in the seroprevalence of Herpes simplex virus type-2. Age patterns in the prevalence of short-duration STD and current risk behaviours were similar across sites but all-titre serological syphilis was more prevalent among older participants in Rakai and Masaka than Mwanza. Conclusions: Differences between trial populations included higher reported risk behaviour and higher rates of curable STD in Mwanza compared to Rakai and Masaka. These differences probably relate to previous reductions in risk behaviour in Uganda and may explain, at least in part, the contrasting results of these trials.
Association of bronchial hyperresponsiveness and lung function with C-reactive protein (CRP): a population based study

Background: C-reactive protein (CRP), a marker of systemic inflammation, is a powerful predictor of adverse cardiovascular events. Respiratory impairment is also associated with cardiovascular risk. Although some studies have found an inverse relationship between lung function and markers of systemic inflammation, only one study has reported a relationship between lung function and CRP levels. In contrast, little is known about the relationship between bronchial hyperresponsiveness (BHR) and systemic inflammation. The association between lung function and CRP and between BHR and CRP has been investigated. Methods: As part of the European Community Respiratory Health Survey follow up study serum CRP levels, forced expiratory volume in 1 second (FEV1), and BHR to methacholine (⩾20% decrease in FEV1 to <4 mg methacholine) were measured in 259 adults aged 28–56 years free of cardiovascular disease or respiratory infection. Results: Mean (SD) FEV1 (adjusted for age, sex, height, and smoking status) was lower in subjects with a high CRP level (high tertile) (3.29 (0.44) l/s v 3.50 (0.44) l/s; p<0.001) and BHR was more frequent (41.9% v 24.9%; p = 0.005) than in subjects with lower CRP levels (low+middle tertiles). Similar results were obtained when the potential confounding factors were taken into account. Similar patterns of results were found in non-smokers and in non-asthmatic subjects. Conclusions: Increased CRP levels are strongly and independently associated with respiratory impairment and more frequent BHR. These results suggest that both respiratory impairment and BHR are associated with a systemic inflammatory process.
Cytokeratin Expression at Different Stages in Sweat Gland Development of C57BL/6J Mice

Sweat glands exhibit a documented role in epidermal reepithelialization after wounding. However, the regenerative potential of sweat glands has remained underappreciated due to the absence of useful markers for the analysis of determination and differentiation processes in the developing eccrine sweat gland from epithelium. Although the current knowledge of keratin expression in most of the different origins has been described, it remains widely shared and not unified in eccrine sweat glands of C57BL/6J mice that are commonly used as animal models for sweat gland and wound healing studies, both at the molecular and cellular levels. Aiming to answer this question, we have investigated the changes in cytokeratin expression patterns during the embryonic, neonatal, juvenile, and young adult stages (E12.5, E17.5, P0.5, P5, and P28). In this article, we demonstrate that the morphology of murine sweat gland progenitor cells are similar to epidermal stem cells before birth (E12.5 and E17.5); at postnatal stages, the duct formed gradually and curled to glob. K8 and K19 were expressed in the eccrine sweat gland cells at all times and highly expressed after birth at both gene and protein levels. Also, histological results revealed K8 and K19 positive cells localized in the secretary portion of glands. Meanwhile, K14 strongly expressed both in vivo and in vitro at E12.5, while it weakly expressed at other stages. Moreover, K10 was rarely detected before birth, but it expressed positively in vivo and in vitro only at the protein level after birth. These data indicate the pattern of main cytokeratin expression at different stages during murine sweat gland development and might provide an efficient tool for sweat gland research and exciting potential for developing targeted therapies for wound healing.
Scenario-Based Rewards Management

The turbulent environment of the last two decades has made it difficult to manage employee rewards well. When revenues vary while compensation costs remain fixed it impacts profitability in private sector firms and makes it difficult for public sector entities to remain within budgets. Organizations need to use scenario based planning to develop robust rewards strategies that will work reasonably well in a variety of possible futures. Current strategies and programs should be evaluated to ensure they are sustainable. Alternative approaches to rewarding employees that make rewards costs more variable enables them to be better aligned with revenues.
High expression and anterograde axonal transport of aminoterminal sonic hedgehog in the adult hamster brain

Sonic hedgehog (SHH) is considered to play an important role in tissue induction and patterning during development, particularly in determining neuronal cell fate in the ventral neural tube and in the embryonic forebrain. SHH precursor is autoproteolytically cleaved to an aminoterminal fragment (SHHN) which retains all known SHH biological activities. Here, we demonstrate the expression of a 22‐kDa SHHN immunoreactive peptide in developing and adult hamster brain regions using a rabbit antiserum directed against a mouse SHHN fragment. Interestingly, SHHN was developmentally regulated with the highest expression observed in the adult brain, was resistant to Triton X‐100 solubilization at 4 °C and partitioned with the raft component ganglioside GM1 during density gradient centrifugation. In rat brain, Shh transcripts were identified by double in situ hybridization in GABAergic neurons located in various basal forebrain nuclei including globus pallidus, ventral pallidum, medial septum‐diagonal band complex, magnocellular preoptic nucleus and in cerebellar Purkinje cells as well as in motoneurons of several cranial nerve nuclei and of the spinal cord. We show that radiolabelled SHHN peptides are synthesized in the adult hamster retina and are transported axonally along the optic nerve to the superior colliculus in vivo. Our data indicate that SHHN is associated with cholesterol rich raft‐like microdomains and anterogradely transported in the adult brain, and suggest that the roles of this extracellular protein are more diverse than originally thought.
Association of beta-defensin 1 single nucleotide polymorphisms with Crohn's disease

Objective. It has been suggested that deficient defensin expression is associated with the chronic inflammation of Crohn's disease. The regional localization of Crohn's disease, ileal or colonic disease can be linked to different defensin profiles. As constitutive β-defensin 1 has a colonic expression, we considered it of interest to investigate single nucleotide polymorphisms (SNPs) of the β-defensin 1 gene (DEFB1) in Crohn's disease. Material and methods. Three SNPs of the DEFB1 gene, DEFB1 G-20A (rs11362), DEFB1 C-44G (rs1800972) and DEFB1 G-52A (rs1799946), were genotyped either by Custom TaqMan® SNP genotyping assays or by restriction fragment length polymorphisms (RFLP) in 190 patients with Crohn's disease and 95 Hungarian controls. Results. It was found that the G-20A and C-44G SNPs had a strong association with the colonic and ileocolonic localizations of the disease, respectively, but no association was detected for the ileal localization. A significantly higher frequency of the GA genotype of G-20A was observed among patients with colonic localization (60%) as compared with healthy controls (39%), with an odds ratio (OR) of 2.39. The GG genotype of C-44G SNP, which is regarded as a protective genotype, was much less frequent (4%) among patients than among controls (12%), OR 3.367. Conclusions. These results indicate that genetic variations in the DEFB1 gene encoding constitutive human β-defensin 1 may be associated with the risk for Crohn's disease and may determine disease phenotype, e.g. colonic localization.
Analog-to-Digital Conversion Based on a Voltage-to-Frequency Converter

In this paper we discuss a method of analog-to-digital conversion based on a voltage-to-frequency converter (VFC). The basic principle of a VFC circuit is given in order to derive the exact relationship between the characteristics of the output pulse train and the input voltage. We illustrate this theoretical analysis with an example of a simple VFC circuit. The VFC output signal has to be transformed in a binary number proportional to the VFC input voltage. This is done by a digital circuit interfacing the VFC and the computer and a simple calculation in the computer. Finally, we discuss some elements influencing the quantization error of the conversion.
Approximations of Lyapunov-Krasovskii functionals of complete type with given cross terms in the derivative for the stability of time delay systems

Sufficient conditions expressed in terms of the piecewise linear approximation of the Lyapunov matrix of the time delay system for the derivative condition and the bound condition of the Lyapunov-Krasovskii stability Theorem are provided. These conditions can be utilized to verify if a given constructed Lyapunov matrix or its approximation gives rise to a functional that satisfies the Lyapunov-Krasovskii theorem. They can also be employed in a constructive manner.
Climate change, conflict and health

Summary Future climate change is predicted to diminish essential natural resource availability in many regions and perhaps globally. The resulting scarcity of water, food and livelihoods could lead to increasingly desperate populations that challenge governments, enhancing the risk of intra- and interstate conflict. Defence establishments and some political scientists view climate change as a potential threat to peace. While the medical literature increasingly recognises climate change as a fundamental health risk, the dimension of climate change-associated conflict has so far received little attention, despite its profound health implications. Many analysts link climate change with a heightened risk of conflict via causal pathways which involve diminishing or changing resource availability. Plausible consequences include: increased frequency of civil conflict in developing countries; terrorism, asymmetric warfare, state failure; and major regional conflicts. The medical understanding of these threats is inadequate, given the scale of health implications. The medical and public health communities have often been reluctant to interpret conflict as a health issue. However, at times, medical workers have proven powerful and effective peace advocates, most notably with regard to nuclear disarmament. The public is more motivated to mitigate climate change when it is framed as a health issue. Improved medical understanding of the association between climate change and conflict could strengthen mitigation efforts and increase cooperation to cope with the climate change that is now inevitable.
Influence of the Diadinoxanthin Pool Size on Photoprotection in the Marine Planktonic Diatom Phaeodactylum tricornutum 1

The pool size of the xanthophyll cycle pigment diadinoxanthin (DD) in the diatom Phaeodactylum tricornutum depends on illumination conditions during culture. Intermittent light caused a doubling of the DD pool without significant change in other pigment contents and photosynthetic parameters, including the photosystem II (PSII) antenna size. On exposure to high-light intensity, extensive de-epoxidation of DD to diatoxanthin (DT) rapidly caused a very strong quenching of the maximum chlorophyll fluorescence yield (F m, PSII reaction centers closed), which was fully reversed in the dark. The non-photochemical quenching of the minimum fluorescence yield (F o, PSII centers open) decreased the quantum efficiency of PSII proportionally. For bothF m and F o, the non-photochemical quenching expressed asF/F′ − 1 (with F′ the quenched level) was proportional to the DT concentration. However, the quenching of F o relative to that ofF m was much stronger than random quenching in a homogeneous antenna could explain, showing that the rate of photochemical excitation trapping was limited by energy transfer to the reaction center rather than by charge separation. The cells can increase not only the amount of DT they can produce, but also its efficiency in competing with the PSII reaction center for excitation. The combined effect allowed intermittent light grown cells to down-regulate PSII by 90% and virtually eliminated photoinhibition by saturating light. The unusually rapid and effective photoprotection by the xanthophyll cycle in diatoms may help to explain their dominance in turbulent waters.
Hyperproduction of γ-glutamyl transpeptidase from Bacillus licheniformis ER15 in the presence of high salt concentration

ABSTRACT Background: Microbial γ-glutamyl transpeptidases (GGTs) have been exploited in biotechnological, pharmaceutical, and food sectors for the synthesis of various γ-glutamyl compounds. But, till date, no bacterial GGTs are commercially available in the market because of lower levels of production from various sources. In the current study, production of GGT from Bacillus licheniformis ER15 was investigated to achieve high GGT titers. Results: Hyperproduction of GGT from B. licheniformis ER15 was achieved with 6.4-fold enhancement (7921.2 ± 198.7 U/L) by optimization of culture medium following one-variable-at-a-time strategy and statistical approaches. Medium consisting of Na2HPO4: 0.32% (w/v); KH2PO4: 0.15% (w/v); starch: 0.1% (w/v); soybean meal: 0.5% (w/v); NaCl: 4.0% (w/v), and MgCl2: 5 mM was found to be optimal for maximum GGT titers. Maximum GGT titers were obtained, in the optimized medium at 37°C and 200 rpm, after 40 h. It was noteworthy that GGT production was a linear function of sodium chloride concentration, as observed during response surface methodology. While investigating the role of NaCl on GGT production, it was found that NaCl drastically decreased subtilisin concentration and indirectly increasing GGT recovery. Conclusion: B. licheniformis ER15 is proved to be a potential candidate for large-scale production of GGT enzyme and its commercialization.