Miracle-dz/UniFAR-FTUs huggingface dataset:
Ganetespib radiosensitization for liver cancer therapy

ABSTRACT Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33–1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies.
Scrub typhus Meningoencephalitis in Children from aTertiary Care Centre, Uttarakhand, India

Meningoencephalitis, a potentially fatal complication of scrub typhus is known to occur but has not been well documented in children. Objectives: To document the epidemiological, clinical and laboratory parameters of scrub typhus meningoencephalitis in children to help the clinician in clinching the diagnosis of scrub typhus infection from Kumaon region. Materials and methods: This is a prospective one year study (June 2015 to July 2016) in which epidemiological, clinical, laboratory profile and detail of cerebrospinal fluid (CSF) analysis and outcome of the scrub typhus meningoencephalitis cases were recorded. Diagnosis of scrub typhus was confirmed by positive IgM Enzyme Linked Immune Sorbent assay (ELISA), IgM Immuno Fluorescence Assay (IFA) and/ or by nested polymerase chain reaction (PCR). Results: A total of 13 children (<18years) presenting with fever, headache and neck rigidity were confirmed as scrub typhus meningoencephalitis during post monsoon season. Myalgia, facial suffusion, seizures, altered sensorium and eschar were found in 84%, 46%, 23%, 30.1% and 15.4% of patients, respectively. Renal, respiratory and gastrointestinal (GIT) involvements were observed in 46%, 61.54%, and 75% of patients respectively. Splenomegaly was seen in 7(53.8%) of patients. Thrombocytopenia (92.3%) and raised transaminase (100%) along with CSF lymphocytosis (100%) were consistent findings. Mean CSF protein, cells and sugar were 80 mg/dl, 27cells/cumm and 63.8 mg/dl respectively. All patients had received azithromycin or doxycyclineand outcome was favorable. Conclusion: In hilly areas scrub typhus should be considered as one of the differential diagnosis in children with suspected aseptic meningoencephalitis, especially when accompanied with raised transaminase level and thrombocytopenia.
Patterns of molecular evolution in pathogenesis-related proteins

The genes encoding 13 classes of pathogenesis-related (PR) proteins were examined for positive selection using maximum-likelihood (ML) models of codon substitution. The study involved 194 sequences from 54 species belonging to 37 genera. Although the sizes of the sequences examined varied from 237 bp for PR12 to 1,110 bp for PR7, most classes (9 out of 13) contained sequences made up of more than 400 nucleotides. Signs of positive selection were obtained for sites in PR proteins 4, 6, 8, 9 and 15 using an ML-based Bayesian method and likelihood ratio tests. These results confirm the importance of positive selection in proteins related to defense mechanisms already observed in a wide array of organisms.
Molecular Regulation of Temperature-Dependent Floral Induction in Tulipa gesneriana1

Identification of putative regulatory genes in the ambient temperature flowering time pathway of tulip highlights several orthologs in Arabidopsis flowering control. The vegetative-to-reproductive phase change in tulip (Tulipa gesneriana) is promoted by increasing temperatures during spring. The warm winters of recent years interfere with this process and are calling for new adapted cultivars. A better understanding of the underlying molecular mechanisms would be of help, but unlike the model plant Arabidopsis (Arabidopsis thaliana), very little is known about floral induction in tulip. To shed light on the gene regulatory network controlling flowering in tulip, RNA sequencing was performed on meristem-enriched tissue collected under two contrasting temperature conditions, low and high. The start of reproductive development correlated with rounding of the shoot apical meristem and induction of TGSQA expression, a tulip gene with a high similarity to Arabidopsis APETALA1. Gene Ontology enrichment analysis of differentially expressed genes showed the overrepresentation of genes potentially involved in floral induction, bulb maturation, and dormancy establishment. Expression analysis revealed that TERMINAL FLOWER1 (TgTFL1) and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1-like1 (TgSOC1-like1) might be repressors, whereas TgSOC1-like2 likely is an activator, of flowering. Subsequently, the flowering time-associated expression of eight potential flowering time genes was confirmed in three tulip cultivars grown in the field. Additionally, heterologous functional analyses in Arabidopsis resulted in flowering time phenotypes in line with TgTFL1 being a floral repressor and TgSOC1-like2 being a floral activator in tulip. Taken together, we have shown that long before morphological changes occur in the shoot apical meristem, the expression of floral repressors in tulip is suppressed by increased ambient temperatures, leading either directly or indirectly to the activation of potential flowering activators shortly before the commencement of the phase change.
The Action of Sevoflurane on Vascular Smooth Muscle of Isolated Mesenteric Resistance Arteries (Part 2): Mechanisms of Endothelium-independent Vasorelaxation

Background The precise mechanisms behind the direct inhibitory action of sevoflurane on vascular smooth muscle have not been fully elucidated. Methods Endothelium-denuded smooth muscle strips were prepared from rat small mesenteric arteries. Isometric force and intracellular Ca2+ concentration ([Ca2+]i) were measured simultaneously in the fura-2–loaded strips. In another series of experiments, only isometric force was measured in the &bgr;-escin-membrane–permeabilized strips. Results Sevoflurane (3–5%) inhibited the increases in both the [Ca2+]i and the force induced by either norepinephrine (0.5–10 &mgr;m) or 40 mm K+. Sevoflurane still inhibited the increase in [Ca2+]i induced by norepinephrine after depletion of intracellular Ca2+ stores with ionomycin, although it little influenced the increase in [Ca2+]i induced by norepinephrine after treatment with verapamil. In the fura-2–loaded membrane-intact muscle, sevoflurane caused a rightward shift of Ca2+-force relation during force development to stepwise increment of extracellular Ca2+ concentration during 40-mm K+ depolarization in either the presence or the absence of norepinephrine. In contrast, sevoflurane did not influence Ca2+-activated contraction in the &bgr;-escin–permeabilized muscle, in which &agr;-adrenergic receptor coupling was not retained. Conclusions The inhibitory effects of sevoflurane on both norepinephrine- and potassium chloride (KCl)–induced contractions are caused by reduction of [Ca2+]i in vascular smooth muscle and inhibition of the myofilament Ca2+ sensitivity. The [Ca2+]i-reducing effect of sevoflurane observed in both the norepinephrine- and the K+-stimulated muscle is mainly caused by inhibition of voltage-gated Ca2+ influx. The inhibitory effect of sevoflurane on Ca2+ activation of contractile proteins seems to be mediated by the cell membrane or by some diffusible substances that are lost in the &bgr;-escin–permeabilized cells.
PilR, a Transcriptional Regulator for Pilin and Other Genes Required for Fe(III) Reduction in Geobacter sulfurreducens

Growth using Fe(III) as a terminal electron acceptor is a critical physiological process in Geobacter sulfurreducens. However, the mechanisms of electron transfer during Fe(III) reduction are only now being understood. It has been demonstrated that the pili in G. sulfurreducens function as microbial nanowires conducting electrons onto Fe(III) oxides. A number of c-type cytochromes have also been shown to play important roles in Fe(III) reduction. However, the regulatory networks controlling the expression of the genes involved in such processes are not well known. Here we report that the expression of pilA, which encodes the pilistructural protein, is directly regulated by a two-component regulatory system in which PilR functions as an RpoN-dependent enhancer binding protein. Surprisingly, a deletion of the pilR gene affected not only insoluble Fe(III) reduction, which requires pili, but also soluble Fe(III) reduction, which, in contrast, does not require pili. Gene expression profiling using whole-genome DNA microarray and quantitative RT-PCR analyses obtained with a PilR-deficient mutant revealed that the expression of pilA and other pilin-related genes are downregulated, while many c-type cytochromes involved in Fe(III) reduction were differentially regulated. This is the first instance of an enhancer binding protein implicated in regulating genes involved in Fe(III) respiratory functions.
Impact of weight loss and eating difficulties on health‐related quality of life up to 10 years after oesophagectomy for cancer

Severe weight loss is experienced by patients with eating difficulties after surgery for oesophageal cancer. The aim of this prospective cohort study was to asssess the influence of eating difficulties and severe weight loss on health‐related quality of life (HRQoL) up to 10 years after oesophagectomy.
Heart rate, health, and hurtful behavior.

Hostility is a risk factor for cardiovascular events. When challenged, individuals high on hostility exhibit a hyperreactive psychophysiological response to stressors, thereby increasing risk for developing cardiovascular disease. However, low resting heart rate (HR) is associated with physical aggression and hostility in children, adolescents, and adults. Based on a community sample of 296 men (mean age = 32.0), we (a) address whether aggression/hostility relates to physical health through relationships with cardiovascular levels at rest and in response to stressors, and (b) determine how relations between aggression and health are altered by including psychophysiological indices in statistical models. The Cook-Medley cynical/hostile attitudes and the Buss-Perry physical aggression and hostility measures assessed aggression. Health was assessed as systolic blood pressure (SBP), report of medical conditions, and a metabolic composite. Reactivity to stressors was assessed with HR, SBP, and diastolic blood pressure. Aggression was negatively related to both resting HR and reactivity. High resting HR and reactivity were, however, positively related to poor health. Thus, the relationship between aggression and HR and reactivity suppressed an overall relationship between high aggression/hostility and poor health. In the presence of covariates for socioeconomic status, race, health behaviors, and medications, the relationship between aggression and health was significantly strengthened when HR level and reactivity were included in models. In sum, at early midlife, low HR among aggressive and hostile individuals is related to less health risk. Aggression and hostility have a deleterious influence on health, but primarily among individuals with higher HR and possibly greater cardiovascular reactivity.
Measuring the Natural Rate of Interest: International Trends and Determinants

U.S. estimates of the natural rate of interest – the real short-term interest rate that would prevail absent transitory disturbances – have declined dramatically since the start of the global financial crisis. For example, estimates using the Laubach-Williams (2003) model indicate the natural rate in the United States fell to close to zero during the crisis and has remained there through the end of 2015. Explanations for this decline include shifts in demographics, a slowdown in trend productivity growth, and global factors affecting real interest rates. This paper applies the Laubach-Williams methodology to the United States and three other advanced economies – Canada, the Euro Area, and the United Kingdom. We find that large declines in trend GDP growth and natural rates of interest have occurred over the past 25 years in all four economies. These country-by-country estimates are found to display a substantial amount of comovement over time, suggesting an important role for global factors in shaping trend growth and natural rates of interest.
Exploring the benefits of respite services to family caregivers: methodological issues and current findings

ABSTRACT Objectives: There is growing emphasis on empirical validation of the efficacy of community-based services for older people and their families, but research on services such as respite care faces methodological challenges that have limited the growth of outcome studies. We identify problems associated with the usual research approaches for studying respite care, with the goal of stimulating use of novel and more appropriate research designs that can lead to improved studies of community-based services. Method: Using the concept of research validity, we evaluate the methodological approaches in the current literature on respite services, including adult day services, in-home respite and overnight respite. Results: Although randomized control trials (RCTs) are possible in community settings, validity is compromised by practical limitations of randomization and other problems. Quasi-experimental and interrupted time series designs offer comparable validity to RCTs and can be implemented effectively in community settings. Conclusion: An emphasis on RCTs by funders and researchers is not supported by scientific evidence. Alternative designs can lead to development of a valid body of research on community services such as respite.
Associations of smoking with cardiometabolic profile and renal function in a Romanian population-based sample from the PREDATORR cross-sectional study

Abstract Background: The impact of smoking on morbidity is well known, but in Romania, limited data are available regarding the smoking prevalence and relationship with cardiometabolic profile and kidney function. Objectives: To assess the association of smoking with cardiometabolic traits and kidney function, in a Romanian population-based sample from the PREDATORR study. Methods: PREDATORR was an epidemiological cross-sectional study. Between 2012 and 2014, participants were randomly selected from the lists of general practitioners and enrolled if they were aged 20 to 79 years, born and living in the past 10 years in Romania. Sociodemographic and lifestyle characteristics were collected through interviewer-administered questionnaires. Results: Overall, 2704 participants were included in the analysis, 18% of them being current smokers and 30.8% former smokers. Current smokers compared to non-smokers had higher total cholesterol (220.6 ± 50.4 versus 213.9 ± 86.8 mg/dl, P = 0.017), LDL-cholesterol (137.8 ± 45.2 versus 130.7 ± 83.7 mg/dl, P = 0.004) and glomerular filtration rate (96.9 ± 16.8 versus 90.7 ± 19.1 ml/min/1.73 m2, P <0.001) in women and higher triglycerides (170.7 ± 129.8 versus 144.3 ± 94.2 mg/dl, P = 0.007), glomerular filtration rate (97.6 ± 17 versus 90.3 ± 18 ml/min/1.73 m2, P < 0.001) and lower HDL-cholesterol (48 ± 15.5 versus 50.4 ± 14.1 mg/dl, P = 0.002) in men. Active smoking was associated with hypercholesterolaemia [OR: 1.40 (95% CI: 1.01–1.96), P = 0.04] and low HDL-cholesterolaemia [OR: 1.39 (95% CI: 1.01–1.91), P = 0.04] and negatively associated with overweight/obesity [OR: 0.67 (95% CI: 0.48–0.94), P = 0.02]. Male former smokers had higher prevalence of abdominal obesity (82.4% versus 76.4%, P = 0.02), hypertriglyceridaemia (43.6% versus 35.6%, P = 0.01), hypertension (64% versus 56.4%, P = 0.01) and ischaemic vascular disease (40.5% versus 30.9%, P = 0.003) than male non-smokers. Conclusion: The PREDATORR study showed a high prevalence of smoking in the adult Romanian population providing data on the association of smoking with cardiometabolic traits.
Prevalence of Work Related Musculoskeletal Disorders Among Physicians, Surgeons and Dentists: A Comparative Study

Background: Work related musculoskeletal disorders (MSDs) are one of the common occupational hazards among health care providers. Aim: The objective of this study was to evaluate MSDs in terms of perception of pain experienced by physicians, surgeons and dental surgeons during professional work. Subjects and Methods : The study was conducted with 100 physicians practicing either modern or alternative medicine, 100 surgeons of various specialties and 100 dental surgeons. Self-reporting work related questionnaire on MSDs were distributed, including information on the location of MSD symptoms in the past 12 months and the pain experienced. Results: Musculoskeletal pain was most prevalent among dentists 61% (61/100), followed by surgeons 37% (37/100) and physicians 20% (20/100). Nearly 15% of physicians (3/20), 40% (15/37) of Surgeons and 60% (35/61) of Dentists had MSD problems in more than one site. Conclusion: Within the limitations of the study, there is a higher prevalence of MSDs experienced by dental surgeons than physicians and surgeons. More research is needed on musculoskeletal problems with dental surgeons and other specialty doctors with an emphasis on a larger sample sizes and correlating other factors such as age and sex of the doctor, duration of practice, working hours per week, physical activity and working environment.
A spatio-temporal analysis of forest loss related to cocaine trafficking in Central America

A growing body of evidence suggests that criminal activities associated with drug trafficking networks are a progressively important driver of forest loss in Central America. However, the scale at which drug trafficking represents a driver of forest loss is not presently known. We estimated the degree to which narcotics trafficking may contribute to forest loss using an unsupervised spatial clustering of 15 spatial and temporal forest loss patch metrics developed from global forest change data. We distinguished anomalous forest loss from background loss patches for each country exhibiting potential ‘narco-capitalized’ signatures which showed a statistically significant dissimilarity from other patches in terms of size, timing, and rate of forest loss. We also compared annual anomalous forest loss with the number of cocaine shipments and volume of cocaine seized, lost, or delivered at country- and department-level. For Honduras, results from linear mixed effects models showed a highly significant relationship between anomalous forest loss and the timing of increased drug trafficking (F = 9.90, p = 0.009) that also differed significantly from temporal patterns of background forest loss (t-ratio = 2.98, p = 0.004). Other locations of high forest loss in Central America showed mixed results. The timing of increased trafficking was not significantly related to anomalous forest loss in Guatemala and Nicaragua, but significantly differed in patch size compared to background losses. We estimated that cocaine trafficking could account for between 15% and 30% of annual national forest loss in these three countries over the past decade, and 30% to 60% of loss occurred within nationally and internationally designated protected areas. Cocaine trafficking is likely to have severe and lasting consequences in terms of maintaining moist tropical forest cover in Central America. Addressing forest loss in these and other tropical locations will require a stronger linkage between national and international drug interdiction and conservation policies.
Influence of Water Content on Frequency Domain Spectroscopy Characteristics of Transformer Oil and Insulation Paper

As a non-destructive electrical diagnostic technique,frequency domain spectroscopy is quite applicable to field diagnosis of the state of transformer insulation.Considering the great hazard of water content to transformer oilpaper insulation system,the influences of water content on dielectric properties of mineral oil and different kinds of oil-impregnated papers,as well as comparison of dielectric properties for plain paper,insulation pressboard,and thermal upgraded paper with the same water content,are studied with the help of the Concept 80 broadband dielectric spectroscopy measurement system.Results show that the dielectric properties of mineral oil-paper samples are remarkably affected by water content.The DC conductivity of mineral oil increases exponentially with water content;at the frequency range of 10-3～10-1 Hz,the real part of complex permittivity for oil-impregnated paper increases linearly with moisture content.Therefore,with the help of dissipation factor(DC conductivity)of insulation oil,as well as the real part of complex permittivity of insulation papers,water content of transformer oil and oil-impregnated paper can be diagnosed,respectively.
Oncogenic PI3K and its role in cancer

Purpose of review The purpose of this review is to examine the contribution of the PI3K signaling pathway to the development of human tumors and to propose further studies to elucidate how to develop therapeutics for patients with mutations in this pathway. Recent findings More than 30% of various solid tumor types were recently found to contain mutations in PIK3CA, the catalytic subunit of PI3K. Further analysis of key genes in this pathway identified an additional eight genes altered in tumors. These were generally found to be mutated in a mutually exclusive manner, thus increasing the mutation frequency of the pathway to 40% in colorectal cancers and emphasizing the importance of the PI3K pathway in tumorigenesis. Functional analyses of PIK3CA mutations revealed that they increase its enzymatic activity, stimulate AKT signaling, allow growth factor-independent growth as well as increasing cell invasion and metastasis. Summary The PI3K signaling pathway is dysregulated by a variety of mechanisms in a large fraction of human tumors. Both mutational and functional analyses have shown that PIK3CA is an oncogene that plays an important role in tumor progression. Mutant members of the PI3K pathway, including PIK3CA, are good targets for therapeutic intervention because most of them are kinases, making them attractive for drug development. Gaining further insights into PIK3CA oncogenic mechanisms may produce new biomarkers and help the development of targeted therapeutics.