Miracle-dz/UniFAR-FTUs huggingface dataset:
Candida albicans Als1p: an adhesin that is a downstream effector of the EFG1 filamentation pathway

Filamentation and adherence to host cells are critical virulence factors of Candida albicans. Multiple filamentation regulatory pathways have been discovered in C. albicans using Saccharomyces cerevisiae as a model. In S. cerevisiae, these pathways converge on Flo11p, which functions as a downstream effector of filamentation and also mediates cell–cell adherence (flocculation). In C. albicans, such effector(s) have not yet been identified. Here, we demonstrate that the cell surface protein Als1p is an effector of filamentation in C. albicans. We show that Als1p expression is controlled by the transcription factor Efg1p, which is known to be a key regulator of filamentation in C. albicans. Further, disruption of ALS1 inhibited filamentation, and autonomous expression of Als1p restored filamentation in an efg1 homozygous null mutant. Thus, Als1p functions as a downstream effector of the EFG1 filamentation pathway. In addition, we found that Als1p mediates both flocculation and adherence of C. albicans to endothelial cells in vitro. As a cell surface glycoprotein that mediates filamentation and adherence, Als1p has both structural and functional similarity to S. cerevisiae Flo11p. Consistent with our in vitro results, Als1p was required for both normal filamentation and virulence in the mouse model of haematogenously disseminated candidiasis.
Redefining Self: Patients’ Decision Making About Treatment for Multiple Sclerosis

ABSTRACT The treatment of multiple sclerosis (MS) has become possible with the advent of disease-modifying therapies, but little is known about patients’ experiences when faced with a complex array of treatment options. The purpose of this phenomenological study was to explore the lived experience of making a first decision about treatment with disease-modifying therapies for relapsing-remitting MS. Nine participants shared their perspectives on negotiating the decision to accept, refuse, or delay treatment. All individuals described a core theme in which decision making about treatment was part of a process of coming to a “redefined self. ” This core theme included reflections about self-image, quality of life, goals, and being a person with MS. Six common themes supporting this core theme were (a) weighing and deciding what’s important, (b) acknowledging the illness as part of oneself, (c) playing the mental game, (d) seeking credible resources, (e) evaluating symptoms and fit with quality of life, and (f) managing the roles and involvement of family. The findings of this study provide a greater understanding about the experience of making a therapeutic choice for those with MS and offer insights for nurses when supporting patients faced with options about treatment.
Adjuvant Treatment of Pancreatic Carcinoma in a Clinically Adapted Mouse Resection Model

Background: The high rate of local recurrence after radical resection of pancreatic adenocarcinoma fosters intensive efforts to develop new approaches for adjuvant treatment. The established animal models show significant limitations in simulating an adjuvant therapeutic setting. For optimal approximation to the clinical situation we therefore improved a murine orthotopic human xenotransplantation model. Methods: Subtotal pancreatectomy in mice was performed after orthotopic inoculation of human pancreatic cancer cells and manifestation of solid tumours. The natural course of disease, tumour growth and metastases were analysed. Gemcitabine as a cytotoxic drug was tested in vitro on the cell line used in this model and the effect of adjuvant treatment with gemcitabine in vivo was investigated. Results: All tumour-resected animals showed local recurrence. Organ metastases occurred in 67% in resected compared to 25% of non-resected animals. Gemcitabine in vitro was ineffective, but as adjuvant monotherapy resulted in a highly significant reduction of tumour weight and metastatic events. Conclusion: Subtotal pancreatectomy for xenotransplanted pancreatic cancer in SCID beige mice is feasible. Due to high rates of local recurrence and increased organ metastases, this model offers a relevant option for preclinical adjuvant testing, especially as in vitro and in vivo effects of cytotoxic drugs differ enormously.
Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR‐ligand mismatch after dose‐reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen‐matched or ‐mismatched unrelated donors. The ATG group had more prior high‐dose chemotherapies (P < 0·001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0·001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0·03) and platelets (P = 0·02) and in a lower incidence of acute graft versus host disease (GvHD) grades II–IV (24% vs. 47%, P = 0·06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%, P = 0·001). The cumulative incidence of treatment‐related mortality at 2 years was 26% [95% confidence interval (CI) = 12–37%] for ATG vs. 28% (95% CI = 15–55%) for alemtuzumab, P = 0·7. There was no significant difference in the estimated 2‐year overall and progression‐free survival between ATG and alemtuzumab: 54% (95% CI: 39–75%) vs. 45% (95% CI: 28–73%) and 30% (95% CI: 16–55%) vs. 36% (95% CI: 20–62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2·37; P = 0·05) while killer immunoglobulin‐like receptor (KIR)‐ligand mismatch was protective for relapse (P < 0·0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR‐ligand mismatched transplantation in multiple myeloma.
Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells

Telomerase reverse transcriptase (TRT) is a tumor-associated antigen expressed in the vast majority of human tumors and is presently one of the most promising target candidates for a therapeutic cancer vaccine. TRT is also expressed at low level in selected tissues and should be considered a self antigen. In the present study we sought to develop cytotoxic T lymphocytes (CTL) responses directed against human (h)TRT peptides with low relative affinity for which the available repertoire is to be preferentially spared from tolerance. This was accomplished by using analogue peptides of hTRT whose relative affinity for the MHC was increased by a targeted (→Tyr) substitution in position one. By immunizing HLA A2.1 transgenic mice with these analogue peptides, we identified one such low relative affinity peptide (p572) that is endogenously processed and presented by HLA A2.1 in tumor cells, and is recognized by specific CTL. We used the highly immunogenic analogue peptide to successfully induce TRT-specific CTL in cancer patients and normal donors. CTL against p572-lysed human and mouse tumor cells but not activated autologous B cells. This peptide represents, therefore, an important candidate component of a cancer vaccine based on a TRT substrate and validates the strategy of targeting peptides with low affinity for the MHC for cancer immunotherapy.
Contractile properties of the human diaphragm during chronic hyperinflation.

BACKGROUND In patients with chronic obstructive pulmonary disease (COPD) and hyperinflation of the lungs, dysfunction of the diaphragm may contribute to respiratory decompensation. We evaluated the contractile function of the diaphragm in well-nourished patients with stable COPD, using supramaximal, bilateral phrenic-nerve stimulation, which provides information about the strength and inspiratory action of the diaphragm. METHODS In eight patients with COPD and five control subjects of similar age, the transdiaphragmatic pressure generated by the twitch response to phrenic-nerve stimulation was recorded at various base-line lung volumes, from functional residual capacity to total lung capacity, and during relaxation and graded voluntary efforts at functional residual capacity (twitch occlusion). RESULTS At functional residual capacity, the twitch transdiaphragmatic pressure ranged from 10.9 to 26.6 cm of water (1.07 to 2.60 kPa) in the patients and from 19.8 to 37.1 cm of water (1.94 to 3.64 kPa) in the controls, indicating considerable overlap between the two groups. The ratio of esophageal pressure to twitch transdiaphragmatic pressure, an index of the inspiratory action of the diaphragm, was -0.50 +/- 0.05 in the patients, as compared with -0.43 +/- 0.02 in the controls (indicating more efficient inspiratory action in the patients than in the controls). At comparable volumes, the twitch transdiaphragmatic pressure and esophageal-to-transdiaphragmatic pressure ratio were higher in the patients than in normal subjects, indicating that the strength and inspiratory action of the diaphragm in the patients were actually better than in the controls. Twitch occlusion (a measure of the maximal activation of the diaphragm) indicated near-maximal activation in the patients with COPD, and the maximal transdiaphragmatic pressure was 106.9 +/- 13.8 cm of water (10.48 +/- 1.35 kPa). CONCLUSIONS The functioning of the diaphragms of the patients with stable COPD is as good as in normal subjects at the same lung volume. Compensatory phenomena appear to counterbalance the deleterious effects of hyperinflation on the contractility and inspiratory action of the diaphragm in patients with COPD. Our findings cast doubt on the existence of chronic fatigue of the diaphragm in such patients and therefore on the need for therapeutic interventions aimed at improving diaphragm function.
Children's perspectives on how parents protect them from secondhand smoke in their homes and cars in socioeconomically contrasting communities: a qualitative study.

INTRODUCTION Children are particularly vulnerable to the health effects of secondhand smoke (SHS) and are mainly exposed in the home and the car. Reducing children's SHS exposure is a tobacco control goal, yet few studies have explored children's perspectives on SHS. This study examines children's accounts of the strategies family members employ to protect them from SHS and is the first to examine how these may be constrained or facilitated in communities with contrasting smoking prevalence rates. METHODS Individual, paired, and group interviews using topic guides and visual stimulus methods were conducted with 38 children aged 10-15 years who lived in 2 Scottish communities of contrasting socioeconomic status and had a close family member who smoked. Transcripts were analyzed thematically. RESULTS Parents were reported to employ spatial and dispersal measures to reduce children's SHS exposure in homes and cars. Smoking was restricted to certain rooms and to times when those considered more vulnerable were absent. Less distance between smokers and children and more smoking in the home were reported in the disadvantaged community, reflecting less space within homes and greater parental smoking. Participants expressed strong negative views about smoking in cars and the perceived ineffectiveness of dispersal measures in this context. CONCLUSIONS Although there was general awareness that SHS exposure was potentially harmful, SHS in the home was considered safe by some participants if certain conditions were met, particularly by those from the disadvantaged area. The implications of these findings for tobacco control programs and media campaigns, particularly those targeted at disadvantaged groups, are discussed.
DNA Methylation in Tumor and Matched Normal Tissues from Non-Small Cell Lung Cancer Patients

We used MethyLight assays to analyze DNA methylation status of 27 genes on 49 paired cancerous and noncancerous tissue samples from non-small cell lung cancer (NSCLC) patients who underwent surgical resection. Seven genes (RARB, BVES, CDKN2A, KCNH5, RASSF1, CDH13, and RUNX) were found to be methylated significantly more frequently in tumor tissues than in noncancerous tissues. Only methylation of CCND2 and APC was frequently detected in both cancerous and noncancerous tissues, supporting the hypothesis that the methylation of these two genes is a preneoplastic change and may be associated with tobacco smoking exposure. Methylation of any one of eight genes (RASSF1, DAPK1, BVES, CDH13, MGMT, KCNH5, RARB, or CDH1) was present in 80% of NSCLC tissues but only in 14% of noncancerous tissues. Detection of methylation of these genes in blood might have utility in monitoring and detecting tumor recurrence in early-stage NSCLC after curative surgical resection. (Cancer Epidemiol Biomarkers Prev 2008;17(3):645–54)
Mitotic Histone H3 Phosphorylation by Vaccinia-Related Kinase 1 in Mammalian Cells

ABSTRACT Mitotic chromatin condensation is essential for cell division in eukaryotes. Posttranslational modification of the N-terminal tail of histone proteins, particularly by phosphorylation by mitotic histone kinases, may facilitate this process. In mammals, aurora B is believed to be the mitotic histone H3 Ser10 kinase; however, it is not sufficient to phosphorylate H3 Ser10 with aurora B alone. We show that histone H3 is phosphorylated by vaccinia-related kinase 1 (VRK1). Direct phosphorylation of Thr3 and Ser10 in H3 by VRK1 both in vitro and in vivo was observed. Loss of VRK1 activity was associated with a marked decrease in H3 phosphorylation during mitosis. Phosphorylation of Ser10 by VRK1 is similar to that by aurora B. Moreover, expression and chromatin localization of VRK1 depended on the cell cycle phase. Overexpression of VRK1 resulted in a dramatic condensation of nuclei. Our findings collectively support a role of VRK1 as a novel mitotic histone H3 kinase in mammals.
Long-term outcome in intensive care unit survivors after mechanical ventilation for intracerebral hemorrhage

ObjectiveTo evaluate long-term survival and functional outcome in intensive care unit survivors after mechanical ventilation for intracerebral hemorrhage. DesignRetrospective chart review and prospective follow-up study. SettingOutpatient follow-up. PatientsBetween 1997 and 2000, 120 patients were mechanically ventilated for an intracerebral hemorrhage at our intensive care unit. Sixty-two patients were discharged from hospital (in-hospital mortality = 48%). Sixty patients were evaluated for survival and functional outcome (two were lost to follow-up). Time between discharge and follow-up was ≥1 yr and was a mean of 27 ± 14 months (range, 12–56). InterventionsNone. Measurements and Main ResultsPatients’ physicians were first asked about survival, and patients or proxies were interviewed by phone. Barthel Index and modified Rankin Scale scores were collected, and demographic information and general data were reviewed. The estimated life-table survival curve after discharge was 64.6% at 1 yr and 57% at 3 yrs. In the 24 patients who died, the mean time between discharge and death was 5 ± 6 months. Probability of death after discharge significantly increased if age at admission was >65 yrs (p < .01; odds ratio, 3.5; 95% confidence interval, 1.4–9.1) and if Glasgow Coma Scale score at discharge was <15 (p < .01; odds ratio, 3.9; 95% confidence interval, 1.6–9.5). In the 36 long-term survivors, Barthel Index was 67.5 ± 15 (median ± median absolute dispersion) and modified Rankin Scale score was 2.6 ± 0.5. Fifteen patients (42%) had a slight or no disability (Barthel Index ≥90 and modified Rankin Scale score ≤2), whereas 21 patients (58%) had moderate or severe disability (Barthel Index ≤85 and modified Rankin Scale score >2). ConclusionsProbability of survival at 3 yrs after mechanical ventilation for an intracerebral hemorrhage was >50%. Age was an important determinant of long-term survival. Forty-two percent of long-term survivors were independent for activities of daily living. Only a few long-term survivors had a very high degree of disability.
Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10–Dependent Apoptosis by Carfilzomib and Selinexor

Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line–derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers. Mol Cancer Ther; 15(1); 60–71. ©2015 AACR.
Response of naked neck (Nana) and normal (nana) broiler chickens to dietary energy levels in a subtropical climate

1. The comparative response of naked neck (Nana) broiler chickens and their normally feathered (nana) full sibs to varied dietary energy levels was assessed under natural ambient conditions in a subtropical climate in two separate trials, one in winter (19·0 to 26·0°C) and the other in summer (28·1 to 37·4°C). 2. The chickens were fed on diets with 10·9, 11·5 or 12·1 MJ ME/kg and with a constant protein content of 200 g/kg from 1 to 42 d of age. 3. Both genotypes showed similar body weight, food intake and food conversion efficiency at 42 d of age. Body weight and food conversion efficiency improved on the diet with the highest energy content. 4. Apparent retention (AR) of crude protein (CP) was higher in nana chickens than in their Nana sibs in the winter trial, while no differences were observed for AR of dry matter (DM), crude fibre (CF), ether extract (EE) or calcium. In the summer trial, no difference in nutrient retention was seen between the genotypes. Increasing dietary energy had a positive influence on AR of DM, CP and EE. 5. The relative weights of feathers and skin were lower in Nana chickens than in their normal counterparts. Ready-to-cook yields were greater at the high dietary energy content, while abdominal fat increased with increasing energy content. Nana chickens had more skin protein and less fat in breast muscle and skin than their normal sibs in the summer trial. 6. It was concluded that the Nana broiler chickens showed similar performance and did not differ in dietary energy requirements in comparison to their nana sibs under natural ambient conditions in a subtropical climate.
Muscle co-activation and its influence on running performance and risk of injury in elite Kenyan runners

ABSTRACT The relationship between muscle co-activation and energy cost of transport and risk of injury (initial loading rate and joint stiffness) has not been jointly studied. Fourteen elite Kenyan male runners were tested at two speeds (12 and 20 km · h−1), where oxygen consumption, kinematic, kinetic and electromyography were recorded. Electromyography of seven lower limb muscles was recorded. Pre-activation and ground contact of agonist:antagonist co-activation was determined. All muscles displayed higher activity during pre-activation except rectus femoris (RF). Conversely, no differences were found during ground contact except for higher biceps femoris (BF) at 20 km · h−1. Knee stiffness was correlated to RF–BF co-activation during both pre-activation and ground contact at both running speeds. However, energy cost of transport was only positively correlated to the above-mentioned muscle pairs at 20 km · h−1 (r = 0620, P = 0.032; r = 0.682, P = 0.015, respectively). These findings emphasise the influence of neuromuscular control and performance and its support to musculoskeletal system to optimise function and modulate risk of injury. Further, neuromuscular activity during terminal swing is also important and necessary to execute and maintain performance.
Bidirectional isolated ZVS DC-DC converter with auxiliary active switch for high-power energy storage applications

This paper describes topology and control algorithm of a bidirectional isolated converter with controlled semiconductors at the voltage-fed and current-fed parts. A bidirectional switch connected in series with the transformer winding at the current-fed side features zero-current switching and allows achieving zero-voltage-switching of transistors at the voltage-fed side by utilising leakage inductance of the isolated transformer. The topology is proposed for high power battery or fuel cell systems. The proposed ideas are verified with simulations in MATLAB and evaluation prototype.
Long‐term effects of in utero and lactational exposure to butyl paraben in female rats

Parabens are used as preservatives in cosmetic, pharmaceutical, and food industries, and are frequently detected as contaminants in human fluids and tissues. The endocrine disrupting effects of parabens in female rodents include uterotrophic response, steroidogenesis impairment, and ovarian disturbances. The objective of this study was to determine the effects of maternal butyl paraben (BP) exposure on female sexual development. Pregnant Wistar rats were treated subcutaneously with either corn oil or BP at doses of 10, 100, or 200 mg/kg, from gestational day (GD) 12 until GD 20 for female foetal gonad evaluation, and from GD 12 until the end of lactation to evaluate sexual parameters on the female offspring. Immature female rats were also used in the uterotrophic assay to evaluate the possible estrogenic action of parabens. Our results revealed that, in this experimental protocol, BP did not show estrogenic activity at the doses used and did not impair sexual development and fertility capacity in the female rats, but impaired sexual behavior. We conclude that brain sexual development may be more sensitive to BP effects and we speculate that doses higher than 100 mg/kg (the male lowest observed adverse effect level (LOAEL) for rodent reproductive parameters) would be necessary to promote damages in the female reproduction, regarding the same protocol of exposure. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 776–788, 2017.