Miracle-dz/UniFAR-FTUs huggingface dataset:
STIM, ORAI AND TRPC CHANNELS IN THE CONTROL OF CALCIUM ENTRY SIGNALS IN SMOOTH MUSCLE

1 Ca2+ entry signals are crucial in the control of smooth muscle contraction. Smooth muscle cells are unusual in containing plasma membrane (PM) Ca2+ entry channels that respond to voltage changes, receptor activation and Ca2+ store depletion. 2 Activation of these channel subtypes is highly coordinated. The TRPC6 channel, widely expressed in most smooth muscle cell types, is largely non‐selective to cations and is activated by diacylglycerol arising from receptor‐induced phosholipase C activation. 3 Receptor activation results largely in Na+ ion movement through TRPC6 channels, depolarization and subsequent activation of voltage‐dependent L‐type Ca2+ channels. The TRPC6 channels also appear to be activated by mechanical stretch, resulting again in depolarization and L‐type Ca2+ channel activation. Such a coupling may be crucial in mediating the myogenic tone response in vascular smooth muscle. 4 The emptying of stores mediated by inositol 1,4,5‐trisphosphate receptors triggers the endoplasmic reticulum (ER) Ca2+ sensing protein stromal‐interacting molecule (STIM) 1 to translocate into defined ER–PM junctional areas in which coupling occurs to Orai proteins, which serve as highly Ca2+‐selective low‐conductance Ca2+ entry channels. 5 These ER‐PM junctional domains may serve as crucial sites of interaction and integration between the function of store‐operated, receptor‐operated and voltage‐operated Ca2+ channels. The STIM, Orai and TRPC channels represent highly promising new pharmacological targets through which such control may be induced.
Cytotoxic effect of Shiga toxin-1 on human proximal tubule cells.

BACKGROUND Cytolytic Shiga toxins (Stx) are believed to be largely responsible for renal damage in post-diarrheal hemolytic-uremic syndrome (D + HUS). Despite the general belief that endothelial cells are the primary target of Stx, there is evidence that proximal tubules may be a site of toxin action. We hypothesized that cultured proximal tubular cells are sensitive to the cytotoxic effects of Stx. METHODS Cultured human proximal tubular cells were exposed to Stx-1 in the presence and absence of a variety of inflammatory factors likely to be elevated in the kidney or serum of patients with D + HUS. Cell survival, protein synthesis, total cell levels and synthesis of Stx receptors (GB3), and Stx binding were measured. RESULTS Proximal tubules were extremely sensitive to the cytotoxic effect of Stx-1 with an LD50 at least equal to, if not less than, that seen with Vero cells. Interleukin-1 (IL-1), lipopolysaccharide (LPS), and butyrate (but not tumor necrosis factor or interleukin-6) up-regulated proximal tubule sensitivity to Stx-1. IL-1 increased Stx-1 binding, but did not alter total cell levels or synthesis of GB3, the glycosphingolipid receptor for Stx-1. In contrast, LPS and butyrate, despite increasing Stx-1 sensitivity, had no effect on Stx-1 binding. CONCLUSIONS These studies indicate that proximal tubules are exquisitely sensitive to Stx-1 cytotoxicity and that inflammatory factors can increase toxin responsiveness through a variety of mechanisms. It is suggested that proximal tubules may be an important early target of Stx-1 action in D + HUS.
Rejection of porcine islet xenografts mediated by CD4+ T cells activated through the indirect antigen recognition pathway

Olack BJ, Jaramillo A, Benshoff ND, Kaleem Z, Swanson CJ, Lowell JA, Mohanakumar T. Rejection of porcine islet xenografts mediated by CD4+ T cells activated through the indirect antigen recognition pathway. Xenotransplantation 2002; 9: 393–401. © Blackwell Munksgaard, 2002
Comparison of Three Popular Exercise Modalities on V˙O2max in Overweight and Obese.

INTRODUCTION In this prospective randomized trial, we examined the effect of three popular exercise training modalities on maximal oxygen uptake (V˙O2max) in overweight and obese individuals. In addition, we examined possible concomitant adaptations in endurance exercise performance (time to exhaustion (TTE)), citrate synthase (CS) activity, venous and arterial function, blood volume, and calculated stroke volume (SV). METHODS Thirty subjects were recruited (age, 41 ± 9 yr; weight, 91 ± 14 kg; height, 173 ± 8 cm; body mass index, 30 ± 4 kg·m(-2)) and randomized to either 6 wk of 4 × 4-min high-intensity interval training (4HIIT) at 85%-95% of HRmax, 10 × 1-min HIIT (1HIIT) at V˙O2max load, or 45-min moderate-intensity continuous training (MICT) at 70% of HRmax. V˙O2max, TTE, CS activity, venous and arterial function, as well as blood volume were measured before and after the training period. O2 pulse was calculated and used to estimate SV. Analysis was conducted per protocol. RESULTS Only 4HIIT increased V˙O2max (P < 0.01) and significantly more compared with 1HIIT (P = 0.04) and MICT (P = 0.03) (4HIIT, 10%; 1HIIT, 3.3%; and MICT, 3.1%). All groups increased TTE (4HIIT, 198%; 1HIIT, 116%; MICT, 52%), with a higher increase after 4HIIT compared with that after MICT (P = 0.02). Calculated SV increased only after 4HIIT (14.4%). Plasma volume and hemoglobin mass increased after 1HIIT only (5.6% and 6.5%); however, no group differences were found. All groups increased CS activity (4HIIT, 35%; 1HIIT, 35%; MICT, 56%), with no group differences. Arterial inflow (15.7%) and venous outflow (22.7%) decreased after MICT, but there were no group differences. CONCLUSIONS 4HIIT was superior to 1HIIT and MICT in improving V˙O2max likely because of an increased SV.
Long-term course of substance use disorders among patients with severe mental illness.

OBJECTIVE This study assessed the long-term course of substance abuse and dependence among severely mentally ill patients. METHODS A prospective, naturalistic, seven-year follow-up of severely mentally ill outpatients (most with schizophrenia and schizoaffective disorder) successfully located and reassessed 79.1 percent (N = 148) of the patients from the original study group. The follow-up study group was assessed for alcohol and drug use at baseline and seven-year follow-up by their case manager or primary clinician using the Case Manager Rating Scale (CMRS) for the assessment of substance-related problems among severely mentally ill patients. RESULTS The prevalence of active substance use disorder changed little from baseline to follow-up. Alcohol abuse or dependence was present in 24 percent of the patients at baseline and 21 percent at follow-up, and drug abuse or dependence was present in 20 percent at baseline and 17 percent at follow-up. However, those with initial alcohol abuse had a higher rate of remission (67 percent) than those with initial alcohol dependence (33 percent). Similarly, those with initial drug abuse had a higher rate of remission (54 percent) than those with initial drug dependence (31 percent). CONCLUSIONS The higher rates of change for those with initial substance abuse compared with substance dependence suggest that distinguishing between abuse and dependence may have important implications for assessment and prognosis of individuals with a dual diagnosis of a substance use disorder and severe mental illness.
Effect of PM10 pollution in Bangkok on children with and without asthma

This study aimed to investigate the effects of PM10 concentrations exceeding the Thai national standard (24‐hr average, >120 μg/m3) on daily reported respiratory symptoms and peak expiratory flow rate (PEFR) of schoolchildren with and without asthma in Bangkok. The 93 asthmatic and 40 nonasthmatic schoolchildren were randomly recruited from a school located in a highly congested traffic area. Daily respiratory symptoms and PEFR of each child were evaluated and recorded in the diary for 31 successive school days. During the study period, 24‐hr average PM10 levels ranged between 46–201 μg/m3. PM10 levels exceeded 120 μg/m3 for 14 days. We found that when PM10 levels were >120 μg/m3, the daily reported nasal irritation of asthmatic children was significantly higher than when PM10 levels were ≤120 μg/m3. In addition, when PM10 levels were >120 μg/m3, nonasthmatic children had a significantly higher daily reported combination of any respiratory symptoms. PEFR did not change with different ambient PM10 levels in both groups. This study suggests that elevated levels of PM10 concentrations in Bangkok affect respiratory symptoms of schoolchildren with and without asthma. Pediatr Pulmonol. 2004; 37:187–192. © 2004 Wiley‐Liss, Inc.
Radiogenomics: towards a personalized radiation oncology

Purpose of review This article evaluates the field of radiogenomics within recent developments in genomics and radiation biology. Recent findings Many pediatric cancer survivors have undergone treatment with radiation, putting them at risk for long-term side-effects associated with this therapy, especially cardiac disease and secondary malignancies. Advancements in our understanding of radiation biology have led to the understanding that genetics plays a major role in determining a patient's susceptibility to developing long-term side-effects, leading to the field of ‘radiogenomics’. Although initial candidate gene studies did not demonstrate replicable genetic variants that affected radiosensitivity, genome-wide association studies have recently begun to identify genes that may help explain some of the observed variation in radiosensitivity. As genomic sciences continues to progress and whole genome studies become more accessible, our understanding of the genes responsible for radiosensitivity will continue to progress. Summary The field of radiogenomics continues to evolve with the availability and improved cost of genomic technologies allowing the study of an increasing fraction of the human genome. Studies into genetic factors influencing individual radiosensitivity will increase our understanding of radiobiology and improve our ability to counsel patients on the adverse effects they will likely experience.
V‐GENE Repertoire and Hypermutation of Rheumatoid Factors Produced in Rheumatoid Synovial Inflammation and Immunized Healthy Donors a

We have compared RF from normal, immunized donors and RF derived from the synovial tissues of RA patients. We have found a difference in the preferential use of VL and VH gene families. In both conditions, RFs were found to have accumulated somatic mutations. However, there was a striking difference in the patterns of mutation. RFs from normals were characterized by a very low R:S ratio in the CDR1+2, considerably lower than seen among the RARFs. In addition, there was little increase in affinity with increasing numbers of mutations in a group of clonally related RFs from an immunized normal. This contrasts with RF from RA, where there is evidence of both affinity maturation and class switching. Together these data suggest that in healthy persons there is a controlling mechanism to limit the affinity of RF autoantibodies, and that this is lost in RA. The higher affinity of the RA-derived RF may be of significance in the pathology of the disease.
Anxiety and depression have no influence on the cancellation and pregnancy rates of a first IVF or ICSI treatment.

BACKGROUND After many years of research, the impact of psychological distress on the IVF treatment outcome is still unclear. This study aimed to determine the influences of anxiety and depression before and during IVF or ICSI treatment on the cancellation and pregnancy rates of inductees. METHODS In a multicentre prospective cohort study, we assessed anxiety and depression at baseline and the procedural anxiety level one day before oocyte retrieval, with the short versions of the State Anxiety Inventory (STAI) and the Beck Depression Inventory-Primary Care (BDI-PC). The effect of baseline anxiety and depression on the cancellation and pregnancy rates of 783 women in their first IVF or ICSI treatment was evaluated. We also determined if a change in anxiety from the start of treatment until just before oocyte retrieval affects the pregnancy rate. The predictive value of distress was assessed while controlling for several factors in subfertility treatment. RESULTS Neither baseline nor procedural anxiety, nor depression affected the ongoing pregnancy rates, with odds ratios (ORs) of 1.04 (95% CI 0.82-1.33), 0.96 (95% CI 0.77-1.20) and 0.85 (95% CI 0.65-1.10), respectively. Neither did the anxiety gain score affect the pregnancy rate, OR 1.08 (95% CI 0.83-1.41). A cancellation of treatment could not be predicted by either anxiety or depression, OR 1.16 (95% CI 0.83-1.63) and 0.85 (95% CI 0.59-1.22), respectively. CONCLUSIONS Inductees in IVF treatment can be reassured that anxiety and depression levels before and during treatment have no significant influence on the cancellation and pregnancy rates.
Race and Ethnic Differences in Early Childhood Maltreatment in the United States

Objective: In the United States, over 6 million children were referred to child protective services in 2012. Black children are overrepresented among children investigated for child abuse and neglect. Understanding why black children are disproportionately reported for maltreatment is critical to informing policy and practice solutions. Two competing theories attribute disproportionality to either racial bias or concentrated risk factors. Although prior work has focused on national data, this study examines the relationship between risk factors and maltreatment at the state level, focusing on outcomes for young children. Method: We examine the relationship between early childhood poverty and maltreatment victimization across white, black, and Hispanic children (0–3 years). Using state-level data (N = 48), we determine ratios of disproportionate outcomes in child maltreatment and associations to poverty and other risk factors. Results: Study findings for state-level data show greater disproportionality of black and Hispanic children living in poverty relative to their white counterparts. This imbalance is associated with greater disproportionality in maltreatment rates. Results also indicate that disproportionality of maltreatment rates was associated with state disproportionality in rates of unmarried and teenage mothers for blacks and Hispanics. Conclusion: Exposure to risks such as poverty is an important factor driving the overrepresentation of minority groups in the child welfare system. Effective strategies for reducing maltreatment must include strategies for reducing poverty and supporting young at-risk mothers.
Predictors of fatigue in patients with heart failure.

AIMS AND OBJECTIVES The purpose of this study was to examine the level of fatigue perceived by patients with heart failure and to explore the potential factors influencing fatigue. DESIGN A cross-sectional, correlational design was used. METHODS A convenience sample of 105 patients was recruited between July and September 2003 in northern Taiwan. The patients were interviewed, and their perceived fatigue was assessed with the modified Piper Fatigue Scale. The factors influencing fatigue were determined using a stepwise linear regression model. RESULTS The majority of patients with heart failure experienced mild-to-moderate fatigue. Patients with higher levels of fatigue had worse physical functioning and more severe symptomatic and psychological distress. Symptomatic distress, psychological distress (depression and anxiety), New York Heart Association class, activities of daily living (ADL) and appraisal support by health care providers could explain 57.4% of the total variance of fatigue. Symptomatic distress was the strongest predictor of fatigue. CONCLUSION Higher levels of fatigue were found in patients with heart failure who had symptomatic or psychological distress. Additional research focusing on developing effective methods to reduce fatigue in patients with heart failure is recommended. RELEVANCE TO CLINICAL PRACTICE Nurses should help patients with heart failure to monitor their symptoms and report them to health care providers. Early management of symptoms and support by health care providers may reduce patients' fatigue, help maintain their physical functioning and improve their quality of life.
Seizure Risk in Offspring of Parents with Generalized Versus Partial Epilepsy

Summary: Genetic factors are commonly assumed to play a more important role in generalized than in partial epilepsy. This study tested this hypothesis by comparing risks of unprovoked seizures in offspring of individuals with generalized versus partial epilepsy. Overall, seizure incidence was no higher in offspring of persons with generalized epilepsy than in offspring of those with partial epilepsy. The number of affected offspring was about three times that expected from population incidence rates, regardless of whether the parent had partial or generalized epilepsy. For the subgroup of generalized cases with absence seizures, however, seizure incidence in offspring was about three times as high as for partial cases. The higher incidence in offspring of absence cases was only partly explained by a higher proportion of absence than partial cases with two factors associated with high risk in relatives, namely early age at onset and idiopathic epilepsy. Offspring of absence cases had higher risk than offspring of other cases not only for absence seizures, but for other seizure types as well, suggesting that absence epilepsy is not genetically distinct from other seizure types of epilepsy. These results suggest that the higher incidence sometimes observed in relatives of patients with generalized epilepsy is due to a small proportion of generalized cases with extremely high familial risks– most generalized epilepsies are no more likely than partial epilepsies to have a genetic basis.
Nuclear receptor ecdysone‐induced protein 75 is required for larval–pupal metamorphosis in the Colorado potato beetle Leptinotarsa decemlineata (Say)

20‐hydroxyecdysone (20E) and juvenile hormone (JH) are key regulators of insect development. In this study, three Leptinotarsa decemlineata Ecdysone‐induced protein 75 (LdE75) cDNAs (LdE75A, B and C) were cloned from L. decemlineata. The three LdE75 isoforms were highly expressed just before or right after each moult. Within the fourth larval instar, they showed a small rise and a big peak 40 and 80 h after ecdysis. The expression peaks of the three LdE75s coincided with the peaks of circulating 20E levels. In vitro midgut culture and in vivo bioassay revealed that 20E and an ecdysteroid agonist halofenozide (Hal) enhanced LdE75 expression in the day 1 final larval instars. Conversely, a decrease in 20E by feeding a double‐stranded RNA (dsRNA) against an ecdysteroidogenesis gene, Shade (LdSHD), repressed the expression of LdE75. Moreover, Hal upregulated the expression of the three LdE75s in LdSHD‐silenced larvae. Thus, 20E pulses activate the transcription of LdE75s. Furthermore, ingesting dsE75‐1 and dsE75‐2 from a common fragment of the three isoforms successfully knocked down these LdE75s, and caused developmental arrest. Finally, knocking down LdE75s significantly repressed the transcription of three ecdysteroidogenesis genes, lowered the 20E titre and affected the expression of two 20E‐response genes. Silencing LdE75s also induced the expression of a JH biosynthesis gene, increased JH titre and activated the transcription of a JH early‐inducible gene. Thus, Ld E75s are required for larval–pupal metamorphosis and act mainly by modulating 20E and JH titres and mediating their signalling pathways.
Obstacles predicting lack of a regular provider and delays in seeking care for patients at an urban public hospital.

OBJECTIVE To determine the correlation among obstacles to medical care, lack of a regular source of care, and delays in seeking care. DESIGN Cross-sectional survey of patients presenting for ambulatory care during a 7-day period. Multiple logistic regression models were used to identify obstacles independently associated with outcome variables. SETTING Urban public hospital. PATIENTS A total of 3897 disadvantaged and predominantly minority patients. MAIN OUTCOME MEASURES Lack of a regular source of medical care and delay in seeking medical care for a new problem. RESULTS The majority (61.6%) of patients reported no regular source of care. Of 2341 patients reporting a new medical problem, 48.4% waited more than 2 days before seeking medical care. No health insurance (adjusted odds ratio [OR], 2.2; 95% confidence interval [CI], 1.89 to 2.61), no transportation (OR, 1.44; 95% CI, 1.23 to 1.70), exposure to violence (OR, 1.21; 95% CI, 1.08 to 1.45), and living in a supervised setting (OR, 1.50; 95% CI, 1.00 to 2.25) were independent predictors of lack of a regular source of care. No insurance (OR, 1.24; 95% CI, 1.02 to 1.51), no transportation (OR, 1.45; 95% CI, 1.19 to 1.77), and less than a high school education (OR, 1.22; 95% CI, 1.08 to 1.49) were independent predictors of delaying care for a new medical problem. CONCLUSIONS Obstacles in addition to lack of insurance impede provision of medical care to disadvantaged patients. The adoption of universal health care coverage alone will not guarantee access to appropriate medical care.
Discovery of O-GlcNAc-modified Proteins in Published Large-scale Proteome Data*

The attachment of N-acetylglucosamine to serine or threonine residues (O-GlcNAc) is a post-translational modification on nuclear and cytoplasmic proteins with emerging roles in numerous cellular processes, such as signal transduction, transcription, and translation. It is further presumed that O-GlcNAc can exhibit a site-specific, dynamic and possibly functional interplay with phosphorylation. O-GlcNAc proteins are commonly identified by tandem mass spectrometry following some form of biochemical enrichment. In the present study, we assessed if, and to which extent, O-GlcNAc-modified proteins can be discovered from existing large-scale proteome data sets. To this end, we conceived a straightforward O-GlcNAc identification strategy based on our recently developed Oscore software that automatically analyzes tandem mass spectra for the presence and intensity of O-GlcNAc diagnostic fragment ions. Using the Oscore, we discovered hundreds of O-GlcNAc peptides not initially identified in these studies, and most of which have not been described before. Merely re-searching this data extended the number of known O-GlcNAc proteins by almost 100 suggesting that this modification exists even more widely than previously anticipated and the modification is often sufficiently abundant to be detected without enrichment. However, a comparison of O-GlcNAc and phospho-identifications from the very same data indicates that the O-GlcNAc modification is considerably less abundant than phosphorylation. The discovery of numerous doubly modified peptides (i.e. peptides with one or multiple O-GlcNAc or phosphate moieties), suggests that O-GlcNAc and phosphorylation are not necessarily mutually exclusive, but can occur simultaneously at adjacent sites.