The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket

P pili are hairlike polymeric structures that mediate binding of uropathogenic Escherichia coli to the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in-zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism

A synthetic electric force acting on neutral atoms

Electromagnetism is a simple example of a gauge theory where the underlying potentials -- the vector and scalar potentials -- are defined only up to a gauge choice. The vector potential generates magnetic fields through its spatial variation and electric fields through its time-dependence. We experimentally produce a synthetic gauge field that emerges only at low energy in a rubidium Bose-Einstein condensate: the neutral atoms behave as charged particles do in the presence of a homogeneous effective vector potential. We have generated a synthetic electric field through the time dependence of an effective vector potential, a physical consequence even though the vector potential is spatially uniform

Bilateral Assessment of Functional Tasks for Robot-assisted Therapy Applications

This article presents a novel evaluation system along with methods to evaluate bilateral coordination of arm function on activities of daily living tasks before and after robot-assisted therapy. An affordable bilateral assessment system (BiAS) consisting of two mini-passive measuring units modeled as three degree of freedom robots is described. The process for evaluating functional tasks using the BiAS is presented and we demonstrate its ability to measure wrist kinematic trajectories. Three metrics, phase difference, movement overlap, and task completion time, are used to evaluate the BiAS system on a bilateral symmetric (bi-drink) and a bilateral asymmetric (bi-pour) functional task. Wrist position and velocity trajectories are evaluated using these metrics to provide insight into temporal and spatial bilateral deficits after stroke. The BiAS system quantified movements of the wrists during functional tasks and detected differences in impaired and unimpaired arm movements. Case studies showed that stroke patients compared to healthy subjects move slower and are less likely to use their arm simultaneously even when the functional task requires simultaneous movement. After robot-assisted therapy, interlimb coordination spatial deficits moved toward normal coordination on functional tasks

Autonomic Modulation and Health-Related Quality of Life among Schizophrenic Patients Treated with Non-Intensive Case Management

Schizophrenia is associated with autonomic dysfunction and this may increase cardiovascular mortality. Past studies on autonomic modulation of schizophrenic patients focused on inpatients rather than individuals in a community setting, especially those receiving non-intensive case management (non-ICM). Besides, autonomic modulation and its association with health-related quality of life (HRQoL) in this population remain unexplored.A total of 25 schizophrenic patients treated by non-ICM and 40 healthy volunteers were matched by age, gender and body mass index; smokers were excluded. Between the two groups, we compared the individuals' 5 min resting assessments of heart rate variability and their HRQoL, which was measured using EuroQoL-5D (EQ-5D). Patients with schizophrenia were assessed for psychopathology using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). We examined the relationship between heart rate variability measurements, HRQoL scores, PANSS scores, and other clinical variables among the schizophrenic patients treated by non-ICM.Compared to the controls, patients with schizophrenia showed a significant impairment of autonomic modulation and a worse HRQoL. Cardiovagal dysfunction among the schizophrenic patients could be predicted independently based on lower educational level and more negative symptoms. Sympathetic predominance was directly associated with anticholinergics use and EQ-5D using a visual analogue scale (EQ-VAS).Patients with schizophrenia treated by non-ICM show a significant impairment of their autonomic function and HRQoL compared to the controls. Since the sympathovagal dysfunction is associated with more negative symptoms or higher VAS score, the treatment of the negative symptoms as well as the monitoring of HRQoL might help to manage cardiovascular risk among these individuals. In addition, EQ-VAS scores must be interpreted more cautiously in such a population

A cohort study: temporal trends in prevalence of antecedents, comorbidities and mortality in Aboriginal and non-Aboriginal Australians with first heart failure hospitalization, 2000-2009

Abstract Background/objectives: Little is known about trends in risk factors and mortality for Aboriginal Australians with heart failure (HF). This population-based study evaluated trends in prevalence of risk factors, 30-day and 1-year all-cause mortality following first HF hospitalization among Aboriginal and non-Aboriginal Western Australians in the decade 2000-2009. Methods: Linked-health data were used to identify patients (20-84 years), with a first-ever HF hospitalization. Trends in demographics, comorbidities, interventions and risk factors were evaluated. Logistic and Cox regression models were fitted to test and compare trends over time in 30-day and 1-year mortality. Results: Of 17,379 HF patients, 1,013 (5.8 %) were Aboriginal. Compared with 2000-2002, the prevalence (as history) of myocardial infarction and hypertension increased more markedly in 2006-2009 in Aboriginal (versus non-Aboriginal) patients, while diabetes and chronic kidney disease remained disproportionately higher in Aboriginal patients. Risk factor trends, including the Charlson comorbidity index, increased over time in younger Aboriginal patients. Risk-adjusted 30-day mortality did not change over the decade in either group. Risk-adjusted 1-year mortality (in 30-day survivors) was non-significantly higher in Aboriginal patients in 2006-2008 compared with 2000-2002 (hazard ratio (HR) 1.44; 95 % CI 0.85-2.41; p-trend = 0.47) whereas it decreased in non-Aboriginal patients (HR 0.87; 95 % CI 0.78-0.97; p-trend = 0.01). Conclusions: Between 2000 and 2009, the prevalence of HF antecedents increased and remained disproportionately higher in Aboriginal (versus non-Aboriginal) HF patients. Risk-adjusted 1-year mortality did not improve in Aboriginal patients over the period in contrast with non-Aboriginal patients. These findings highlight the need for better prevention and post-HF care in Aboriginal Australians

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Asymmetry of Early Endosome Distribution in C. elegans Embryos

development, we examined the distribution and dynamics of early endosomes (EEs) in embryos.EEs are primarily found at the cell periphery with an initially uniform distribution after fertilization. Strikingly, we find that during the first cell cycle, EEA-1 positive EEs become enriched at the anterior cortex. In contrast, the Golgi compartment shows no asymmetry in distribution. Asymmetric enrichment of EEs depends on acto-myosin contractility and embryonic PAR polarity. In addition to their localization at the cortex, EEs are also found around the centrosome. These EEs move rapidly (1.3um/s) from the cortex directly to the centrosome, a speed comparable to that of the minus end directed motor dynein.We speculate that the asymmetry of early endosomes might play a role in cell asymmetries or fate decisions

Perspectives on the chemical etiology of breast cancer.

Multiple factors, known and unknown, contribute to human breast cancer. Hereditary, hormonal, and reproductive factors are associated with risk of breast cancer. Environmental agents, including chemical carcinogens, are modifiable risk factors to which over 70% of breast cancers have been attributed. Polymorphisms of drug-metabolizing enzymes may influence risk of breast cancer from environmental chemicals, dietary agents, and endogenous steroids. The environmental factors discussed in this review include pollutants, occupational exposures, tobacco smoke, alcohol, and diet. Aromatic amines are discussed as potential mammary carcinogens, with a focus on heterocyclic amine food pyrolysis products. These compounds are excreted into the urine after consumption of meals containing cooked meats and have recently been detected in the breast milk of lactating women

Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population

Background: The distribution and the potential gene-gene and gene-environment interaction of selected metabolic genetic polymorphisms was investigated in relation to gastric cancer risk in an Italian population. Methods: One hundred and seven cases and 254 hospital controls, matched by age and gender, were genotyped for CYP1A1, CYP2E1, mEH, GSTM1, GSTT1, NAT2 and SULT1A1 polymorphisms. Haplotype analysis was performed for EPHX1 exons 3 and 4, as well as CYP2E1 RsaI (*5 alleles) and CYP2E1 DraI (*5A or *6 alleles). The effect modification by alcohol and cigarette smoking was tested with the heterogeneity test, while the attributable proportion (AP) was used to measure the biological interaction from the gene-gene interaction analysis. Results: Gastric cancer risk was found to be associated with the inheritance of GSTT1 null genotype (OR = 2.10, 95%CI: 1.27-3.44) and the SULT1A1 His/His genotype (OR = 2.46, 95%CI: 1.03-5.90). No differences were observed for the haplotype distributions among cases and controls. For the first time an increased risk was detected among individuals carrying the *6 variant allele of CYP2E1 if ever-drinkers (OR = 3.70; 95%CI: 1.45-9.37) with respect to never-drinkers (OR = 0.18; 95% CI: 0.22-1.46) (p value of heterogeneity among the two estimates = 0.001). Similarly, the effect of SULT1A1 variant genotype resulted restricted to ever-smokers, with an OR of 2.58 (95%CI: 1.27-5.25) for the carriers of His allele among smokers, and an OR of 0.86 (95%CI: 0.45-1.64) among never-smokers (p value of heterogeneity among the two estimates = 0.03). The gene-gene interaction analyses demonstrated that individuals with combined GSTT1 null and NAT2 slow acetylators had an additional increased risk of gastric cancer, with an OR of 3.00 (95%CI: 1.52-5.93) and an AP of 52%. Conclusion: GSTT1, SULT1A1 and NAT2 polymorphisms appear to modulate individual's susceptibility to gastric cancer in this Italian population, particularly when more than one unfavourable genotype is present, or when combined with cigarette smoke. The increased risk for the carriers of CYP2E1*5A or *6 alleles among drinkers need to be confirmed by larger prospective studies