Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility

Quantifying measures to limit wind driven resuspension of sediments for improvement of the ecological quality in some shallow Dutch lakes

Although phosphorus loadings are considered the main pressure for most shallow lakes, wind-driven resuspension can cause additional problems for these aquatic ecosystems. We quantified the potential effectiveness of measures to reduce the contribution of resuspended sediments, resulting from wind action, to the overall light attenuation for three comparable shallow peat lakes with poor ecological status in the Netherlands: Loosdrecht, Nieuwkoop, and Reeuwijk (1.8–2.7 m depth, 1.6–2.5 km fetch). These measures are: 1. wave reducing barriers, 2. water level fluctuations, 3. capping of the sediment with sand, and 4. combinations of above. Critical shear stress of the sediments for resuspension (Vcrit), size distribution, and optical properties of the suspended material were quantified in the field (June 2009) and laboratory. Water quality monitoring data (2002–2009) showed that light attenuation by organic suspended matter in all lakes is high. Spatial modeling of the impact of these measures showed that in Lake Loosdrecht limiting wave action can have significant effects (reductions from 6% exceedance to 2% exceedance of Vcrit), whereas in Lake Nieuwkoop and Lake Reeuwijk this is less effective. The depth distribution and shape of Lake Nieuwkoop and Lake Reeuwijk limit the role of wind-driven resuspension in the total suspended matter concentration. Although the lakes are similar in general appearance (origin, size, and depth range) measures suitable to improve their ecological status differ. This calls for care when defining the programme of measures to improve the ecological status of a specific lake based on experience from other lakes.

Service use and costs for people with headache: a UK primary care study

This paper aims to estimate the service and social costs of headache presenting in primary care and to identify predictors of headache costs. Patients were recruited from GP practices in England and service use and lost employment recorded. Predictors of cost were identified using regression models. Service and social costs were available on 288 and 282 patients, respectively. Average service costs over 3 months were £117 whilst total costs (including lost production) were £582. Patients referred to neurologists had service costs that were £82 higher than those not referred (90% CI £36–£128). Costs including lost employment were higher by £150, but this was not significant (90% CI -£139–£439). The annual mean service and social costs, weighted to represent population rates of referral, were £468 and £2328, respectively. Higher costs were significantly related to pain. Age was linked to higher service costs and lower social costs. The figures extrapolated to the whole of the UK suggest £956 million due to service use and £4.8 billion including lost employment. These are likely to be underestimates because many people experiencing headaches do not consult their GP

Clinicoradiological manifestations of paraganglioma syndromes associated with succinyl dehydrogenase enzyme mutation

BACKGROUND: Paragangliomas are rare tumours derived from the autonomic nervous system that have increasingly been recognised to have a genetic predisposition. Mutations of the enzyme succinyl dehydrogenase (SDH) have proven to result in paraganglioma formation. There are four subunits (A through D) that form the enzyme complex and are associated with different genophenotypic expressions of disease. SDHB and SDHD mutations are more common, whereas SDHA and SDHC mutations are rare. Patients with SDHB mutations are prone to extra-adrenal pheochromocytomas, malignant disease and extra-paraganglial neoplasia, whereas SDHD mutations have a greater propensity for multiple, benign head and neck paragangliomas. METHODS: Diagnosis of a sporadic paraganglioma or pheochromocytoma should lead to a full genetic workup of the patient and family if SDH mutations are found. RESULTS: Further annual screening will be required depending on the mutation, which can have a significant impact on radiologists and the resources of the radiology department. CONCLUSION: We present our imaging experience with a series of patients with proven SDH mutations resulting in paragangliomas with a review of the literature

Tolerance to the Neuron-Specific Paraneoplastic HuD Antigen

Experiments dating back to the 1940's have led to the hypothesis that the brain is an immunologically privileged site, shielding its antigens from immune recognition. The paraneoplastic Hu syndrome provides a powerful paradigm for addressing this hypothesis; it is believed to develop because small cell lung cancers (SCLC) express the neuron-specific Hu protein. This leads to an Hu-specific tumor immune response that can develop into an autoimmune attack against neurons, presumably when immune privilege in the brain is breached. Interestingly, all SCLC express the onconeural HuD antigen, and clinically useful tumor immune responses can be detected in up to 20% of patients, yet the paraneoplastic neurologic syndrome is extremely rare. We found that HuD-specific CD8+ T cells are normally present in the mouse T cell repertoire, but are not expanded upon immunization, although they can be detected after in vitro expansion. In contrast, HuD-specific T cells could be directly activated in HuD null mice, without the need for in vitro expansion. Taken together, these results demonstrate robust tolerance to the neuronal HuD antigen in vivo, and suggest a re-evaluation of the current concept of immune privilege in the brain

Attentional Window Set by Expected Relevance of Environmental Signals

The existence of an attentional window—a limited region in visual space at which attention is directed—has been invoked to explain why sudden visual onsets may or may not capture overt or covert attention. Here, we test the hypothesis that observers voluntarily control the size of this attentional window to regulate whether or not environmental signals can capture attention. We have used a novel approach to test this: participants eye-movements were tracked while they performed a search task that required dynamic gaze-shifts. During the search task, abrupt onsets were presented that cued the target positions at different levels of congruency. The participant knew these levels. We determined oculomotor capture efficiency for onsets that appeared at different viewing eccentricities. From these, we could derive the participant's attentional window size as a function of onset congruency. We find that the window was small during the presentation of low-congruency onsets, but increased monotonically in size with an increase in the expected congruency of the onsets. This indicates that the attentional window is under voluntary control and is set according to the expected relevance of environmental signals for the observer's momentary behavioral goals. Moreover, our approach provides a new and exciting method to directly measure the size of the attentional window

Breast cancer receptor status and stage at diagnosis in over 1,200 consecutive public hospital patients in Soweto, South Africa: a case series

Introduction: Estimates of the proportion of estrogen receptor negative (ERN) and triple-negative (TRN) breast cancer from sub-Saharan Africa are variable and include high values. Large studies of receptor status conducted on non-archival tissue are lacking from this region. Methods: We identified 1218 consecutive women (91% black) diagnosed with invasive breast cancer from 2006–2012 at a public hospital in Soweto, South Africa. Immunohistochemistry based ER, progesterone receptor (PR) and human epidermal factor 2 (HER2) receptors were assessed at diagnosis on pre-treatment biopsy specimens. Mutually adjusted associations of receptor status with stage, age, and race were examined using risk ratios (RRs). ER status was compared with age-stratified US Surveillance Epidemiology and End Results program (SEER) data. Results: 35% (95% confidence interval (CI): 32–38) of tumors were ERN, 47% (45–52) PRN, 26% (23–29) HER2P and 21% (18–23) TRN. Later stage tumors were more likely to be ERN and PRN (RRs 1.9 (1.1-2.9) and 2.0 (1.3-3.1) for stage III vs. I) but were not strongly associated with HER2 status. Age was not strongly associated with ER or PR status, but older women were less likely to have HER2P tumors (RR, 0.95 (0.92-0.99) per 5 years). During the study, stage III + IV tumors decreased from 66% to 46%. In black women the percentage of ERN (37% (34–40)) and PRN tumors (48% (45–52)) was higher than in non-black patients (22% (14–31) and 34% (25–44), respectively, P = 0.004 and P = 0.02), which remained after age and stage adjustment. Age-specific ERN proportions in black South African women were similar to those of US black women, especially for women diagnosed over age 50. Conclusion: Although a greater proportion of black than non-black South African women had ER-negative or TRN breast cancer, in all racial groups in this study breast cancer was predominantly ER-positive and was being diagnosed at earlier stages over time. These observations provide initial indications that late-stage aggressive breast cancers may not be an inherent feature of the breast cancer burden across Africa

Multifunctionality of silver closo-boranes

Silver compounds share a rich history in technical applications including photography, catalysis, photocatalysis, cloud seeding and as antimicrobial agents. Here we present a class of silver compounds (Ag2B10H10 and Ag2B12H12) that are semiconductors with a bandgap at 2.3?eV in the green visible light spectrum. The silver boranes have extremely high ion conductivity and dynamic-anion facilitated Ag(+) migration is suggested based on the structural model. The ion conductivity is enhanced more than two orders of magnitude at room temperature (up to 3.2?mS?cm(-1)) by substitution with AgI to form new compounds. Furthermore, the closo-boranes show extremely fast silver nano-filament growth when excited by electrons during transmission electron microscope investigations. Ag nano-filaments can also be reabsorbed back into Ag2B12H12. These interesting properties demonstrate the multifunctionality of silver closo-boranes and open up avenues in a wide range of fields including photocatalysis, solid state ionics and nano-wire production

Accreting Millisecond X-Ray Pulsars

Accreting Millisecond X-Ray Pulsars (AMXPs) are astrophysical laboratories without parallel in the study of extreme physics. In this chapter we review the past fifteen years of discoveries in the field. We summarize the observations of the fifteen known AMXPs, with a particular emphasis on the multi-wavelength observations that have been carried out since the discovery of the first AMXP in 1998. We review accretion torque theory, the pulse formation process, and how AMXP observations have changed our view on the interaction of plasma and magnetic fields in strong gravity. We also explain how the AMXPs have deepened our understanding of the thermonuclear burst process, in particular the phenomenon of burst oscillations. We conclude with a discussion of the open problems that remain to be addressed in the future.Comment: Review to appear in "Timing neutron stars: pulsations, oscillations and explosions", T. Belloni, M. Mendez, C.M. Zhang Eds., ASSL, Springer; [revision with literature updated, several typos removed, 1 new AMXP added