Proteomic Identification of IPSE/alpha-1 as a Major Hepatotoxin Secreted by Schistosoma mansoni Eggs

The flatworm disease, schistosomiasis, is a major public health problem in sub-Saharan Africa, South America and East Asia. A hallmark of infection with Schistosoma mansoni is the immune response to parasite eggs trapped in the liver and other organs. This response involves an infiltration of cells that surround the parasite egg forming a “granuloma.” In mice deprived of T-cells, this granulomatous response is lacking, and toxic products released by eggs quickly cause liver damage and death. Thus the granulomata protect the host from toxic egg products. Only one hepatotoxic molecule, omega-1, has been described to date. We set out to identify other S. mansoni egg hepatotoxins using liver cells grown in culture. We first showed that live eggs, their secretions, and pure omega-1 are toxic. Using a physical separation technique to prepare fractions from whole egg secretions, we identified the presence of IPSE/alpha-1, a protein that is known to strongly influence the immune system. We showed that IPSE/alpha-1 is also hepatotoxic, and that toxicity of both omega-1 and IPSE/alpha-1 can be prevented by first mixing the proteins with specific neutralizing antibodies. Both proteins constitute the majority of hepatotoxicity released by eggs

The Ecm11-Gmc2 complex promotes synaptonemal complex formation through assembly of transverse filaments in budding yeast

During meiosis, homologous chromosomes pair at close proximity to form the synaptonemal complex (SC). This association is mediated by transverse filament proteins that hold the axes of homologous chromosomes together along their entire length. Transverse filament proteins are highly aggregative and can form an aberrant aggregate called the polycomplex that is unassociated with chromosomes. Here, we show that the Ecm11-Gmc2 complex is a novel SC component, functioning to facilitate assembly of the yeast transverse filament protein, Zip1. Ecm11 and Gmc2 initially localize to the synapsis initiation sites, then throughout the synapsed regions of paired homologous chromosomes. The absence of either Ecm11 or Gmc2 substantially compromises the chromosomal assembly of Zip1 as well as polycomplex formation, indicating that the complex is required for extensive Zip1 polymerization. We also show that Ecm11 is SUMOylated in a Gmc2-dependent manner. Remarkably, in the unSUMOylatable ecm11 mutant, assembly of chromosomal Zip1 remained compromised while polycomplex formation became frequent. We propose that the Ecm11-Gmc2 complex facilitates the assembly of Zip1 and that SUMOylation of Ecm11 is critical for ensuring chromosomal assembly of Zip1, thus suppressing polycomplex formation

Evaluation of nationwide referral pathways, investigation and treatment of suspected cauda equina syndrome in the United Kingdom.

Purpose: Cauda equina syndrome (CES) is a spinal emergency with clinical symptoms and signs that have low diagnostic accuracy. National guidelines in the United Kingdom (UK) state that all patients should undergo an MRI prior to referral to specialist spinal units and surgery should be performed at the earliest opportunity. We aimed to evaluate the current practice of investigating and treating suspected CES in the UK. Materials and Methods: A retrospective, multicentre observational study of the investigation and management of patients with suspected CES was conducted across the UK, including all patients referred to a spinal unit over 6 months between 1st October 2016 and 31st March 2017. Results: A total of 28 UK spinal units submitted data on 4441 referrals. Over half of referrals were made without any previous imaging (n = 2572, 57.9%). Of all referrals, 695 underwent surgical decompression (15.6%). The majority of referrals were made out-of-hours (n = 2229/3517, 63.4%). Patient location and pre-referral imaging were not associated with time intervals from symptom onset or presentation to decompression. Patients investigated outside of the spinal unit experienced longer time intervals from referral to undergoing the MRI scan. Conclusions: This is the largest known study of the investigation and management of suspected CES. We found that the majority of referrals were made without adequate investigations. Most patients were referred out-of-hours and many were transferred for an MRI without subsequently requiring surgery. Adherence to guidelines would reduce the number of referrals to spinal services by 72% and reduce the number of patient transfers by 79%

Comparative efficacy of the Cognitive Behavioral Analysis System of Psychotherapy versus Supportive Psychotherapy for early onset chronic depression: design and rationale of a multisite randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Effective treatment strategies for chronic depression are urgently needed since it is not only a common and particularly disabling disorder, but is also considered treatment resistant by most clinicians. There are only a few studies on chronic depression indicating that traditional psycho- and pharmacological interventions are not as effective as in acute, episodic depression. Current medications are no more effective than those introduced 50 years ago whereas the only psychotherapy developed specifically for the subgroup of chronic depression, the Cognitive Behavioral Analysis System of Psychotherapy (CBASP), faired well in one large trial. However, CBASP has never been directly compared to a non-specific control treatment.</p> <p>Methods/Design</p> <p>The present article describes the study protocol of a multisite parallel-group randomized controlled trial in Germany. The purpose of the study is to estimate the efficacy of CBASP compared to supportive psychotherapy in 268 non-medicated early-onset chronically depressed outpatients. The intervention includes 20 weeks of acute treatment with 24 individual sessions followed by 28 weeks of continuation treatment with another 8 sessions. Depressive symptoms are evaluated 20 weeks after randomisation by means of the 24-item Hamilton Rating Scale of Depression (HRSD). Secondary endpoints are depressive symptoms after 12 and 48 weeks, and remission after 12, 20, and 48 weeks. Primary outcome will be analysed using analysis of covariance (ANCOVA) controlled for pre-treatment scores and site. Analyses of continuous secondary variables will be performed using linear mixed models. For remission rates, chi-squared tests and logistic regression will be applied.</p> <p>Discussion</p> <p>The study evaluates the comparative effects of a disorder-specific psychotherapy and a well designed non-specific psychological approach in the acute and continuation treatment phase in a large sample of early-onset chronically depressed patients.</p> <p>Trial registration</p> <p>ClinicalTrials.gov (<a href="http://www.clinicaltrials.gov/ct2/show/NCT00970437">NCT00970437</a>).</p

The Cosmological Constant

This is a review of the physics and cosmology of the cosmological constant. Focusing on recent developments, I present a pedagogical overview of cosmology in the presence of a cosmological constant, observational constraints on its magnitude, and the physics of a small (and potentially nonzero) vacuum energy.Comment: 50 pages. Submitted to Living Reviews in Relativity (http://www.livingreviews.org/), December 199

A Plant-Specific Transcription Factor IIB-Related Protein, pBRP2, Is Involved in Endosperm Growth Control

General transcription factor IIB (TFIIB) and TFIIB-related factor (BRF), are conserved RNA polymerase II/III (RNAPII/III) selectivity factors that are involved in polymerase recruitment and transcription initiation in eukaryotes. Recent findings have shown that plants have evolved a third type of B-factor, plant-specific TFIIB-related protein 1 (pBRP1), which seems to be involved in RNAPI transcription. Here, we extend the repertoire of B-factors in plants by reporting the characterization of a novel TFIIB-related protein, plant-specific TFIIB-related protein 2 (pBRP2), which is found to date only in the Brassicacea family. Unlike other B-factors that are ubiquitously expressed, PBRP2 expression is restricted to reproductive organs and seeds as shown by RT-PCR, immunofluorescence labelling and GUS staining experiments. Interestingly, pbrp2 loss-of-function specifically affects the development of the syncytial endosperm, with both parental contributions required for wild-type development. pBRP2, is the first B-factor to exhibit cell-specific expression and regulation in eukaryotes, and might play a role in enforcing bi-parental reproduction in angiosperms

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques