Two randomized crossover multicenter studies investigating gastrointestinal symptoms after bread consumption in individuals with noncoeliac wheat sensitivity: do wheat species and fermentation type matter?

Background: Many individuals reduce their bread intake due to the belief that wheat is the cause of their gastrointestinal (GI) symptoms. Different grains and processing methods may impact tolerability. Objective: We investigated the effects of six different types of bread on GI symptoms in individuals with self-reported non-coeliac wheat sensitivity (NCWS). Methods: Two parallel randomised double-blind crossover multicentre studies were conducted. NCWS individuals, in whom coeliac disease and wheat allergy were ruled out, received five slices of (study A, n=20) yeast fermented (YF) or (study B, n=20) sourdough fermented (SF) bread made of bread wheat, spelt or emmer on three separate intervention days. Each test day was preceded by a run-in period of 3 days and separated by a wash-out period of at least 7 days. GI symptoms were evaluated by change in symptom score (test day minus average of the 3-day run-in period) on a 0-100mm visual analogue scale (delta VAS). Responders were defined as an increase in delta VAS of at least 15mm for overall GI symptoms, abdominal discomfort, abdominal pain, bloating and/or flatulence. Results: The overall change in GI symptoms did not differ between breads of different grains (YF p=0.267; SF p=0.144). The number of responders was also comparable for both YF (6 to wheat, 5 to spelt, and 7 to emmer, p=0.761) and SF breads (9 to wheat, 7 to spelt, and 8 to emmer, p=0.761). Conclusion: The majority of NCWS individuals experienced GI symptoms for at least one of the breads, but on a group level, no differences were found between different grain types for either YF or SF breads. Clinical Trial Registry: ClinicalTrials.gov, NCT0408447

Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication

The Mre11 nuclease is involved in early responses to DNA damage, often mediated by its role in DNA end processing. MRE11 mutations and aberrant expression are associated with carcinogenesis and cancer treatment outcomes. While, in recent years, progress has been made in understanding the role of Mre11 nuclease activities in DNA double-strand break repair, their role during replication has remained elusive. The nucleoside analog gemcitabine, widely used in cancer therapy, acts as a replication chain terminator; for a cell to survive treatment, gemcitabine needs to be removed from replicating DNA. Activities responsible for this removal have, so far, not been identified. We show that Mre11 3′ to 5′ exonuclease activity removes gemcitabine from nascent DNA during replication. This contributes to replication progression and gemcitabine resistance. We thus uncovered a replication-supporting role for Mre11 exonuclease activity, which is distinct from its previously reported detrimental role in uncontrolled resection in recombination-deficient cell

NEUTRINOS FROM PRIMORDIAL BLACK HOLES

The emission of particles from black holes created in the early Universe has detectable astrophysical consequences. The most stringent bound on their abundance has been obtained from the absence of a detectable diffuse flux of 100 MeV photons. Further scrutiny of these bounds is of interest as they, for instance, rule out primordial black holes as a dark matter candidate. We here point out that these bounds can, in principle, be improved by studying the diffuse cosmic neutrino flux. Measurements of near-vertical atmospheric neutrino fluxes in a region of low geomagnetic latitude can provide a competitive bound. The most favorable energy to detect a possible diffuse flux of primordial black hole origin is found to be a few MeV. We also show that measurements of the diffuse $\nu _\tau$ flux is the most promising to improve the existing bounds deduced from gamma-ray measurements. Neutrinos from individual black hole explosions can be detected in the GeV-TeV energy region. We find that the kilometer-scale detectors, recently proposed, are able to establish competitive bounds.Comment: 19 pages plus 9 uuencoded and compressed postscript figure

Beta functions of topologically massive supergravity

We compute the one-loop beta functions of the cosmological constant, Newton's constant and the topological mass in topologically massive supergravity in three dimensions. We use a variant of the proper time method supplemented by a simple choice of cutoff function. We also employ two different analytic continuations of AdS3 and consider harmonic expansions on the 3-sphere as well as a 3-hyperboloid, and then show that they give the same results for the beta functions. We find that the dimensionless coefficient of the Chern-Simons term, 28, has vanishing beta function. The flow of the cosmological constant and Newton's constant depends on 28; we study analytically the structure of the flow and its fixed points in the limits of small and large ?. Open Access, \ua9 2014 The Authors

A mixed-methods study to define Textbook Outcome for the treatment of patients with uncomplicated symptomatic gallstone disease with hospital variation analyses in Dutch trial data

Background: International consensus on the ideal outcome for treatment of uncomplicated symptomatic gallstone disease is absent. This mixed-method study defined a Textbook Outcome (TO) for this large group of patients. Methods: First, expert meetings were organised with stakeholders to design the survey and identify possible outcomes. To reach consensus, results from expert meetings were converted in a survey for clinicians and for patients. During the final expert meeting, clinicians and patients discussed survey outcomes and a definitive TO was formulated. Subsequently, TO-rate and hospital variation were analysed in Dutch hospital data from patients with uncomplicated gallstone disease. Results: First expert meetings returned 32 outcomes. Outcomes were distributed in a survey among 830 clinicians from 81 countries and 645 Dutch patients. Consensus-based TO was defined as no more biliary colic, no biliary and surgical complications, and the absence or reduction of abdominal pain. Analysis of individual patient data showed that TO was achieved in 64.2% (1002/1561). Adjusted-TO rates showed modest variation between hospitals (56.6-74.9%). Conclusion: TO for treatment of uncomplicated gallstone disease was defined as no more biliary colic, no biliary and surgical complications, and absence or reduction of abdominal pain.TO may optimise consistent outcome reporting in care and guidelines for treating uncomplicated gallstone disease

Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle

Neuronal activity within the central nervous system (CNS) strictly depends on homeostasis and therefore does not tolerate uncontrolled entry of blood components. It has been generally believed that under normal conditions, the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB) prevent immune cell entry into the CNS. This view has recently changed when it was realized that activated T cells are able to breach the BBB and the BCSFB to perform immune surveillance of the CNS. Here we propose that the immune privilege of the CNS is established by the specific morphological architecture of its borders resembling that of a medieval castle. The BBB and the BCSFB serve as the outer walls of the castle, which can be breached by activated immune cells serving as messengers for outside dangers. Having crossed the BBB or the BCSFB they reach the castle moat, namely the cerebrospinal fluid (CSF)-drained leptomeningeal and perivascular spaces of the CNS. Next to the CNS parenchyma, the castle moat is bordered by a second wall, the glia limitans, composed of astrocytic foot processes and a parenchymal basement membrane. Inside the castle, that is the CNS parenchyma proper, the royal family of sensitive neurons resides with their servants, the glial cells. Within the CSF-drained castle moat, macrophages serve as guards collecting all the information from within the castle, which they can present to the immune-surveying T cells. If in their communication with the castle moat macrophages, T cells recognize their specific antigen and see that the royal family is in danger, they will become activated and by opening doors in the outer wall of the castle allow the entry of additional immune cells into the castle moat. From there, immune cells may breach the inner castle wall with the aim to defend the castle inhabitants by eliminating the invading enemy. If the immune response by unknown mechanisms turns against self, that is the castle inhabitants, this may allow for continuous entry of immune cells into the castle and lead to the death of the castle inhabitants, and finally members of the royal family, the neurons. This review will summarize the molecular traffic signals known to allow immune cells to breach the outer and inner walls of the CNS castle moat and will highlight the importance of the CSF-drained castle moat in maintaining immune surveillance and in mounting immune responses in the CNS

Bringing Stellar Evolution & Feedback Together: Summary of proposals from the Lorentz Center Workshop, 2022

Stars strongly impact their environment, and shape structures on all scales throughout the universe, in a process known as ``feedback''. Due to the complexity of both stellar evolution and the physics of larger astrophysical structures, there remain many unanswered questions about how feedback operates, and what we can learn about stars by studying their imprint on the wider universe. In this white paper, we summarize discussions from the Lorentz Center meeting `Bringing Stellar Evolution and Feedback Together' in April 2022, and identify key areas where further dialogue can bring about radical changes in how we view the relationship between stars and the universe they live in.Comment: Accepted to the Publications of the Astronomical Society of the Pacifi

Hydrothermal Alteration of Ultramafic Rocks in Ladon Basin, Mars - Insights From CaSSIS, HiRISE, CRISM, and CTX

The evolution of the Ladon basin has been marked by intense geological activity and the discharge of huge volumes of water from the Martian highlands to the lowlands in the late Noachian and Hesperian. We explore the potential of the ExoMars Trace Gas Orbiter/Color and Stereo Surface Imaging System color image data set for geological interpretation and show that it is particularly effective for geologic mapping in combination with other data sets such as HiRISE, Context, and Compact Reconnaissance Imaging Spectrometer for Mars. The study area displays dark lobate flows of upper Hesperian to early Amazonian age, which were likely extruded from a regional extensional fault network. Spectral analysis suggests that these flows and the underlying rocks are ultramafic. Two distinct altered levels are observed below the lobate flows. The upper, yellow-orange level shows hundreds of structurally controlled narrow ridges reminiscent of ridges of listwanite, a suite of silicified, fracture-controlled silica-carbonate rocks derived from an ultramafic source and from serpentine. In addition to serpentinite, the detected mineral assemblages may include chlorite, carbonates, and talc. Kaolin minerals are detected in the lower, white level, which could have formed by groundwater alteration of plagioclase in the volcanic pile. Volcanism, tectonics, hydrothermal activity, and kaolinization are interpreted to be coeval, with hydrothermal activity and kaolinization controlled by the interactions between the aquifer and the hot, ultramafic lobate flows. Following our interpretations, East Ladon may host the first listwanite ridges described on Mars, involving a hydrothermal system rooted in a Hesperian aquifer and affecting ultramafic rocks from a magmatic source yet to be identified