A yeast model of the ALS protein Matrin3 uncovers Hsp90 and its co-chaperone Sti1 as modifiers of misfolding and toxicity

The MATR3 gene encoding the protein Matrin3 is implicated in the pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Matrin3 forms neuronal cytoplasmic and nuclear inclusions in ALS-affected neurons. Additionally, 13 heterozygous missense mutations in MATR3 are identified in ALS patients. To further explore Matrin3 misfolding and toxicity, we established and characterized a yeast model. We demonstrate that wild type Matrin3 and the ALS-associated variant F115C are toxic and form inclusions in yeast. Our further characterization uncovers substantial modification of Matrin3 toxicity and inclusion formation by Hsp90 and its co-chaperones, specifically Sti1. Thus, our study demonstrates how specific branches of cellular protein quality control regulate the misfolding and toxicity of Matrin3.Summary StatementWe established and characterized a yeast model expressing human Matrin3, a protein implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Using this yeast model and mammalian neuronal cells, we showed that Matrin3 mislocalizes and forms inclusions, is cytotoxic, and increases sensitivity to cellular stress. We also uncovered that Hsp90 and particularly its co-chaperone Sti1 alter Matrin3 toxicity.

Anomaly Detection of Budgetary Allocations Using Machine-Learning-Based Techniques

In Nigeria, a crucial responsibility of the executive arms of the government is to submit annual budgetary allocations to the national assembly for approval. Due to the diversity and complexity of the budget, the national assembly is mandated to carry out its constitutional duty of scrutinizing the budget to discover irregularity or anomaly, make recommendations, or substantial modification upon what it received. This is very challenging, particularly in Nigeria where there are many different ethnicities and regional, to ensure inclusiveness, the national assembly must carry out its constitutional duty diligently and carefully without fear or favor that often has unintended consequences. This might not be very easy to accomplish within a short period. Thus, this research aims at detecting an anomaly in the budget that will ease the legislative duty thereby facilitating the process of appropriation. The concept of Clustering for Machine learning technique was used for the detection of an anomaly, where the detected ones are noted and indicated for critical examination.

Photon–Photon Interactions and the Opacity of the Universe in Gamma Rays

We discuss the topic of the transparency of the Universe in gamma rays due to extragalactic background light, and its cosmological and physical implications. Rather than a review, this is a personal account on the development of 30 years of this branch of physical science. Extensive analysis of the currently available information appears to us as revealing a global coherence among the astrophysical, cosmological, and fundamental physics data, or, at least, no evident need so far of substantial modification of our present understanding. Deeper data from future experiments will verify to what extent and in which directions this conclusion should be modified.

Stages of Gut Development as a Useful Tool to Prevent Gut Alterations in Piglets

During the prenatal, neonatal, and weaning periods, the porcine gastrointestinal tract undergoes several morpho-functional, changes together with substantial modification of the microbial ecosystem. Modifications of the overall structure of the small intestine also occur, as well as a rapid increase of the volume, mainly in the last period of gestation: intestinal villi, starting from jejunum, appears shortly before the sixth week of gestation, and towards the end of the third month, epithelial cells diversify into enterocytes, goblet cells, endocrine, and Paneth cells. Moreover, in the neonatal period, colostrum induces an increase in intestinal weight, absorptive area, and brush border enzyme activities: intestine doubles its weight and increases the length by 30% within three days of birth. During weaning, intestinal environment modifies drastically due to a replacement of highly digestible sow milk by solid feed: profound changes in histological parameters and enzymatic activity are associated with the weaning period, such as the atrophy of the villi and consequent restorative hypertrophy of the crypts. All these modifications are the result of a delicate and precise balance between the proliferation and the death of the cells that form the intestinal mucosa (i.e., mitosis and apoptosis) and the health conditions of the piglet. An in-depth knowledge of these phenomena and of how they can interfere with the correct intestinal function can represent a valid support to predict strategies to improve gut health in the long-term and to prevent weaning gut alterations; thus, reducing antimicrobial use.

Successes, surprises and pitfalls in modular polyketide synthase engineering: generation of ring-contracted stambomycins

The modular organization of the type I polyketide synthases (PKSs) would seem propitious for rational engineering of desirable analogous. However, despite decades of efforts, such experiments remain largely inefficient. Here, we combined multiple, state-of-the-art approaches including modification of docking domains, use of modules of varying domain composition, alternative interdomain fusion sites, and targeted adaptation of key domain-domain interfaces, to reprogram the stambomycin PKS by deleting seven internal modules – the most substantial modification to an intact system reported to date. One such system produced the target 37-membered mini-stambomycin metabolites, a reduction in chain length of 14 carbons relative to the 51-membered parental compounds, but also substantial quantities of shunt metabolites released from the multienzyme subunit upstream of the newly-installed junction. Our data also provide evidence for an unprecedented off-loading mechanism of such stalled intermediates involving the C-terminal thioesterase domain acting on chains located four modules upstream. The yields of all metabolites were substantially reduced compared to the wild type compounds, likely reflecting the poor tolerance to the non-native substrates of the modules downstream of the introduced interfaces. Taken together, our data demonstrate that even ‘optimized’ PKS engineering strategies remain inadequate for efficient production of target polyketide derivatives, and highlight several areas for future investigation.

EAES Recommendations for Recovery Plan in Minimally Invasive Surgery Amid COVID-19 Pandemic

Background COVID-19 pandemic presented an unexpected challenge for the surgical community in general and Minimally Invasive Surgery (MIS) specialists in particular. This document aims to summarize recent evidence and experts’ opinion and formulate recommendations to guide the surgical community on how to best organize the recovery plan for surgical activity across different sub-specialities after the COVID-19 pandemic. Methods Recommendations were developed through a Delphi process for establishment of expert consensus. Domain topics were formulated and subsequently subdivided into questions pertinent to different surgical specialities following the COVID-19 crisis. Sixty-five experts from 24 countries, representing the entire EAES board, were invited. Fifty clinicians and six engineers accepted the invitation and drafted statements based on specific key questions. Anonymous voting on the statements was performed until consensus was achieved, defined by at least 70% agreement. Results A total of 92 consensus statements were formulated with regard to safe resumption of surgery across eight domains, addressing general surgery, upper GI, lower GI, bariatrics, endocrine, HPB, abdominal wall and technology/research. The statements addressed elective and emergency services across all subspecialties with specific attention to the role of MIS during the recovery plan. Eighty-four of the statements were approved during the first round of Delphi voting (91.3%) and another 8 during the following round after substantial modification, resulting in a 100% consensus. Conclusion The recommendations formulated by the EAES board establish a framework for resumption of surgery following COVID-19 pandemic with particular focus on the role of MIS across surgical specialities. The statements have the potential for wide application in the clinical setting, education activities and research work across different healthcare systems.

"Wychódźc", "Pcim" i "Rzgów". Grupy spółgłoskowe w nazwach miejscowości w świetle fonotaktyki polskiej

The paper undertakes an interesting and largely under-researched issue of initial and final consonant clusters in many Polish place names which are either unattested in common words or occur only in isolated cases, as illustrated by the examples provided in the title. The presentation of the relevant language data is followed by a brief description of the historical sources of such clusters which involve sound changes (e.g. disappearance of weak vowels, palatalization and segment metathesis), as well as borrowings from other languages and local dialects. Next, the discussion focuses on the place the names in question should occupy in the Polish phonotactic system. The authors argue that equating phonotactic well-formedness with structures attested in language and ill-formedness with those which are unattested is too simplistic. A solid analysis of the aforementioned issues requires a substantial modification and introduction of several subtler distinctions. They claim, therefore, that phonotactic restrictions form a scale, with well-formed and ill-formed sound sequences appearing at its extremities and with rare consonant clusters and those found only in place names and some borrowings located in the middle.

Impact and Repercussion of the SARS-CoV-2 Pandemic in the Assisted Reproduction Units in Spain

Summary: During the months of March, April and May of 2020 the Spanish Assisted Reproduction Units had to stop their assistance activity due to the health situation caused by the COVID-19 pandemic. Its reactivation has required a substantial modification in the way of working in them, changing the assistance routines and designing protocols that guarantee, as much as possible, the security of patients and staff of the centers devoted to reproductive medicine.It is analyzed the medical and biological arguments that have been assessed in order to advise the reopening of the Assisted Reproduction Units within the current context of the pandemic in Spain and the European Union.

Spatial Reasoning about String Loops and Holes in Temporal ASP

This paper introduces a new formalism for the automated solution of spatial scenarios involving strings and holed objects. In particular, we revisit a previous formalisation that allows string loops to be treated as holes, but make a substantial modification by removing a previous limitation that prevented a string to cross its own loops. The formalisation introduced in the present paper relies on string segments as basic entities and achieves a greater degree of elaboration tolerance by using inertia to describe those parts of the physical scenario that are unaffected by a given action. As a representation language, we have used Temporal Answer Set Programming since it provides a simple and natural way to deal with time and inertia while, at the same time, it is accompanied by the automated tool 'telingo' that allows a systematic testing of the effects of any sequence of actions. As an illustrative example, we have studied the African Ring puzzle, a problem involving loops crossed by a unique string, and provided the first formalisation of its solution, to the best of our knowledge.

On the peculiar torque reversals and the X-ray luminosity history of the accretion-powered X-ray pulsar 4U 1626–67

ABSTRACT The X-ray luminosity (Lx) and the rotational properties of 4U 1626–67 have been measured at regular intervals during the last four decades. It has been recorded that the source underwent torque reversals twice. We have tried to understand whether these eccentrical sign-switches of the spin period derivative ($\dot{P}$) of 4U 1626–67 could be accounted for with the existing torque models. We have found that the observed source properties are better estimated with the distances close to the lower limit of the previously predicted distance range (5−13 kpc). Furthermore, assuming an inclined rotator, we have considered the partial accretion/ejection from the inner disc radius that leads to different Lx–$\dot{P}$ profiles than the aligned rotator cases. We have concluded that the oblique rotator assumption with the inclination angle χ ∼ (10°−30°) brings at least equally best fitting to the observed Lx and $\dot{P}$ of 4U 1626–67. More importantly, the estimated change of the mass accretion rate, which causes the change in observed Lx of 4U 1626–67 is much less than that is found in an aligned rotator case. In other words, without the need for a substantial modification of mass accretion rate from the companion star, the range of the observed Lx could be explained naturally with an inclined magnetic axis and rotation axis of the neutron star.