Mammalian splicing factor SF1 interacts with SURP domains of U2 snRNP-associated proteins

Splicing factor 1 (SF1) recognizes the branch point sequence (BPS) at the 3′ splice site during the formation of early complex E, thereby pre-bulging the BPS adenosine, thought to facilitate subsequent base-pairing of the U2 snRNA with the BPS. The 65-kDa subunit of U2 snRNP auxiliary factor (U2AF65) interacts with SF1 and was shown to recruit the U2 snRNP to the spliceosome. Co-immunoprecipitation experiments of SF1-interacting proteins from HeLa cell extracts shown here are consistent with the presence of SF1 in early splicing complexes. Surprisingly almost all U2 snRNP proteins were found associated with SF1. Yeast two-hybrid screens identified two SURP domain-containing U2 snRNP proteins as partners of SF1. A short, evolutionarily conserved region of SF1 interacts with the SURP domains, stressing their role in protein-protein interactions. A reduction of A complex formation in SF1-depleted extracts could be rescued with recombinant SF1 containing the SURP-interaction domain, but only partial rescue was observed with SF1 lacking this sequence. Thus, SF1 can initially recruit the U2 snRNP to the spliceosome during E complex formation, whereas U2AF65 may stabilize the association of the U2 snRNP with the spliceosome at later times. In addition, these findings may have implications for alternative splicing decision

A new scenario-based framework for conflict resolution in water allocation in transboundary watersheds

One of the main causes of water conflicts in transboundary watersheds all over the world is represented by the increasing water demand due to urban, industrial, and agricultural development. In this context, water scarcity plays a critical role since, during a drought period, water supply is not su cient to cover the demand of all water uses. In this work, we have conceptualized and developed a new scenario-based framework able to improve the sustainability and equity of water allocation among two or more riparian countries. The proposed approach is in accordance with the United Nations Watercourses Convention. It considers a hydraulic/hydrologic model, a water-management model, and combines them with multi-criteria decision analysis (MCDA) and what if scenario analysis (WISA). The suggested framework was applied to the transboundary watershed of Cuareim/Quaraí river (Uruguay/Brazil) to tackle a real water-sharing conflict. It resulted in being very flexible in exploring various policy options and test and quantifying them with di erent scenarios to reach an objective and impartial decision in a water-sharing issue. This framework can e ectively be applied to any other transboundary watershed to resolve any possible conflict related to water-allocation/water-management matter

Recent Progress in Polymorphism-Based Population Genetic Inference

The recent availability of whole-genome sequencing data affords tremendous power for statistical inference. With this, there has been great interest in the development of polymorphism-based approaches for the estimation of population genetic parameters. These approaches seek to estimate, for example, recently fixed or sweeping beneficial mutations, the rate of recurrent positive selection, the distribution of selection coefficients, and the demographic history of the population. Yet despite estimating similar parameters using similar data sets, results between methodologies are far from consistent. We here summarize the current state of the field, compare existing approaches, and attempt to reconcile emerging discrepancies. We also discuss the biases in selection estimators introduced by ignoring the demographic history of the population, discuss the biases in demographic estimators introduced by assuming neutrality, and highlight the important challenge to the field of achieving a true joint estimation procedure to circumvent these confounding effect

Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety, and tolerability of dimethyl fumarate in Friedreich Ataxia (DMF-FA-201)

IntroductionFriedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2 in vitro and in vivo, and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients.MethodsThe aim of our study is to investigate if DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23.EndpointsThe primary endpoint will be a change in FXN gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level, cardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales.ConclusionsThis is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration in-vivo

Parental experiences of homeschooling during the COVID-19 pandemic: differences between seven European countries and between children with and without mental health conditions

The aim of the present study was to examine parental experiences of homeschooling during the COVID-19 pandemic in families with or without a child with a mental health condition across Europe. The study included 6720 parents recruited through schools, patient organizations and social media platforms (2002 parents with a child with a mental health condition and 4718 without) from seven European countries: The United Kingdom (n=508), Sweden (n=1436), Spain (n=1491), Belgium (n=508), the Netherlands (n=324), Germany (n=1662) and Italy (n=794). Many parents reported negative effects of homeschooling for themselves and their child, and many found homeschooling to be of poor quality, with insufficient support from schools. In most countries, contact with teachers was limited, leaving parents with primary responsibility for managing homeschooling. Parents also reported increased levels of stress, worry, social isolation, and domestic conflict. A small number of parents reported increased parental alcohol/drug use. Some differences were found between countries and some negative experiences were more common in families with a child with a mental health condition. However, differences between countries and between families with and without a mental health condition were generally small, indicating that many parents across countries reported negative experiences. Some parents also reported positive experiences of homeschooling. The adverse effects of homeschooling will likely have a long-term impact and contribute to increased inequalities. Given that school closures may be less effective than other interventions, policymakers need to carefully consider the negative consequences of homeschooling during additional waves of the COVID-19 pandemic and future pandemics

Analysis of interacting partners and alternative splicing isoforms of human Splicing Factor 1

During the splicing reaction, introns are removed from the pre-mRNA and exons are joined together. This process occurs in a stepwise manner and is carried out by the spliceosome, which consists of five snRNPs and hundreds of proteins. Splicing Factor 1 (SF1) acts at the onset of spliceosome assembly by recognizing the intron branch-point sequence (BPS) in the early complex E. SF1 is then displaced from the pre-mRNA and the BPS is recognized by U2 snRNP in complex A. In this study, we identified novel SF1-interacting partners by performing yeast-two-hybrid screens and co-immunoprecipitation coupled to mass spectrometry. Our results show that SF1 interacts both in vitro and in HeLa nuclear extracts with SURP domains of the U2 snRNP-associated proteins SF3a120 and CHERP. This interaction is required for efficient formation of complex A by promoting the association of U2 snRNP with the spliceosome

Reassembling the social in entrepreneurial innovation and academic entrepreneurship studies: the "amphibious scientist" phenomenon

The chapter focuses on the phenomenon of the amphibious scientist in the context of the dynamics of entrepreneurial teams in high tech academic spin-offs. In particular, it aims at introducing the study of the processes of academic entrepreneurship in terms of translation of scientific, financial and commercial practices from the social contexts of life sciences into new organizational forms. The amphibious scientist phenomenon emerges from the comparison of the foundation of a spin-off with the results of previous research on the establishment of the organisational standard in the biotech sector. By applying the Actor-Network-Theory perspective, the chapter provides interesting insights in the literature of entrepreneurial innovation and academic entrepreneurship

Video-assisted thoracoscopic surgery lobectomy learning curve: what program should be offered in a residency course?

Video-assisted thoracoscopic (VAT) procedures are emerging for treatment of both benign and malignant thoracic diseases and substituting classical approaches, such as thoracotomies, thanks to several advantages concerning postoperative morbidity rates and overall patients’ outcome (i.e., postoperative pain, chronic pain and quality of life). However, a VAT approach needs an established learning curve making procedures as safe as in open surgery. With regard of trainee surgeons, notwithstanding an increasing number of learning tools and strategies, such as simulation programs (i.e., black-boxes, wet labs, cadaver or animal labs, 3D virtual reality simulators) and direct observation both of live surgery and videos with a supportive evidence base from benchtop studies, there remains inconsistent adoption in surgical educations