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Abstract Internal variability arising from the inherently chaotic nature of the climate system has amplified or obscured human-caused changes, especially at regional scales in the extratropics, where its contribution to climate variability is the largest. It is virtually certain that this will continue in the near-term. We here focus on the Northern Europe region, whose variability is largely controlled by the North Atlantic Oscillation (NAO) and the Atlantic Meridional Overturning Circulation (AMOC) through remote dynamical and thermodynamic processes, and introduce the concept of internal variability storylines (IVS) to explore, understand, and quantify the role of the two combined drivers of internal variability in the modulation of the anthropogenic warming by 2040 in winter. Based on a large ensemble of historical-scenario simulations, we show that the high-impact IVS, characterised by weak AMOC decline and a decadal shift of the NAO toward dominant positive phase, leads faster to warmer-wetter conditions independently of actual and future greenhouse gases emissions. By contrast, amplified AMOC reduction and more recurrent negative NAO can considerably damp both warming and wettening at near-term. In the latter IVS, we provide evidence that winter-severe conditions similar to those in 2010, that had been responsible for widespread socio-economic disruptions, remain almost as likely to occur by 2040. Reframing the uncertain climate outcomes into the physical science space in a conditional form through the prism of IVS makes climate information relevant for accurate risk assessments and adaptation planning.

Mixed methods research plays an important role in understanding and supporting the implementation of inclusive education policies and practices around the world. The aim of this scoping review was to assess the rigour of 66 mixed methods research texts in inclusive education by applying Harrison, Reilly, and Creswell's (2020) Rigorous Mixed Methods Framework and the PRISMA-ScR guidelines. Overall, studies showed medium levels of rigour, although there was significant variability, with theses and dissertations reflecting higher rigour than peer reviewed articles. Results suggest that scholars can deepen their application of mixed methods by thoughtfully integrating qualitative and quantitative approaches to gain insights into the complex and contextualized processes that characterize inclusive education.

Rigor evaluation in mixed methods research is a growing need. Linking rigor to Hong and Pluye's (2019) concepts of methodological and reporting quality, the purpose of this article is to operationalize and expand Harrison et al.'s (2020) Rigorous Mixed Methods Framework. Drawing from a systematic methodological review of 66 inclusive education studies, we (a) operationalize each element of the original framework, and (b) present arguments for two additional advanced elements, paradigm and ethics. Contributions to the field of mixed methods include situating the concept of rigor in the quality literature, expanding a rigor tool by developing guiding questions, and offering both conceptual and empirical justification for including paradigm and ethics in the rigor tool.

Summary: Sphingolipid levels are crucial determinants of neurodegenerative disorders and therefore require tight regulation. The Orm protein family and ceramides inhibit the rate-limiting step of sphingolipid biosynthesis—the condensation of L-serine and palmitoyl-coenzyme A (CoA). The yeast isoforms Orm1 and Orm2 form a complex with the serine palmitoyltransferase (SPT). While Orm1 and Orm2 have highly similar sequences, they are differentially regulated, though the mechanistic details remain elusive. Here, we determine the cryoelectron microscopy structure of the SPT complex containing Orm2. Complementary in vitro activity assays and genetic experiments with targeted lipidomics demonstrate a lower activity of the SPT-Orm2 complex than the SPT-Orm1 complex. Our results suggest a higher inhibitory potential of Orm2, despite the similar structures of the Orm1- and Orm2-containing complexes. The high conservation of SPT from yeast to man implies different regulatory capacities for the three human ORMDL isoforms, which might be key for understanding their role in sphingolipid-mediated neurodegenerative disorders.

This paper explores positive and negative attitudes towards the inclusion of children with disabilities in schools among primary and secondary school teachers in Trinidad via qualitative methods. Data is collected from 15 primary and secondary school teachers using semi-structured interviews and constant comparison analysis is employed to identify the themes. Among the teachers in the positive attitude category, two themes emerged, namely humanistic beliefs and recognition of benefits indicating the existence of a philosophy of inclusiveness. For teachers in the negative attitude category, two distinct themes emerged corresponding to limitations for children with and without disabilities and the lack of support for inclusion. The findings indicate the need for professional development for in-service teachers and the urgency for a compulsory pre-service programme for new teachers in Trinidad.

Tracing the phylogenetic relationships between species is one of the fundamental objectives of evolutionary biology. Since Charles Darwin’s seminal work in the 19th century, considerable progress has been made towards establishing a tree of life that summarises the evolutionary history of species. Nevertheless, substantial uncertainties still remain. Specifically, the relationships at the origins of teleost fishes have been the subject of extensive debate over the last 50 years. This question has major implications for various research fields: there are almost 30,000 species in the teleost group, which includes invaluable model organisms for biomedical, evolutionary and ecological studies. Here, we present the work in which we solved this enigma. We demonstrated that eels are more closely related to bony-tongued fishes than to the rest of teleost fishes. We achieved this by taking advantage of new genomic data and leveraging innovative phylogenetic markers. Notably, in addition to traditional molecular phylogeny methods based on the evolution of gene sequences, we also considered the evolution of gene order along the DNA molecule. We discuss the challenges and opportunities that these new markers represent for the field of molecular phylogeny, and in particular the possibilities they offer for re-examining other controversial branches in the tree of life.

Rhyacophila masudi sp. nov. from Northwest Himalaya of India is described and illustrated. The species mostly occurs in the Pir Panjal Region of Jammu and Kashmir, India. With this new addition, the genus Rhyacophila is represented by 166 valid species from India.

Two new records of the genus Lepidostoma Rambur are reported from India. These include L. diespiter (Malicky & Sangpradub, 2001) and L. kamba (Mosely, 1939b) collected from Himachal Pradesh and Uttarakhand in India. With these new additions, the genus Lepidostoma Rambur is represented by 51 valid species from India. Complete redescriptions of these two species with illustrations are also provided. Also, L. sonomax (Mosely, 1939) is reported from Uttarakhand for the first time. Potential threats to these species and other freshwater biota are noted.

Abstract Sphingolipids are structural membrane components that also function in cellular stress responses. The serine palmitoyltransferase (SPT) catalyzes the rate-limiting step in sphingolipid biogenesis. Its activity is tightly regulated through multiple binding partners, including Tsc3, Orm proteins, ceramides, and the phosphatidylinositol-4-phosphate (PI4P) phosphatase Sac1. The structural organization and regulatory mechanisms of this complex are not yet understood. Here, we report the high-resolution cryo-EM structures of the yeast SPT in complex with Tsc3 and Orm1 (SPOT) as dimers and monomers and a monomeric complex further carrying Sac1 (SPOTS). In all complexes, the tight interaction of the downstream metabolite ceramide and Orm1 reveals the ceramide-dependent inhibition. Additionally, observation of ceramide and ergosterol binding suggests a co-regulation of sphingolipid biogenesis and sterol metabolism within the SPOTS complex.

P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and mediates the bioavailability and pharmacokinetics of many drugs (Juliano and Ling, 1976; Ueda et al., 1986; Sharom, 2011). Decades of structural and biochemical studies have provided insights into how Pgp binds diverse compounds (Loo and Clarke, 2000; Loo et al., 2009; Aller et al., 2009; Alam et al., 2019; Nosol et al., 2020; Chufan et al., 2015), but how they are translocated through the membrane has remained elusive. Here, we covalently attached a cyclic substrate to discrete sites of Pgp and determined multiple complex structures in inward- and outward-facing states by cryoEM. In conjunction with molecular dynamics simulations, our structures trace the substrate passage across the membrane and identify conformational changes in transmembrane helix 1 (TM1) as regulators of substrate transport. In mid-transport conformations, TM1 breaks at glycine 72. Mutation of this residue significantly impairs drug transport of Pgp in vivo, corroborating the importance of its regulatory role. Importantly, our data suggest that the cyclic substrate can exit Pgp without the requirement of a wide-open outward-facing conformation, diverting from the common efflux model for Pgp and other ABC exporters. The substrate transport mechanism of Pgp revealed here pinpoints critical targets for future drug discovery studies of this medically relevant system.

This paper examines the accommodations for the inclusion of children with disabilities in regular schools in Trinidad. A multiphase mixed methods design consisting of three phases is used. In the first phase, the environmental accommodations essential for the inclusion of children with disabilities in schools are identified. This information is obtained through interviews with parents and advocates of children with various disabilities. Five themes emerge, namely, qualified human resources, educational materials, physical access, supportive learning systems, and supportive school policies and rules. A questionnaire is then developed in the second phase based on these qualitative findings which is administered to a representative sample of primary and secondary schools in the third phase. Qualitative data are also collected in the third phase. Particularly, data on inclusive education policy are collected from primary and secondary schools and data on legislation supporting inclusion from government officials. The integrated findings indicate that existing environmental accommodations, law, and policy do not fully support the inclusion of children with disabilities in Trinidad. They further illustrate the need for national discourses to move beyond access to maximum participation, and for stronger legislation to ensure inclusion in schools.

Objective: The purpose of this scoping review is to provide valuable insights for clinicians and researchers for designing rehabilitative interventions targeting the trunk and core for individuals who have experienced traumatic events, such as stroke or spinal cord injury, or are grappling with neurological diseases such as multiple sclerosis and Parkinson’s disease. We investigated training methods used to enhance balance, trunk control, and core stability. Methods: We conducted an extensive literature search across several electronic databases, including Web of Science, PubMed, SCOPUS, Google Scholar, and IEEE Xplore. Results: A total of 109 articles met the inclusion criteria and were included in this review. The results shed light on the diversity of rehabilitation methods that target the trunk and core. These methods have demonstrated effectiveness in improving various outcomes, including balance, trunk control, gait, the management of trunk muscles, overall independence, and individuals’ quality of life. Conclusions: Our scoping review provides an overview on the methods and technologies employed in trunk rehabilitation and core strengthening, offering insights into the added value of core training and specific robotic training, focusing on the importance of different types of feedback to enhance training effectiveness.