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The field of dark matter detection is a highly visible and highly competitive one. In this paper, we propose recommendations for presenting dark matter direct detection results particularly suited for weak-scale dark matter searches, although we believe the spirit of the recommendations can apply more broadly to searches for other dark matter candidates, such as very light dark matter or axions. To translate experimental data into a final published result, direct detection collaborations must make a series of choices in their analysis, ranging from how to model astrophysical parameters to how to make statistical inferences based on observed data. While many collaborations follow a standard set of recommendations in some areas, for example the expected flux of dark matter particles (to a large degree based on a paper from Lewin and Smith in 1995), in other areas, particularly in statistical inference, they have taken different approaches, often from result to result by the same collaboration. We set out a number of recommendations on how to apply the now commonly used Profile Likelihood Ratio method to direct detection data. In addition, updated recommendations for the Standard Halo Model astrophysical parameters and relevant neutrino fluxes are provided. The authors of this note include members of the DAMIC, DarkSide, DARWIN, DEAP, LZ, NEWS-G, PandaX, PICO, SBC, SENSEI, SuperCDMS, and XENON collaborations, and these collaborations provided input to the recommendations laid out here. Wide-spread adoption of these recommendations will make it easier to compare and combine future dark matter results.

MicroRNAs are predicted to regulate thousands of mammalian genes, but relatively few targets have been experimentally validated and few microRNA loss-of-function phenotypes have been assigned. As an alternative to chemically modified antisense oligonucleotides, we developed microRNA inhibitors that can be expressed in cells, as RNAs produced from transgenes. Termed 'microRNA sponges', these competitive inhibitors are transcripts expressed from strong promoters, containing multiple, tandem binding sites to a microRNA of interest. When vectors encoding these sponges are transiently transfected into cultured cells, sponges derepress microRNA targets at least as strongly as chemically modified antisense oligonucleotides. They specifically inhibit microRNAs with a complementary heptameric seed, such that a single sponge can be used to block an entire microRNA seed family. RNA polymerase II promoter (Pol II)-driven sponges contain a fluorescence reporter gene for identification and sorting of sponge-treated cells. We envision the use of stably expressed sponges in animal models of disease and development.

Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases. The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis. Here authors show that trehalose, an mTOR-independent autophagy inducer, alleviates the pathological phenotypes in a mouse model of neurodegenerative disease. Trehalose acts by inhibiting Akt, which normally suppresses TFEB via an mTORC1-independent mechanism.

Two-dimensional perovskites have emerged as more intrinsically stable materials for solar cells. Chemical tuning of spacer organic cations has attracted great interest due to their additional functionalities. However, how the chemical nature of the organic cations affects the properties of two-dimensional perovskites and devices is rarely reported. Here we demonstrate that the selection of spacer cations (i.e., selective fluorination of phenethylammonium) affects the film properties of two-dimensional perovskites, leading to different device performance of two-dimensional perovskite solar cells (average n = 4). Structural analysis reveals that different packing arrangements and orientational disorder of the spacer cations result in orientational degeneracy and different formation energies, largely explaining the difference in film properties. This work provides key missing information on how spacer cations exert influence on desirable electronic properties and device performance of two-dimensional perovskites via the weak and cooperative interactions of these cations in the crystal lattice. Two dimensional halide perovskites solar cells have attracted research interest due to their higher stability compared to three dimensional counterparts. Here Hu et al. show that fine tuning of the chemical structure of the spacer cations leads to different packing arrangements and device efficiency.

Splicing factors such as BUD31 are identified in a synthetic-lethal screen with cells overexpressing the transcription factor MYC; oncogenic MYC leads to an increase in pre-mRNA synthesis, and spliceosome inhibition impairs the growth and tumorigenicity of MYC-dependent breast cancers, suggesting that spliceosome components may be potential therapeutic targets for MYC-driven cancers. Tolerating overexpressed MYC The transcription factor MYC is frequently amplified or overexpressed in cancer and drives increased RNA and protein production. Here, Thomas Westbrook and colleagues identify the splicing factor BUD31 in a synthetic lethal screen with cells overexpressing MYC and show that other splicing factors are also required for cells to tolerate overexpressed MYC. Oncogenic MYC leads to an increase in pre-mRNA synthesis, and inhibition of the spliceosome impairs the growth and tumorigenicity of MYC-dependent breast cancer cells. Spliceosome components may therefore be potential therapeutic targets for MYC-driven cancers. MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs 1 , 2 , 3 . Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts 4 , 5 , 6 , 7 . While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly 8 . Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

Background Targeted lung cancer screening is effective in reducing mortality by upwards of twenty percent. However, screening is not universally available and uptake is variable and socially patterned. Understanding screening behaviour is integral to designing a service that serves its population and promotes equitable uptake. We sought to review the literature to identify barriers and facilitators to screening to inform the development of a pilot lung screening study in Scotland. Methods We used Arksey and O’Malley’s scoping review methodology and PRISMA-ScR framework to identify relevant literature to meet the study aims. Qualitative, quantitative and mixed methods primary studies published between January 2000 and May 2021 were identified and reviewed by two reviewers for inclusion, using a list of search terms developed by the study team and adapted for chosen databases. Results Twenty-one articles met the final inclusion criteria. Articles were published between 2003 and 2021 and came from high income countries. Following data extraction and synthesis, findings were organised into four categories: Awareness of lung screening , Enthusiasm for lung screening , Barriers to lung screening , and Facilitators or ways of promoting uptake of lung screening . Awareness of lung screening was low while enthusiasm was high. Barriers to screening included fear of a cancer diagnosis, low perceived risk of lung cancer as well as practical barriers of cost, travel and time off work. Being health conscious, provider endorsement and seeking reassurance were all identified as facilitators of screening participation. Conclusions Understanding patient reported barriers and facilitators to lung screening can help inform the implementation of future lung screening pilots and national lung screening programmes.

microRNAs have recently emerged as master regulators of gene expression during development and cell differentiation. Although profound changes in gene expression also occur during antigen-induced T cell differentiation, the role of miRNAs in the process is not known. We compared the miRNA expression profiles between antigen-specific naïve, effector and memory CD8+ T cells using 3 different methods--small RNA cloning, miRNA microarray analysis and real-time PCR. Although many miRNAs were expressed in all the T cell subsets, the frequency of 7 miRNAs (miR-16, miR-21, miR-142-3p, miR-142-5p, miR-150, miR-15b and let-7f) alone accounted for approximately 60% of all miRNAs, and their expression was several fold higher than the other expressed miRNAs. Global downregulation of miRNAs (including 6/7 dominantly expressed miRNAs) was observed in effector T cells compared to naïve cells and the miRNA expression levels tended to come back up in memory T cells. However, a few miRNAs, notably miR-21 were higher in effector and memory T cells compared to naïve T cells. These results suggest that concomitant with profound changes in gene expression, miRNA profile also changes dynamically during T cell differentiation. Sequence analysis of the cloned mature miRNAs revealed an extensive degree of end polymorphism. While 3'end polymorphisms dominated, heterogeneity at both ends, resembling drosha/dicer processing shift was also seen in miR-142, suggesting a possible novel mechanism to generate new miRNA and/or to diversify miRNA target selection. Overall, our results suggest that dynamic changes in the expression of miRNAs may be important for the regulation of gene expression during antigen-induced T cell differentiation. Our study also suggests possible novel mechanisms for miRNA biogenesis and function.

A model in which the stellar wind of the fast-moving red supergiant Betelgeuse is photoionized by radiation from external sources can explain the dense, almost static shell recently discovered around the star, and predicts both that debris from Betelgeuse’s eventual supernova explosion will violently collide with the shell and that other red supergiants should have similar, but much more massive, shells. Inside the Betelgeuse shell The discovery in 2012 of a static, dense gaseous shell around the nearby red supergiant Betelgeuse raised doubts about the assumption that it was a fast-moving star with a powerful stellar wind that drives a bow shock into its surroundings. These two physically distinct structures cannot both be formed by the hydrodynamic interaction of the wind with the interstellar medium. Hilding Neilson and colleagues describe a model in which Betelgeuse's wind is photoionized by radiation from external sources, where pressure induced by photoionization generates a standing shock in the neutral part of the wind. This forms an almost-static photoionization-confined shell, confining gas close to the star, where it can interact with ejecta from a future supernova explosion. This provides a natural explanation for the many supernovae with the signatures of circumstellar interaction. Betelgeuse, a nearby red supergiant, is a fast-moving star with a powerful stellar wind that drives a bow shock into its surroundings 1 , 2 , 3 , 4 . This picture has been challenged by the discovery of a dense and almost static shell 5 that is three times closer to the star than the bow shock and has been decelerated by some external force. The two physically distinct structures cannot both be formed by the hydrodynamic interaction of the wind with the interstellar medium. Here we report that a model in which Betelgeuse’s wind is photoionized by radiation from external sources can explain the static shell without requiring a new understanding of the bow shock. Pressure from the photoionized wind generates a standing shock in the neutral part of the wind 6 and forms an almost static, photoionization-confined shell. Other red supergiants should have much more massive shells than Betelgeuse, because the photoionization-confined shell traps up to 35 per cent of all mass lost during the red supergiant phase, confining this gas close to the star until it explodes. After the supernova explosion, massive shells dramatically affect the supernova light curve, providing a natural explanation for the many supernovae that have signatures of circumstellar interaction.

People with multiple and persistent physical symptoms have impaired quality of life and poor experiences of health care. We aimed to evaluate the effectiveness of a community-based symptom-clinic intervention in people with multiple and persistent physical symptoms, hypothesising that this symptoms clinic plus usual care would be superior to usual care only. The Multiple Symptoms Study 3 was a pragmatic, multicentre, parallel-group, individually randomised controlled trial conducted in 108 general practices in the UK National Health Service in four regions of England between Dec 6, 2018, and June 30, 2023. Participants were individually randomised (1:1) to the symptom-clinic intervention plus usual care or to usual care only via a computer-generated, pseudo-random list stratified by trial centre. Allocation was done by the trial statistician and concealed with a centralised, web-based randomisation system; masking participants was not possible due to the nature of the intervention. The symptom-clinic intervention was a sequence of up to four medical consultations that aimed to elicit a detailed clinical history, fully hear and validate the participant, offer rational explanations for symptoms, and assist the participant to develop ways of managing their symptoms; it was delivered by general practitioners with an extended role. The primary outcome was Patient Health Questionnaire-15 (PHQ-15) score 52 weeks after randomisation, analysed by intention to treat. The trial is registered on the ISRCTN registry (ISRCTN57050216). 354 participants were randomly assigned; 178 (50%) were assigned to receive the community-based symptoms clinic plus usual care and 176 (50%) were assigned to receive usual care only. At the primary-outcome point of 52 weeks, PHQ-15 scores were 14·1 (SD 3·7) in the group receiving usual care and 12·2 (4·5) in the group receiving the intervention. The adjusted between-group difference of –1·82 (95% CI –2·67 to –0·97) was statistically significantly in favour of the intervention group (p<0·0001). There were 39 adverse events in the group receiving usual care and 36 adverse events in the group receiving the intervention. There were no statistically significant between-group differences in the proportion of participants who had non-serious adverse events (–0·03, 95% CI –0·11 to 0·05) or serious adverse events (0·02, –0·02 to 0·07). No serious adverse event was deemed to be related to the trial intervention. Our symptom-clinic intervention, which focused on explaining persistent symptoms to participants in order to support self-management, led to sustained improvement in multiple and persistent physical symptoms. UK National Institute for Health and Care Research.

The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell survival and autophagy, and its activity is regulated by amino acid availability. Rag GTPase-GATOR1 interactions inhibit mTORC1 in the absence of amino acids, and GATOR1 release and activation of RagA/B promotes mTORC1 activity in the presence of amino acids. However, the factors that play a role in Rag-GATOR1 interaction are still poorly characterized. Here, we show that the tyrosine kinase Src is crucial for amino acid-mediated activation of mTORC1. Src acts upstream of the Rag GTPases by promoting dissociation of GATOR1 from the Rags, thereby determining mTORC1 recruitment and activation at the lysosomal surface. Accordingly, amino acid-mediated regulation of Src/mTORC1 modulates autophagy and cell size expansion. Finally, Src hyperactivation overrides amino acid signaling in the activation of mTORC1. These results shed light on the mechanisms underlying pathway dysregulation in many cancer types. The growth-promoting activity of mTORC1 is regulated by amino acid availability via the Rag GTPases. Here, the authors demonstrate Src-dependent control of cell size and autophagy through disruption of the Rag GTPase–GATOR1 complex and mTORC1 activation at the lysosomal surface.