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Over the past decade, advancements in molecular biology have contributed to changes in the diagnostic classification of Spitz neoplasms, including Spitz nevi, atypical Spitz tumors, and Spitz melanomas. The recent World Health Organization classification of skin tumors identifies fusion kinases, including NTRK1, NTRK2, and NTRK3, as critical drivers of these lesions. New fusion genes have continued to expand the spectrum of known molecular alterations, particularly within the category of Spitz NTRK-rearranged lesions. We present 2 new cases of NTRK-rearranged Spitz lesions: an atypical Spitz tumor with common LMNA::NTRK1 fusion and an atypical Spitz tumor with a rare PRDX1::NTRK1 fusion. Clinical, histopathological, immunohistochemical, and molecular analyses were performed to diagnose these patients. This report adds to the growing body of knowledge on NTRK-rearranged Spitz lesions and underscores the importance of integrating molecular findings with morphological and immunohistochemical data for the accurate classification and understanding of these neoplasms.

The ARID1A and ARID1B subunits are mutually exclusive components of the BAF variant of SWI/SNF chromatin remodeling complexes. Loss of function mutations in ARID1A are frequently observed in various cancers, resulting in a dependency on the paralog ARID1B for cancer cell proliferation. However, ARID1B has never been targeted directly, and the high degree of sequence similarity to ARID1A poses a challenge for the development of selective binders. In this study, we used mRNA display to identify peptidic ligands that bind with nanomolar affinities to ARID1B and showed high selectivity over ARID1A. Using orthogonal biochemical, biophysical, and chemical biology tools, we demonstrate that the peptides engage two different binding pockets, one of which directly involves an ARID1B-exclusive cysteine that could allow covalent targeting by small molecules. Our findings impart the first evidence of the ligandability of ARID1B, provide valuable tools for drug discovery, and suggest opportunities for the development of selective molecules to exploit the synthetic lethal relationship between ARID1A and ARID1B in cancer.

Purpose: This paper follows the call for more future-oriented practices within organisations, particularly in relation to how they respond to growing concerns about Earth’s sustainability and life on the Planet. This study aims to explore how the data produced by major scientific projects in the Space sector can support future-oriented accountability practices by enabling both a projection and an imagination of a more or less distant future, thereby feeding into accountability practices. Design/methodology/approach: We rely upon a multiple interpretative case study analysis and interview-based data from three main organisations in the Earth observation (EO) value chain: an International Space Company, a Research Centre of Energy Transition and a European Private Equity Firm. Findings: We find that future-oriented accountability practices can be fed by a creative assemblage of scientific data provided by Space sector’s programmes with different sources of knowledge and information. These data are embedded into a broader accountability system, connecting different actors through a “value chain”: from the data providers, gathering data from Space, to the primary users, working on data modelling and analysis, to the end users, such as local authorities, public and private organisations. The predictive data and expertise exchanged throughout the value chain feed into future-oriented accountability efforts across different time-space contexts, as a projected and imagined, more or less distant, future informs the actions and accounts in the present. Originality/value: This research extends the literature on the time dimension of accountability. We show how a creative assemblage of scientific data with different sources of knowledge and information –such as those provided by Space sector’s programmes and EO data – enable organisations to both project the present into (a more or less distant) future and imagine this future differently while taking responsibility, and accounting for, what could be done and desired in response to it. We also contribute to the limited literature on accountability in the Space sector by examining the intricate accountability dynamics underpinning the relationships among the different actors in the EO data value chain.

AbstractObjectiveRecent literature has suggested that individuals with autism spectrum disorder (ASD) or autistic traits (ATs) would be more likely to encounter traumatic events in their lifetime and to develop post-traumatic stress disorder (PTSD). However, the nature of this relationship has not yet been fully elucidated. The aims of this study were to evaluate the relationship between AT and PTSD and to investigate which specific autistic dimension was more associated with trauma and stress-related symptoms.MethodsA total of 68 subjects with ASD and 64 healthy controls (HCs) were assessed with the Adult Autism Subthreshold Spectrum (AdAS Spectrum) and the Trauma and Loss Spectrum (TALS) questionnaires. Statistical analyses included Mann–Whitney Utest, chi-square test, calculation of Spearman’s coefficients, and logistic regression analysis.ResultsPatients with significant AT reported a 30% rate of PTSD and higher TALS total and domain scores than HCs, among whom no PTSD was found instead. Significant positive correlations were reported between AdAS Spectrum and TALS-SR scores in the whole sample. AdAS Spectrum total scores were statistically predictive of the presence of PTSD. High scores at AdAS Spectrum Inflexibility and adherence to routineand Restrictive interest and ruminationdomains were identified as positive predictors of a probable PTSD.ConclusionCompared to HCs, subjects with significant AT are more likely to present symptoms of PTSD. In particular, AT related to ruminative thinking, narrow interests, and sensorial reactivity would seem to predict the presence of post-traumatic stress symptomatology.

Human neutrophil elastase (HNE) plays an essential role in host defense against bacteria but is also involved in several respiratory diseases. Recent reports suggest that compounds exhibiting a combination of HNE inhibitory activity with antiradical properties may be therapeutically beneficial for the treatment of respiratory diseases involving inflammation and oxidative stress. We report here the synthesis and biological evaluation of novel ebselen analogues exhibiting HNE inhibitory and antiradical activities. HNE inhibition was evaluated in an enzymatic system using human HNE, whereas antiradical activity was evaluated in a cell-based assay system using phorbol 12-myristate 13-acetate (PMA)-stimulated murine bone marrow leukocytes as the source of reactive oxygen species (ROS). HNE inhibition was due to the N–CO group targeting Ser195-OH at position 2 of the scaffold, while antiradical activity was due to the presence of the selenium atom. The most active compounds 4d, 4f, and 4jexhibited a good balance between anti-HNE (IC50= 0.9–1.4 μM) and antiradical activity (IC50= 0.05–0.7 μM). Additionally, the solid-state structure of 4dwas determined and compared to that of the similar compound N-propionyl-1,2-benzisoselenazol-3(2H)-one.

Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis1–8(EAE), an experimental model for multiple sclerosis. However, little is known about the stability of these astrocyte subsets and their ability to integrate past stimulation events. Here we report the identification of an epigenetically controlled memory astrocyte subset that exhibits exacerbated pro-inflammatory responses upon rechallenge. Specifically, using a combination of single-cell RNA sequencing, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, focused interrogation of cells by nucleic acid detection and sequencing, and cell-specific in vivo CRISPR–Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP-citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) that is used by histone acetyltransferase p300 to control chromatin accessibility. The number of ACLY+p300+memory astrocytes is increased in acute and chronic EAE models, and their genetic inactivation ameliorated EAE. We also detected the pro-inflammatory memory phenotype in human astrocytes in vitro; single-cell RNA sequencing and immunohistochemistry studies detected increased numbers of ACLY+p300+astrocytes in chronic multiple sclerosis lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, multiple sclerosis. These findings may guide novel therapeutic approaches for multiple sclerosis and other neurologic diseases.

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α–NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.

We respond to the call for more research into the entanglement between multiple (including non-visual and non-verbal) modes of communication within organizations by exploring the relationships between rhetoric and materiality. We draw on archival sources concerning the Founder’s Building at Royal Holloway College (1874–1897). We discuss the building as a multimodal material object, inherently multiple, fluid and messy: the Founder’s Building is open to multiple encounters with sociality through multiple modes of communication. We find that such ‘messiness’ explains how the spatial, aural, sensual and visual modes embedded in a material object engage with each other, as well as with other visual, verbal and numerical modes, in the crafting of rhetoric: different modes sustain and oppose each other and evolve through absences and presences. We find that the messiness of material objects explains the engagement between rhetoric and materiality: materiality can limit or augment rhetoric, and materiality and rhetoric can co-evolve when the ‘rhetors’ (such as the founder and the governors of the College) and their audiences (such as students, visitors and tax authorities) attempt to transform the object (the Founder’s Building) into always something else, even an absent object.

•Retinal atrophy in multiple sclerosis (MS) reflects neuroaxonal loss•Retinal thinning was assessed in EXPAND substudy of secondary progressive MS (SPMS)•Siponimod reduced thinning of some retinal layers vs placebo after 1 to 2 years•Retinal atrophy is a potential biomarker of therapeutic efficacy in SPMS

Tolebrutinib is a potent, brain-penetrant and bioactive Bruton's tyrosine kinase (BTK) inhibitor that targets B cells and microglia and has the potential to modulate both peripheral and central pathologic processes in multiple sclerosis (MS) that lead to disability accumulation. Tolebrutinib is being investigated in four phase 3 trials across the spectrum of MS, including non-relapsing secondary progressive MS (nrSPMS) for which there are no approved treatments.

Frexalimab is a second-generation anti-CD40L monoclonal antibody that blocks the costimulatory CD40/CD40L pathway, which is important for activation and function of adaptive and innate immunity. In the phase 2 trial (NCT04879628) in participants with relapsing MS (RMS),frexalimab was well-tolerated and showed an 89% reduction in new gadolinium-enhancing (Gd+)T1 lesions in the high-dose arm vs placebo at week 12. In the ongoing open-label extension, 96%of participants in the high-dose arm were free of Gd+ T1 lesions at week 48.

In a Phase 2 trial (NCT04879628), frexalimab demonstrated effi cacy and safety with high-dosetreatment showing 89% reducti on (versus placebo) in new gadolinium-enhancing T1-lesions atWeek 12 (W12) in parti cipants with relapsing multi ple sclerosis (RMS).

Frexalimab is a second-generation anti-CD40L antibody that blocks the costimulatory CD40/CD40L pathway, which is important in regulating adaptive and innate immunity. In the double-blind period (DBP) of the phase 2 trial in participants with relapsing multiple sclerosis (RMS; NCT04879628), frexalimab treatment was well-tolerated and efficacious at reducing disease activity. Frexalimab 1200 mg intravenous (IV) every 4 weeks (q4w) decreased new gadolinium-enhancing (Gd+) T1 lesions by 89% vs placebo at W12. The treatment effect was sustained over 48 weeks in the open-label extension (OLE).

Frexalimab, a second-generation anti-CD40L monoclonal antibody, demonstrated safety and efficacy in participants with relapsing multiple sclerosis (pwRMS) in the12-week (W) double-blind period of a phase 2 trial (NCT04879628), with an 89% reduction in new gadolinium-enhancing lesions in the high-dose group versusplacebo. This was accompanied by a 24% reduction in plasma neurofilament light (pNfL), a biomarker of neuroaxonal damage. Here, we describe changes in pNfL levelswith frexalimab treatment until W48.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system1. Astrocytes are heterogeneous glial cells that are resident in the central nervous system and participate in the pathogenesis of multiple sclerosis and its model experimental autoimmune encephalomyelitis2,3. However, few unique surface markers are available for the isolation of astrocyte subsets, preventing their analysis and the identification of candidate therapeutic targets; these limitations are further amplified by the rarity of pathogenic astrocytes. Here, to address these challenges, we developed focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), a high-throughput microfluidic cytometry method that combines encapsulation of cells in droplets, PCR-based detection of target nucleic acids and droplet sorting to enable in-depth transcriptomic analyses of cells of interest at single-cell resolution. We applied FIND-seq to study the regulation of astrocytes characterized by the splicing-driven activation of the transcription factor XBP1, which promotes disease pathology in multiple sclerosis and experimental autoimmune encephalomyelitis4. Using FIND-seq in combination with conditional-knockout mice, in vivo CRISPR–Cas9-driven genetic perturbation studies and bulk and single-cell RNA sequencing analyses of samples from mouse experimental autoimmune encephalomyelitis and humans with multiple sclerosis, we identified a new role for the nuclear receptor NR3C2 and its corepressor NCOR2 in limiting XBP1-driven pathogenic astrocyte responses. In summary, we used FIND-seq to identify a therapeutically targetable mechanism that limits XBP1-driven pathogenic astrocyte responses. FIND-seq enables the investigation of previously inaccessible cells, including rare cell subsets defined by unique gene expression signatures or other nucleic acid markers.

Purpose: This study aims to explore the engagement between accounting and music in the social and relational construction of accountability. The authors conceive this construction as a dynamic and recursive interplay between the giving of different accounts and the responses that these accounts provoke. The authors investigate the emotional dimension of this interplay, as it is also triggered by music, feeding back into how accountability is constructed and evolves over time. Design/methodology/approach: This study relies upon a historical analysis of archival and secondary sources about the main music concert organized in 1913 by the founder of “Accademia Chigiana”, one of the leading music academies in Italy. The concert celebrated the first centenary of the birth of Giuseppe Verdi, a worldwide famous Italian music composer, and icon of Italian national sentiment. Findings: This study shows that music and accounting were profoundly intertwined in the social and relational construction of accountability for the 1913 concert. Accountability evolved through different accounts, also linked to music, and the complex emotional reactions these accounts provoked in the audiences, citizens, media and institutions, leading to always further responses and accounts in the ongoing construction of accountability. Originality/value: This study extends prior literature on the chameleonic nature of accountability, as well as on its relational and emotional dimensions. The study shows that accountability is relationally constructed and evolves over time through the giving of accounts and the emotional reaction they provoke from others, feeding into further responses and accounts of the accountable subject. The authors show how the chameleonic nature of accountability permeates not only the accounts and the relations of accountability but also the subjects giving and demanding the accounts: these subjects change as chameleons through their interactions and emotions, feeding into the dynamic construction of accountability. The authors also show how arts, like music, can participate in the chameleonic nature of accountability and of its subjects, precisely by engaging with their emotional reactions and responses.

Social determinants of health are the conditions in which people are born, grow, live, work and age. These circumstances are the non-medical factors that influence health outcomes. Evidence indicates that health behaviours, comorbidities and disease-modifying therapies all contribute to multiple sclerosis (MS) outcomes; however, our knowledge of the effects of social determinants — that is, the ‘risks of risks’ — on health has not yet changed our approach to MS. Assessing and addressing social determinants of health could fundamentally improve health and health care in MS; this approach has already been successful in improving outcomes in other chronic diseases. In this narrative Review, we identify and discuss the body of evidence supporting an effect of many social determinants of health, including racial background, employment and social support, on MS outcomes. It must be noted that many of the published studies were subject to bias, and screening tools and/or practical interventions that address these social determinants are, for the most part, lacking. The existing work does not fully explore the potential bidirectional and complex relationships between social determinants of health and MS, and the interpretation of findings is complicated by the interactions and intersections among many of the identified determinants. On the basis of the reviewed literature, we consider that, if effective interventions targeting social determinants of health were available, they could have substantial effects on MS outcomes. Therefore, funding for and focused design of studies to evaluate and address social determinants of health are urgently needed.

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)1—a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR–NF-κB–C/EBPβ signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.

In 2021, the UK Reset and Reform report highlighted areas of improvement within the NHS. Sue Thomas and Gavin Giovannoni evaluate the impact of the report over the last year.

It is well known that if a fruit is harvested extremely early its development and function are interrupted, and it may never attain full maturity and optimal quality. Reports revealing insights regarding the alterations of maturation, ripening and postharvest quality in very early picked fruits are rare. We examined the effects of early harvesting on tomatoes by characterizing different accessions at the molecular, physiological, and biochemical levels. We found that even very early–harvested fruits could achieve postharvest maturation and ripening though with some defects in pigment and cuticle formation, and seeds from very early–harvested fruits could still germinate and develop as normal and healthy plants. One critical regulator of tomato cuticle integrity, SlCER1–2, was shown to contribute to cuticle defects in very early–harvested fruits. Very early fruit harvest still allowing ripening and seed development indicate that the genetic and physiological programs of later maturation and ripening are set into motion early in fruit development and are not dependent on complete fruit expansion nor attachment to the plant.

EGFRaberrations are reported in a subset of myofibroblastic lesions with kinase domain duplication (EGFR-KDD) and exon 20 mutations being assigned to infantile fibrosarcomas (IFS), mesoblastic nephroma, and fibrous hamartoma of infancy (FHI), respectively. In this retrospective study, we correlated molecular findings with the histomorphology of 14 myofibroblastic lesions harboring such genetic changes identified by NGS. We additionally performed DNA methylation profiling (DNAmp) and immunohistochemistry. Lesions were from 10 males and 4 females with a mean age of 3 years (range, 0.3-14) and occurred subcutaneously in the upper limbs (n = 5), lower limbs (n = 3), back/thorax (n = 5), and the nasal cavity (n = 1). Eleven were cured by surgery, including 1 relapsed case. Two patients were lost to follow-up. One case was very recent, and the patient was biopsied. Histologically, the lesions showed a wide spectrum varying from classic FHI (n = 9) to IFS (n = 1) or lipofibromatosis-like tumors (LFT-like) (n = 2) or dermatofibrosarcoma protuberans-like (DFSP-like) (n = 1) to a predominantly myxoid spindle cell lesion (n = 1). Immunohistochemically, all neoplasms stained with CD34, whereas S100 was positive in 2/14. EGFR expression was observed in 9/10 cases. Molecularly, the IFS and 1 LFT-like harbored EGFR-KDD, whereas an exon 20 mutation was identified in all FHI, 1 LFT-like, the DFSP-like, and in predominant myxoid spindle cell lesion. By DNAmp, all but 2 cases formed a well-defined cluster, demonstrating that these lesions are also epigenetically related. In conclusion, EGFRkinase domain aberrations found in FHI, IFS, LFT-like, DFSP-like, and a spindle cell lesion with a predominant myxoid stroma of children and adolescents showed that these neoplasms with a broad morphologic spectrum belong to the group of protein kinase–related lesions with a distinct epigenetic signature. Molecular analyses, including DNAmp, help to identify and characterize this emerging category and become mandatory when targeted treatment is considered.

Purpose: The paper explores the process of construction of the “accountable self”, particularly as this process engages with the spirituality of the self. This study examines the “space of accountability” within which the accountable self constructs itself as such and investigates how different accounts of the self are drawn upon in the making of this space, both defining and transcending it. Design/methodology/approach: The paper relies upon archival material concerning accounting and accountability practices about the project for building the altar of St. Ignatius in the Church of Gesù, Rome, Italy (1691–1706). This study examines calculative and narrative accounts about the project from the perspective of the superintendent, who was the sole person accountable for the building works. Findings: Whereas calculative accounts enabled the self to account for actions within the specific space of accountability of the project, narrative accounts opened up this space, providing for a testimony of actions and a gift of accountability towards future indefinite others. This process was prompted by the spirituality of the self and the narcissistic gratification of fulfilling this spirituality. Originality/value: The paper adds to the literature on the accountable self and to theological perspectives into accountability. This study suggests exploring how different accounts of the self engage with each other through testimony, gift, narcissism and spirituality in the construction of the accountable self, providing for a “transcendent” space of accountability. This research also adds to studies on narrative accounts by showing that they are drawn upon alongside calculative accounts in the construction of the transcendent, accountable self.

The solid-state investigation of the diastereomeric salts (S)-ibuprofen (S-Ibu), (S)-naproxen, (S-Nap), and (S)-ketoprofen (S-Ket) with (R)-(+)- and (S)-(−)-1-phenylethylamine, R-PEA, and S-PEA respectively, has been carried out by using a combination of experimental and in-silicotools. The focus was on their crystal packing and on the stability/transformation of their solid forms under different experimental conditions with the final aim of extracting useful information on the forces/features which could be exploited for the chiral separation of the corresponding racemic compounds. All the salts are 21-column crystals, each column consisting of API and 1-phenylethylamine ions assembled via the 1-phenylethylammonium-carboxylate supramolecular heterosynthon which originates a R43(10) pattern, the intercolumns contacts being definitely weaker. In spite of an overall similarity in the crystal packing forces and motifs of the anhydrous salts, the temperature stability range suggests that the homochiral species are the most stable. The fact that the homochiral salt of S-Ket (S-Ket_S-PEA) is stable toward the hydration, at variance with the heterochiral one (S-Ket_R-PEA), further confirms this hypothesis. On the other hand, preliminary sorption tests show that S-Ket and S-Ibu preferentially capture the homochiral PEA (S-Nap is not selective). This behavior has been correlated to the almost planar boundary surfaces which characterize and differentiate the 21sheets in S-Ket_S-PEAand S-Ibu_S-PEAsalts with respect to the corresponding heterochiral ones.