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Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.

Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin1,2. However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice. These defects persist even when Grn-/- microglia are cultured ex vivo. In addition, single-nucleus RNA sequencing reveals selective loss of excitatory neurons at disease end-stage, which is characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn-/- microglia are sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, deletion of the genes encoding C1qa and C3 mitigates microglial toxicity and rescues TDP-43 proteinopathy and neurodegeneration. These results uncover previously unappreciated contributions of chronic microglial toxicity to TDP-43 proteinopathy during neurodegeneration.

Paragangliomas are neuroendocrine tumors of the autonomic nervous system that are variably clinically functional and have a potential for metastasis. Up to 40% occur in the setting of a hereditary syndrome, most commonly due to germline mutations in succinate dehydrogenase (SDHx) genes. Immunohistochemically, paragangliomas are characteristically GATA3-positive and cytokeratin-negative, with loss of SDHB expression in most hereditary cases. In contrast, the rare paragangliomas arising in the cauda equina (CEP) or filum terminale region have been shown to be hormonally silent, clinically indolent, and have variable keratin expression, suggesting these tumors may represent a separate pathologic entity. We retrospectively evaluated 17 CEPs from 11 male and 6 female patients with a median age of 38 years (range 21-82), none with a family history of neuroendocrine neoplasia. Six of the 17 tumors demonstrated prominent gangliocytic or ganglioneuromatous differentiation. By immunohistochemistry, none of the CEPs showed GATA3 positivity or loss of SDHB staining; all 17 CEPs were cytokeratin positive. Genome-wide DNA methylation profiling was performed on 12 of the tumors and compared with publicly available genome-wide DNA methylation data. Clustering analysis showed that CEPs form a distinct epigenetic group, separate from paragangliomas of extraspinal sites, pheochromocytomas, and other neuroendocrine neoplasms. Copy number analysis revealed diploid genomes in the vast majority of CEPs, whereas extraspinal paragangliomas were mostly aneuploid with recurrent trisomy 1q and monosomies of 1p, 3, and 11, none of which were present in the cohort of CEP. Together, these findings indicate that CEPs likely represent a distinct entity. Future genomic studies are needed to further elucidate the molecular pathogenesis of these tumors.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

BACKGROUND:Psoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors. CASE PRESENTATION:A 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis. CONCLUSION:Patients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity.

Subducted plates often stagnate in the mantle transition zone (MTZ), and the fate of the stagnant slabs is still debatable. They may sink into the lower mantle, or remain partially trapped in the MTZ, but it is uncertain whether they can return to the upper mantle. We report geochemical evidence of late-Miocene (~6 Ma) basalts from, and upper mantle seismic evidence beneath Shuangyashan, an area above the slab tear of the stagnant Pacific plate in eastern Asia, to show how the slab returns to the upper mantle from the MTZ. Remarkably high δ57Fe, Gd/Yb and low δ26Mg, Ti/Eu, CaO/Al2O3 values of Shuangyashan basalts suggest that the subducted Pacific oceanic crust had been entrained to their upper mantle source. Therefore, the return of oceanic crust from the MTZ to the upper mantle appears to have been driven by upwelling triggered by tearing of the stagnant slab right beneath this area. Meanwhile, local shear splitting measurements reveal a circular pattern of anisotropy in the upper mantle with delay times diminishing toward the slab tear, suggesting that the slab-fragment-bearing upwelling subsequently turned into lateral flows in the upper mantle, and contributed to a wider intraplate magmatism above the stagnant slab. This finding, together with other widespread intraplate volcanism from eastern Asia, extending for approximately 6,000 km, demonstrates that a subduction-induced tear can lead to the destruction and partial return of stagnant slab material, and thus lead to the cycling of subducted crustal materials and the generation of subduction-induced intraplate magmatism. [ABSTRACT FROM AUTHOR]

BACKGROUND: Fertiliser applications are well‐established tools in pasture‐based agricultural landscapes. This study focuses on the impact of phosphorus (P) fertiliser on grass grub (Costelytra giveni), a major pasture pest. This research investigates the interplay between P, plant growth, and grass grub fitness in Epichloë endophyte‐infected perennial ryegrass (Epichloë sp. LpTG‐3 strain AR37) and meadow fescue infected with E. uncinata (strain MaxR; AR1017), alongside their endophyte‐free counterparts. In a glasshouse trial, plants were grown in P‐enriched soil with varying Olsen P levels (9, 18, 28 or 78 mg L−1), and grass grubs were introduced. Their survival and weight gain, and plant performance were measured. In a bioassay, grass grubs were placed in specimen vials with P‐enriched soils (Olsen P levels 9, 18, 28 and 78 mg L−1) and provided with identical plant material to assess their diet consumption and weight gain. RESULTS: In the glasshouse trial, results highlighted a notable decrease in the survival of grass grub on plants infected with MaxR endophyte, but not with AR37, as well as increasing soil Olsen P levels in both plant species. While grass grub decreased plant performance at the low Olsen P level (9 mg L−1), this effect diminished with increasing P. Likewise, results from the bioassay showed a decrease in diet consumption with increasing soil Olsen P levels. In both trials increasing Olsen P levels correlated with diminished grass grub performance, revealing a nuanced relationship between soil fertility and pest dynamics. CONCLUSION: The study underscores the pivotal role of selected Epichloë endophyte–grass associations in mitigating grass grub damage across varying phosphorus levels. This study highlights the potential to integrate P applications for sustainable pest control against grass grub. Further field trials are required to validate these findings. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid-liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.

Allotetraploid white clover (Trifolium repens) formed during the last glaciation through hybridisation of two European diploid progenitors from restricted niches: one coastal, the other alpine. Here, we examine which hybridisation‐derived molecular events may have underpinned white clover's postglacial niche expansion. We compared the transcriptomic frost responses of white clovers (an inbred line and an alpine‐adapted ecotype), extant descendants of its progenitor species and a resynthesised white clover neopolyploid to identify genes that were exclusively frost‐induced in the alpine progenitor and its derived subgenomes. From these analyses we identified galactinol synthase, the rate‐limiting enzyme in biosynthesis of the cryoprotectant raffinose, and found that the extant descendants of the alpine progenitor as well as the neopolyploid white clover rapidly accumulated significantly more galactinol and raffinose than the coastal progenitor under cold stress. The frost‐induced galactinol synthase expression and rapid raffinose accumulation derived from the alpine progenitor likely provided an advantage during early postglacial colonisation for white clover compared to its coastal progenitor. Summary statement: Cold induction of galactinol synthase expression and raffinose accumulation are likely alpine progenitor‐derived traits contributing to postglacial niche expansion in allotetraploid white clover. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine alcohol-related unintentional injury (ARUI) prevalence as well as the associated correlates and predictors in a nationally representative sample of collegiate athletes. We utilized a cross-sectional secondary data analysis of undergraduate varsity and club sport athletes who drank alcohol at least once in their lifetime from the spring 2018 American College Health Association-National College Health Assessment II survey data (N = 8,715). Including the main outcome variable of ARUI, we examined both individual-level and institutional-level indicators in relation to report of ARUI prevalence in the past 12 months. The ARUI prevalence was 15.1%. The strongest predictors of having had an ARUI in the past year were alcohol use in past 30 days; heavy episodic drinking (HED); not utilizing protective behaviors when drinking; high level of stress in the past year; intentionally injuring oneself; and seriously considered suicide when drinking. Identifying the correlates and predictors of ARUI in college athletes will support education and intervention to reduce high-risk alcohol consumption and associated consequences, like ARUI. [ABSTRACT FROM AUTHOR]