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Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq (n = 6) and exome sequencing (n = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted. Vestibular schwannomas are benign tumours which can lead to neurological symptoms and morbidity. Here, the authors use single cell RNA-seq and ATAC-seq to identify Schwann cell subtypes in the tumour microenvironment which mimic a nerve injury phenotype. [ABSTRACT FROM AUTHOR]

Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell–cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.A study identifies 41 consensus gene expression meta-programs that are coordinately upregulated in subpopulations of malignant cells across tumour types, providing a comprehensive picture of hallmarks of intratumour heterogeneity. [ABSTRACT FROM AUTHOR]

Wilhelm (Forthcom Synth 199:6357–6369, 2021) has recently defended a criterion for comparing structure of mathematical objects, which he calls Subgroup. He argues that Subgroup is better than SYM ∗ , another widely adopted criterion. We argue that this is mistaken; Subgroup is strictly worse than SYM ∗ . We then formulate a new criterion that improves on both SYM ∗ and Subgroup, answering Wilhelm’s criticisms of SYM ∗ along the way. We conclude by arguing that no criterion that looks only to the automorphisms of mathematical objects to compare their structure can be fully satisfactory. [ABSTRACT FROM AUTHOR]

In his book Philosophy of Logic, Putnam (1971) presents a short argument which reads like—and indeed, can be reconstructed as—a formal proof that a nominalistic physics is impossible. The aim of this paper is to examine Putnam's proof and show that it is not compelling. The precise way in which the proof fails yields insight into the relation that a nominalistic physics should bear to standard physics and into Putnam's indispensability argument. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma (GBM) is the most common and deadliest brain tumor with unrelenting and rapid disease progression. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Treatment failure and resistance is the rule and despite advances in imaging technology, early detection of treatment failure or impending resistance remains a challenge. There is a dire, unmet, need in clinical practice for minimally-invasive diagnostic tools to enable timely understanding of disease progression and treatment response. Here, we aim to address this clinical need by leveraging a unique characteristic of GBM: the overexpression of the α2 variant of the IL-13 receptor in over 75% of GBM tumors. Methods: In this study we examined patients with primary GBM from Penn State and Cleveland Clinic compared to healthy controls. Results: IL13Rα2 was detectable in plasma of GBM patients using ELISA but detection could be optimized by PEG precipitation to enrich for extracellular vesicles (EVs). Patients with GBM had elevated levels of plasma IL13Rα2, which correlated to levels of this receptor in the tumor tissue. Elevated plasma levels of IL13Rα2 predicted longer overall survival (OS) (19.8 vs. 13.2 months). Similarly, detection of IL13Rα2 + cells in tumor tissue also predicted longer OS (22.1 vs. 12.2 months). Conclusion: These findings strongly suggest that expression of the IL13Rα2 receptor confer survival advantage in GBM patients, which can be determined through a minimally-invasive liquid biopsy. Detection of plasma IL13Rα2 can also be used to select GBM patients for targeted tumor therapy. [ABSTRACT FROM AUTHOR]

Within the context of general relativity, the Heraclitus asymmetry property requires that no distinct pair of spacetime events have the same local structure Manchak and Barrett(2023). Here, we explore Heraclitus-maximal worlds – those which are “as large as they can be” with respect to the Heraclitus property. Using Zorn’s lemma, we prove that such worlds exist and highlight a number of their properties. If attention is restricted to Heraclitus-maximal worlds, we show senses in which observers have the epistemic resources to know which world they inhabit. [ABSTRACT FROM AUTHOR]

This paper presents a simple pair of first-order theories that are not definitionally (nor Morita) equivalent, yet are mutually conservatively translatable and mutually ‘surjectively’ translatable. We use these results to clarify the overall geography of standards of equivalence and to show that the structural commitments that theories make behave in a more subtle manner than has been recognized. [ABSTRACT FROM AUTHOR]

As we enter a chronic phase of the SARS-CoV-2 pandemic, with uncontrolled infection rates in many places, relative regional susceptibilities are a critical unknown for policy planning. Tests for SARS-CoV-2 infection or antibodies are indicative but unreliable measures of exposure. Here instead, for four highly-affected countries, we determine population susceptibilities by directly comparing country-wide observed epidemic dynamics data with that of their main metropolitan regions. We find significant susceptibility reductions in the metropolitan regions as a result of earlier seeding, with a relatively longer phase of exponential growth before the introduction of public health interventions. During the post-growth phase, the lower susceptibility of these regions contributed to the decline in cases, independent of intervention effects. Forward projections indicate that non-metropolitan regions will be more affected during recurrent epidemic waves compared with the initially heavier-hit metropolitan regions. Our findings have consequences for disease forecasts and resource utilisation. [ABSTRACT FROM AUTHOR]

Most conservation research aims to inform management of environmental challenges, but scientific evidence is used inconsistently in environmental programmes and practice. We used semi-structured retrospective interviews to ask 12 environmental scientists and 14 practitioners (land managers, park rangers, project managers and planners from natural resource management agencies) about factors that facilitated and hindered the use of scientific input during 15 environmental projects. We used the common factors from interviews to develop a process model describing how scientific input informs programmes and practice. The model emphasised the social dimensions of environmental projects which are often overlooked when these projects are planned, managed and evaluated. It highlighted the pivotal role of relationships in achieving outcomes which include creating practical, useful products and tools, and robust, credible and trusted evidence. By clarifying the process of how scientific knowledge informs environmental programmes and practice, the model enabled us to provide guidance about how to undertake transdisciplinary work and suggest indicators to track progress. Although derived from environmental projects, the guidance is likely to apply to other fields, particularly where different disciplines work together. [ABSTRACT FROM AUTHOR]

The purported fact that geometric theories formulated in terms of points and geometric theories formulated in terms of lines are 'equally correct' is often invoked in arguments for conceptual relativity, in particular by Putnam and Goodman. We discuss a few notions of equivalence between first-order theories, and we then demonstrate a precise sense in which this purported fact is true. We argue, however, that this fact does not undermine metaphysical realism. [ABSTRACT FROM AUTHOR]

Quine often argued for a simple, untyped system of logic rather than the typed systems that were championed by Russell and Carnap, among others. He claimed that nothing important would be lost by eliminating sorts, and the result would be additional simplicity and elegance. In support of this claim, Quine conjectured that every many-sorted theory is equivalent to a single-sorted theory. We make this conjecture precise, and prove that it is true, at least according to one reasonable notion of theoretical equivalence. Our clarification of Quine's conjecture, however, exposes the shortcomings of his argument against many-sorted logic. [ABSTRACT FROM AUTHOR]

Glymour (1970, 1977, 1980) and Quine (1975) propose two different formal criteria for theoretical equivalence. In this paper we examine the relationships between these criteria. [ABSTRACT FROM AUTHOR]

Morbillivirus infection of marine mammals has been documented across all of the world's oceans. Whilst infection is generally demonstrated using a variety of histopathological and serological techniques, where possible, the use of molecular techniques is being used to enable accurate genetic typing of virus strains through sequence analysis. Here, we present genetic data from dolphins and pilot whales affected by morbillivirus infection in the recent outbreak in the Mediterranean Sea during a six-month period from the end of October 2006 to April 2007. To date, very few studies have looked at characterizing outbreaks of morbillivirus infections in whale species at the molecular level. Here, we provide a full sequence for the haemagglutinin (H) gene from material derived from both a dolphin and a pilot whale from the 2007 outbreak in the Mediterranean Sea and show this virus to be 100% identical across the region analysed. Furthermore, we compare partial sequence data from the nucleocapsid (N) gene of the pilot whale material with previously published data and show evidence for strong protein conservation between these different isolates. Finally, we discuss the current classification of cetacean morbilliviruses as a single species. [ABSTRACT FROM AUTHOR]

Three-dimensional interdigitated electrodes (IDEs) have been investigated as sensing elements for biosensors. Electric field and current density were simulated in the vicinity of these electrodes as a function of the electrode width, gap, and height to determine the optimum geometry. Both the height and the gap between the electrodes were found to have significant effect on the magnitude and distribution of the electric field and current density near the electrode surface, while the width of the electrodes was found to have a smaller effect on field strength and current density. IDEs were fabricated based on these simulations and their performance tested by detecting C-reactive protein (CRP), a stress-related protein and an important biomarker for inflammation, cardiovascular disease risk indicator, and postsurgical recuperation. CRP-specific antibodies were immobilized on the electrode surface and the formation of an immunocomplex (IC) with CRP was monitored. Electrochemical impedance spectroscopy (EIS) was employed as the detection technique. EIS data at various concentrations (1 pg/mL to 10 μg/mL) of CRP spiked in buffer or diluted human serum was collected and fitted into an equivalent electrical circuit model. Change in resistance was found to be the parameter most sensitive to change in CRP concentration. The sensor response was linear from 0.1 ng/mL to 1 μg/mL in both buffer and 5% human serum samples. The CRP samples were validated using a commercially available ELISA for CRP detection. Hence, the viability of IDEs and EIS for the detection of serum biomarkers was established without using labeled or probe molecules. [ABSTRACT FROM AUTHOR]

Background: Based on results from randomized, controlled clinical trials, lithium monotherapy or lithium with the addition of an antipsychotic remains a first-line treatment option for both acute and long-term mood stabilization in bipolar mania. However, response to lithium is poor in bipolar patients who exhibit clinical characteristics such as rapid cycling and mixed manic states, suggesting that they may have a biologically and genetically distinct form of bipolar disorder. A test that could predict response to lithium based upon genetic factors would have significant clinical value. Methods: Eight clinical characteristics were assessed in 92 lithium responders and 92 nonresponders; all probands were from families recruited for linkage studies. Lithium response was rated retrospectively from a standardized interviews and medical records. Eight candidate genes were selected from those reported to be associated with susceptibility to illness, lithium response, or lithium mechanism of action. Sixty-seven single nucleotide polymorphisms (SNPs) were genotyped in these subjects and analyzed for association with the defined clinical characteristics. Results: Using q-value analysis for multiplicity correction, we found significant interactions between lithium response and SNPs (rs1387923 and rs1565445) in the gene encoding neurotrophic tyrosine kinase receptor type 2 (NTRK2) and suicidal ideation, and between SNP rs2064721 in the gene encoding inositol polyphosphate-1-phosphatase (INPP1) and post-traumatic stress disorder. Conclusion: These data support the idea that response to lithium has a multi-genetic etiology dependent upon manifestations of other clinical co-diagnoses. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) administration mimics many of the symptoms of mania and can produce psychosis after chronic use. Both rodents and man display interindividual variation in response to METH. The molecular mechanisms underlying these differences might be relevant to both stimulant addiction and endogenous psychosis. We treated 50 Sprague–Dawley rats acutely with METH (4.0 mg/kg) and 10 control rats with saline, and measured their behavior for 3 h after drug administration. Animals were divided into high responders (HR) (top 20%) and low responders (LR) (lowest 20%) based on their stereotypy response. They were killed 24 h after injection. Total RNA was extracted from the prefrontal cortex (PFC) and the expression of approximately 30 000 transcripts were analyzed using Affymetrix 230 2.0 GeneChips. Real-time reverse transcription-polymerase chain reaction was used to validate the expression of a select group of genes. Forty-three genes exhibited significant differences in expression in HR vs LR 24 h after METH treatment including a group of immediate-early genes (IEGs) (eg, c-fos, junB, NGFI-B, serum-regulated glucocorticoid kinase). These IEG expression differences were accompanied by the significant downregulation of many of these genes compared to saline in the HR but not LR, suggesting a differential responsiveness of signal transduction pathways in these two groups of rats. In addition, the expression of other transcription factors in the PFC was significantly different in HR compared to LR. These gene expression changes may contribute to individual differences in responsiveness to stimulants and the development of mania and psychosis.Neuropsychopharmacology (2006) 31, 2359–2367. doi:10.1038/sj.npp.1301162; published online 19 July 2006 [ABSTRACT FROM AUTHOR]

Members of the morbillivirus genus, canine distemper (CDV), phocine distemper virus (PDV), and the cetacean viruses of dolphins and porpoises exhibit high levels of CNS infection in their natural hosts. CNS complications are rare for measles virus (MV) and are not associated with rinderpest virus (RPV) and peste des petits ruminants virus (PPRV) infection. However, it is possible that all morbilliviruses infect the CNS but in some hosts are rapidly cleared by the immune response. In this study, we assessed whether RPV and PPRV have the potential to be neurovirulent. We describe the outcome of infection, of selected mouse strains, with isolates of RPV, PPRV, PDV, porpoise morbillivirus (PMV), dolphin morbillivirus (DMV), and a wild-type strain of MV. In the case of RPV virus, strains with different passage histories have been examined. The results of experiments with these viruses were compared with those using neuroadapted and vaccine strains of MV, which acted as positive and negative controls respectively. Intracerebral inoculation with RPV (Saudi/81) and PPRV (Nigeria75/1) strains produced infection in Balb/C and Cd1, but not C57 suckling mice, whereas the CAM/RB rodent-adapted strain of MV infected all three strains of mice. Weanling mice were only infected by CAM/RB. Intranasal and intraperitoneal inoculation failed to produce infection with any virus strains. We have shown that, both RPV and PPRV,in common with other morbilliviruses are neurovirulent in a permissive system. Transient infection of the CNS of cattle and goats with RPV and PPRV, respectively, remains a possibility, which could provide relevant models for the initial stages of MV infection in humans. [ABSTRACT FROM AUTHOR]

With increasing age, the thoracic aorta shows progressive fibroplastic intimal thickening, which is thought to be pre-atheromatous. A similar progressive intimal thickening in the renal cortical arteries is the distinguishing feature of the nephrosclerosis which underlies essential hypertension. Therefore, the earliest detectable youthful precursors of atherosclerosis and hypertension show strong morphological resemblances to each other. In this study, close statistical associations have been shown between the two types of arterial intimal fibroplasia. Both conditions show similar sigmoid growth curves from ages 6 to 70 years, thereby generating correlations across age groups of r=0.99 in New Orleans and r=0.95 in Mexico City. Specimens gathered in New Orleans were found to have about 1.4 times greater arterial intimal thickening than specimens from Mexico City, and this excess was seen at all ages in both the aortas and the renal cortical arteries. It seems likely that intimai fibroplasia of arteries is reflecting similar biological principles at all levels of the vascular tree. Whatever etiological factors vary between New Orleans and Mexico City, those factors appear to act directly at a tissue level to promote the early precursors of atherosclerosis and of the nephrosclerosis that underlies hypertension. [ABSTRACT FROM AUTHOR]

Spinal cord injury leads to a massive response of innate immune cells in non-regenerating mammals, but also in successfully regenerating zebrafish. However, the role of the immune response in successful regeneration is poorly defined. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in spinal-lesioned zebrafish larvae. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary for repair. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Tnf-α and Il-1β. Inhibiting Tnf-α does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro-regenerative role of Tnf-α. In contrast, decreasing Il-1β levels or number of Il-1β+ neutrophils rescue functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1β function impairs regeneration in irf8 and wildtype animals. Hence, inflammation is dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish. While proinflammatory signalling is preventive to axon regrowth, activated macrophages can be beneficial, for example by limiting the inflammation. This study uses mutant zebrafish lines that lack macrophages and/or microglia to show that peripheral macrophages are necessary in axon regrowth following complete transection of spinal cord. [ABSTRACT FROM AUTHOR]

Human mitochondrial DNA polymerase, encoded by POLG, contains a polyglutamine tract encoded by a CAG microsatellite repeat. Analysis of POLG genotypes in different populations identified an association between absence of the common, tenrepeat allele and male infertility typified by a range of sperm quality defects but excluding azoospermia. [ABSTRACT FROM AUTHOR]