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Rationale We evaluated locomotor hyperactivity induced in BALB/C mice by an N-methyl- d -aspartate receptor antagonist MK-801 as an assay for the detection of antipsychotic drugs. Objectives We assessed the effects of antipsychotic drugs to validate the assay (study 1), selective dopamine and serotonin ligands for pharmacological characterisation of the model (study 2) and a number of compounds with efficacy in models of schizophrenia to understand the predictive validity of the model (study 3). Methods Adult males ( n  = 9/group) were pretreated with a test compound, habituated to locomotor activity cages before receiving MK-801 (0.32 mg/kg) and activity recorded for a further 75 or 120 min. In study 1, we tested haloperidol, clozapine, olanzapine, risperidone, ziprasidone, aripiprazole, sertindole and quetiapine. In study 2, we tested SCH23390 (D 1 antagonist), sulpiride (D 2 /D 3 antagonist), raclopride (D 2 /D 3 antagonist), SB-277011 (D 3 antagonist), L-745,870 (D 4 antagonist), WAY100635 (5-HT 1A antagonist), 8-OH-DPAT (5-HT 1A agonist), ketanserin (5-HT 2A /5-HT 2C antagonist) and SB-242084 (5-HT 2C antagonist). In study 3, we tested xanomeline (M 1 /M 4 receptor agonist), LY379268 (mGluR2/3 receptor agonist), diazepam (GABA A modulator) and thioperamide (H 3 receptor antagonist). Results All antipsychotics suppressed MK-801-induced hyperactivity in a dose-dependent and specific manner. The effects of antipsychotics appear to be mediated via dopamine D 1 , D 2 and 5-HT 2 receptors. Xanomeline, LY379268 and diazepam were active in this assay while thioperamide was not. Conclusions MK-801-induced hyperactivity in BALB/C mice model of positive symptoms has shown predictive validity with novel compounds acing at M 1 /M 4 , mGluR2/3 and GABA A receptors and can be used as a screening assay for detection of novel pharmacotherapies targeting those receptors.

Immature lithic arenite (55:7:38) of the Guaviare River in the Andean foothills of southern Colombia passes rapidly into sublithic arenite (87:3:10) as it travels eastward and downstream for 800 km across a low tropical savannah of the Colombian Llanos immediately east of the Andes. The sands of its long tributary, the Inirida River, are exceptionally pure (99:0:1) because they are derived from weathered molassic sands that underlie the Llanos. Small, isolated Precambrian crystalline monadnocks that pierce this Andean molasse have little influence on sand composition. This area has a seasonal rainfall of 2 to over 5 m and an average temperature of 26 to 27°C. The petrology of these streams has great significance, because it shows how effectively a seasonal tropical climate can alter the provenance and plate tectonic interpretation of ancient sandstones of foreland basins.

Base editing requires that the target sequence satisfy the protospacer adjacent motif requirement of the Cas9 domain and that the target nucleotide be located within the editing window of the base editor. To increase the targeting scope of base editors, we engineered six optimized adenine base editors (ABEmax variants) that use SpCas9 variants compatible with non-NGG protospacer adjacent motifs. To increase the range of target bases that can be modified within the protospacer, we use circularly permuted Cas9 variants to produce four cytosine and four adenine base editors with an editing window expanded from ~4–5 nucleotides to up to ~8–9 nucleotides and reduced byproduct formation. This set of base editors improves the targeting scope of cytosine and adenine base editing. Wider editing windows and different PAM requirements enable a broad set of genomic positions to be targeted with A and C base editors.

Radiation therapy is one of the most common and effective strategies used to treat cancer. The irradiation is usually performed with a fractionated scheme, where the dose required to kill tumour cells is given in several sessions, spaced by specific time intervals, to allow healthy tissue recovery. In this work, we examined the DNA repair dynamics of cells exposed to radiation delivered in fractions, by assessing the response of histone-2AX (H2AX) phosphorylation (γ-H2AX), a marker of DNA double strand breaks. γ-H2AX foci induction and disappearance were monitored following split dose irradiation experiments in which time interval between exposure and dose were varied. Experimental data have been coupled to an analytical theoretical model, in order to quantify key parameters involved in the foci induction process. Induction of γ-H2AX foci was found to be affected by the initial radiation exposure with a smaller number of foci induced by subsequent exposures. This was compared to chromatin relaxation and cell survival. The time needed for full recovery of γ-H2AX foci induction was quantified (12 hours) and the 1:1 relationship between radiation induced DNA double strand breaks and foci numbers was critically assessed in the multiple irradiation scenarios.

Two gold nanostructures with controllable subnanometre separation are used to follow the evolution of plasmonic modes; the distance at which quantum tunnelling sets in is determined, and a quantum limit for plasmonic field confinement is estimated. Subnanometre plasmonic interactions Confining and enhancing light at nanometre length scales using plasmonic effects has become a widely used tool for applications including imaging, sensing, transformation optics and photovoltaics. To exploit plasmonics at even smaller, subnanometre length scales, it becomes essential to include quantum effects for a full description. Here, Jeremy Baumberg and colleagues. use two gold nanostructures with controllable subnanometre separation and carefully follow the evolution of the plasmonic modes. They can pinpoint at what distance quantum tunnelling sets in, and establish a quantum limit for plasmonic-field enhancement. The findings are relevant to future nanoplasmonic approaches and nanometer-scale photochemistry. When two metal nanostructures are placed nanometres apart, their optically driven free electrons couple electrically across the gap. The resulting plasmons have enhanced optical fields of a specific colour tightly confined inside the gap. Many emerging nanophotonic technologies depend on the careful control of this plasmonic coupling, including optical nanoantennas for high-sensitivity chemical and biological sensors 1 , nanoscale control of active devices 2 , 3 , 4 , and improved photovoltaic devices 5 . But for subnanometre gaps, coherent quantum tunnelling becomes possible and the system enters a regime of extreme non-locality in which previous classical treatments 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 fail. Electron correlations across the gap that are driven by quantum tunnelling require a new description of non-local transport, which is crucial in nanoscale optoelectronics and single-molecule electronics. Here, by simultaneously measuring both the electrical and optical properties of two gold nanostructures with controllable subnanometre separation, we reveal the quantum regime of tunnelling plasmonics in unprecedented detail. All observed phenomena are in good agreement with recent quantum-based models of plasmonic systems 15 , which eliminate the singularities predicted by classical theories. These findings imply that tunnelling establishes a quantum limit for plasmonic field confinement of about 10 −8 λ 3 for visible light (of wavelength λ ). Our work thus prompts new theoretical and experimental investigations into quantum-domain plasmonic systems, and will affect the future of nanoplasmonic device engineering and nanoscale photochemistry.

The amygdala, hippocampus and hypothalamus are critical stress regulatory areas that undergo functional maturation for stress responding initially established during gestational and early postnatal brain development. Fetal alcohol spectrum disorder (FASD), a consequence of prenatal alcohol exposure (PAE), results in cognitive, mood and behavioral disorders. Prenatal alcohol exposure negatively impacts components of the brain stress response system, including stress-associated brain neuropeptides and glucocorticoid receptors in the amygdala, hippocampus and hypothalamus. While PAE generates a unique brain cytokine expression pattern, little is known about the role of Toll-like receptor 4 (TLR4) and related proinflammatory signaling factors, as well as anti-inflammatory cytokines in PAE brain stress-responsive regions. We hypothesized that PAE sensitizes the early brain stress response system resulting in dysregulated neuroendocrine and neuroimmune activation. A single, 4-h exposure of maternal separation stress in male and female postnatal day 10 (PND10) C57Bl/6 offspring was utilized. Offspring were from either prenatal control exposure (saccharin) or a limited access (4 h) drinking-in-the-dark model of PAE. Immediately after stress on PND10, the hippocampus, amygdala and hypothalamus were collected, and mRNA expression was analyzed for stress-associated factors (CRH and AVP), glucocorticoid receptor signaling regulators (GAS5, FKBP51 and FKBP52), astrocyte and microglial activation, and factors associated with TLR4 activation including proinflammatory interleukin-1β (IL-1β), along with additional pro- and anti-inflammatory cytokines. Select protein expression analysis of CRH, FKBP and factors associated with the TLR4 signaling cascade from male and female amygdala was conducted. The female amygdala revealed increased mRNA expression in stress-associated factors, glucocorticoid receptor signaling regulators and all of the factors critical in the TLR4 activation cascade, while the hypothalamus revealed blunted mRNA expression of all of these factors in PAE following stress. Conversely, far fewer mRNA changes were observed in males, notably in the hippocampus and hypothalamus, but not the amygdala. Statistically significant increases in CRH protein, and a strong trend in increased IL-1β were observed in male offspring with PAE independent of stressor exposure. Prenatal alcohol exposure creates stress-related factors and TLR-4 neuroimmune pathway sensitization observed predominantly in females, that is unmasked in early postnatal life by a stress challenge.

The origins of religion and of complex societies represent evolutionary puzzles . The 'moralizing gods' hypothesis offers a solution to both puzzles by proposing that belief in morally concerned supernatural agents culturally evolved to facilitate cooperation among strangers in large-scale societies . Although previous research has suggested an association between the presence of moralizing gods and social complexity , the relationship between the two is disputed , and attempts to establish causality have been hampered by limitations in the availability of detailed global longitudinal data. To overcome these limitations, here we systematically coded records from 414 societies that span the past 10,000 years from 30 regions around the world, using 51 measures of social complexity and 4 measures of supernatural enforcement of morality. Our analyses not only confirm the association between moralizing gods and social complexity, but also reveal that moralizing gods follow-rather than precede-large increases in social complexity. Contrary to previous predictions , powerful moralizing 'big gods' and prosocial supernatural punishment tend to appear only after the emergence of 'megasocieties' with populations of more than around one million people. Moralizing gods are not a prerequisite for the evolution of social complexity, but they may help to sustain and expand complex multi-ethnic empires after they have become established. By contrast, rituals that facilitate the standardization of religious traditions across large populations generally precede the appearance of moralizing gods. This suggests that ritual practices were more important than the particular content of religious belief to the initial rise of social complexity.

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood–brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50–100% of mice. Our study identifies a promising multi-targetable PTP4A–ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.

Hepatic stellate cells (HSCs) have a central pathogenetic role in the development of liver fibrosis. However, their fibrosis-independent and homeostatic functions remain poorly understood 1 , 2 , 3 , 4 – 5 . Here we demonstrate that genetic depletion of HSCs changes WNT activity and zonation of hepatocytes, leading to marked alterations in liver regeneration, cytochrome P450 metabolism and injury. We identify R-spondin 3 (RSPO3), an HSC-enriched modulator of WNT signalling, as responsible for these hepatocyte-regulatory effects of HSCs. HSC-selective deletion of Rspo3 phenocopies the effects of HSC depletion on hepatocyte gene expression, zonation, liver size, regeneration and cytochrome P450-mediated detoxification, and exacerbates alcohol-associated and metabolic dysfunction-associated steatotic liver disease. RSPO3 expression decreases with HSC activation and is inversely associated with outcomes in patients with alcohol-associated and metabolic dysfunction-associated steatotic liver disease. These protective and hepatocyte-regulating functions of HSCs via RSPO3 resemble the R-spondin-expressing stromal niche in other organs and should be integrated into current therapeutic concepts. Hepatic stellate cells regulate hepatocyte functions via R-spondin 3.