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Cosmological simulations, as well as mounting evidence from observations, have shown that supermassive black holes play a fundamental role in regulating the formation of stars throughout cosmic time. This has been clearly demonstrated in the case of galaxy clusters in which powerful feedback from the central black hole is preventing the hot intracluster gas from cooling catastrophically, thus reducing the expected star formation rates by orders of magnitude. These conclusions, however, have been almost entirely based on nearby clusters. Based on new Chandra X-ray observations, we present the first observational evidence for massive, runaway cooling occurring in the absence of supermassive black hole feedback in the high-redshift galaxy cluster SpARCS104922.6 + 564032.5 (z = 1.709). The hot intracluster gas appears to be fueling a massive burst of star formation (≈900 M o˙ yr-1) that is offset by dozens of kpc from the central galaxy. The burst is co-spatial with the coolest intracluster gas but not associated with any galaxy in the cluster. In less than 100 million years, such runaway cooling can form the same amount of stars as in the Milky Way. Therefore, intracluster stars are not only produced by tidal stripping and the disruption of cluster galaxies, but can also be produced by runaway cooling of hot intracluster gas at early times. Overall, these observations show the dramatic impact when supermassive black hole feedback fails to operate in clusters. They indicate that in the highest overdensities, such as clusters and protoclusters, runaway cooling may be a new and important mechanism for fueling massive bursts of star formation in the early universe.

Adult humans generally experience a 0.5-1%/year loss in whole-body skeletal muscle mass and a reduction of muscle strength by 1.5-5%/year beginning at the age of 50 years. This results in sarcopenia (aging-related progressive losses of skeletal muscle mass and strength) that affects 10-16% of adults aged ≥ 60 years worldwide. Concentrations of some amino acids (AAs) such as branched-chain AAs, arginine, glutamine, glycine, and serine are reduced in the plasma of older than young adults likely due to insufficient protein intake, reduced protein digestibility, and increased AA catabolism by the portal-drained viscera. Acute, short-term, or long-term administration of some of these AAs or a mixture of proteinogenic AAs can enhance blood flow to skeletal muscle, activate the mechanistic target of rapamycin cell signaling pathway for the initiation of muscle protein synthesis, and modulate the metabolic activity of the muscle. In addition, some AA metabolites such as taurine, β-alanine, carnosine, and creatine have similar physiological effects on improving muscle mass and function in older adults. Long-term adequate intakes of protein and the AA metabolites can aid in mitigating sarcopenia in elderly adults. Appropriate combinations of animal- and plant-sourced foods are most desirable to maintain proper dietary AA balance.

This article evaluates and elucidates the intersections across social and economic determinants of health and social structures that maintain current inequities and structural violence with a focus on the impact on imMigrants (immigrants and migrants), refugees, and those who remain invisible (e.g., people without immigration status who reside in the United States) from Black, Indigenous, and People of Color communities. Psychology has a history of treating individuals and families without adequately considering how trauma is cyclically and generationally maintained by structural violence, inequitable resources, and access to services. The field has not fully developed collaboration within an interdisciplinary framework or learning from best practices through international/global partnerships. Psychology has also been inattentive to the impact of structural violence prominent in impoverished communities. This structural harm has taken the form of the criminalization of imMigrants and refugees through detention, incarceration, and asylum citizenship processes. Most recently, the simultaneous occurrence of multiple catastrophic events, such as COVID-19, political polarization and unrest, police violence, and acceleration of climate change, has created a hypercomplex emergency for marginalized and vulnerable groups. We advance a framework that psychologists can use to inform, guide, and integrate their work. The foundation of this framework is select United Nations Sustainable Development Goals to address health inequities. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Culture and social structure are not separated analytical domains but intertwined phenomena observable in personal networks. Drawing on a personal networks dataset of migrants in the United States and Spain, we show that the country of origin, a proxy for diverse languages and cultural institutions, and religion may be predicted by specific combinations of personal network structural measures (closeness, clustering, betweenness, average degree, etc). We obtain similar results applying three different methods (a multinomial logistic regression, a Random Forest algorithm, and an artificial neural network). This finding is explained within the framework of the Grid/Group theory that has long posed the interdependence of social structural and cultural features of human groups., (© The Author(s) 2022. Published by Oxford University Press on behalf of National Academy of Sciences.)

A 14-year-old girl presented with fevers, joint pain, leukocytosis, and painful, fluctuant skin lesions, preceded by a 2-week history of abdominal cramping and diarrhea. Workup revealed bowel-associated-dermatosis-arthritis syndrome (BADAS) in the setting of ulcerative colitis, a rare finding in the pediatric population., (© 2022 Wiley Periodicals LLC.)

The pathogenesis of inherited genome instability neurodegenerative syndromes remains largely unknown. Here, we report new disease-relevant murine models of genome instability–driven neurodegeneration involving disabled ATM and APTX that develop debilitating ataxia. We show that neurodegeneration and ataxia result from transcriptional interference in the cerebellum via aberrant messenger RNA splicing. Unexpectedly, these splicing defects were restricted to only Purkinje cells, disrupting the expression of critical homeostatic regulators including ITPR1 , GRID2 , and CA8 . Abundant genotoxic R loops were also found at these Purkinje cell gene loci, further exacerbating DNA damage and transcriptional disruption. Using ATAC-seq to profile global chromatin accessibility in the cerebellum, we found a notably unique chromatin conformation specifically in Purkinje chromatin at the affected gene loci, thereby promoting susceptibility to DNA damage. These data reveal the pathogenic basis of DNA damage in the nervous system and suggest chromatin conformation as a feature in directing genome instability–associated neuropathology.

Aicardi-Goutières syndrome (AGS) is a monogenic type I interferonopathy characterized by neurodevelopmental defects and upregulation of type I interferon signaling and neuroinflammation. Mutations in genes that function in nucleic acid metabolism, including RNASEH2, are linked to AGS. Ribonuclease H2 (RNASEH2) is a genome surveillance factor critical for DNA integrity by removing ribonucleotides incorporated into replicating DNA. Here we show that RNASEH2 is necessary for neurogenesis and to avoid activation of interferon-responsive genes and neuroinflammation. Cerebellar defects after RNASEH2B inactivation are rescued by p53 but not cGAS deletion, suggesting that DNA damage signaling, not neuroinflammation, accounts for neuropathology. Coincident inactivation of Atm and Rnaseh2 further affected cerebellar development causing ataxia, which was dependent upon aberrant activation of non-homologous end-joining (NHEJ). The loss of ATM also markedly exacerbates cGAS-dependent type I interferon signaling. Thus, DNA damage-dependent signaling rather than type I interferon signaling underlies neurodegeneration in this class of neurodevelopmental/neuroinflammatory disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: This work assesses the safety of resident-performed intravitreal injections by comparing the incidence of postinjection endophthalmitis associated with residents vs surgical retina attendings., Methods: In this retrospective noninferiority cohort study, the Current Procedural Technology code for an intravitreal injection was used to identify patients from July 1, 2015, to October 31, 2018, at a single-center Veterans Affairs hospital where patients receive intravitreal injections from attending vitreoretinal surgeons and residents. The medical record for each injection was reviewed for the training level of the proceduralist, indication, medication, and laterality. The main outcome was the incidence of postinjection endophthalmitis occurring within 30 days of an intravitreal injection, which was confirmed by at least 2 medical-record reviewers., Results: In this cohort of 593 patients, most were male (97.0%), and the average age was 70.3 years (±10.8 years). Of the 6934 injections given, 3877 (55.9%) were performed by residents and 3057 (44.1%) by attendings. Of the 5 cases of endophthalmitis identified, 3 were associated with a resident-performed injection in his or her fourth year of postgraduate training. The difference (0.012%; 95% CI, -0.168% to 0.169%) in the incidence of postinjection endophthalmitis between residents (0.077%) and attendings (0.065%) did not cross the predetermined noninferiority limit (0.200%)., Conclusions: At our teaching clinic, resident-performed injections were not associated with an elevated risk of endophthalmitis when compared with attending-performed injections. Under varying levels of supervision, residents appeared to demonstrate appropriate sterile injection technique., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In 2013, the U.S. Department of Agriculture Food Safety and Inspection Service (USDA-FSIS) began transitioning to whole genome sequencing (WGS) for foodborne disease outbreak- and recall-associated isolate identification of select bacterial species. While WGS offers greater precision, certain hurdles must be overcome before widespread application within the food industry is plausible. Challenges include diversity of sequencing platform outputs and lack of standardized bioinformatics workflows for data analyses. We sequenced DNA from USDA-FSIS approved, non-pathogenic E. coli surrogates and a derivative group of rifampicin-resistant mutants (rif R ) via both Oxford Nanopore MinION and Illumina MiSeq platforms to generate and annotate complete genomes. Genome sequences from each clone were assembled separately so long-read, short-read, and combined sequence assemblies could be directly compared. The combined sequence data approach provides more accurate completed genomes. The genomes from these isolates were verified to lack functional key E. coli elements commonly associated with pathogenesis. Genetic alterations known to confer rif R were also identified. As the food industry adopts WGS within its food safety programs, these data provide completed genomes for commonly used surrogate strains, with a direct comparison of sequence platforms and assembly strategies relevant to research/testing workflows applicable for both processors and regulators.

Purpose: The authors aim to describe the visual outcomes and postoperative complications of concurrent pars plana vitrectomy and scleral-fixated intraocular lens (IOL) placement using Gore-Tex suture., Methods: A retrospective review of medical records was performed on 27 eyes of 27 patients undergoing concurrent pars plana vitrectomy and scleral-fixated IOL with Gore-Tex suture. Outcome measures were change in preoperative and postoperative visual acuity, final manifest refraction, and incidence of intraoperative and postoperative complications., Results: The mean age was 69.2 ± 11.3 years; there were 16 male patients (59%). The duration of follow-up ranged from 33 to 576 days with a mean of 200 ± 143 days. All patients received Bausch + Lomb Akreos AO60 IOL. The overall mean best-corrected visual acuity in Snellen equivalent improved from 20/276 preoperatively to 20/44 postoperatively ( P < .001). The mean postoperative manifest spherical equivalent refraction was -0.35 ± 1.34 diopters (D). Seventy-five percent of eyes were ± 1.0 D of target refraction. Postoperative complications included corneal edema (26.0%), ocular hypertension (25.9%), hypotony (7.4%), cystoid macular edema (7.4%), vitreous hemorrhage (7.4%), and hyphema (3.7%). No cases of suture breakage, IOL dislocation, retinal detachment, or uveitis-glaucoma-hyphema syndrome were identified., Conclusions: The use of Gore-Tex suture for posterior chamber IOL fixation resulted in favorable outcomes. No suture-related complications occurred during the follow-up period. Final refraction in this setting is typically within ± 1.0 D of target., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Objectives: While immediate diagnosis and irrigation is standard chemical eye burn practice, it is unknown to what extent specific pH measurements influence management, given the frequent clinical availability of narrow-spectrum nitrazine pH strips. We hypothesize that exclusive broad-spectrum pH strip implementation leads to more accurate measurement and expedited ophthalmologic consultation., Methods: At a Level I trauma center over 25 months, all emergent adult ophthalmology consultations for chemical burns were included in a pre-intervention (n = 22) and post-intervention (n = 20) study design. During this time, narrow-spectrum nitrazine pH strips available to non-obstetric emergency department (ED) staff were exclusively replaced by broad-spectrum strips. Causative chemical, time from triage to ophthalmology consultation, examination findings, ocular pH by ED and ophthalmology staff, and irrigation quantity were analyzed., Results: Most burns were alkaline. Time from triage (p = 0.043) and irrigation quantity following consultation (p = 0.047) each decreased following exclusive ED implementation of broad-spectrum pH strips. There was greater pH congruence between consulting and primary physicians after intervention (p = 0.03)., Conclusions: Exclusive non-obstetric implementation of broad-spectrum pH strips may allow greater accuracy and faster management of ocular chemical burns. Availability of narrow-spectrum pH strips may be dangerous clinically by falsely reassuring the examiner with inherent inaccuracy., (© 2018 by the Society for Academic Emergency Medicine.)

Importance: The Infectious Diseases Society of America recommends ophthalmologic examinations for everyone with positive Candida blood culture results (candidemia) to screen for endophthalmitis, a practice that remains controversial because of multiple concerns for its limited usefulness and potential for harm., Objective: To determine guideline efficacy by reconciling discrepancies in the incidence of endophthalmitis and evaluating outcomes of studies assessing ophthalmologic screening for candidemia., Evidence Review: PubMed literature searches, including the search terms candidemia, fungemia, chorioretinitis, and endophthalmitis, identified longitudinal studies prior to 2018 of patients who underwent ophthalmologic evaluations in the setting of positive fungal blood culture results regardless of symptoms or clinical status. Additional studies not captured by these queries were found by manually scanning references within the articles captured by the queries. Ambiguous studies of patients with concomitant bacterial or viral infections were excluded., Findings: Thirty-eight applicable studies of 7472 patients who underwent ophthalmologic screening for candidemia or fungemia were identified. Criteria were compared with the conventional definition of endophthalmitis based on present (concordant) or absent (discordant) frank vitreous involvement. Concordant (59 of 6693 [0.9%]) and discordant (114 of 779 [14.6%]) endophthalmitis incidence rates differed by 13.8% (95% CI, 11.4%-16.4%; P < .001). Visual acuity for each case was recorded verbatim as subjective report provided by each study, when available. None of the concordant endophthalmitis cases reported direct, intraocular, microscopic evidence of Candida or other fungal organisms. Outcomes were available for 19 patients with concordant endophthalmitis; 6 died within 4 weeks of screening. The rate of substantial vision loss was associated (φ = 0.58; 95% CI, 0.01-0.86; P = .046) with additional invasive intervention (3 of 6 [50.0%]) compared with medical management alone (0 of 6)., Conclusions and Relevance: In this systematic review without meta-analysis, inconsistent definitions of endophthalmitis accounted for discrepancies of its incidence and overreporting among patients with candidemia, contributing to bias and resulting in the construction of guidelines. As few as 3 of 7472 patients had potential improvement, while routine examination overall could lead to additional interventions and harm in this population. These findings suggest that indiscriminate screening based on candidemia alone does not appear to be supported by the literature and should be reevaluated for inclusion as a recommendation from the Infectious Diseases Society of America.

Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brainstem tumors with frequent histone H3 K27M mutations and recurrent alterations in PDGFRA and TP53. We generated genetically engineered inducible mice and showed that H3.3 K27M enhanced neural stem cell self-renewal while preserving regional identity. Neonatal induction of H3.3 K27M cooperated with activating platelet-derived growth factor receptor α (PDGFRα) mutant and Trp53 loss to accelerate development of diffuse brainstem gliomas that recapitulated human DIPG gene expression signatures and showed global changes in H3K27 posttranslational modifications, but relatively restricted gene expression changes. Genes upregulated in H3.3 K27M tumors were enriched for those associated with neural development where H3K27me3 loss released the poised state of apparently bivalent promoters, whereas downregulated genes were enriched for those encoding homeodomain transcription factors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Frequent oxidative modification of the neural genome is a by-product of the high oxygen consumption of the nervous system. Rapid correction of oxidative DNA lesions is essential, as genome stability is a paramount determinant of neural homeostasis. Apurinic/apyrimidinic endonuclease 1 (APE1; also known as "APEX1" or "REF1") is a key enzyme for the repair of oxidative DNA damage, although the specific role(s) for this enzyme in the development and maintenance of the nervous system is largely unknown. Here, using conditional inactivation of murine Ape1 , we identify critical roles for this protein in the brain selectively after birth, coinciding with tissue oxygenation shifting from a placental supply to respiration. While mice lacking APE1 throughout neurogenesis were viable with little discernible phenotype at birth, rapid and pronounced brain-wide degenerative changes associated with DNA damage were observed immediately after birth leading to early death. Unexpectedly, Ape1 Nes-cre mice appeared hypothermic with persistent shivering associated with the loss of thermoregulatory serotonergic neurons. We found that APE1 is critical for the selective regulation of Fos1-induced hippocampal immediate early gene expression. Finally, loss of APE1 in combination with p53 inactivation resulted in a profound susceptibility to brain tumors, including medulloblastoma and glioblastoma, implicating oxidative DNA lesions as an etiologic agent in these diseases. Our study reveals APE1 as a major suppressor of deleterious oxidative DNA damage and uncovers specific and broad pathogenic consequences of respiratory oxygenation in the postnatal nervous system., Competing Interests: The authors declare no conflict of interest.

Family physicians spend substantial time counseling patients with psychiatric conditions, unhealthy behaviors, and medical adherence issues. Maintaining efficiency while providing counseling is a major challenge. There are several effective, structured counseling strategies developed for use in primary care settings. The transtheoretical (stages of change) model assesses patients' motivation for change so that the physician can select the optimal counseling approach. Structured sequential strategies such as the five A's (ask, advise, assess, assist, arrange) and FRAMES (feedback, responsibility of patient, advice to change, menu of options, empathy, self-efficacy enhancement) are effective for patients who are responsive to education about health risk behavior. For patients ambivalent about change, motivational interviewing is more likely to be successful. Capitalizing on a teachable moment may enhance the effectiveness of health behavior change counseling. The BATHE (background, affect, troubles, handling, and empathy) strategy is useful for patients with psychiatric conditions and psychosocial issues. Patients should be referred for subspecialty mental health or substance abuse treatment if they do not respond to these brief interventions.

Purpose: To present data on chemical ocular burns in children seen at a single tertiary care facility resulting from accidental eye exposure to the contents of laundry detergent pods., Methods: All emergent pediatric ophthalmology consultations specific for chemical ocular burns at a level I trauma center were included as part of a prospective quality improvement investigation over a 13-month period. Age, causative agent, and examination findings at presentation and final follow-up were recorded and analyzed., Results: A total of 12 children with chemical ocular burns were seen during the study period. All patients were ≤5 years of age. Most chemical ocular burn consultations (n = 8) were specific to ocular exposure of laundry detergent pod contents; the remainder were associated with conventional cleaning agents or pesticides (n = 4). There was a significant association between laundry detergent pod as causative agent and a patient age of 2-5 years, compared to <2 years and any other agent (P = 0.018 [Fisher exact test])., Conclusions: In our study, laundry detergent pods were the most frequent cause of chemical ocular burns in children. Additionally, preschoolers may be at a higher risk of sustaining these injuries. Increased public awareness, product safety improvements, and/or regulation may be advisable to decrease the ocular hazards associated with laundry detergent pods., (Copyright © 2018 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Sample size determination for open-ended questions or qualitative interviews relies primarily on custom and finding the point where little new information is obtained (thematic saturation). Here, we propose and test a refined definition of saturation as obtaining the most salient items in a set of qualitative interviews (where items can be material things or concepts, depending on the topic of study) rather than attempting to obtain all the items. Salient items have higher prevalence and are more culturally important. To do this, we explore saturation, salience, sample size, and domain size in 28 sets of interviews in which respondents were asked to list all the things they could think of in one of 18 topical domains. The domains-like kinds of fruits (highly bounded) and things that mothers do (unbounded)-varied greatly in size. The datasets comprise 20-99 interviews each (1,147 total interviews). When saturation was defined as the point where less than one new item per person would be expected, the median sample size for reaching saturation was 75 (range = 15-194). Thematic saturation was, as expected, related to domain size. It was also related to the amount of information contributed by each respondent but, unexpectedly, was reached more quickly when respondents contributed less information. In contrast, a greater amount of information per person increased the retrieval of salient items. Even small samples (n = 10) produced 95% of the most salient ideas with exhaustive listing, but only 53% of those items were captured with limited responses per person (three). For most domains, item salience appeared to be a more useful concept for thinking about sample size adequacy than finding the point of thematic saturation. Thus, we advance the concept of saturation in salience and emphasize probing to increase the amount of information collected per respondent to increase sample efficiency., Competing Interests: The authors have declared that no competing interests exist.

Meiotic synapsis and recombination between homologs permits the formation of cross-overs that are essential for generating chromosomally balanced sperm and eggs. In mammals, surveillance mechanisms eliminate meiotic cells with defective synapsis, thereby minimizing transmission of aneuploidy. One such surveillance mechanism is meiotic silencing, the inactivation of genes located on asynapsed chromosomes, via ATR-dependent serine-139 phosphorylation of histone H2AFX (γH2AFX). Stimulation of ATR activity requires direct interaction with an ATR activation domain (AAD)-containing partner. However, which partner facilitates the meiotic silencing properties of ATR is unknown. Focusing on the best-characterized example of meiotic silencing, meiotic sex chromosome inactivation, we reveal this AAD-containing partner to be the DNA damage and checkpoint protein TOPBP1. Conditional TOPBP1 deletion during pachynema causes germ cell elimination associated with defective X chromosome gene silencing and sex chromosome condensation. TOPBP1 is essential for localization to the X chromosome of silencing "sensors," including BRCA1, and effectors, including ATR, γH2AFX, and canonical repressive histone marks. We present evidence that persistent DNA double-strand breaks act as silencing initiation sites. Our study identifies TOPBP1 as a critical factor in meiotic sex chromosome silencing., Competing Interests: The authors declare no conflict of interest.

Recent observations have revealed massive galactic molecular outflows that may have the physical conditions (high gas densities) required to form stars. Indeed, several recent models predict that such massive outflows may ignite star formation within the outflow itself. This star-formation mode, in which stars form with high radial velocities, could contribute to the morphological evolution of galaxies, to the evolution in size and velocity dispersion of the spheroidal component of galaxies, and would contribute to the population of high-velocity stars, which could even escape the galaxy. Such star formation could provide in situ chemical enrichment of the circumgalactic and intergalactic medium (through supernova explosions of young stars on large orbits), and some models also predict it to contribute substantially to the star-formation rate observed in distant galaxies. Although there exists observational evidence for star formation triggered by outflows or jets into their host galaxy, as a consequence of gas compression, evidence for star formation occurring within galactic outflows is still missing. Here we report spectroscopic observations that unambiguously reveal star formation occurring in a galactic outflow at a redshift of 0.0448. The inferred star-formation rate in the outflow is larger than 15 solar masses per year. Star formation may also be occurring in other galactic outflows, but may have been missed by previous observations owing to the lack of adequate diagnostics.

Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of noncoding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts. Overexpression of wild-type APE1 or the R237C variant in the nontransformed C127I mouse cell line had no effect on proliferation, cell cycle status, steady-state DNA damage levels, mitochondrial function, or cellular transformation. A human cell line heterozygous for an APE1 knockout allele had lower levels of endogenous APE1, increased cellular sensitivity to DNA-damaging agents, impaired proliferation with time, and a distinct global gene expression pattern consistent with a stress phenotype. Our results indicate that: (i) the tumor-associated R237C variant is a possible susceptibility factor, but not likely a driver of cancer cell phenotypes, (ii) overexpression of APE1 does not readily promote cellular transformation, and (iii) haploinsufficiency at the APE1 locus can have profound cellular consequences, consistent with BER playing a critical role in proliferating cells. Environ. Mol. Mutagen. 58:84-98, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The DNA damage response (DDR) orchestrates a network of cellular processes that integrates cell-cycle control and DNA repair or apoptosis, which serves to maintain genome stability. DNA-PKcs (the catalytic subunit of the DNA-dependent kinase, encoded by PRKDC), ATM (ataxia telangiectasia, mutated), and ATR (ATM and Rad3-related) are related PI3K-like protein kinases and central regulators of the DDR. Defects in these kinases have been linked to neurodegenerative or neurodevelopmental syndromes. In all cases, the key neuroprotective function of these kinases is uncertain. It also remains unclear how interactions between the three DNA damage-responsive kinases coordinate genome stability, particularly in a physiological context. Here, we used a genetic approach to identify the neural function of DNA-PKcs and the interplay between ATM and ATR during neurogenesis. We found that DNA-PKcs loss in the mouse sensitized neuronal progenitors to apoptosis after ionizing radiation because of excessive DNA damage. DNA-PKcs was also required to prevent endogenous DNA damage accumulation throughout the adult brain. In contrast, ATR coordinated the DDR during neurogenesis to direct apoptosis in cycling neural progenitors, whereas ATM regulated apoptosis in both proliferative and noncycling cells. We also found that ATR controls a DNA damage-induced G 2 /M checkpoint in cortical progenitors, independent of ATM and DNA-PKcs. These nonoverlapping roles were further confirmed via sustained murine embryonic or cortical development after all three kinases were simultaneously inactivated. Thus, our results illustrate how DNA-PKcs, ATM, and ATR have unique and essential roles during the DDR, collectively ensuring comprehensive genome maintenance in the nervous system., Significance Statement: The DNA damage response (DDR) is essential for prevention of a broad spectrum of different human neurologic diseases. However, a detailed understanding of the DDR at a physiological level is lacking. In contrast to many in vitro cellular studies, here we demonstrate independent biological roles for the DDR kinases DNA-PKcs, ATM, and ATR during neurogenesis. We show that DNA-PKcs is central to DNA repair in nonproliferating cells, and restricts DNA damage accumulation, whereas ATR controls damage-induced G 2 checkpoint control and apoptosis in proliferating cells. Conversely, ATM is critical for controlling apoptosis in immature noncycling neural cells after DNA damage. These data demonstrate functionally distinct, but cooperative, roles for each kinase in preserving genome stability in the nervous system., (Copyright © 2017 the authors 0270-6474/17/370893-13$15.00/0.)

Supermassive black holes in galaxy centres can grow by the accretion of gas, liberating energy that might regulate star formation on galaxy-wide scales. The nature of the gaseous fuel reservoirs that power black hole growth is nevertheless largely unconstrained by observations, and is instead routinely simplified as a smooth, spherical inflow of very hot gas. Recent theory and simulations instead predict that accretion can be dominated by a stochastic, clumpy distribution of very cold molecular clouds--a departure from the 'hot mode' accretion model--although unambiguous observational support for this prediction remains elusive. Here we report observations that reveal a cold, clumpy accretion flow towards a supermassive black hole fuel reservoir in the nucleus of the Abell 2597 Brightest Cluster Galaxy (BCG), a nearby (redshift z = 0.0821) giant elliptical galaxy surrounded by a dense halo of hot plasma. Under the right conditions, thermal instabilities produce a rain of cold clouds that fall towards the galaxy's centre, sustaining star formation amid a kiloparsec-scale molecular nebula that is found at its core. The observations show that these cold clouds also fuel black hole accretion, revealing 'shadows' cast by the molecular clouds as they move inward at about 300 kilometres per second towards the active supermassive black hole, which serves as a bright backlight. Corroborating evidence from prior observations of warmer atomic gas at extremely high spatial resolution, along with simple arguments based on geometry and probability, indicate that these clouds are within the innermost hundred parsecs of the black hole, and falling closer towards it.

Polynucleotide kinase-phosphatase (PNKP) is a DNA repair factor possessing both 5'-kinase and 3'-phosphatase activities to modify ends of a DNA break prior to ligation. Recently, decreased PNKP levels were identified as the cause of severe neuropathology present in the human microcephaly with seizures (MCSZ) syndrome. Utilizing novel murine Pnkp alleles that attenuate expression and a T424GfsX48 frame-shift allele identified in MCSZ individuals, we determined how PNKP inactivation impacts neurogenesis. Mice with PNKP inactivation in neural progenitors manifest neurodevelopmental abnormalities and postnatal death. This severe phenotype involved defective base excision repair and non-homologous end-joining, pathways required for repair of both DNA single- and double-strand breaks. Although mice homozygous for the T424GfsX48 allele were lethal embryonically, attenuated PNKP levels (akin to MCSZ) showed general neurodevelopmental defects, including microcephaly, indicating a critical developmental PNKP threshold. Directed postnatal neural inactivation of PNKP affected specific subpopulations including oligodendrocytes, indicating a broad requirement for genome maintenance, both during and after neurogenesis. These data illuminate the basis for selective neural vulnerability in DNA repair deficiency disease., (© 2015 The Authors.)

Pilocytic astrocytomas (PAs) are increasingly tested for KIAA1549-BRAF fusions. We used reverse transcription polymerase chain reaction for the 3 most common KIAA1549-BRAF fusions, together with BRAF V600E and histone H3.3 K27M analyses to identify relationships of these molecular characteristics with clinical features in a cohort of 32 PA patients. In this group, the overall BRAF fusion detection rate was 24 (75%). Ten (42%) of the 24 had the 16-9 fusion, 8 (33%) had only the 15-9 fusion, and 1 (4%) of the patients had only the 16-11 fusion. In the PAs with only the 15-9 fusion, 1 PA was in the cerebellum and 7 were centered in the midline outside of the cerebellum, that is, in the hypothalamus (n = 4), optic pathways (n = 2), and brainstem (n = 1). Tumors within the cerebellum were negatively associated with fusion 15-9. Seven (22%) of the 32 patients had tumor-related deaths and 25 of the patients (78%) were alive between 2 and 14 years after initial biopsy. Age, sex, tumor location, 16-9 fusion, and 15-9 fusion were not associated with overall survival. Thus, in this small cohort, 15-9 KIAA1549-BRAF fusion was associated with midline PAs located outside of the cerebellum; these tumors, which are generally difficult to resect, are prone to recurrence.

Background: Despite the widespread popularity of social media, little is known about the extent or context of pain-related posts by users of those media., Objective: The aim was to examine the type, context, and dissemination of pain-related tweets., Methods: We used content analysis of pain-related tweets from 50 cities to unobtrusively explore the meanings and patterns of communications about pain. Content was examined by location and time of day, as well as within the context of online social networks., Results: The most common terms published in conjunction with the term "pain" included feel (n=1504), don't (n=702), and love (n=649). The proportion of tweets with positive sentiment ranged from 13% in Manila to 56% in Los Angeles, CA, with a median of 29% across cities. Temporally, the proportion of tweets with positive sentiment ranged from 24% at 1600 to 38% at 2400, with a median of 32%. The Twitter-based social networks pertaining to pain exhibited greater sparsity and lower connectedness than did those social networks pertaining to common terms such as apple, Manchester United, and Obama. The number of word clusters in proportion to node count was greater for emotion terms such as tired (0.45), happy (0.43), and sad (0.4) when compared with objective terms such as apple (0.26), Manchester United (0.14), and Obama (0.25)., Conclusions: Taken together, our results suggest that pain-related tweets carry special characteristics reflecting unique content and their communication among tweeters. Further work will explore how geopolitical events and seasonal changes affect tweeters' perceptions of pain and how such perceptions may affect therapies for pain.

Land-based production of high-quality protein by livestock and poultry plays an important role in improving human nutrition, growth, and health, as well as economical and social developments worldwide. With exponential growth of the global population and marked rises in meat consumption per capita, demands for animal-source protein are expected to increase by 72% between 2013 and 2050. This raises concerns about the sustainability and environmental impacts of animal agriculture. An attractive solution to meeting the increasing needs for animal products and mitigating undesired effects of agricultural practices is to enhance the efficiency of animal growth, reproduction, and lactation. Breeding techniques may help achieve this goal, but have only met with limited success. A promising, mechanism-based approach is to optimize the proportion and amounts of amino acids in diets for maximizing whole-body protein synthesis and feed efficiency. Improvements in farm animal productivity will not only decrease the contamination of soils, groundwater, and air by excessive manure, but will also help sustain animal agriculture to produce high-quality protein for the expanding population in the face of diminishing resources., (© 2014 New York Academy of Sciences.)

DNA damage is considered to be a prime factor in several spinocerebellar neurodegenerative diseases; however, the DNA lesions underpinning disease etiology are unknown. We observed the endogenous accumulation of pathogenic topoisomerase-1 (Top1)-DNA cleavage complexes (Top1ccs) in murine models of ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy 1. We found that the defective DNA damage response factors in these two diseases cooperatively modulated Top1cc turnover in a non-epistatic and ATM kinase-independent manner. Furthermore, coincident neural inactivation of ATM and DNA single-strand break repair factors, including tyrosyl-DNA phosphodiesterase-1 or XRCC1, resulted in increased Top1cc formation and excessive DNA damage and neurodevelopmental defects. Notably, direct Top1 poisoning to elevate Top1cc levels phenocopied the neuropathology of the mouse models described above. Our results identify a critical endogenous pathogenic lesion associated with neurodegenerative syndromes arising from DNA repair deficiency, indicating that genome integrity is important for preventing disease in the nervous system.