The neural circuit mechanisms underlying emotion states remain poorly understood. Drosophila offers powerful genetic approaches for dissecting neural circuit function, but whether flies exhibit ...emotion-like behaviors has not been clear. We recently proposed that model organisms may express internal states displaying “emotion primitives,” which are general characteristics common to different emotions, rather than specific anthropomorphic emotions such as “fear” or “anxiety.” These emotion primitives include scalability, persistence, valence, and generalization to multiple contexts. Here, we have applied this approach to determine whether flies’ defensive responses to moving overhead translational stimuli (“shadows”) are purely reflexive or may express underlying emotion states. We describe a new behavioral assay in which flies confined in an enclosed arena are repeatedly exposed to an overhead translational stimulus. Repetitive stimuli promoted graded (scalable) and persistent increases in locomotor velocity and hopping, and occasional freezing. The stimulus also dispersed feeding flies from a food resource, suggesting both negative valence and context generalization. Strikingly, there was a significant delay before the flies returned to the food following stimulus-induced dispersal, suggestive of a slowly decaying internal defensive state. The length of this delay was increased when more stimuli were delivered for initial dispersal. These responses can be mathematically modeled by assuming an internal state that behaves as a leaky integrator of stimulus exposure. Our results suggest that flies’ responses to repetitive visual threat stimuli express an internal state exhibiting canonical emotion primitives, possibly analogous to fear in mammals. The mechanistic basis of this state can now be investigated in a genetically tractable insect species.
•A novel behavioral assay using repeated, visual threat stimuli is characterized•Flies show persistent defensive responses including running, jumping, and freezing•Velocity and hopping frequency scale with stimulus number and with stimulus frequency•Drosophila genetics can now be used to investigate a persistent defensive state
Using a novel, repetitive, visual threat stimulus paradigm (termed ReVSA), Gibson et al. investigate a defensive state in Drosophila, perhaps analogous to fear. ReVSA behaviors include running, jumping, and freezing. Defensive states can now be probed in a genetically tractable insect species.
The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic "writer" with H3K27 methyltransferase activity, catalyzing the ...addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss-of-function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2-associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590). EED-associated overgrowth (Cohen-Gibson syndrome; OMIM #617561) is caused by germline heterozygous mutations in Embryonic Ectoderm Development (EED), and manifests overgrowth and intellectual disability (OGID), along with other features similar to Weaver syndrome. Most recently, rare coding variants in SUZ12 have also been described that present with clinical characteristics similar to the previous two syndromes. Here we review the PRC2 complex and clinical syndromes of OGID associated with core components EZH2, EED, and SUZ12.
There is a well-recognised but unexplained association between lower urinary tract symptoms including urgency and urgency incontinence and falls in older people. It has been hypothesised that urinary ...urgency acts as a source of divided attention, leading to gait changes which increase falls risk. This study aimed to assess whether urinary urgency acts as a source of divided attention in older adults with overactive bladder (OAB).
27 community-dwelling adults aged 65 years and over with a clinical diagnosis of OAB underwent 3-Dimensional Instrumented Gait Analysis under three conditions; bladder empty, when experiencing urgency, and when being distracted by the n-back test. Temporal-spatial gait and kinematic gait data were compared between each condition using repeated measures ANOVA.
Gait velocity decreased from 1.1ms-1 in the bladder empty condition to 1.0ms-1 with urgency and 0.9ms-1 with distraction (p = 0.008 and p<0.001 respectively). Stride length also decreased, from 1.2m to 1.1m with urgency and 1.0m with distraction (p<0.001 for both). The presence of detrusor overactivity did not influence these results (p = 0.77).
In older adults with OAB, urinary urgency induced similar changes in gait to those caused by a distracting task. These gait changes are associated with increased fall risk. This may be part of the explanation for the association between falls and lower urinary tract symptoms in older people. Future research should examine the effect of pharmacological treatment of OAB on gait and on the effect of dual-task training on gait when experiencing urgency.
MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in ...other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.
We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.
Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.
JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.
To assess cochlear implant (CI) outcomes, and factors affecting outcomes, for children with aplasia/ hypoplasia of the cochlea nerve. We also developed a new grading system for the nerves of the ...internal auditory meatus (IAM) and cochlea nerve classification.
Retrospective patient review.
Tertiary referral hospital and cochlear implant program.
Children 0 to 16 years inclusive with a CI who had absent/hypoplastic cochlea nerve on magnetic resonance imaging (MRI).
Cochlear implant.
MRI, trans-tympanic electrical auditory brainstem response, intraoperative electrical auditory brainstem response, Neural Response Telemetry, Categories of Auditory Perception score, Main mode of communication.
Fifty CI recipients (26 males and 24 females) were identified, 21 had bilateral CIs, 27 had developmental delay. MRI showed cochlea nerve aplasia in 64 ears, hypoplasia in 25 ears, and a normal nerve in 11 ears. Main mode of communication was analyzed for 41 children: 21 (51%) used verbal language (15 speech alone, 5 speech plus some sign, 1 bilingual in speech and sign), and 20 (49%) used sign language (10 sign alone, 9 sign plus some speech, 1 tactile sign). Seventy-three percent of children used some verbal language. Cochlea nerve aplasia/ hypoplasia and developmental delay were both significant factors affecting main mode of communication. Categories of Auditory Performance scores were available for 59 CI ears; 47% with CN Aplasia (IAM nerve grades 0-III) and 89% with CN hypoplasia (IAM nerve grade IV) achieved Categories of Auditory Performance scores of 5 to 7 (some verbal understanding) (p = 0.003).
Our results are encouraging and useful when counselling families regarding the likelihood of language outcomes and auditory understanding.
Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per ...tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of therapeutic targets. We hypothesized that monoallelic inactivation of the allele retained in tumors can selectively kill cancer cells but not somatic cells, which retain both alleles. We identified 5664 variants in 1278 essential genes that undergo LOH in cancer and evaluated the potential for each to be targeted using allele-specific gene-editing, RNAi, or small-molecule approaches. We further show that allele-specific inactivation of either of two essential genes (PRIM1 and EXOSC8) reduces growth of cells harboring that allele, while cells harboring the non-targeted allele remain intact. We conclude that LOH of essential genes represents a rich class of non-driver cancer vulnerabilities.
Following our discovery that constitutional mutations in EED can cause overgrowth, we screened our cohort of patients with Weaver-like features for mutations in this gene. Here we describe a second ...patient with a different, rare and de novo mutation in EED. Phenotypic overlap with our first case of EED-associated overgrowth is significant. Now that we have found two unrelated families of different ethnicities, with a similar rare phenotype, both associated with de novo mutations in this member of the PRC2 complex, we are confident that EED is indeed a novel overgrowth gene.
The aberrant localization of proteins in cells is a key factor in the development of various diseases, including cancer and neurodegenerative disease. To better understand and potentially manipulate ...protein localization for therapeutic purposes, we engineered bifunctional compounds that bind to proteins in separate cellular compartments. We show these compounds induce nuclear import of cytosolic cargoes, using nuclear-localized BRD4 as a "carrier" for co-import and nuclear trapping of cytosolic proteins. We use this system to calculate kinetic constants for passive diffusion across the nuclear pore and demonstrate single-cell heterogeneity in response to these bifunctional molecules with cells requiring high carrier to cargo expression for complete import. We also observe incorporation of cargo into BRD4-containing condensates. Proteins shown to be substrates for nuclear transport include oncogenic mutant nucleophosmin (NPM1c) and mutant PI3K catalytic subunit alpha (PIK3CA
), suggesting potential applications to cancer treatment. In addition, we demonstrate that chemically induced localization of BRD4 to cytosolic-localized DNA-binding proteins, namely, IRF1 with a nuclear export signal, induces target gene expression. These results suggest that induced localization of proteins with bifunctional molecules enables the rewiring of cell circuitry, with significant implications for disease therapy.
Increased spatial resolution has been shown to be an important factor in enabling machine learning to map burn extent and severity with extremely high accuracy. Unfortunately, the acquisition of ...drone imagery is a labor-intensive endeavor, making the capture of drone imagery impractical for large catastrophic fires, which account for the majority of the area burned each year in the western US. To overcome this difficulty, satellites, such as PlanetScope, are now available which can produce imagery with remarkably high spatial resolution (approximately three meters). In addition to having higher spatial resolution, PlanetScope imagery contains up to eight bands in the visible and near-infrared spectra. This study examines the efficacy of each of the eight bands observed in PlanetScope imagery using a variety of feature selection methods, then uses these bands to map the burn extent and biomass consumption of three wildland fires. Several classifications are produced and compared based on the available bands, resulting in highly accurate maps with slight improvements as additional bands are utilized. The near-infrared band proved contribute most to increased mapping accuracy, while the green 1 and yellow bands contributed the least.
Recent studies have detailed the genomic landscape of primary endometrial cancers, but the evolution of these cancers into metastases has not been characterized. We performed whole-exome sequencing ...of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed The Cancer Genome Atlas (TCGA) data, identifying new recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor gene NRIP1 in 12% of patients. We found that likely driver events were present in both primary and metastatic tissue samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity in endometrial cancers and relative homogeneity across metastatic sites.
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