When deformed beyond their elastic limits, crystalline solids flow plastically via particle rearrangements localized around structural defects. Disordered solids also flow, but without obvious ...structural defects. We link structure to plasticity in disordered solids via a microscopic structural quantity, “softness,” designed by machine learning to be maximally predictive of rearrangements. Experimental results and computations enabled us to measure the spatial correlations and strain response of softness, as well as two measures of plasticity: the size of rearrangements and the yield strain. All four quantities maintained remarkable commonality in their values for disordered packings of objects ranging from atoms to grains, spanning seven orders of magnitude in diameter and 13 orders of magnitude in elastic modulus. These commonalities link the spatial correlations and strain response of softness to rearrangement size and yield strain, respectively.
Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of ...anxiety, depression and substance abuse. These disorders are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate. Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain regions underlies primates' capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex, a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.
Increasing the intensity to which high power laser pulses are focused has opened up new research possibilities, including promising new approaches to particle acceleration and phenomena such as high ...field quantum electrodynamics. Whilst the intensity achievable with a laser pulse of a given power can be increased via tighter focusing, the focal spot profile also plays an important role in the interaction physics. Here we show that the spatial-intensity distribution, and specifically the ratio of the intensity in the peak of the laser focal spot to the halo surrounding it, is important in the interaction of ultraintense laser pulses with solid targets. By comparing proton acceleration measurements from foil targets irradiated with by a near-diffraction-limited wavelength scale focal spot and larger F-number focusing, we find that this spatial-intensity contrast parameter strongly influences laser energy coupling to fast electrons. We find that for multi-petawatt pulses, spatial-intensity contrast is potentially as important as temporal-intensity contrast.
Sleep disturbance is prevalent in cancer with detrimental effects on health outcomes. Sleep problems are seldom identified or addressed in cancer practice. The purpose of this review was to identify ...the evidence base for the assessment and management of cancer-related sleep disturbance (insomnia and insomnia syndrome) for oncology practice. The search of the health literature included grey literature data sources and empirical databases from June 2004 to June 2012. The evidence was reviewed by a Canadian Sleep Expert Panel, comprised of nurses, psychologists, primary care physicians, oncologists, physicians specialized in sleep disturbances, researchers and guideline methodologists to develop clinical practice recommendations for pan-Canadian use reported in a separate paper. Three clinical practice guidelines and 12 randomized, controlled trials were identified as the main source of evidence. Additional guidelines and systematic reviews were also reviewed for evidence-based recommendations on the assessment and management of insomnia not necessarily in cancer. A need to routinely screen for sleep disturbances was identified and the randomized, controlled trial (RCT) evidence suggests benefits for cognitive behavioural therapy for improving sleep quality in cancer. Sleep disturbance is a prevalent problem in cancer that needs greater recognition in clinical practice and in future research.
The corticotrophin-releasing hormone (CRH) system integrates the stress response and is associated with stress-related psychopathology. Previous reports have identified interactions between childhood ...trauma and sequence variation in the CRH receptor 1 gene (CRHR1) that increase risk for affective disorders. However, the underlying mechanisms that connect variation in CRHR1 to psychopathology are unknown. To explore potential mechanisms, we used a validated rhesus macaque model to investigate association between genetic variation in CRHR1, anxious temperament (AT) and brain metabolic activity. In young rhesus monkeys, AT is analogous to the childhood risk phenotype that predicts the development of human anxiety and depressive disorders. Regional brain metabolism was assessed with (18)F-labeled fluoro-2-deoxyglucose (FDG) positron emission tomography in 236 young, normally reared macaques that were also characterized for AT. We show that single nucleotide polymorphisms (SNPs) affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and amygdala, components of the neural circuit underlying AT. We also find evidence for association between SNPs in CRHR1 and metabolism in the intraparietal sulcus and precuneus. These translational data suggest that genetic variation in CRHR1 affects the risk for affective disorders by influencing the function of the neural circuit underlying AT and that differences in gene expression or the protein sequence involving exon 6 may be important. These results suggest that variation in CRHR1 may influence brain function before any childhood adversity and may be a diathesis for the interaction between CRHR1 genotypes and childhood trauma reported to affect human psychopathology.
This article reviews the modern literature on two key aspects of the central circuitry of emotion: the prefrontal cortex (PFC) and the amygdala. There are several different functional divisions of ...the PFC, including the dorsolateral, ventromedial, and orbital sectors. Each of these regions plays some role in affective processing that shares the feature of representing affect in the absence of immediate rewards and punishments as well as in different aspects of emotional regulation. The amygdala appears to be crucial for the learning of new stimulus-threat contingencies and also appears to be important in the expression of cue-specific fear. Individual differences in both tonic activation and phasic reactivity in this circuit play an important role in governing different aspects of anxiety. Emphasis is placed on affective chronometry, or the time course of emotional responding, as a key attribute of individual differences in propensity for anxiety that is regulated by this circuitry.
Meditation refers to a family of mental training practices that are designed to familiarize the practitioner with specific types of mental processes. One of the most basic forms of meditation is ...concentration meditation, in which sustained attention is focused on an object such as a small visual stimulus or the breath. In age-matched participants, using functional MRI, we found that activation in a network of brain regions typically involved in sustained attention showed an inverted u-shaped curve in which expert meditators (EMs) with an average of 19,000 h of practice had more activation than novices, but EMs with an average of 44,000 h had less activation. In response to distracter sounds used to probe the meditation, EMs vs. novices had less brain activation in regions related to discursive thoughts and emotions and more activation in regions related to response inhibition and attention. Correlation with hours of practice suggests possible plasticity in these mechanisms.
This review of challenging diagnostic issues concerning high-grade endometrial carcinomas is derived from the authors' review of the literature followed by discussions at the Endometrial Cancer ...Workshop sponsored by the International Society of Gynecological Pathologists in 2016. Recommendations presented are evidence-based, insofar as this is possible, given that the levels of evidence are weak or moderate due to small sample sizes and nonuniform diagnostic criteria used in many studies. High-grade endometrioid carcinomas include FIGO grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas, undifferentiated carcinomas, and carcinosarcomas. FIGO grade 3 endometrioid carcinoma is diagnosed when an endometrioid carcinoma exhibits >50% solid architecture (excluding squamous areas), or when an architecturally FIGO grade 2 endometrioid carcinoma exhibits marked cytologic atypia, provided that a glandular variant of serous carcinoma has been excluded. The most useful immunohistochemical studies to make the distinction between these 2 histotypes are p53, p16, DNA mismatch repair proteins, PTEN, and ARID1A. Endometrial clear cell carcinomas must display prototypical architectural and cytologic features for diagnosis. Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas. Of note, clear cells are found in all types of high-grade endometrial carcinomas, leading to a tendency to overdiagnose clear cell carcinoma. Undifferentiated carcinoma (which when associated with a component of low-grade endometrioid carcinoma is termed "dedifferentiated carcinoma") is composed of sheets of monotonous, typically dyscohesive cells, which can have a rhabdoid appearance; they often exhibit limited expression of cytokeratins and epithelial membrane antigen, are usually negative for PAX8 and hormone receptors, lack membranous e-cadherin and commonly demonstrate loss of expression of DNA mismatch repair proteins and SWI-SNF chromatin remodeling proteins. Carcinosarcomas must show unequivocal morphologic evidence of malignant epithelial and mesenchymal differentiation.
Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with ...endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer.
To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287–395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots.
We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3′ partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations.
Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6–7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.
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