Search

Single-crystal nanowires are of broad interest for applications in nanotechnology. However, such wires are subject to both the Rayleigh-Plateau instability and an ovulation process that are expected to lead to their break up into particle arrays. Single crystal Ru nanowires were fabricated with axes lying along different crystallographic orientations. Wires bound by equilibrium facets along their length did not break up through either a Rayleigh-Plateau or ovulation process, while wires with other orientations broke up through a combination of both. Mechanistic insight is provided using a level-set simulation that accounts for strongly anisotropic surface energies, providing a framework for design of morphologically stable nanostructures.

The addition of 108 infrasound sensors—a legacy of the temporary USArray Transportable Array (TA) deployment—to the Alaska regional network provides an unprecedented opportunity to quantify the effects of a diverse set of site conditions on ambient infrasound noise levels. TA station locations were not chosen to optimize infrasound performance, and consequently span a dramatic range of land cover types, from temperate rain forest to exposed tundra. In this study, we compute power spectral densities for 2020 data and compile new ambient infrasound low- and high-noise models for the region. In addition, we compare time series of root-mean-squared (rms) amplitudes with wind data and high-resolution land cover data to derive noise–wind speed relationships for several land cover categories. We observe that noise levels for the network are dominated by wind, and that network noise is generally higher in the winter months when storms are more frequent and the microbarom is more pronounced. Wind direction also exerts control on noise levels, likely as a result of infrasound ports being systematically located on the east side of the station huts. We find that rms amplitudes correlate with site land cover type, and that knowledge of both land cover type and wind speed can help predict infrasound noise levels. Our results show that land cover data can be used to inform infrasound station site selection, and that wind–noise models that incorporate station land cover type are useful tools for understanding general station noise performance.

Abstract The impacts of wildfires along the wildland urban interface (WUI) on atmospheric particulate concentrations and composition are an understudied source of air pollution exposure. To assess the residual impacts of the 2021 Marshall Fire (Colorado), a wildfire that predominantly burned homes and other human-made materials, on homes within the fire perimeter that escaped the fire, we performed a combination of fine particulate matter (PM2.5) filter sampling and chemical analysis, indoor dust collection and chemical analysis, community scale PurpleAir PM2.5 analysis, and indoor particle number concentration measurements. Following the fire, the chemical speciation of dust collected in smoke-affected homes in the burned zone showed elevated concentrations of the biomass burning marker levoglucosan (medianlevo = 4147 ng g−1), EPA priority toxic polycyclic aromatic hydrocarbons (median Σ16PAH = 1859.3 ng g−1), and metals (median Σ20Metals = 34.6 mg g−1) when compared to samples collected in homes outside of the burn zone 6 months after the fire. As indoor dust particles are often resuspended and can become airborne, the enhanced concentration of hazardous metals and organics within dust samples may pose a threat to human health. Indoor airborne particulate organic carbon (median = 1.91 μg m−3), particulate elemental carbon (median = .02 μg m−3), and quantified semi-volatile organic species in PM2.5 were found in concentrations comparable to ambient air in urban areas across the USA. Particle number and size distribution analysis at a heavily instrumented supersite home located immediately next to the burned area showed indoor particulates in low concentrations (below 10 μg m−3) across various sizes of PM (12 nm–20 μm), but were elevated by resuspension from human activity, including cleaning. Graphical Abstract

Opioid use disorder has become an epidemic in the United States, fueled by the widespread availability of fentanyl, which produces rapid and intense euphoria followed by severe withdrawal and emotional distress. We developed a new preclinical model of fentanyl seeking in outbred male and female rats using volitional oral self-administration that can be readily applied in labs without intravascular access. Using a traditional two lever operant procedure, rats learned to take oral fentanyl vigorously, escalated intake across sessions, and readily reinstated responding to conditioned cues after extinction. Oral self-administration also revealed individual and sex differences that are essential to studying substance use risk propensity. During a behavioral economics task, rats displayed inelastic demand curves and maintained stable intake across a wide range of fentanyl concentrations. Oral SA was also neatly patterned, with distinct “ loading” and “ maintenance” phases of responding within each session. Using our software DeepSqueak, we analyzed thousands of ultrasonic vocalizations (USVs), which are innate expressions of current emotional state in rats. Rats produced 50 kHz USVs during loading then shifted quickly to 22 kHz calls despite ongoing maintenance oral fentanyl taking, reflecting a transition to negative reinforcement. Using fiber photometry, we found that the lateral habenula differentially processed drug-cues and drug-consumption depending on affective state, with potentiated modulation by drug cues and consumption during the negative affective maintenance phase. Together, these results indicate a rapid progression from positive to negative reinforcement occurs even within an active drug taking session, revealing a within-session opponent process.Significance StatementThe United States opioid epidemic is defined by rampant and treatment resistant fentanyl use. Better understanding of neural substrates underlying this phenomenon is essential to slowing the opioid crisis. Intravenous and vapor self-administration (SA) are the standard models for studying fentanyl use in rodents, however they many carry pragmatic downsides. Here, we used a novel oral fentanyl self-administration model that provides key translational and technical benefits and can be readily applied in other labs to study the neurobiology of fentanyl SA. This method captured individual and sex differences necessary for studying substance use risk propensity and uncovered a rapid shift in affective state in rats, suggesting and shift from positive to negative reinforcement within each fentanyl taking session.

Earthquake ground motions in the vicinity of receivers couple with the atmosphere to generate pressure perturbations that are detectable by infrasound sensors. These so-called local infrasound signals traverse very short source-to-receiver paths, so that they often exhibit a remarkable correlation with seismic velocity waveforms at collocated seismic stations, and there exists a simple relationship between vertical seismic velocity and pressure time series. This study leverages the large regional network of infrasound sensors in Alaska to examine local infrasound from several light to great Alaska earthquakes. We estimate seismic velocity time series from infrasound pressure records and use these converted infrasound recordings to compute earthquake magnitudes. This technique has potential utility beyond the novelty of recording seismic velocities on pressure sensors. Because local infrasound amplitudes from ground motions are small, it is possible to recover seismic velocities at collocated sites where the broadband seismometers have clipped. Infrasound-derived earthquake magnitudes exhibit good agreement with seismically derived values. This proof-of-concept demonstration of computing seismic magnitudes from infrasound sensors illustrates that infrasound sensors may be utilized as proxy vertical-component seismometers, making a new data set available for existing seismic techniques. Because single-sensor infrasound stations are relatively inexpensive and are becoming ubiquitous, this technique could be used to augment existing regional seismic networks using a readily available sensor platform.

Descriptive statistics for HNSC patients from the CHANCE study by p16 cytoplasmic/nuclear status.

Additional multiplex staining coexpression and ROI quantification.

Introduction Many patients with esophageal cancer are not candidates for surgical resection with curative intent, given the advanced stage of disease at presentation. Palliative surgery is one treatment option, but relative survival of palliative surgery has not been described. This study aims to describe the outcomes of palliative surgery in patients with esophageal cancer. Methods We used the National Cancer Database to identify patients with esophageal cancer who received palliative surgery or non-surgical palliation—which consisted of palliative radiation and palliative chemotherapy without any surgery. The outcome of interest was overall survival. Characteristics of patients were compared between the palliative surgery group and the non-surgical group using rank sum test or chi square test. Survival differences between groups were compared using Kaplan Meier estimate and log rank test, and Cox proportional hazards model. Results A total of 14,589 patients were included in the analysis, including 2,812 (19.2%) receiving palliative surgery and 11,777 (80.7%) receiving non-surgical palliation (6,512 palliative radiation and 5,265 palliative chemotherapy). Median overall survival in palliative surgery patients was 5.5 mo, shorter than non-surgical palliation (6.4 mo, P = 0.004). However, when correcting for age, sex, nodal status, metastases, Charlson score, histology, academic center, and private insurance, there was no difference in survival between palliative surgery and non-surgical palliation in Cox proportional hazard modeling (HR 1.03 (0.975-1.090), P = 0.281). Conclusions Palliative surgery in advanced esophageal cancer is associated with poor overall survival but is similar to other palliative modalities. Palliative Surgery for esophageal cancer patients should be used sparingly given these poor outcomes.

Summary Few predictors of response to topical corticosteroid (tCS) treatment have been identified in eosinophilic esophagitis (EoE). We aimed to determine whether baseline gene expression predicts histologic response to tCS treatment for EoE. We analyzed prospectively collected samples from incident EoE cases who were treated with tCS for 8 weeks in a development cohort (prospective study) or in an independent validation cohort (clinical trial). Whole transcriptome RNA expression was determined from a baseline (pre-treatment) RNA-later preserved esophageal biopsy. Baseline expression was compared between histologic responders (

Over 70% of oropharyngeal head and neck squamous cell carcinoma (HNSC) cases in the United States are positive for human papillomavirus (HPV) yet biomarkers for stratifying oropharyngeal HNSC patient risk are limited. We used immunogenomics to identify differentially expressed genes in immune cells of HPV(+) and HPV(−) squamous carcinomas. Candidate genes were tested in clinical specimens using both qRT-PCR and IHC and validated by IHC using the Carolina Head and Neck Cancer Study tissue microarray of HNSC cases. We performed multiplex immunofluorescent staining to confirm expression within the immune cells of HPV(+) tumors, ROC curve analyses, and assessed survival outcomes. The neuronal gene Synaptogyrin-3 (SYNGR3) is robustly expressed in immune cells of HPV(+) squamous cancers. Multiplex immunostaining and single-cell RNA sequencing analyses confirmed SYNGR3 expression in T cells, but also unexpectedly in B cells of HPV(+) tumors. ROC curve analyses revealed that combining SYNGR3 and p16 provides more sensitivity and specificity for HPV detection compared with p16 IHC alone. Patients with SYNGR3-high HNSC have significantly better prognosis with 5-year OS and DSS rates of 60% and 71%, respectively. Moreover, combining p16 localization and SYNGR3 expression can further risk stratify HPV(+) patients such that high cytoplasmic, low nuclear p16 do significantly worse (HR, 8.6; P = 0.032) compared with patients with high cytoplasmic, high nuclear p16. SYNGR3 expression in T and B cells is associated with HPV status and enhanced survival outcomes of patients with HNSC. Significance: These findings indicate that codetection of SYNGR3 in immune cells and p16 in tumor cells by IHC can more reliably identify the HPV(+) subgroup of patients with low-risk head and neck cancer that may be appropriate for clinical trials involving treatment deescalation.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, Htt(Q175/+), and from wild-type controls. We used 14- to 15-month-old male mice, a time point at which multiple behavioral, neuroanatomical, and neurophysiological changes are present but at which there is no known cell death. Thousands of differentially expressed genes (DEGs) were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell type-specific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes. Typically, these genes were repressed in their primary cell type, yet de-repressed in other striatal cell types. Integration with existing epigenomic and transcriptomic data suggest that partial loss-of-function of the polycomb repressive complex 2 (PRC2) may underlie many of these transcriptional changes, leading to deficits in the maintenance of cell identity across virtually all cell types in the adult striatum. SIGNIFICANCE STATEMENT Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by specific loss of medium spiny neurons (MSNs) in the striatum, accompanied by more subtle changes in many other cell types. It is thought that changes in transcriptional regulation are an important underlying mechanism, but cell type-specific gene expression changes are not well understood, particularly at time points relevant to the onset of disease-related symptoms. Single-nucleus (sn)RNA-seq in a genetically precise mouse model enabled us to identify novel patterns of transcriptional dysregulation because of HD mutations, including bidirectional dysregulation of many cell type identity genes that may be driven by partial loss-of-function of the polycomb repressive complex (PRC). Identifying these regulators of transcriptional dysregulation in HD can be leveraged to design novel disease-modifying therapeutics.

PURPOSE: Rib fractures, though typically associated with blunt trauma, can also result from complications of medical or surgical care, including cardiopulmonary resuscitation. The purpose of this study is to describe the demographics and outcomes of iatrogenic rib fractures. METHODS: Patients with rib fractures were identified in the 2016 National Inpatient Sample. Mechanism of injury was defined as blunt traumatic rib fracture (BTRF) or iatrogenic rib fracture (IRF). IRF was identified as fractures from the following mechanisms: complications of care, drowning, suffocation, and poisoning. Differences between BTRF and IRF were compared using rank-sum test, chi-square test, and multivariable regression. RESULTS: 34,644 patients were identified: 33,464 BTRF and 1,180 IRF. IRF patients were older and had higher rates of many comorbid medical disorders. IRF patients were more likely to have flail chest (6.1% vs 3.1%, p

[Image: see text] Focal adhesion kinase (FAK) is a tyrosine kinase with prominent roles in protein scaffolding, migration, angiogenesis, and anchorage-independent cell survival and is an attractive target for the development of cancer therapeutics. However, current FAK inhibitors display dual kinase inhibition and/or significant activity on several kinases. Although multitargeted activity is at times therapeutically advantageous, such behavior can also lead to toxicity and confound chemical-biology studies. We report a novel series of small molecules based on a tricyclic pyrimidothiazolodiazepinone core that displays both high potency and selectivity for FAK. Structure–activity relationship (SAR) studies explored modifications to the thiazole, diazepinone, and aniline “tail,” which identified lead compound BJG-03-025. BJG-03-025 displays potent biochemical FAK inhibition (IC(50) = 20 nM), excellent kinome selectivity, activity in 3D-culture breast and gastric cancer models, and favorable pharmacokinetic properties in mice. BJG-03-025 is a valuable chemical probe for evaluation of FAK-dependent biology.

To evaluate the contemporary trends in outcomes and resource use associated with transcatheter aortic valve replacement (TAVR) in the United States.We identified patients who underwent TAVR between January 1, 2012, and December 31, 2017, in the National Readmission Database. We assessed temporal trends in clinical outcomes, length-of-stay, non-home discharges, and cost of the index TAVR hospitalization. We also evaluated the changes in the burden of hospitalizations before and after TAVR.A total of 89,202 patients were included. In-hospital mortality decreased from 5.3% (188) in 2012 to 1.6% (484) in 2017 (adjusted odds ratio: 0.37, 95% CI: 0.30 to 0.46). Risk-adjusted incidences of new dialysis, vascular complications, blood transfusion, and mechanical ventilation decreased, but strokes and pacemaker implantations remained unchanged. Length of stay decreased from median of 7 (interquartile range [IQR]: 4 to 11) to 2 (IQR: 2 to 5) days (P.001). Risk-adjusted non-home discharges decreased from 32.2% (1134) to 15.5% (386) (P.001). Median cost of the TAVR hospitalization decreased from $56,022 (IQR: $43,690 to $75,174) to $46,101 (IQR: $36,083 to $59,752) (P.001). Pre-TAVR admissions at 30, 90, and 180 days decreased from 21.6% (713), 39.5% (1160), and 50.5% (1009) in 2012 to 15.5% (4451), 30.2% (7186), and 36.8% (5928) in 2017, respectively (P.001). Similarly, re-hospitalizations at 30, 90, and 180 days post-TAVR decreased from 17.5% (531), 27.9% (657), and 34.2% (521) to 12.4% (3486), 21.1% (4783), and 29.1% (4306), respectively (P.001). The expenditure on index, pre-, and post-TAVR hospitalizations increased from $0.53 to $2.8 billion between 2012 and 2017.This study reflects the changes in the characteristics and outcomes of TAVR in the United States between 2012 and 2017. It also shows the temporal decrease in resource use, cost, and burden of hospitalizations among patients undergoing TAVR in the United States, but an increase in the overall expenditure on TAVR-related hospitalizations.

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2(–)). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER(+) tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.

Serotonin is a key mediator of stress, anxiety, and depression, and novel therapeutic targets within serotonin neurons are needed to combat these disorders. To determine how stress alters the translational profile of serotonin neurons, we sequenced ribosome associated RNA from these neurons after repeated stress in male and female mice. We identified numerous sex- and stress-regulated genes. In particular, Fkbp5 mRNA, which codes for the glucocorticoid receptor co-chaperone protein FKBP51, was consistently upregulated in male and female mice following stress. Pretreatment with a selective FKBP51 inhibitor into the dorsal raphe prior to repeated forced swim stress decreased resulting stress-induced anhedonia. Our results support previous findings linking FKBP51 to stress-related disorders and provide the first evidence suggesting that FKBP51 function may be an important regulatory node integrating circulating stress hormones and serotonergic regulation of stress responses.

Background Microglia have recently been implicated in opioid dependence and withdrawal. Mu Opioid (MOR) receptors are expressed in microglia, and microglia form intimate connections with nearby neurons. Accordingly, opioids have both direct (MOR mediated) and indirect (neuron-interaction mediated) effects on microglia function. Methods To investigate this directly, we used RNA sequencing of ribosome-associated RNAs from striatal microglia (RiboTag-Seq) after the induction of morphine tolerance and followed by naloxone precipitated withdrawal (n=16). We validated the RNA-Seq data by combining fluorescent in-situ hybridization with immunohistochemistry for microglia (n=18). Finally, we expressed and activated the Gi/o-coupled hM4Di DREADD receptor in CX3CR1-expressing cells during morphine withdrawal (n=18). Results We detected large, inverse changes in RNA translation following opioid tolerance and withdrawal. WGCNA analysis revealed an intriguing network of cAMP-associated genes that are known to be involved in microglial motility, morphology, and interactions with neurons that were downregulated with morphine tolerance and upregulated rapidly by withdrawal. Three-dimensional histological reconstruction of microglia allowed for volumetric, visual colocalization of mRNA within individual microglia that validated our bioinformatics results. Direct activation of Gi/o-coupled DREADD receptors in CX3CR1-expressing cells exacerbated signs of opioid withdrawal rather than mimicking the effects of morphine. Conclusions These results indicate that Gi-signaling and cAMP-associated gene networks are inversely engaged during opioid tolerance and early withdrawal, perhaps revealing a role of microglia in mitigating the consequences of opioids.

Previous studies have found correlations between parent input and child language outcomes, providing prima facie evidence for a causal relation. However, this could also reflect the effects of shared genes. The present study removed this genetic confound by measuring English vocabulary growth in 29 preschool-aged children (21 girls) aged 31-73 months and 17 infants (all girls) aged 15-32 months adopted from China and Eastern Europe and comparing it to speech produced by their adoptive mothers. Vocabulary growth in both groups was correlated with maternal input features; in infants with mean-length of maternal utterance, and in preschoolers with both mean-length of utterance and lexical diversity. Thus, input effects on language outcomes persist even in the absence of genetic confounds.

Deciphering the origin, age, and composition of deep marine organic carbon remains a challenge in understanding the dynamics of the marine carbon cycle. In particular, the composition of aged organic carbon and what allows its persistence in the deep ocean and in sediment is unresolved. Here, we observe that both high and low temperature hydrothermal vents at the 9° 50′ N; 104° 17.5 W East Pacific Rise (EPR) vent field are a source for (sub)micron-sized graphite particles. We demonstrate that commonly applied analytical techniques for quantification of organic carbon detect graphite. These analyses thereby classify graphite as either dissolved or particulate organic carbon, depending on the particle size and filtration method, and overlook its relevance as a carbon source to the deep ocean. Settling velocity calculations indicate the potential for these (sub)micron particles to become entrained in the buoyant plume and distributed far from the vent fields. Thus, our observations provide direct evidence for hydrothermal vents acting as a source of old carbon to the deep ocean., Deciphering the origin, age, and composition of deep marine organic carbon remains a challenge for understanding the dynamics of the marine carbon cycle. Here, the authors identify (sub)micron-sized graphite emanating from both high and low temperature hydrothermal vents along the East Pacific Rise, and suggest graphite is a source of old carbon in the deep ocean.

Significance The Fe-catalyzed oxidation of sulfide by dioxygen in hydrothermal vent plumes is shown to be a source of reactive oxygen species (ROS) to the deep ocean. ROS are a class of powerful oxidants, the most reactive of which can react with recalcitrant organic molecules at near diffusion limited rates. ROS production in hydrothermal systems may be comparable to the known photochemical yields of ROS in surface waters. The discovery of this abundant hydrothermal source of ROS demonstrates a mechanism for the alteration of refractory organic matter in the deep ocean., Historically, the production of reactive oxygen species (ROS) in the ocean has been attributed to photochemical and biochemical reactions. However, hydrothermal vents emit globally significant inventories of reduced Fe and S species that should react rapidly with oxygen in bottom water and serve as a heretofore unmeasured source of ROS. Here, we show that the Fe-catalyzed oxidation of reduced sulfur species in hydrothermal vent plumes in the deep oceans supported the abiotic formation of ROS at concentrations 20 to 100 times higher than the average for photoproduced ROS in surface waters. ROS (measured as hydrogen peroxide) were determined in hydrothermal plumes and seeps during a series of Alvin dives at the North East Pacific Rise. Hydrogen peroxide inventories in emerging plumes were maintained at levels proportional to the oxygen introduced by mixing with bottom water. Fenton chemistry predicts the production of hydroxyl radical under plume conditions through the reaction of hydrogen peroxide with the abundant reduced Fe in hydrothermal plumes. A model of the hydroxyl radical fate under plume conditions supports the role of plume ROS in the alteration of refractory organic molecules in seawater. The ocean’s volume circulates through hydrothermal plumes on timescales similar to the age of refractory dissolved organic carbon. Thus, plume-generated ROS can initiate reactions that may affect global ocean carbon inventories.

Genetic approaches in model organisms have consistently demonstrated that molecular traits such as gene expression are under genetic regulation, similar to clinical traits. The resulting expression quantitative trait loci (eQTL) have revolutionized our understanding of genetic regulation and identified numerous candidate genes for clinically relevant traits. More recently, these analyses have been extended to other molecular traits such as protein abundance, metabolite levels, and miRNA expression. Here, we performed global hepatic eQTL and microRNA expression quantitative trait loci (mirQTL) analysis in a population of Diversity Outbred mice fed two different diets. We identified several key features of eQTL and mirQTL, namely differences in the mode of genetic regulation (cis or trans) between mRNA and miRNA. Approximately 50% of mirQTL are regulated by a trans-acting factor, compared to ∼25% of eQTL. We note differences in the heritability of mRNA and miRNA expression and variance explained by each eQTL or mirQTL. In general, cis-acting variants affecting mRNA or miRNA expression explain more phenotypic variance than trans-acting variants. Finally, we investigated the effect of diet on the genetic architecture of eQTL and mirQTL, highlighting the critical effects of environment on both eQTL and mirQTL. Overall, these data underscore the complex genetic regulation of two well-characterized RNA classes (mRNA and miRNA) that have critical roles in the regulation of clinical traits and disease susceptibility

Objective Psychiatric comorbidities disproportionately affect patients with cancer. While identified risk factors for prolonged length of stay (LOS) after esophagectomy are primarily medical comorbidities, the impact of psychiatric comorbidities on perioperative outcomes is unclear. We hypothesized that psychiatric comorbidities would prolong LOS in patients with esophageal cancer. Methods The 2016 National Inpatient Sample (NIS) was used to identify patients with esophageal cancer receiving esophagectomy. Concurrent psychiatric illness was categorized using Clinical Classifications Software Refined for ICD-10, creating 34 psychiatric diagnosis groups (PDGs). Only PDGs with >1% prevalence in the cohort were included in the analysis. The outcome of interest was hospital LOS. Bivariable testing was performed to determine the association of PDGs and demographic factors on LOS using rank sum test. Multivariable regression analysis was performed using backward selection from bivariable testing (α ≤ 0.05). Results We identified 1,730 patients who underwent esophagectomy for esophageal cancer in the 2016 NIS. The median LOS was 8 days (IQR 5-12). In bivariable testing, a concurrent diagnosis of anxiety was the only PDG associated with LOS (9 days (IQR 6-14) with anxiety diagnosis versus 8 days (IQR 5-12) with no anxiety diagnosis, p = 0.022). Multivariable modeling showed an independent association between anxiety diagnosis and increased LOS (OR 4.82 (1.25-25.23), p = 0.022). Anxiety was not associated with increased hospital cost or in-hospital mortality. Conclusions This analysis demonstrates an independent effect of anxiety prolonging postoperative LOS after esophagectomy in the United States. These findings may influence perioperative care, patient expectations, and resource allocation.

Repeated cycles of alcohol intoxication and withdrawal both induce profound changes in gene expression that can contribute to the physiological and behavioral consequences of ethanol. Since neuroinflammation is an important consequence of these changes, we used a novel strategy to investigate the impact of repeated cycles of chronic intermittent ethanol vapor and withdrawal on the RNAs actively undergoing translation in striatal microglia. RiboTag was selectively expressed in the microglia of transgenic mice and was used to immunopurify the RNA “translatome” from striatal microglia, yielding a snapshot of RNA translation during alcohol intoxication and after 8 hours of withdrawal. We obtained highly enriched microglial RNAs and analyzed these in individual animals by deep sequencing. We found a dramatic shift in gene expression during acute intoxication compared to air-exposed controls, with increases in genes and pathways associated with cytokine signaling, indicating increased neuroinflammation and microglial activation. After 8 hours of ethanol withdrawal, many inflammatory pathways remained upregulated but phagocytotic and proapoptotic pathways were increased. Using an unbiased bioinformatic method, weighted gene coexpression network analysis, multiple differentially expressed gene modules were identified. One in particular was differentially expressed in ethanol intoxicated vs. withdrawing animals, and there was a strong correlation between the centrality of the genes to this gene network and their individual statistical significance in differential expression. The unfolded protein response was over-represented in this network after withdrawal. The induction of this pathway in microglia is important since this cellular stress response can either lead towards restoration of normal function or apoptosis.

As the critical dimensions of interconnects are scaled towards and then below the mean free path of Cu (39 nm at room temperature), the resistivity is found to increase. The increase in resistivity, termed the resistivity size-effect, results in resistance increases beyond Ohm’s law of dimensional scaling and leads to large power consumption and limits improvements in computing performance.The resistivity size-effect in Cu is the result of electron scattering at grain boundaries and surfaces. Thus, for interconnects beyond Cu, epitaxial single crystal metals, absent of grain boundaries, have been investigated. Electrochemical deposition of epitaxial Co on an epitaxial Ru seed layer has provided proof-of-principle demonstration of room temperature deposition for potential implementation in BEOL technology. An electron transport model based on a tight-binding (TB) approach has been used to compute the conductivity of Ru lines. The TB based approach allows conductivity of structures comprising large ensembles of atoms (105-106) to be computed.

Expanded trinucleotide repeats cause many human diseases, including Huntington’s disease (HD). Recent studies indicate that somatic instability of these repeats contributes to pathogenesis in several expansion disorders. We find that lowering huntingtin protein (HTT) levels reduces somatic instability of both the Htt and Atxn2 CAG tracts in knockin mouse models, and the HTT CAG tract in human iPSC-derived neurons, revealing an unexpected role for HTT in regulating somatic instability.

SummaryProgressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntington’s disease (HD), but direct relationships between the huntingtin (HTT) protein and chromatin remain poorly described. Here, using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that HTT reproducibly occupies specific locations in the mouse genome, including thousands of genomic loci that are differentially occupied in striatal tissue from a knock-in mouse model of HD (B6.HttQ111/+) versus wildtype controls. ChIP-seq of histone modifications, generated in parallel, revealed genotype-specific colocalization of HTT with trimethylation of histone 3 lysine 27 (H3K27me3), a repressive chromatin mark. Near genes that are differentially regulated in HD, greater HTT occupancy in HttQ111/+ vs. wildtype mice predicted increased H3K27me3, reduced histone 3 lysine 4 (H3K4me3), a marker of poised and active promoters, and down-regulated gene expression. Altered huntingtin-chromatin interactions may therefore play a direct role in driving transcriptional dysregulation in HD.

Trimethylamine-N-oxide (TMAO), a microbial choline metabolism byproduct that is processed in the liver and excreted into circulation, is associated with increased atherosclerotic lesion formation and cardiovascular disease risk. Genetic regulators of TMAO levels are largely unknown. In the present study, we used 288 mice from a genetically heterogeneous mouse population [Diversity Outbred (DO)] to determine hepatic microRNA associations with TMAO in the context of an atherogenic diet. We also validated findings in two additional animal models of atherosclerosis: liver-specific insulin receptor knockout mice fed a chow diet (LIRKO) and African green monkeys fed high-fat/high-cholesterol diet. Small RNA-sequencing analysis in DO mice, LIRKO mice, and African green monkeys identified only one hepatic microRNA (miR-146a-5p) that is aberrantly expressed across all three models. Moreover, miR-146a-5p levels are associated with circulating TMAO after atherogenic diet in each of these models. We also performed high-resolution genetic mapping and identified a novel quantitative trait locus on Chromosome 12 for TMAO levels. This interval includes two genes, Numb and Dlst, which are inversely correlated with both miR-146a and TMAO and are predicted targets of miR-146a. Both of these genes have been validated as direct targets of miR-146a, though in other cellular contexts. This is the first report to our knowledge of a link between miR-146 and TMAO. Our findings suggest that miR-146-5p, as well as one or more genes at the Chromosome 12 QTL (possibly Numb or Dlst), is strongly linked to TMAO levels and likely involved in the control of atherosclerosis.

The lateral habenula (LHb) integrates critical information regarding aversive stimuli that shapes decision making and behavioral responses. The three major LHb outputs innervate dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and the rostromedial tegmental nucleus (RMTg). LHb neurons that project to these targets are segregated and nonoverlapping, and this led us to consider whether they have distinct molecular phenotypes and adaptations to stress exposure. In order to capture a time-locked profile of gene expression after repeated forced swim stress, we used intersectional expression of RiboTag in rat LHb neurons and next-gen RNA sequencing to interrogate the RNAs actively undergoing translation from each of these pathways. The “translatome” in the neurons comprising these pathways was similar at baseline, but diverged after stress, especially in the neurons projecting to the RMTg. Using weighted gene co-expression network analysis, we found one module comprising genes downregulated after stress in the RMTg-projecting LHb neurons; there was an overrepresentation of genes associated with phosphoinositide 3 kinase (PI3K) signaling in this module. Reduced PI3K signaling in RMTg-projecting LHb neurons may be a compensatory adaptation that alters the functional balance of LHb outputs to GABAergic vs. monoaminergic neurons following repeated stress exposure.