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Background: Marital status has been shown to have protective effects for married patients with various cancers. We sought to determine effects of marital status on perioperative outcomes after robotic-assisted pulmonary lobectomy (RAPL). Methods: We retrospectively analyzed 709 consecutive patients who underwent RAPL between 2010 and 2022 by one surgeon. Patients were stratified by marital status at time of surgery. The Married group included married, domestically partnered, and co-habitating patients (N = 473). The Unmarried group included never married, divorced, and widowed individuals (N = 236). Demographics, preoperative comorbidities, intraoperative and postoperative complications, estimated blood loss (EBL), chest tube duration, hospital length of stay (LOS), tumor characteristics, and survival data were analyzed utilizing Student's t-test, Wilcoxon rank-sum test, Chi-square, or Fisher's exact test as appropriate, with significance at p≤0.05. Results: Unmarried patients were more likely to be female, while married patients were more likely to experience robotic-associated intraoperative complications and greater intraoperative estimated blood loss. Kaplan-Meier survival analysis revealed no difference in 5-year overall survival based on marital status. Other perioperative outcomes, intraoperative complications (except robotic-associated), postoperative complications, demographic history (except gender), and preoperative comorbidities did not significantly differ between the two groups. Conclusion: This study challenges the existing reports in the literature that marriage confers cancer treatment outcomes advantage and prolonged survival among cancer patients. Social support, in terms of a spouse or domestic partner, may be less protective in early-stage lung cancer and after minimally invasive pulmonary lobectomy compared to other cancer populations.

Background: Atrial fibrillation is a common arrhythmia previously linked to systemic inflammation, which has been correlated with leukocyte and prealbumin levels. We sought to identify predictors of postoperative atrial fibrillation (POAF) following robotic-assisted pulmonary lobectomy. Methods: This retrospective cohort study included 709 consecutive patients who underwent robotic-assisted lobectomy by one surgeon over 10.7 years. We compared demographics, preoperative comorbidities, perioperative leukocyte, prealbumin levels, complications, chest tube (CT) duration, and hospital length of stay (LOS) using Student's t-test, Chi-square (or Fisher's exact) test, or Wilcoxon rank sums test, with significance at p ≤ 0.05. Multivariable analysis investigated predictors of POAF, CT duration, hospital LOS, and overall survival (OS). Kaplan-Meier analysis estimated OS with 95% confidence intervals. Results: Preoperative atrial fibrillation or chronic steroid or immunosuppressant use excluded 131 patients, and 578 remaining patients were classified as POAF (n=76) or No POAF (n=502). Patients with new-onset POAF were older and had higher incidences of preoperative hypertension and hyperlipidemia, intraoperative complications, and postoperative anemia. The lowest postoperative prealbumin levels were reduced, and peak postoperative leukocyte counts were elevated in POAF patients. Multivariable analysis identified that patients with POAF had longer hospital LOS and lower postoperative prealbumin as factors that independently predict both POAF and increased hospital LOS. Conclusions: New-onset POAF patients had a substantial perioperative inflammatory burden characterized by preoperative hypertension, postoperative leukocytosis, and decreased prealbumin and had prolonged hospital LOS compared with patients without POAF. Postoperative leukocyte and prealbumin levels should be monitored, as these pro-inflammatory markers may forecast POAF.

Abstract Background Gene regulation is critical for proper cellular function. Next-generation sequencing technology has revealed the presence of regulatory networks that regulate gene expression and essential cellular functions. Studies investigating the epigenome have begun to uncover the complex mechanisms regulating transcription. Assay for transposase-accessible chromatin by sequencing (ATAC-seq) is quickly becoming the assay of choice for many epigenomic investigations. However, whether intervention-mediated changes in accessible chromatin determined by ATAC-seq can be harnessed to generate intervention-inducible reporter constructs has not been systematically assayed. Results We used the insulin signaling pathway as a model to investigate chromatin regions and gene expression changes using ATAC- and RNA-seq in insulin-treated Drosophila S2 cells. We found correlations between ATAC- and RNA-seq data, especially when stratifying differentially-accessible chromatin regions by annotated feature type. In particular, our data demonstrated a weak but significant correlation between chromatin regions annotated to enhancers (1-2 kb from the transcription start site) and downstream gene expression. We cloned candidate enhancer regions upstream of luciferase and demonstrate insulin-inducibility of several of these reporters. Conclusions Insulin-induced chromatin accessibility determined by ATAC-seq reveals enhancer regions that drive insulin-inducible reporter gene expression.

Abstract Assay for transposase-accessible chromatin by sequencing (ATAC-seq) is rapidly becoming the assay of choice to investigate chromatin-mediated gene regulation, largely because of low input requirements, a fast workflow, and the ability to interrogate the entire genome in an untargeted manner. Many studies using ATAC-seq use mammalian or human-derived tissues, and established protocols work well in these systems. However, ATAC-seq is not yet widely used in Drosophila. Vinegar flies present several advantages over mammalian systems that make them an excellent model for ATAC-seq studies, including abundant genetic tools that allow straightforward targeting, transgene expression, and genetic manipulation that are not available in mammalian models. Because current ATAC-seq protocols are not optimized to use flies, we developed an optimized workflow that accounts for several complicating factors present in Drosophila. We examined parameters affecting nuclei isolation, including input size, freezing time, washing, and possible confounds from retinal pigments. Then, we optimized the enzymatic steps of library construction to account for the smaller Drosophila genome size. Finally, we used our optimized protocol to generate ATAC-seq libraries that meet ENCODE quality metrics. Our optimized protocol enables extensive ATAC-seq experiments in Drosophila, thereby leveraging the advantages of this powerful model system to understand chromatin-mediated gene regulation.

This data article provides the summary data from tests comparing various Gaussian process software packages. Each spreadsheet represents a single function or type of function using a particular input sample size. In each spreadsheet, a row gives the results for a particular replication using a single package. Within each spreadsheet there are the results from eight Gaussian process model-fitting packages on five replicates of the surface. There is also one spreadsheet comparing the results from two packages performing stochastic kriging. These data enable comparisons between the packages to determine which package will give users the best results.

Céline Mirjolet,1 Julien Boudon,2 Alexis Loiseau,2 Sandy Chevrier,1 Romain Boidot,1 Alexandra Oudot,3 Bertrand Collin,3 Etienne Martin,1 Pattayil Alias Joy,4 Nadine Millot,2 Gilles Créhange1 1Department of Radiation Oncology, Center Georges-François Leclerc, Dijon, France; 2Laboratoire Interdisciplinaire Carnot de Bourgogne, Dijon, France; 3Preclinical Imaging Platform, Nuclear Medicine Department, Center Georges-François Leclerc, Dijon, France; 4CSIR-National Chemical Laboratory (CSIR-NCL), Pune, India Abstract: Around 40% of high-risk prostate cancer patients who undergo radiotherapy (RT) will experience biochemical failure. Chemotherapy, such as docetaxel (DTX), can enhance the efficacy of RT. Multidrug resistance mechanisms often limit drug efficacy by decreasing intracellular concentrations of drugs in tumor cells. It is, therefore, of interest to develop nanocarriers of DTX to maintain the drug inside cancer cells and thus improve treatment efficacy. The purpose of this study was to investigate the use of titanate nanotubes (TiONts) to develop a TiONts-DTX nanocarrier and to evaluate its radiosensitizing in vivo efficacy in a prostate cancer model. In vitro cytotoxic activity of TiONts-DTX was evaluated using an MTS assay. The biodistribution of TiONts-DTX was analyzed in vivo by single-photon emission computed tomography. The benefit of TiONts-DTX associated with RT was evaluated in vivo. Eight groups with seven mice in each were used to evaluate the efficacy of the nanohybrid combined with RT: control with buffer IT injection ± RT, free DXL ± RT, TiONts ± RT and TiONts-DXL ± RT. Mouse behavior, health status and tumor volume were monitored twice a week until the tumor volume reached a maximum of 2,000 mm3. More than 70% of nanohybrids were localized inside the tumor 96 h after administration. Tumor growth was significantly slowed by TiONts-DTX associated with RT, compared with free DTX in the same conditions (P=0.013). These results suggest that TiONts-DTX improved RT efficacy and might enhance local control in high-risk localized prostate cancer. Keywords: prostate cancer, docetaxel nanocarrier, titanate nanotubes, radiosensitivity, nanoparticle

Abstract Our understanding of the physiological and pathological functions of brain lipids is limited by the inability to analyze these molecules at cellular resolution. Here, we present a method that enables the detection of lipids in identified single neurons from live mammalian brains. Neuronal cell bodies are captured from perfused mouse brain slices by patch clamping, and lipids are analyzed using an optimized nanoflow liquid chromatography/mass spectrometry protocol. In a first application of the method, we identified more than 40 lipid species from dentate gyrus granule cells and CA1 pyramidal neurons of the hippocampus. This survey revealed substantial lipid profile differences between neurons and whole brain tissue, as well as between resting and physiologically stimulated neurons. The results suggest that patch clamp-assisted single neuron lipidomics could be broadly applied to investigate neuronal lipid homeostasis in healthy and diseased brains.

The hippocampus is thought to encode information by altering synaptic strength via synaptic plasticity. Some forms of synaptic plasticity are induced by lipid-based endocannabinoid signaling molecules that act on cannabinoid receptors (CB1). Endocannabinoids modulate synaptic plasticity of hippocampal pyramidal cells and stratum radiatum interneurons; however, the role of endocannabinoids in mediating synaptic plasticity of stratum oriens interneurons is unclear. These feedback inhibitory interneurons exhibit presynaptic long-term potentiation (LTP), but the exact mechanism is not entirely understood. We examined whether oriens interneurons produce endocannabinoids, and whether endocannabinoids are involved in presynaptic LTP. Using patch-clamp electrodes to extract single cells, we analyzed the expression of endocannabinoid biosynthetic enzyme mRNA by reverse transcription and then real-time PCR (RT-PCR). The cellular expression of calcium-binding proteins and neuropeptides were used to identify interneuron subtype. RT-PCR results demonstrate that stratum oriens interneurons express mRNA for both endocannabinoid biosynthetic enzymes and the type I metabotropic glutamate receptors (mGluRs), necessary for endocannabinoid production. Immunohistochemical staining further confirmed the presence of diacylglycerol lipase alpha, an endocannabinoid-synthesizing enzyme, in oriens interneurons. To test the role of endocannabinoids in synaptic plasticity, we performed whole-cell experiments using high-frequency stimulation to induce long-term potentiation in somatostatin-positive cells. This plasticity was blocked by AM-251, demonstrating CB1-dependence. In addition, in the presence of a fatty acid amide hydrolase inhibitor (URB597; 1 µM) and MAG lipase inhibitor (JZL184; 1 µM) that increase endogenous anandamide and 2-arachidonyl glycerol, respectively, excitatory current responses were potentiated. URB597-induced potentiation was blocked by CB1 antagonist AM-251 (2 µM). Collectively, this suggests somatostatin-positive oriens interneuron LTP is CB1-dependent.

Several studies have documented a global pattern of phonological advancement that is consistentwith ongoing climate change. However, themagnitude of these phenological shifts is highly variable across taxa and locations. This variability of phenological responses has been difficult to explainmechanistically. To examine how the evolution of multitrait cueing strategies could produce variable responses to climate change, we constructed a model in which organisms evolve strategies that integrate multiple environmental cues to inform anticipatory phenological decisions.We simulated the evolution of phenological cueing strategies in multiple environments, using historic climate data from78 locations in North America and Hawaii to capture features of climatic correlation structures in the real world.Organisms in our model evolved diverse strategies that were spatially autocorrelated across locations on a continental scale, showing that similar strategies tend to evolve in similar climates. Within locations, organisms often evolved a wide range of strategies that showed similar response phenotypes and fitness outcomes under historical conditions. However, these strategies responded differently to novel climatic conditions, with variable fitness consequences. Our model shows how the evolution of phenological cueing strategies can explain observed variation in phenological shifts and unexpected responses to climate change.

ObjectivesURB937, a peripheral fatty acid amide hydrolase (FAAH) inhibitor, exerts profound analgesic effects in animal models. We examined, in rats, (1) the pharmacokinetic profile of oral URB937; (2) the compound's ability to elevate levels of the representative FAAH substrate, oleoylethanolamide (OEA); and (3) the compound's tolerability after oral administration.MethodsWe developed a liquid chromatography/tandem mass spectrometry (LC/MS-MS) method to measure URB937 and used a pre-existing LC/MS-MS assay to quantify OEA. FAAH activity was measured using a radioactive substrate. The tolerability of single or repeated (once daily for 2 weeks) oral administration of supramaximal doses of URB937 (100, 300, 1000 mg/kg) was assessed by monitoring food intake, water intake and body weight, followed by post-mortem evaluation of organ structure.Key findingsURB937 was orally available in male rats (F = 36%), but remained undetectable in brain when administered at doses that maximally inhibit FAAH activity and elevate OEA in plasma and liver. Acute and subchronic treatment with high doses of URB937 was well-tolerated and resulted in FAAH inhibition in brain.ConclusionsPain remains a major unmet medical need. The favourable pharmacokinetic and pharmacodynamic properties of URB937, along with its tolerability, encourage further development studies on this compound.

Changes in phenology are a common response to climate change, but their impact on population dynamics is often ambiguous and at‐risk species are omitted from most analyses.We assessed the relationship between change in abundance and change in phenology for 114 butterfly populations of 31 at‐risk species from five families in 10 US states. We used data from Pollard‐walk and similar monitoring programmes for which count data were collected on multiple occasions per year. We also collected information from managers on site‐level management interventions.To estimate abundance, we first fit separate smoothing splines for each species at each site. Yearly abundance was estimated as the area under the activity curve for that year, and from this, we estimated abundance trends over the period for which we had population data. Phenological shifts were measured as the changes in median activity date, beginning of flight season, duration of flight season and phenological constancy (negative of the magnitude of trends in median activity date). We also evaluated the association of ecological traits (voltinism, diet breadth, position within geographic range, ecoregion, overwintering stage and seasonality) and management (proportion of years with interventions) with trends in abundance and in phenology.Across all populations, the estimated trend in abundance was −0.085, equivalent to an 8.1% decline/year. Positive trends in abundance were associated with smaller shifts in the median flight date (higher constancy). We also found strong associations between trends in abundance and management interventions, with increased management associated with increasing abundance trends. In general, ecological traits were not strongly associated with trends in phenology or trends in abundance.Synthesis and applications: Populations with less phenological constancy are more likely to be rapidly declining and populations with more frequent management interventions are increasing. These results suggest that one key outcome of management interventions may be to mitigate some of the impacts of climate change, which in turn may contribute to higher population growth. These results also imply that managers may need to alter the timing of appropriate management to synchronize with activities of at‐risk species as species shift their phenology. [ABSTRACT FROM AUTHOR]

We provide field evidence that individuals engage in motivated optimism in the face of impending risk. Congruent with a dynamic anticipatory utility model, we demonstrate that belief distortions are time and stake dependent. Our study leverages variation in the time span between the survey and the externally imposed date when workers are required to return to their workplaces during the COVID-19 pandemic. We show that, as the work return date approaches, individuals become relatively more optimistic about the increased infection risk associated with going back to the workplace, and about how severely their health may be impacted if they get infected. Belief distortions are larger among those facing potential health complications conditional on infection. Our results are informative about when and for whom interventions will be most effective. [ABSTRACT FROM AUTHOR]

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Several studies have documented a global pattern of phenological advancement that is consistent with ongoing climate change. However, the magnitude of these phenological shifts is highly variable across taxa and locations. This variability of phenological responses has been difficult to explain mechanistically. To examine how the evolution of multi-trait cueing strategies could produce variable responses to climate change, we constructed a model in which organisms evolve strategies that integrate multiple environmental cues to inform anticipatory phenological decisions. We simulated the evolution of phenological cueing strategies in multiple environments, using historic climate data from 78 locations in North America and Hawaii to capture features of climatic correlation structures in the real world. Organisms in our model evolved diverse strategies that were spatially autocorrelated across locations on a continental scale, showing that similar strategies tend to evolve in similar climates. Within locations, organisms often evolved a wide range of strategies that showed similar response phenotypes and fitness outcomes under historical conditions. However, these strategies responded differently to novel climatic conditions, with variable fitness consequences. Our model shows how the evolution of phenological cueing strategies can explain observed variation in phenological shifts and unexpected responses to climate change.

Our understanding of the physiological and pathological functions of brain lipids is limited by the inability to analyze these molecules at cellular resolution. Here, we present a method that enables the detection of lipids in identified single neurons from live mammalian brains. Neuronal cell bodies are captured from perfused mouse brain slices by patch clamping, and lipids are analyzed using an optimized nanoflow liquid chromatography/mass spectrometry protocol. In a first application of the method, we identified more than 40 lipid species from dentate gyrus granule cells and CA1 pyramidal neurons of the hippocampus. This survey revealed substantial lipid profile differences between neurons and whole brain tissue, as well as between resting and physiologically stimulated neurons. The results suggest that patch clamp-assisted single neuron lipidomics could be broadly applied to investigate neuronal lipid homeostasis in healthy and diseased brains.

The endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), a key modulator of synaptic transmission in mammalian brain, is produced in dendritic spines and then crosses the synaptic junction to depress neurotransmitter release. Here we report that 2-AG-dependent retrograde signaling also mediates an enduring enhancement of glutamate release, as assessed with independent tests, in the lateral perforant path (LPP), one of two cortical inputs to the granule cells of the dentate gyrus. Induction of this form of long-term potentiation (LTP) involved two types of glutamate receptors, changes in postsynaptic calcium, and the postsynaptic enzyme that synthesizes 2-AG. Stochastic optical reconstruction microscopy confirmed that CB1 cannabinoid receptors are localized presynaptically to LPP terminals, while the inhibition or knockout of the receptors eliminated LPP-LTP. Suppressing the enzyme that degrades 2-AG dramatically enhanced LPP potentiation, while overexpressing it produced the opposite effect. Priming with a CB1 agonist markedly reduced the threshold for LTP. Latrunculin A, which prevents actin polymerization, blocked LPP-LTP when applied extracellularly but had no effect when infused postsynaptically into granule cells, indicating that critical actin remodeling resides in the presynaptic compartment. Importantly, there was no evidence for the LPP form of potentiation in the Schaffer-commissural innervation of field CA1 or in the medial perforant path. Peripheral injections of compounds that block or enhance LPP-LTP had corresponding effects on the formation of long-term memory for cues conveyed to the dentate gyrus by the LPP. Together, these results indicate that the encoding of information carried by a principal hippocampal afferent involves an unusual, regionally differentiated form of plasticity.

The Drosophila brain contains tens of thousands of distinct cell types. Thousands of different transgenic lines reproducibly target specific neuron subsets, yet most still express in several cell types. Furthermore, most lines were developed without a priori knowledge of where the transgenes would be expressed. To aid in the development of cell type-specific tools for neuronal identification and manipulation, we developed an iterative assay for transposase-accessible chromatin (ATAC) approach. Open chromatin regions (OCRs) enriched in neurons, compared to whole bodies, drove transgene expression preferentially in subsets of neurons. A second round of ATAC-seq from these specific neuron subsets revealed additional enriched OCR2s that further restricted transgene expression within the chosen neuron subset. This approach allows for continued refinement of transgene expression, and we used it to identify neurons relevant for sleep behavior. Furthermore, this approach is widely applicable to other cell types and to other organisms. [ABSTRACT FROM AUTHOR]

Tolerance occurs when, following an initial experience with a substance, more of the substance is required subsequently to induce identical behavioral effects. Tolerance is not well‐understood, and numerous researchers have turned to model organisms, particularly Drosophila melanogaster, to unravel its mechanisms. Flies have high translational relevance for human alcohol responses, and there is substantial overlap in disease‐causing genes between flies and humans, including those associated with Alcohol Use Disorder. Numerous Drosophila tolerance mutants have been described; however, approaches used to identify and characterize these mutants have varied across time and labs and have mostly disregarded any impact of initial resistance/sensitivity to ethanol on subsequent tolerance development. Here, we analyzed our own, as well as data published by other labs to uncover an inverse correlation between initial ethanol resistance and tolerance phenotypes. This inverse correlation suggests that initial resistance phenotypes can explain many 'perceived' tolerance phenotypes, thus classifying such mutants as 'secondary' tolerance mutants. Additionally, we show that tolerance should be measured as a relative increase in time to sedation between an initial and second exposure rather than an absolute change in time to sedation. Finally, based on our analysis, we provide a method for using a linear regression equation to assess the residuals of potential tolerance mutants. These residuals provide predictive insight into the likelihood of a mutant being a 'primary' tolerance mutant, where a tolerance phenotype is not solely a consequence of initial resistance, and we offer a framework for understanding the relationship between initial resistance and tolerance. [ABSTRACT FROM AUTHOR]

We present the results of a Monte-Carlo study of the sensitivity of the planned IceCube detector to predicted fluxes of muon neutrinos at TeV to PeV energies. A complete simulation of the detector and data analysis is used to study the detector's capability to search for muon neutrinos from sources such as active galaxies and gamma-ray bursts. We study the effective area and the angular resolution of the detector as a function of muon energy and angle of incidence. We present detailed calculations of the sensitivity of the detector to both diffuse and pointlike neutrino emissions, including an assessment of the sensitivity to neutrinos detected in coincidence with gamma-ray burst observations. After three years of datataking, IceCube will have been able to detect a point source flux of E2*dN/dE = 7*10^-9 cm^-2s^-1GeV at a 5-sigma significance, or, in the absence of a signal, place a 90 percent c.l. limit at a level E2*dN/dE = 2*10^-9 cm^-2s^-1GeV. A diffuse E-2 flux would be detectable at a minimum strength of E2*dN/dE = 1*10^-8 cm^-2s^-1sr^-1GeV. A gamma-ray burst model following the formulation of Waxman and Bahcall would result in a 5-sigma effect after the observation of 200 bursts in coincidence with satellite observations of the gamma-rays.

For thousands of years, humans have enjoyed the novel flavors, increased shelf-life, and nutritional benefits that microbes provide in fermented foods and beverages. Recent sequencing surveys of ferments have mapped patterns of microbial diversity across space, time, and production practices. But a mechanistic understanding of how fermented food microbiomes assemble has only recently begun to emerge. Using three foods as case studies (surface-ripened cheese, sourdough starters, and fermented vegetables), we use an ecological and evolutionary framework to identify how microbial communities assemble in ferments. By combining in situ sequencing surveys with in vitro models, we are beginning to understand how dispersal, selection, diversification, and drift generate the diversity of fermented food communities. Most food producers are unaware of the ecological processes occurring in their production environments, but the theory and models of ecology and evolution can provide new approaches for managing fermented food microbiomes, from farm to ferment. [ABSTRACT FROM AUTHOR]

Of the boreal‐ and Arctic‐breeding North American shorebirds that migrate south through the Caribbean, most individuals continue farther south. However, for many species, some individuals remain beyond the southbound migration period (i.e., throughout the temperate winter and/or summer). This variation among individuals adds complexity to observation data, obscures migration patterns, and could prevent the examination of the use of different Caribbean regions by various shorebird species during migration and in the nonmigratory seasons. Here, we present a novel method that leverages a well‐established statistical approach (generalized additive models) to systematically identify migration phenology even for complex passage migrant species with individuals that remain beyond migration. Our method identifies the active migration period using derivatives of a fitted GAM and then calculates phenology metrics based on quantiles of that migration period. We also developed indices to quantify oversummering and overwintering patterns with respect to migration. We analyzed eBird data for 16 North American shorebird species as they traveled South through the insular Caribbean, identifying separate migratory patterns for Cuba, Puerto Rico, Guadeloupe, Aruba, Bonaire, Curaçao, and Trinidad and Tobago. Our results confirm past reports and provide additional detail on shorebird migration in the Caribbean, and identify several previously unpublished regional patterns. Despite Puerto Rico being farther north and closer to continental North America, most species reached Puerto Rico later than other regions, supporting a long‐standing hypothesis that migration strategy (transcontinental vs. transoceanic) leads to geographic differences in migration timing. We also found distinct patterns of migration curves, with some regions and species consistently having either symmetrical or skewed curves; these differences in migration curve shape reflect different migration processes. Our novel method proved reliable and adaptable for most species and serves as a valuable tool for identifying phenological patterns in complex migration data, potentially unlocking previously intractable data. [ABSTRACT FROM AUTHOR]