We present the results of planet formation N-body simulations based on a comprehensive physical model that includes planetary mass growth through mutual embryo collisions and planetesimal/boulder ...accretion, viscous disc evolution, planetary migration and gas accretion on to planetary cores. The main aim of this study is to determine which set of model parameters leads to the formation of planetary systems that are similar to the compact low-mass multiplanet systems that have been discovered by radial velocity surveys and the Kepler mission. We vary the initial disc mass, solids-to-gas ratio and the sizes of the boulders/planetesimals, and for a restricted volume of the parameter space we find that compact systems containing terrestrial planets, super-Earths and Neptune-like bodies arise as natural outcomes of the simulations. Disc models with low values of the solids-to-gas ratio can only form short-period super-Earths and Neptunes when small planetesimals/boulders provide the main source of accretion, since the mobility of these bodies is required to overcome the local isolation masses for growing embryos. The existence of short-period super-Earths around low-metallicity stars provides strong evidence that small, mobile bodies (planetesimals, boulders or pebbles) played a central role in the formation of the observed planets.
This article attempts a double reflection: a methodological interrogation of myself and an autointerrogation of my methodology. Following Ernst Bloch, I structure this reflection around the idea of ...traces, which are brief, narrative, aphoristic speculations on a particular theme. In this article, I (re)produce my own narrative traces, engaging with and representing several moments of strangeness in my methodological praxis as they are recorded in field notes from prior fieldwork with urban secession movements in black and white communities of Atlanta. Building from Bloch's hermeneutic, I treat these moments as traces to be pursued, rather than simple social artifacts of the relational, intersubjective activity of research. Finally, I demonstrate how a geographer might develop that which crystallizes in the interpretation of the trace (i.e., through the intentional reconsideration of the uncanny and recurrent moments of everyday experience) toward the methodological worlding of philosophy as a vibrant, reflexive, human praxis. Key Words: Bloch, interpretation, method, postqualitative analysis, praxis.
Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin ...transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of
Himipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.
With marine protected areas being established worldwide there is a pressing need to understand how the physical setting in which these areas are placed influences patterns of dispersal and ...connectivity of important marine organisms. This is particularly critical for dynamic and complex nearshore marine environments where patterns of genetic structure of organisms are often chaotic and uncoupled from broad scale physical processes. This study determines the influence of habitat heterogeneity (presence of estuaries) on patterns of genetic structure and connectivity of the common kelp, Ecklonia radiata. There was no genetic differentiation of kelp between estuaries and the open coast and the presence of estuaries did not increase genetic differentiation among open coast populations. Similarly, there were no differences in level of inbreeding or genetic diversity between estuarine and open coast populations. The presence of large estuaries along rocky coastlines does not appear to influence genetic structure of this kelp and factors other than physical heterogeneity of habitat are likely more important determinants of regional connectivity. Marine reserves are currently lacking in this bioregion and may be designated in the future. Knowledge of the factors that influence important habitat forming organisms such as kelp contribute to informed and effective marine protected area design and conservation initiatives to maintain resilience of important marine habitats.
Transitional care has been defined as a set of actions designed to ensure the coordination and continuity of health care as patients transfer between different locations or different levels of care ...in the same location. Transitional care, which primarily concerns the relatively brief time interval that begins with preparing a patient to leave one setting and concludes when the patient is received in the next setting, poses challenges that distinguish it from other types of care. Many transitions are unplanned, result from unanticipated medical problems, occur in "real time" during nights and on weekends, involve clinicians who may not have an ongoing relationship with the patient, and happen so quickly that formal and informal support mechanisms cannot respond in a timely manner. This article describes the challenges involved in and potential solutions for improving the quality of transitional care.
Abstract Background Open radical cystectomy (ORC) and urinary diversion in patients with bladder cancer (BCa) are associated with significant perioperative complication risk. Objective To compare ...perioperative complications between robot-assisted radical cystectomy (RARC) and ORC techniques. Design, setting, and participants A prospective randomized controlled trial was conducted during 2010 and 2013 in BCa patients scheduled for definitive treatment by radical cystectomy (RC), pelvic lymph node dissection (PLND), and urinary diversion. Patients were randomized to ORC/PLND or RARC/PLND, both with open urinary diversion. Patients were followed for 90 d postoperatively. Intervention Standard ORC or RARC with PLND; all urinary diversions were performed via an open approach. Outcome measurements and statistical analysis Primary outcomes were overall 90-d grade 2–5 complications defined by a modified Clavien system. Secondary outcomes included comparison of high-grade complications, estimated blood loss, operative time, pathologic outcomes, 3- and 6-mo patient-reported quality-of-life (QOL) outcomes, and total operative room and inpatient costs. Differences in binary outcomes were assessed with the chi-square test, with differences in continuous outcomes assessed by analysis of covariance with randomization group as covariate and, for QOL end points, baseline score. Results and limitations The trial enrolled 124 patients, of whom 118 were randomized and underwent RC/PLND. Sixty were randomized to RARC and 58 to ORC. At 90 d, grade 2–5 complications were observed in 62% and 66% of RARC and ORC patients, respectively (95% confidence interval for difference, −21% to −13%; p = 0.7). The similar rates of grade 2–5 complications at our mandated interim analysis met futility criteria; thus, early closure of the trial occurred. The RARC group had lower mean intraoperative blood loss ( p = 0.027) but significantly longer operative time than the ORC group ( p < 0.001). Pathologic variables including positive surgical margins and lymph node yields were similar. Mean hospital stay was 8 d in both arms (standard deviation, 3 and 5 d, respectively; p = 0.5). Three- and 6-mo QOL outcomes were similar between arms. Cost analysis demonstrated an advantage to ORC compared with RARC. A limitation is the setting at a single high-volume, referral center; our findings may not be generalizable to all settings. Conclusions This trial failed to identify a large advantage for robot-assisted techniques over standard open surgery for patients undergoing RC/PLND and urinary diversion. Similar 90-d complication rates, hospital stay, pathologic outcomes, and 3- and 6-mo QOL outcomes were observed regardless of surgical technique. Patient summary Of 118 patients with bladder cancer who underwent radical cystectomy, pelvic lymph node dissection, and urinary diversion, half were randomized to open surgery and half to robot-assisted laparoscopic surgery. We compared the rate of complications within 90 d after surgery for the open group versus the robotic group and found no significant difference between the two groups. Trial Registration ClinicalTrials.gov identifier NCT01076387 , www.clinicaltrials.gov.
Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) is caused by loss-of-function mutations in SEIPIN, a protein implicated in both adipogenesis and lipid droplet expansion but whose molecular ...function remains obscure. Here, we identify physical and functional interactions between SEIPIN and microsomal isoforms of glycerol-3-phosphate acyltransferase (GPAT) in multiple organisms. Compared to controls, GPAT activity was elevated in SEIPIN-deficient cells and tissues and GPAT kinetic values were altered. Increased GPAT activity appears to underpin the block in adipogenesis and abnormal lipid droplet morphology associated with SEIPIN loss. Overexpression of Gpat3 blocked adipogenesis, and Gpat3 knockdown in SEIPIN-deficient preadipocytes partially restored differentiation. GPAT overexpression in yeast, preadipocytes, and fly salivary glands also formed supersized lipid droplets. Finally, pharmacological inhibition of GPAT in Seipin−/− mouse preadipocytes partially restored adipogenesis. These data identify SEIPIN as an evolutionarily conserved regulator of microsomal GPAT and suggest that GPAT inhibitors might be useful for the treatment of human BSCL2 patients.
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•Loss of SEIPIN function causes Berardinelli-Seip congenital lipodystrophy 2•Lack of SEIPIN increases glycerol-3-phosphate acyltransferase (GPAT) activity•Inhibiting GPAT enhances differentiation of SEIPIN-deficient preadipocytes•Inhibiting GPAT corrects abnormal lipid droplet morphology in SEIPIN deficiency
Pagac et al. find that SEIPIN, which has been linked to Berardinelli-Seip congenital lipodystrophy 2, interacts with microsomal glycerol-3-phosphate acyltransferase (GPAT) and influences its activity. Increased GPAT activity appears to underlie the block in adipogenesis and abnormal lipid droplet morphology associated with SEIPIN loss.
Climate change is driving global declines of marine habitat-forming species through physiological effects and through changes to ecological interactions, with projected trajectories for ocean warming ...and acidification likely to exacerbate such impacts in coming decades. Interactions between habitat-formers and their microbiomes are fundamental for host functioning and resilience, but how such relationships will change in future conditions is largely unknown. We investigated independent and interactive effects of warming and acidification on a large brown seaweed, the kelp Ecklonia radiata, and its associated microbiome in experimental mesocosms. Microbial communities were affected by warming and, during the first week, by acidification. During the second week, kelp developed disease-like symptoms previously observed in the field. The tissue of some kelp blistered, bleached and eventually degraded, particularly under the acidification treatments, affecting photosynthetic efficiency. Microbial communities differed between blistered and healthy kelp for all treatments, except for those under future conditions of warming and acidification, which after two weeks resembled assemblages associated with healthy hosts. This indicates that changes in the microbiome were not easily predictable as the severity of future climate scenarios increased. Future ocean conditions can change kelp microbiomes and may lead to host disease, with potentially cascading impacts on associated ecosystems.
Cancer-associated fibroblasts (CAFs) are a prominent stromal cell type in solid tumors and molecules secreted by CAFs play an important role in tumor progression and metastasis. CAFs coexist as ...heterogeneous populations with potentially different biological functions. Although CAFs are a major component of the breast cancer stroma, molecular and phenotypic heterogeneity of CAFs in breast cancer is poorly understood. In this study, we investigated CAF heterogeneity in triple-negative breast cancer (TNBC) using a syngeneic mouse model, BALB/c-derived 4T1 mammary tumors. Using single-cell RNA sequencing (scRNA-seq), we identified six CAF subpopulations in 4T1 tumors including: 1) myofibroblastic CAFs, enriched for α-smooth muscle actin and several other contractile proteins; 2) 'inflammatory' CAFs with elevated expression of inflammatory cytokines; and 3) a CAF subpopulation expressing major histocompatibility complex (MHC) class II proteins that are generally expressed in antigen-presenting cells. Comparison of 4T1-derived CAFs to CAFs from pancreatic cancer revealed that these three CAF subpopulations exist in both tumor types. Interestingly, cells with inflammatory and MHC class II-expressing CAF profiles were also detected in normal breast/pancreas tissue, suggesting that these phenotypes are not tumor microenvironment-induced. This work enhances our understanding of CAF heterogeneity, and specifically targeting these CAF subpopulations could be an effective therapeutic approach for treating highly aggressive TNBCs.
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