IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure.

Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the limiters of energy expenditure are largely unknown. Here, we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to differentiation, obesity, and aging. Assay for transposase-accessible chromatin sequencing (ATAC-seq), ChIP-seq, and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and C/EBPß recruitment to key enhancer regions. These findings expand our understanding of the relationship between inflammatory signaling pathways and adipose tissue function and provide insight into the physiological control of thermogenesis that could inform future therapy.

Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells.

The mechanisms underlying sterol transport in mammalian cells are poorly understood. In particular, how cholesterol internalized from HDL is made available to the cell for storage or modification is unknown. Here, we describe three ER-resident proteins (Aster-A, -B, -C) that bind cholesterol and facilitate its removal from the plasma membrane. The crystal structure of the central domain of Aster-A broadly resembles the sterol-binding fold of mammalian StARD proteins, but sequence differences in the Aster pocket result in a distinct mode of ligand binding. The Aster N-terminal GRAM domain binds phosphatidylserine and mediates Aster recruitment to plasma membrane-ER contact sites in response to cholesterol accumulation in the plasma membrane. Mice lacking Aster-B are deficient in adrenal cholesterol ester storage and steroidogenesis because of an inability to transport cholesterol from SR-BI to the ER. These findings identify a nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals.

Natural variation in LONELY GUY-Like 1 regulates rice grain weight under warmer night conditions.

Global nighttime temperatures are rising at twice the rate of daytime temperatures and pose a challenge for rice (Oryza sativa) production. High nighttime temperature (HNT) stress affects rice yield by reducing grain weight, size, and fertility. Although the genes associated with these yield parameters have been identified and characterized under normal temperatures, the genetic basis of grain weight regulation under HNT stress remains less explored. We examined the natural variation for rice single grain weight (SGW) under HNT stress imposed during grain development. A genome-wide association analysis identified several loci associated with grain weight under HNT stress. A locus, single grain weight 1 (SGW1), specific to HNT conditions resolved to LONELY GUY-Like 1 (LOGL1), which encodes a putative cytokinin activation enzyme. We demonstrated that LOGL1 contributes to allelic variation at SGW1. Accessions with lower LOGL1 transcript abundance had higher grain weight under HNT. This was supported by higher grain weight of logl1 mutants relative to the wild type under HNT. Compared to logl1 mutants, LOGL1 over-expressers showed increased sensitivity to HNT. We showed that LOGL1 regulates the thiamine biosynthesis pathway, which is under circadian regulation, which in turn is likely perturbed by HNT stress. These findings provide a genetic source to enhance rice adaptation to warming night temperatures and improve our mechanistic understanding of HNT stress tolerance pathways.

Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia (BPH): AUA Guideline Amendment 2023.

PURPOSE: The purpose of this American Urological Association (AUA) Guideline amendment is to provide a useful reference on the effective evidence-based management of male lower urinary tract symptoms secondary/attributed to BPH (LUTS/BPH). MATERIALS AND METHODS: The Minnesota Evidence Review Team searched Ovid MEDLINE, the Cochrane Library, and the Agency for Healthcare Research and Quality (AHRQ) database to identify studies relevant to the management of BPH. The guideline was updated in 2023 to capture eligible literature published between September 2020 and October 2022. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: The BPH amendment resulted in changes to statements/supporting text on combination therapy, photoselective vaporization of the prostate (PVP), water vapor thermal therapy (WVTT), laser enucleation, and prostate artery embolization (PAE). A new statement on temporary implanted prostatic devices (TIPD) was added. In addition, statements on transurethral needle ablation (TUNA) and transurethral microwave thermotherapy (TUMT) were removed and information regarding these legacy technologies was added to the background section. References and the accompanying treatment algorithms were updated to align with the updated text. CONCLUSION: This guideline seeks to improve clinicians' ability to evaluate and treat patients with BPH/LUTS based on currently available evidence. Future studies will be essential to further support these statements to improve patient care.

Conformity of ChatGPT recommendations with the AUA/SUFU guideline on postprostatectomy urinary incontinence.

INTRODUCTION: Artificial intelligence (AI) shows immense potential in medicine and Chat generative pretrained transformer (ChatGPT) has been used for different purposes in the field. However, it may not match the complexity and nuance of certain medical scenarios. This study evaluates the accuracy of ChatGPT 3.5 and 4 in providing recommendations regarding the management of postprostatectomy urinary incontinence (PPUI), considering The Incontinence After Prostate Treatment: AUA/SUFU Guideline as the best practice benchmark. MATERIALS AND METHODS: A set of questions based on the AUA/SUFU Guideline was prepared. Queries included 10 conceptual questions and 10 case-based questions. All questions were open and entered into the ChatGPT with a recommendation to limit the answer to 200 words, for greater objectivity. Responses were graded as correct (1 point); partially correct (0.5 point), or incorrect (0 point). Performances of versions 3.5 and 4 of ChatGPT were analyzed overall and separately for the conceptual and the case-based questions. RESULTS: ChatGPT 3.5 scored 11.5 out of 20 points (57.5% accuracy), while ChatGPT 4 scored 18 (90.0%; p = 0.031). In the conceptual questions, ChatGPT 3.5 provided accurate answers to six questions along with one partially correct response and three incorrect answers, with a final score of 6.5. In contrast, ChatGPT 4 provided correct answers to eight questions and partially correct answers to two questions, scoring 9.0. In the case-based questions, ChatGPT 3.5 scored 5.0, while ChatGPT 4 scored 9.0. The domains where ChatGPT performed worst were evaluation, treatment options, surgical complications, and special situations. CONCLUSION: ChatGPT 4 demonstrated superior performance compared to ChatGPT 3.5 in providing recommendations for the management of PPUI, using the AUA/SUFU Guideline as a benchmark. Continuous monitoring is essential for evaluating the development and precision of AI-generated medical information.

Have urinary function outcomes after radical prostatectomy improved over the past decade?

BACKGROUND: Changes in surgical technique and postoperative care that target improvements in functional outcomes are widespread in the literature. Radical prostatectomy (RP) is one such procedure that has seen multiple advances over the past decade. The objective of this study was to leverage RP as an index case to determine whether practice changes over time produced observable improvements in patient-reported outcomes. METHODS: This study analyzed patients undergoing RP by experienced surgeons at a tertiary care center with prospectively maintained patient-reported outcome data from 2008 to 2019. Four patient-reported urinary function outcomes at 6 and 12 months after RP were defined with a validated instrument: good urinary function (domain score ≥ 17), no incontinence (0 pads per day), social continence (≤1 pad per day), and severe incontinence (≥3 pads per day). Multivariable logistic regressions evaluated changes in outcomes based on the surgical date. RESULTS: Among 3945 patients meeting the inclusion criteria, excellent urinary outcomes were reported throughout the decade but without consistent observable improvements over time. Specifically, there were no improvements in good urinary function at 12 months (P = .087) based on the surgical date, and there were countervailing effects on no incontinence (worsening; P = .005) versus severe incontinence (improving; P = .003). Neither approach (open, laparoscopic, or robotic), nor nerve sparing, nor membranous urethral length mediated changes in outcomes. CONCLUSIONS: In a decade with multiple advances in surgical and postoperative care, there was evidence of improvements in severe incontinence, but no measurable improvements across 3 other urinary outcomes. Although worsening disease factors could contribute to the stable observed outcomes, a more systematic approach to evaluating techniques and implementing patient selection and postoperative care advances is needed. LAY SUMMARY: Although there have been advances in radical prostatectomy over the past decade, consistent observable improvements in postoperative incontinence were not reported by patients. To improve urinary function outcomes beyond the current high standard, the approach to studying innovations in surgical technique needs to be changed, and further development of other aspects of prostatectomy care is needed.

De Novo Urinary Storage Symptoms Are Common after Radical Prostatectomy: Incidence, Natural History and Predictors.

PURPOSE: After radical prostatectomy (RP), clinical complaints of new onset storage symptoms may be related to anastomotic strictures or may accommodate for stress urinary incontinence; however, a subgroup of men will experience de novo storage symptoms in the absence of stricture or stress urinary incontinence. As therapies for overactive bladder have improved, we sought to assess the prevalence, natural history and risk factors of de novo storage dysfunction in continent men. MATERIALS AND METHODS: We retrospectively analyzed urinary symptom questionnaires completed by patients who were continent prior to RP and did not have postoperative anastomotic strictures at our institution from 2002 to 2019. De novo storage dysfunction, assessed as new onset or worsening urgency or frequency, was assessed at 6, 12, 18 and 24 months after RP, and association between it and patient and preoperative factors was determined. RESULTS: A total of 2,619 patients were included in the final analysis. An initial 34% of patients reported de novo storage symptoms at 6 months, which decreased to 26% at later followup. We found evidence that minimally invasive surgery and nonWhite race were associated with reporting worsening symptoms. The association between postoperative hematoma and worsening symptoms was less conclusive but was of clear clinical relevance (OR 3.15; 95% CI 1.04, 9.54; p=0.042). CONCLUSIONS: A significant number of RP patients experience de novo storage symptoms. Patients who underwent minimally invasive surgery are at higher risk. At-risk patients should be counseled on the incidence of de novo storage symptoms and offered early treatment per overactive bladder guidelines.

A modern-day experience with Brunschwig's operation: Outcomes associated with pelvic exenteration.

OBJECTIVE: To evaluate postoperative and oncologic outcomes associated with pelvic exenteration for non-ovarian gynecologic malignancies. METHODS: This was a retrospective review of patients who underwent pelvic exenteration for non-ovarian gynecologic malignancies at our institution from 1/1/2010-12/31/2019. Palliative exenteration cases were excluded from survival analysis. Postoperative complications were early (≤30 days) or late (31-180 days). Complications were graded using a validated institutional scale. Major complications were considered grade ≥ 3. Categorical variables were compared using the chi-square test, and the Kaplan-Meier method was used for survival analysis. RESULTS: Of 100 patients identified, 89 underwent pelvic exenteration for recurrent disease, 5 for palliation, 5 for primary disease, and 1 for persistent disease. Thirty percent had cervical, 27% vulvar, 24% uterine, and 19% vaginal cancer. Sixty-two percent underwent total, 30% anterior, and 8% posterior exenteration. No deaths occurred intraoperatively or within 30 days of surgery. Six patients died after 30 days. Ninety-seven experienced a perioperative complication-49 early, 1 late, and 47 both. Fifty experienced a major complication-22 (44%) early, 19 (38%) late, and 9 (18%) both. No variables were statistically associated with complication development. The 3-year progression-free survival rate was 61.0%; the 3-year overall survival rate was 61.6%. Of 58 surviving patients, 16 (28%) and 4 (7%) were alive after 5 and 10 years, respectively. CONCLUSION: The overall complication rate for pelvic exenteration remains high. No variables demonstrated association with complication development as the rate was nearly 100%. The low rate of perioperative mortality is likely due to improved perioperative care.

Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis.

Liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. Under conditions of excess cholesterol, LXR activation induces the expression of several genes involved in cholesterol efflux, facilitates cholesterol esterification by promoting fatty acid synthesis, and inhibits cholesterol uptake by the low-density lipoprotein receptor. The fact that sterol content is maintained in a narrow range in most cell types and in the organism as a whole suggests that extensive crosstalk between regulatory pathways must exist. However, the molecular mechanisms that integrate LXRs with other lipid metabolic pathways are incompletely understood. Here we show that ligand activation of LXRs in mouse liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as a mediator of this effect. Hepatic LeXis expression is robustly induced in response to a Western diet (high in fat and cholesterol) or to pharmacological LXR activation. Raising or lowering LeXis levels in the liver affects the expression of genes involved in cholesterol biosynthesis and alters the cholesterol levels in the liver and plasma. LeXis interacts with and affects the DNA interactions of RALY, a heterogeneous ribonucleoprotein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the mouse liver. These findings outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis.

Intraoperative Ureteral Stent Use at Radical Cystectomy is Associated with Higher 30-Day Complication Rates.

PURPOSE: Radical cystectomy/urinary diversion is a high risk procedure. Intraoperative stents are commonly utilized to decrease ureteroenteric anastomosis related complications. Institutionally some surgeons routinely use intraoperative stents while others do not, providing an opportunity to compare complication differences. MATERIALS AND METHODS: We queried a prospective database of 283 patients enrolled in a randomized controlled trial evaluating 30-day perioperative complications with goal directed fluid therapy following open radical cystectomy/urinary diversion between 2014 and 2018. Ureteroenteric anastomosis specific complications (ureteral obstruction, urinary leak, urinary infections/sepsis and intra-abdominal abscess) were compared between groups (intraoperative stent vs nonintraoperative stent group) using Fisher exact test and quantified using logistic regression. RESULTS: The nonintraoperative stent group (77 of 283 patients, 27%) was older (median 72 vs 69 years) and was more likely to receive neoadjuvant chemotherapy (53% vs 40%), have baseline renal insufficiency (43% vs 30%) and undergo an ileal conduit (92% vs 53%). However, despite higher comorbidity, the nonintraoperative stent group had a significantly lower rate of ureteroenteric anastomosis complications (14% vs 32%, p=0.004). Since continent diversions may be associated with higher complications, the nonintraoperative stent group with ileal conduit was also compared to intraoperative stent cohorts with ileal conduit, and ureteroenteric anastomosis complications remained lower in the nonintraoperative stent group (14% vs 28%, p=0.043). Multivariable logistic regression showed significantly increased odds of urinary complications with intraoperative stent use (OR 3.55, 95% CI 2.93-4.31; p <0.0001). Importantly there was no obstruction and only 1 leak (1.3%) in the nonintraoperative stent group. CONCLUSIONS: Contrary to conventional belief, we found intraoperative stent use in radical cystectomy/urinary diversion was associated with significantly higher infectious complications and urgent care visits, and significantly increased the odds of 30-day ureteroenteric anastomosis associated complications.

Allelic variation in rice Fertilization Independent Endosperm 1 contributes to grain width under high night temperature stress.

A higher minimum (night-time) temperature is considered a greater limiting factor for reduced rice yield than a similar increase in maximum (daytime) temperature. While the physiological impact of high night temperature (HNT) has been studied, the genetic and molecular basis of HNT stress response remains unexplored. We examined the phenotypic variation for mature grain size (length and width) in a diverse set of rice accessions under HNT stress. Genome-wide association analysis identified several HNT-specific loci regulating grain size as well as loci that are common for optimal and HNT stress conditions. A novel locus contributing to grain width under HNT conditions colocalized with Fie1, a component of the FIS-PRC2 complex. Our results suggest that the allelic difference controlling grain width under HNT is a result of differential transcript-level response of Fie1 in grains developing under HNT stress. We present evidence to support the role of Fie1 in grain size regulation by testing overexpression (OE) and knockout mutants under heat stress. The OE mutants were either unaltered or had a positive impact on mature grain size under HNT, while the knockouts exhibited significant grain size reduction under these conditions.

MADS78 and MADS79 Are Essential Regulators of Early Seed Development in Rice.

MADS box transcription factors (TFs) are subdivided into type I and II based on phylogenetic analysis. The type II TFs regulate floral organ identity and flowering time, but type I TFs are relatively less characterized. Here, we report the functional characterization of two type I MADS box TFs in rice (Oryza sativa), MADS78 and MADS79 Transcript abundance of both these genes in developing seed peaked at 48 h after fertilization and was suppressed by 96 h after fertilization, corresponding to syncytial and cellularized stages of endosperm development, respectively. Seeds overexpressing MADS78 and MADS 79 exhibited delayed endosperm cellularization, while CRISPR-Cas9-mediated single knockout mutants showed precocious endosperm cellularization. MADS78 and MADS 79 were indispensable for seed development, as a double knockout mutant failed to make viable seeds. Both MADS78 and 79 interacted with MADS89, another type I MADS box, which enhances nuclear localization. The expression analysis of Fie1, a rice FERTILIZATION-INDEPENDENT SEED-POLYCOMB REPRESSOR COMPLEX2 component, in MADS78 and 79 mutants and vice versa established an antithetical relation, suggesting that Fie1 could be involved in negative regulation of MADS78 and MADS 79 Misregulation of MADS78 and MADS 79 perturbed auxin homeostasis and carbon metabolism, as evident by misregulation of genes involved in auxin transport and signaling as well as starch biosynthesis genes causing structural abnormalities in starch granules at maturity. Collectively, we show that MADS78 and MADS 79 are essential regulators of early seed developmental transition and impact both seed size and quality in rice.

Endoplasmic reticulum stress pathway mediates the early heat stress response of developing rice seeds.

A transient heat stress occurring during early seed development in rice (Oryza sativa) reduces seed size by altering endosperm development. However, the relationship between the timing of the stress and specific developmental stage on heat sensitivity is not well-understood. To address this, we imposed a series of non-overlapping heat stress treatments and found that young seeds are most sensitive during the first two days after flowering. Temporal transcriptome analysis of developing, heat stressed (35°C) seeds during this window shows that Inositol-requiring enzyme 1 (IRE1)-mediated endoplasmic reticulum (ER) stress response and jasmonic acid (JA) pathways are the early (1-3 h) drivers of heat stress response. We propose that increased JA levels under heat stress may precede ER stress response as JA application promotes the spliced form of OsbZIP50, an ER response marker gene linked to IRE1-specific pathway. This study presents temporal and mechanistic insights into the role of JA and ER stress signalling during early heat stress response of rice seeds that impact both grain size and quality. Modulating the heat sensitivity of the early sensing pathways and downstream endosperm development genes can enhance rice resilience to transient heat stress events.

High night temperature effects on wheat and rice: Current status and way forward.

Rapid increases in minimum night temperature than in maximum day temperature is predicted to continue, posing significant challenges to crop productivity. Rice and wheat are two major staples that are sensitive to high night-temperature (HNT) stress. This review aims to (i) systematically compare the grain yield responses of rice and wheat exposed to HNT stress across scales, and (ii) understand the physiological and biochemical responses that affect grain yield and quality. To achieve this, we combined a synthesis of current literature on HNT effects on rice and wheat with information from a series of independent experiments we conducted across scales, using a common set of genetic materials to avoid confounding our findings with differences in genetic background. In addition, we explored HNT-induced alterations in physiological mechanisms including carbon balance, source-sink metabolite changes and reactive oxygen species. Impacts of HNT on grain developmental dynamics focused on grain-filling duration, post-flowering senescence, changes in grain starch and protein composition, starch metabolism enzymes and chalk formation in rice grains are summarized. Finally, we highlight the need for high-throughput field-based phenotyping facilities for improved assessment of large-diversity panels and mapping populations to aid breeding for increased resilience to HNT in crops.

Pelvic exenteration for recurrent or persistent gynecologic malignancies: Clinical and histopathologic factors predicting recurrence and survival in a modern cohort.

OBJECTIVES: To explore pre-operative factors and their impact on overall survival (OS) in a modern cohort of patients who underwent pelvic exenteration (PE) for gynecologic malignancies. METHODS: A retrospective review was performed for all patients who underwent a PE from 1/1/2010 through 12/31/2018 at our institution. Inclusion criteria were exenteration due to recurrent or progressive carcinoma of the uterus, cervix, vagina or vulva, with histologically confirmed complete surgical resection of the malignancy. Exclusion criteria included PE for palliation of symptoms without recurrence, and for ovarian or rare histologic malignancies. Univariable and multivariable analysis were performed to identify factors predicting prolonged survival. RESULTS: Overall, 71 patients met the inclusion criteria. Median age at time of exenteration was 62 years (range, 28-86 years). Vulvar cancer was the most common primary diagnosis (32%); 30% had cervical cancer; 23%, uterine cancer; 15%, vaginal cancer. Median OS was 55.1 months (95% confidence interval (CI): 36-not estimable) with a median follow-up time of 40.8 months (95% CI: 1-116.1). On univariable analysis, age > 62 years (hazard ratio (HR) 2.71, 95% CI 1.27-5.79), American Society of Anesthesia (ASA) 3-4 (HR: 3.41 (95% CI 1.03-11.29), and vulvar cancer (HR 4.19 (95% CI 1.17-14.96) predicted worse OS. Tumor size and prior progression-free interval (PFI) did not meet statistical significance in OS analyses. On multivariable analysis, there were no significant factors associated with worse OS. CONCLUSIONS: PE performed with curative intent may be considered a treatment option in well-counseled, carefully selected patients, irrespective of tumor size and PFI before exenteration.

The Anatomical Relationships in the Space of Retzius for Penile Implants: An MRI Analysis.

BACKGROUND: The 3-piece inflatable penile prosthesis includes an easy-to-use pump and fluid filled reservoir which is placed in either the space of Retzius (SOR) or in an alternative ectopic location. Reservoir placement in the SOR is a blind procedure despite the SOR being surrounded by many critical structures. To date only a handful of cadaveric studies have described the relevant anatomy. AIM: To use magnetic resonance imaging (MRI) as an in-vivo model to study relevant retropubic anatomy critical for SOR reservoir placement. METHODS: The study population included men with elevated prostate specific antigen or biopsy proven prostate cancer who (i) underwent pelvic MRI, (ii) without prior pelvic or inguinal surgery, and (iii) without pelvic radiation therapy. All MRIs were completed with a 3-Tesla scanner and endorectal coil. Both T1 and T2 weighted images were captured in both axial and sagittal planes. All images were reviewed by 2 independent reviewers under the supervision of a dedicated body MRI radiologist. Bladder volume was calculated using an ellipsoid formula. OUTCOMES: Relevant measurements included (i) the distance between the external inguinal ring (EIR) at the level of the pubic tubercle to the external iliac vein (EIV), (ii) the distance from the EIR at the pubic tubercle to the bladder (accounting for bladder volume) and (iii) the distance from the midline pubic symphysis to the bladder (accounting for bladder volume). Pearson correlation was used to determine correlated measurements. RESULTS: A total of 24 patients were included. Median participant age was 63 years (interquartile range, 59-66). The mean EIR-EIV distance was 3.0 ± 0.4 cm, the mean EIR-bladder distance was 1.8 ± 1.0 cm and the mean distance from the superior pubic symphysis to bladder was 0.9 ± 0.3 cm. There was a weak correlation between bladder volume and distance between the EIR and bladder (r = -0.30, P = .16). CLINICAL IMPLICATIONS: The use of MRI as an in-vivo model is a high-fidelity tool to study real time unaltered anatomy and allows for surgical preparation, diagnosis of anatomic variants and acts as a valuable teaching tool. STRENGTHS & LIMITATIONS: This is the first in-vivo model to report relevant retropubic anatomy in penile implant surgery. Our study is limited by sample size and inclusion of participants with no history of prior pelvic intervention. CONCLUSION: We demonstrate the utility of MRI as an in-vivo model, as opposed to cadaveric models, for the understanding of relevant retropubic anatomy for implant surgeons. Punjani N, Monteiro L, Sullivan J F et al. The Anatomical Relationships in the Space of Retzius for Penile Implants: An MRI Analysis. J Sex Med 2021;18:1830-1834.

Macrophages release plasma membrane-derived particles rich in accessible cholesterol.

Macrophages are generally assumed to unload surplus cholesterol through direct interactions between ABC transporters on the plasma membrane and HDLs, but they have also been reported to release cholesterol-containing particles. How macrophage-derived particles are formed and released has not been clear. To understand the genesis of macrophage-derived particles, we imaged mouse macrophages by EM and nanoscale secondary ion mass spectrometry (nanoSIMS). By scanning EM, we found that large numbers of 20- to 120-nm particles are released from the fingerlike projections (filopodia) of macrophages. These particles attach to the substrate, forming a "lawn" of particles surrounding macrophages. By nanoSIMS imaging we showed that these particles are enriched in the mobile and metabolically active accessible pool of cholesterol (detectable by ALO-D4, a modified version of a cholesterol-binding cytolysin). The cholesterol content of macrophage-derived particles was increased by loading the cells with cholesterol or by adding LXR and RXR agonists to the cell-culture medium. Incubating macrophages with HDL reduced the cholesterol content of macrophage-derived particles. We propose that release of accessible cholesterol-rich particles from the macrophage plasma membrane could assist in disposing of surplus cholesterol and increase the efficiency of cholesterol movement to HDL.

Management of voiding dysfunction associated with pelvic malignancies.

Voiding dysfunction is common after surgical and radiation treatments in patients diagnosed with non-urological pelvic malignancies. Presentation might vary with lower urinary tract symptoms and/or overactive bladder, urinary retention, or incontinence. We reviewed the most recent literature with the aim of describing various types of urinary dysfunction that manifest after radical treatments for non-urological pelvic malignancies. Radical surgical or radiation treatment adversely affect other adjacent pelvic organ function, including viscera, pelvic musculature and the peripheral nervous system. This results in direct organ and indirect functional damage to the genitourinary tract. Multiple surgical and radiation modifications are available nowadays, allowing urologists to offer various treatments for better functional lower urinary tract outcomes. Diagnosing and understanding the type and severity of voiding dysfunction plays a key role in tailoring an appropriate treatment plan. The objective to better functional results relies on maintaining adequate bladder compliance and capacity while permitting volitional emptying, ideally through voiding. Management should routinely start with conservative measures, including pelvic floor muscle training with or without a combination of oral medication for urgency incontinence and clean intermittent catheterization for the management of urinary retention. Concomitant or isolated urinary incontinence can be further managed through multiple established surgical approaches. We attempted to address various treatment available for known lower urinary tract symptoms that might have been caused secondary to non-urological pelvic surgery or radiation. We discuss different diagnostic and treatment modalities individualized for patients with various entities, to help achieve optimal urinary function and improve quality of life.

The LATERAL ROOT DENSITY gene regulates root growth during water stress in wheat.

Drought stress is the major limiting factor in agriculture. Wheat, which is the most widely grown crop in the world, is predominantly cultivated in drought-prone rainfed environments. Since roots play a critical role in water uptake, root response to water limitations is an important component for enhancing wheat adaptation. In an effort to discover novel genetic sources for improving wheat adaptation, we characterized a wheat translocation line with a chromosomal segment from Agropyron elongatum, a wild relative of wheat, which unlike common wheat maintains root growth under limited-water conditions. By exploring the root transcriptome data, we found that reduced transcript level of LATERAL ROOT DENSITY (LRD) gene under limited water in the Agropyron translocation line confers it the ability to maintain root growth. The Agropyron allele of LRD is down-regulated in response to water limitation in contrast with the wheat LRD allele, which is up-regulated by water deficit stress. Suppression of LRD expression in wheat RNAi plants confers the ability to maintain root growth under water limitation. We show that exogenous gibberellic acid (GA) promotes lateral root growth and present evidence for the role of GA in mediating the differential regulation of LRD between the common wheat and the Agropyron alleles under water stress. Suppression of LRD also had a positive pleiotropic effect on grain size and number under optimal growth conditions. Collectively, our findings suggest that LRD can be potentially useful for improving wheat response to water stress and altering yield components.

Trajectories of physical activity, from young adulthood to older adulthood, and pancreatic cancer risk; a population-based case-control study in Ontario, Canada.

BACKGROUND: There is inconsistent evidence on the association between physical activity and pancreatic cancer risk and few studies have investigated early life or life-course physical activity. The objective of this study was to evaluate the association between trajectories of physical activity across the life-course and pancreatic cancer risk. METHODS: A population-based case-control study was conducted (2011-2013) using cases (n = 315) from the Ontario Pancreas Cancer Study and controls (n = 1254) from the Ontario Cancer Risk Factor Study. Self-reported recall of moderate and vigorous physical activity was measured at three time points: young adulthood (20s-30s), mid-adulthood (40s-50s) and older-adulthood (1 year prior to questionnaire completion). Physical activity trajectories were identified using latent class analysis. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression adjusted for covariates: age, sex, race, alcohol, smoking, vegetable, fruit and meat consumption, and family history of pancreatic cancer. RESULTS: Six life-course physical activity trajectories were identified: inactive at all ages (41.2%), low activity at all ages (31.9%), increasingly active (3.6%), high activity in young adulthood with substantial decrease (13.0%), high activity in young adulthood with slight decrease (5.0%), and persistent high activity (5.3%). Compared to the inactive at all ages trajectory, the associations between each trajectory and pancreatic cancer after confounder adjustment were: low activity at all ages (OR: 1.11; 95% CI: 0.75, 1.66), increasingly active (OR: 1.11; 95% CI: 0.56, 2.21), high activity in young adulthood with substantial decrease in older adulthood (OR: 0.76; 95% CI: 0.47, 1.23), high activity in young adulthood with slight decrease in older adulthood (OR: 0.98; 95% CI: 0.62, 1.53), and persistently high activity (OR: 1.50; 95% CI: 0.86, 2.62). When time periods were evaluated separately, the OR for the association between high moderate activity in the 20s-30s and pancreatic cancer was 0.89 (95% CI: 0.64, 1.25) and some sex differences were observed. CONCLUSION: Distinct life-course physical activity trajectories were identified, but there was no evidence that any of the trajectories were associated with pancreatic cancer. Future studies with larger sample sizes are needed to understand the associations between physical activity trajectories over the life-course and pancreatic cancer risk.