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.

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.

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.

Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake.

Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.

Aster-dependent non-vesicular transport facilitates dietary cholesterol uptake.

Intestinal cholesterol absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe (EZ), assists in the initial step of dietary cholesterol uptake. However, how cholesterol moves downstream of NPC1L1 is unknown. Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes, bridging NPC1L1 at the plasma membrane (PM) and ACAT2 in the endoplasmic reticulum (ER). Loss of NPC1L1 diminishes accessible PM cholesterol in enterocytes and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate cholesterol at the PM and display evidence of ER cholesterol depletion, including decreased cholesterol ester stores and activation of the SREBP-2 transcriptional pathway. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, we show that the Aster pathway can be targeted with a small molecule inhibitor to manipulate dietary cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption. One-Sentence Summary: Identification of a targetable pathway for regulation of dietary cholesterol absorption.

The Association Between Low Preoperative Serum Testosterone and Post-radical Prostatectomy Urinary Function.

OBJECTIVE: To determine if hypogonadism leads to delayed urinary function recovery post-radical prostatectomy (RP) by studying the effect of preoperative factors including age, membranous urethral length, radiation therapy, and Body Mass Index on urinary continence in patients with or without hypogonadism. MATERIALS AND METHODS: We identified 1209 patients treated by RP with both pretreatment T and post-treatment urinary outcome. We assessed whether there was an association between low preoperative T level (prenoon T ≤ 300 ng/dL) and continence (using ≤1 pad/d) at 6 and 12months post-RP. Patient-reported continence was used when available, otherwise, surgeon-assessed continence was used. Logistic regression models were used, adjusted for age at RP and nerve-sparing status. RESULTS: Median age at RP was 61 (Intraquatile Range (IQR) 56, 66), 92% of patients had at least one nerve spared and 99% were continent at baseline. Continence in patients with low T was nonsignificantly lower at 6months (odds ratio 0.69, 95% confidence interval 0.44, 1.06; P = .10) and nonsignificantly higher at 12months (odds ratio 1.07, 95% confidence interval 0.71, 1.58; P = .8). Sensitivity analyses excluding patients with preoperative metastasis or treated with androgen deprivation therapy (ADT) and including testosterone as a continuous predictor were consistent with the primary analysis; similarly finding no evidence of an association. CONCLUSION: Although we cannot rule out an effect on early continence, overall the evidence does not suggest that low serum testosterone adversely impacts urinary function recovery after RP. This finding can be used to counsel patients enrolled in neoadjuvant ADT trials or those patients undergoing RP who have had prior ADT, such as in the setting of oligometastatic disease.

Assessment of Patients With Prostate Cancer and Their Understanding of the International Prostate Symptom Score Questionnaire.

Purpose: The International Prostate Symptom Score (IPSS) is a widely used tool for evaluating patient-reported lower urinary tract symptoms. In this study, we assessed patients with prostate cancer and their understanding of IPSS questions. Methods and Materials: Consecutive patients with prostate cancer (N = 144) self-completed an online IPSS questionnaire within 1 week before their visit at our radiation oncology clinic. At the visit, a nurse reviewed each IPSS question to ensure the patient understood it and then verified the patient's answer. Preverified and nurse-verified scores were recorded and analyzed for discrepancies. Results: Complete concordance between preverified and nurse-verified responses to individual IPSS questions existed for 70 men (49%). In terms of overall IPSS score, 61 men (42%) had a lower or improved IPSS after nurse verification, and 9 men (6%) had a higher or worse IPSS. Before verification, patients overstated their symptoms of frequency, intermittency, and incomplete emptying. As a result of the nurse verification, 4 of 7 patients with IPSS in the severe range (20-35) were recategorized to the moderate range (8-19). Sixteen percent of patients whose preverified IPSS were in the moderate range were recategorized after nurse verification to the mild range (0-7). Treatment option eligibility changed for 10% of patients after nurse verification. Conclusions: Patients frequently misunderstand the IPSS questionnaire, leading them to respond in ways that do not accurately reflect their symptoms. Clinicians should verify patient understanding of the IPSS questions, particularly when using the score to determine eligibility for treatments.

Evaluating metabolic and genomic data for predicting grain traits under high night temperature stress in rice.

The asymmetric increase in average nighttime temperatures relative to increase in average daytime temperatures due to climate change is decreasing grain yield and quality in rice. Therefore, a better genome-level understanding of the impact of higher night temperature stress on the weight of individual grains is essential for future development of more resilient rice. We investigated the utility of metabolites obtained from grains to classify high night temperature (HNT) conditions of genotypes, and metabolites and single-nucleotide polymorphisms (SNPs) to predict grain length, width, and perimeter phenotypes using a rice diversity panel. We found that the metabolic profiles of rice genotypes alone could be used to classify control and HNT conditions with high accuracy using random forest or extreme gradient boosting. Best linear unbiased prediction and BayesC showed greater metabolic prediction performance than machine learning models for grain-size phenotypes. Metabolic prediction was most effective for grain width, resulting in the highest prediction performance. Genomic prediction performed better than metabolic prediction. Integrating metabolites and genomics simultaneously in a prediction model slightly improved prediction performance. We did not observe a difference in prediction between the control and HNT conditions. Several metabolites were identified as auxiliary phenotypes that could be used to enhance the multi-trait genomic prediction of grain-size phenotypes. Our results showed that, in addition to SNPs, metabolites collected from grains offer rich information to perform predictive analyses, including classification modeling of HNT responses and regression modeling of grain-size-related phenotypes in rice.

Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis.

In cell models, changes in the 'accessible' pool of plasma membrane (PM) cholesterol are linked with the regulation of endoplasmic reticulum sterol synthesis and metabolism by the Aster family of nonvesicular transporters; however, the relevance of such nonvesicular transport mechanisms for lipid homeostasis in vivo has not been defined. Here we reveal two physiological contexts that generate accessible PM cholesterol and engage the Aster pathway in the liver: fasting and reverse cholesterol transport. During fasting, adipose-tissue-derived fatty acids activate hepatocyte sphingomyelinase to liberate sequestered PM cholesterol. Aster-dependent cholesterol transport during fasting facilitates cholesteryl ester formation, cholesterol movement into bile and very low-density lipoprotein production. During reverse cholesterol transport, high-density lipoprotein delivers excess cholesterol to the hepatocyte PM through scavenger receptor class B member 1. Loss of hepatic Asters impairs cholesterol movement into feces, raises plasma cholesterol levels and causes cholesterol accumulation in peripheral tissues. These results reveal fundamental mechanisms by which Aster cholesterol flux contributes to hepatic and systemic lipid homeostasis.

Towards a Discovery of a Zinc-Dependent Phosphate Transport Road in Plants.

Owing to the impending global scarcity of high-quality sources of phosphate (Pi) fertilizers, lowering its use in crop production requires improved insights into factors stimulating Pi uptake from the soil as well as the efficacious use by plants. Following decades of extensive research on plants' adaptation to Pi deficiency with mitigated success in the field, a better understanding of how plants exposed to zinc (Zn) deficiency accumulate much more Pi provides a novel strategy in comparison to when plants are grown in Zn-rich soils. In this context, we review current knowledge and molecular events involved in the Pi and Zn signaling crosstalk in plants that will bear great significance for agronomical and rudimentary research applications.

Rice Chalky Grain 5 regulates natural variation for grain quality under heat stress.

Heat stress occurring during rice (Oryza sativa) grain development reduces grain quality, which often manifests as increased grain chalkiness. Although the impact of heat stress on grain yield is well-studied, the genetic basis of rice grain quality under heat stress is less explored as quantifying grain quality is less tractable than grain yield. To address this, we used an image-based colorimetric assay (Red, R; and Green, G) for genome-wide association analysis to identify genetic loci underlying the phenotypic variation in rice grains exposed to heat stress. We found the R to G pixel ratio (RG) derived from mature grain images to be effective in distinguishing chalky grains from translucent grains derived from control (28/24°C) and heat stressed (36/32°C) plants. Our analysis yielded a novel gene, rice Chalky Grain 5 (OsCG5) that regulates natural variation for grain chalkiness under heat stress. OsCG5 encodes a grain-specific, expressed protein of unknown function. Accessions with lower transcript abundance of OsCG5 exhibit higher chalkiness, which correlates with higher RG values under stress. These findings are supported by increased chalkiness of OsCG5 knock-out (KO) mutants relative to wildtype (WT) under heat stress. Grains from plants overexpressing OsCG5 are less chalky than KOs but comparable to WT under heat stress. Compared to WT and OE, KO mutants exhibit greater heat sensitivity for grain size and weight relative to controls. Collectively, these results show that the natural variation at OsCG5 may contribute towards rice grain quality under heat stress.

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.

Plant growth stimulation by high CO2 depends on phosphorus homeostasis in chloroplasts.

Elevated atmospheric CO2 enhances photosynthetic rate,1 thereby increasing biomass production in plants. Nevertheless, high CO2 reduces the accumulation of essential nutrients2 such as phosphorus (P),3 which are required for photosynthetic processes and plant growth. How plants ensure enhanced growth despite meager P status remains enigmatic. In this study, we utilize genome-wide association analysis in Arabidopsis thaliana to identify a P transporter, PHT4;3, which mediates the reduction of P in chloroplasts at high CO2. Decreasing chloroplastic P fine-tunes the accumulation of a sugar-P metabolite, phytic acid, to support plant growth. Furthermore, we demonstrate that this adaptive mechanism is conserved in rice. Our results establish a mechanistic framework for sustainable food production against the backdrop of soaring CO2 levels across the world.

Pervasive misannotation of microexons that are evolutionarily conserved and crucial for gene function in plants.

It is challenging to identify the smallest microexons (≤15-nt) due to their small size. Consequently, these microexons are often misannotated or missed entirely during genome annotation. Here, we develop a pipeline to accurately identify 2,398 small microexons in 10 diverse plant species using 990 RNA-seq datasets, and most of them have not been annotated in the reference genomes. Analysis reveals that microexons tend to have increased detained flanking introns that require post-transcriptional splicing after polyadenylation. Examination of 45 conserved microexon clusters demonstrates that microexons and associated gene structures can be traced back to the origin of land plants. Based on these clusters, we develop an algorithm to genome-wide model coding microexons in 132 plants and find that microexons provide a strong phylogenetic signal for plant organismal relationships. Microexon modeling reveals diverse evolutionary trajectories, involving microexon gain and loss and alternative splicing. Our work provides a comprehensive view of microexons in plants.

Health-related Quality of Life for Patients Undergoing Radical Cystectomy: Results of a Large Prospective Cohort.

BACKGROUND: Radical cystectomy (RC) has the potential for profound changes to health-related quality of life (HRQOL). OBJECTIVE: To evaluate a broad range of HRQOL outcomes in a large RC cohort. DESIGN, SETTING, AND PARTICIPANTS: A single-center prospective study enrolled RC patients from 2008 to 2014. We collected 14 separate patient-reported outcome measures at the presurgical visit and at 3, 6, 12, 18, and 24 mo after RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To visualize the patterns of recovery over time across domains, we used generalized estimating equations (GEEs) with nonlinear terms. Given substantial differences in patient selection for the type of urinary diversion, we separately modeled longitudinal HRQOL within conduit and continent diversion groups. The mean pre-RC scores were compared to illustrate the baseline HRQOL differences between diversion groups. RESULTS AND LIMITATIONS: The analyzed cohort included 411 patients (n = 205 ileal conduit, n = 206 continent diversion). At baseline, patients receiving continent diversion reported better mean physical (p < 0.001), urinary (p = 0.006), and sexual function (p < 0.001), but lower social function (p = 0.015). After RC, GEE modeling showed physical function scores decreasing 5/100 points by 6 mo, and subsequently stabilizing or returning to baseline. By 12 mo, social function improved by 10/100 points among continent diversions, while remaining stable among ileal conduits. Global quality of life exceeded baseline scores by 6 mo. Sexual function scores were low before RC, with limited recovery. Psychosocial domains were stable or improved, except for 10/100-point worsening of body image among ileal conduits. CONCLUSIONS: RC patients reported favorable HRQOL recovery within 24 mo in most areas other than body image (ileal conduits) and sexual function (both). Importantly, large measurable decreases in scores were not reported by 3 mo after RC. These contemporary outcomes and the excellent locoregional control provided by RC further support it as the gold standard therapy for high-risk bladder cancer. PATIENT SUMMARY: We review quality of life in the 24 mo following radical cystectomy. Large decreases in health-related quality of life were not reported, with most areas returning to, or exceeding, baseline, except for sexual function and body image.

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.

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.