A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver.

Thyroid hormones (THs) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone-dependent "switch" from corepressor to activator binding to thyroid hormone receptors (TRs), while the mechanism of TH-dependent repression is controversial. To address this, we generated a mouse line in which endogenous TRß1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of TR and defined high-confidence binding sites where TRs functioned at enhancers regulated in the same direction as the nearest gene in a TRß-dependent manner. Remarkably, although positive and negative regulation by THs have been ascribed to different mechanisms, TR binding was highly enriched at canonical DR4 motifs irrespective of the transcriptional direction of the enhancer. The canonical NCoR1/HDAC3 corepressor complex was reduced but not completely dismissed by TH and, surprisingly, similar effects were seen at enhancers associated with negatively as well as positively regulated genes. Conversely, coactivator CBP was found at all TH-regulated enhancers, with transcriptional activity correlating with the ratio of CBP to NCoR rather than their presence or absence. These results demonstrate that, in contrast to the canonical "all or none" coregulator switch model, THs regulate gene expression by orchestrating a shift in the relative binding of corepressors and coactivators.

Edoxaban Antithrombotic Therapy for Atrial Fibrillation and Stable Coronary Artery Disease.

BACKGROUND: Despite consistent recommendations from clinical guidelines, data from randomized trials on a long-term antithrombotic treatment strategy for patients with atrial fibrillation and stable coronary artery disease are still lacking. METHODS: We conducted a multicenter, open-label, adjudicator-masked, randomized trial comparing edoxaban monotherapy with dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) in patients with atrial fibrillation and stable coronary artery disease (defined as coronary artery disease previously treated with revascularization or managed medically). The risk of stroke was assessed on the basis of the CHA2DS2-VASc score (scores range from 0 to 9, with higher scores indicating a greater risk of stroke). The primary outcome was a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, and major bleeding or clinically relevant nonmajor bleeding at 12 months. Secondary outcomes included a composite of major ischemic events and the safety outcome of major bleeding or clinically relevant nonmajor bleeding. RESULTS: We assigned 524 patients to the edoxaban monotherapy group and 516 patients to the dual antithrombotic therapy group at 18 sites in South Korea. The mean age of the patients was 72.1 years, 22.9% were women, and the mean CHA2DS2-VASc score was 4.3. At 12 months, a primary-outcome event had occurred in 34 patients (Kaplan-Meier estimate, 6.8%) assigned to edoxaban monotherapy and in 79 patients (16.2%) assigned to dual antithrombotic therapy (hazard ratio, 0.44; 95% confidence interval [CI], 0.30 to 0.65; P<0.001). The cumulative incidence of major ischemic events at 12 months appeared to be similar in the trial groups. Major bleeding or clinically relevant nonmajor bleeding occurred in 23 patients (Kaplan-Meier estimate, 4.7%) in the edoxaban monotherapy group and in 70 patients (14.2%) in the dual antithrombotic therapy group (hazard ratio, 0.34; 95% CI, 0.22 to 0.53). CONCLUSIONS: In patients with atrial fibrillation and stable coronary artery disease, edoxaban monotherapy led to a lower risk of a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, or major bleeding or clinically relevant nonmajor bleeding at 12 months than dual antithrombotic therapy. (Funded by the CardioVascular Research Foundation and others; EPIC-CAD ClinicalTrials.gov number, NCT03718559.).

Perspectives on improving photosynthesis to increase crop yield.

Improving photosynthesis, the fundamental process by which plants convert light energy into chemical energy, is a key area of research with great potential for enhancing sustainable agricultural productivity and addressing global food security challenges. This perspective delves into the latest advancements and approaches aimed at optimizing photosynthetic efficiency. Our discussion encompasses the entire process, beginning with light harvesting and its regulation and progressing through the bottleneck of electron transfer. We then delve into the carbon reactions of photosynthesis, focusing on strategies targeting the enzymes of the Calvin-Benson-Bassham (CBB) cycle. Additionally, we explore methods to increase CO2 concentration near the Rubisco, the enzyme responsible for the first step of CBB cycle, drawing inspiration from various photosynthetic organisms, and conclude this section by examining ways to enhance CO2 delivery into leaves. Moving beyond individual processes, we discuss two approaches to identifying key targets for photosynthesis improvement: systems modeling and the study of natural variation. Finally, we revisit some of the strategies mentioned above to provide a holistic view of the improvements, analyzing their impact on nitrogen use efficiency and on canopy photosynthesis.

The TOR-EIN2 axis mediates nuclear signalling to modulate plant growth.

The evolutionarily conserved target of rapamycin (TOR) kinase acts as a master regulator that coordinates cell proliferation and growth by integrating nutrient, energy, hormone and stress signals in all eukaryotes1,2. Research has focused mainly on TOR-regulated translation, but how TOR orchestrates the global transcriptional network remains unclear. Here we identify ethylene-insensitive protein 2 (EIN2), a central integrator3-5 that shuttles between the cytoplasm and the nucleus, as a direct substrate of TOR in Arabidopsis thaliana. Glucose-activated TOR kinase directly phosphorylates EIN2 to prevent its nuclear localization. Notably, the rapid global transcriptional reprogramming that is directed by glucose-TOR signalling is largely compromised in the ein2-5 mutant, and EIN2 negatively regulates the expression of a wide range of target genes of glucose-activated TOR that are involved in DNA replication, cell wall and lipid synthesis and various secondary metabolic pathways. Chemical, cellular and genetic analyses reveal that cell elongation and proliferation processes that are controlled by the glucose-TOR-EIN2 axis are decoupled from canonical ethylene-CTR1-EIN2 signalling, and mediated by different phosphorylation sites. Our findings reveal a molecular mechanism by which a central signalling hub is shared but differentially modulated by diverse signalling pathways using distinct phosphorylation codes that can be specified by upstream protein kinases.

Development of a Fit-For-Purpose Multi-Marker Panel for Early Diagnosis of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) suffers from a lack of an effective diagnostic method, which hampers improvement in patient survival. Carbohydrate antigen 19-9 (CA19-9) is the only FDA-approved blood biomarker for PDAC, yet its clinical utility is limited due to suboptimal performance. Liquid chromatography-mass spectrometry (LC-MS) has emerged as a burgeoning technology in clinical proteomics for the discovery, verification, and validation of novel biomarkers. A plethora of protein biomarker candidates for PDAC have been identified using LC-MS, yet few has successfully transitioned into clinical practice. This translational standstill is owed partly to insufficient considerations of practical needs and perspectives of clinical implementation during biomarker development pipelines, such as demonstrating the analytical robustness of proposed biomarkers which is critical for transitioning from research-grade to clinical-grade assays. Moreover, the throughput and cost-effectiveness of proposed assays ought to be considered concomitantly from the early phases of the biomarker pipelines for enhancing widespread adoption in clinical settings. Here, we developed a fit-for-purpose multi-marker panel for PDAC diagnosis by consolidating analytically robust biomarkers as well as employing a relatively simple LC-MS protocol. In the discovery phase, we comprehensively surveyed putative PDAC biomarkers from both in-house data and prior studies. In the verification phase, we developed a multiple-reaction monitoring (MRM)-MS-based proteomic assay using surrogate peptides that passed stringent analytical validation tests. We adopted a high-throughput protocol including a short gradient (<10 min) and simple sample preparation (no depletion or enrichment steps). Additionally, we developed our assay using serum samples, which are usually the preferred biospecimen in clinical settings. We developed predictive models based on our final panel of 12 protein biomarkers combined with CA19-9, which showed improved diagnostic performance compared to using CA19-9 alone in discriminating PDAC from non-PDAC controls including healthy individuals and patients with benign pancreatic diseases. A large-scale clinical validation is underway to demonstrate the clinical validity of our novel panel.

Inulin-gel-based oral immunotherapy remodels the small intestinal microbiome and suppresses food allergy.

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ+ and interleukin-10+ regulatory T cell populations, and restored ileal abundances of Eggerthellaceae and Enterorhabdus in allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases.

Transcriptional control of cone photoreceptor diversity by a thyroid hormone receptor.

Cone photoreceptor diversity allows detection of wavelength information in light, the first step in color (chromatic) vision. In most mammals, cones express opsin photopigments for sensitivity to medium/long (M, "green") or short (S, "blue") wavelengths and are differentially arrayed over the retina. Cones appear early in retinal neurogenesis but little is understood of the subsequent control of diversity of these postmitotic neurons, because cone populations are sparse and, apart from opsins, poorly defined. It is also a challenge to distinguish potentially subtle differences between cell subtypes within a lineage. Therefore, we derived a Cre driver to isolate individual M and S opsin-enriched cones, which are distributed in counter-gradients over the mouse retina. Fine resolution transcriptome analyses identified expression gradients for groups of genes. The postnatal emergence of gradients indicated divergent differentiation of cone precursors during maturation. Using genetic tagging, we demonstrated a role for thyroid hormone receptor ß2 (TRß2) in control of gradient genes, many of which are enriched for TRß2 binding sites and TRß2-regulated open chromatin. Deletion of TRß2 resulted in poorly distinguished cones regardless of retinal location. We suggest that TRß2 controls a bipotential transcriptional state to promote cone diversity and the chromatic potential of the species.

Sodium-Glucose Cotransporter-2 Inhibitors, Dulaglutide, and Risk for Dementia : A Population-Based Cohort Study.

BACKGROUND: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may have neuroprotective effects in patients with type 2 diabetes (T2D). However, their comparative effectiveness in preventing dementia remains uncertain. OBJECTIVE: To compare the risk for dementia between SGLT2 inhibitors and dulaglutide (a GLP-1 RA). DESIGN: Target trial emulation study. SETTING: Nationwide health care data of South Korea obtained from the National Health Insurance Service between 2010 and 2022. PATIENTS: Patients aged 60 years or older who have T2D and are initiating treatment with SGLT2 inhibitors or dulaglutide. MEASUREMENTS: The primary outcome was the presumed clinical onset of dementia. The date of onset was defined as the year before the date of dementia diagnosis, assuming that the time between the onset of dementia and diagnosis was 1 year. The 5-year risk ratios and risk differences comparing SGLT2 inhibitors with dulaglutide were estimated in a 1:2 propensity score-matched cohort adjusted for confounders. RESULTS: Overall, 12 489 patients initiating SGLT2 inhibitor treatment (51.9% dapagliflozin and 48.1% empagliflozin) and 1075 patients initiating dulaglutide treatment were included. In the matched cohort, over a median follow-up of 4.4 years, the primary outcome event occurred in 69 participants in the SGLT2 inhibitor group and 43 in the dulaglutide group. The estimated risk difference was -0.91 percentage point (95% CI, -2.45 to 0.63 percentage point), and the estimated risk ratio was 0.81 (CI, 0.56 to 1.16). LIMITATION: Residual confounding is possible; there was no adjustment for hemoglobin A1c levels or duration of diabetes; the study is not representative of newer drugs, including more effective GLP-1 RAs; and the onset of dementia was not measured directly. CONCLUSION: Under conventional statistical criteria, a risk for dementia between 2.5 percentage points lower and 0.6 percentage point greater for SGLT2 inhibitors than for dulaglutide was estimated to be highly compatible with the data from this study. However, whether these findings generalize to newer GLP-1 RAs is uncertain. Thus, further studies incorporating newer drugs within these drug classes and better addressing residual confounding are required. PRIMARY FUNDING SOURCE: Ministry of Food and Drug Safety of South Korea.

Risk of hepatic events associated with use of sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists, and thiazolidinediones among patients with metabolic dysfunction-associated steatotic liver disease.

OBJECTIVE: To examine the hepatic effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) through a head-to-head comparison with glucagon-like peptide-1 receptor agonists (GLP-1RA) or thiazolidinediones (TZD) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). DESIGN: This population-based cohort study was conducted using a nationwide healthcare claims database (2014-2022) of Korea. We included individuals with MASLD (aged ≥40 years) who initiated SGLT-2i or comparator drugs (GLP-1RA or TZD). Primary outcome was a composite of hepatic decompensation events, including ascites, oesophageal varices with bleeding, hepatic failure or liver transplant. Liver-cause death and all-cause death were also assessed as secondary outcomes. Cox proportional hazards models were used to estimated HRs with 95% CIs. RESULTS: After 1:1 propensity score matching, we included 22 550 patients who initiated SGLT-2i and GLP-1RA (median age=57 years, 60% male), and 191 628 patients who initiated SGLT-2i and TZD (median age=57 years, 72% male). Compared with GLP-1RA, SGLT-2i showed a similar risk of hepatic decompensation events (HR 0.93, 95% CI 0.76 to 1.14). Compared with TZD, SGLT-2i demonstrated a reduced risk of hepatic decompensation events (HR 0.77, 95% CI 0.72 to 0.82). As compared with TZD, the results of secondary analyses showed significantly lower hepatic decompensation event risks with SGLT-2i when stratified by sex (male: HR 0.87 (95% CI 0.80-0.94); female: HR 0.62 (95% CI 0.55-0.69)). CONCLUSIONS: In this nationwide cohort study, SGLT-2i was associated with a lower risk of hepatic decompensation events in patients with MASLD compared with TZD, while demonstrating similar effectiveness to GLP-1RA.

Vpx requires active cellular dNTP biosynthesis to effectively counteract the anti-lentivirus activity of SAMHD1 in macrophages.

HIV-1 replication in primary monocyte-derived macrophages (MDMs) is kinetically restricted at the reverse transcription step due to the low deoxynucleoside triphosphates (dNTP) pools established by host dNTPase, SAM and HD domain containing protein 1 (SAMHD1). Lentiviruses such as HIV-2 and some Simian immunodeficiency virus counteract this restriction using viral protein X (Vpx), which proteosomally degrades SAMHD1 and elevates intracellular dNTP pools. However, how dNTP pools increase after Vpx degrades SAMHD1 in nondividing MDMs where no active dNTP biosynthesis is expected to exists remains unclear. In this study, we monitored known dNTP biosynthesis machinery during primary human monocyte differentiation to MDMs and unexpectedly found MDMs actively express dNTP biosynthesis enzymes such as ribonucleotide reductase, thymidine kinase 1, and nucleoside-diphosphate kinase. During differentiation from monocytes the expression levels of several biosynthesis enzymes are upregulated, while there is an increase in inactivating SAMHD1 phosphorylation. Correspondingly, we observed significantly lower levels of dNTPs in monocytes compared to MDMs. Without dNTP biosynthesis availability, Vpx failed to elevate dNTPs in monocytes, despite SAMHD1 degradation. These extremely low monocyte dNTP concentrations, which cannot be elevated by Vpx, impaired HIV-1 reverse transcription in a biochemical simulation. Furthermore, Vpx failed to rescue the transduction efficiency of a HIV-1 GFP vector in monocytes. Collectively, these data suggest that MDMs harbor active dNTP biosynthesis and Vpx requires this dNTP biosynthesis to elevate dNTP levels to effectively counteract SAMHD1 and relieve the kinetic block to HIV-1 reverse transcription in MDMs.

A formamidopyrimidine derivative from the deoxyguanosine adduct produced by food contaminant acrylamide induces DNA replication block and mutagenesis.

Acrylamide, a common food contaminant, is metabolically activated to glycidamide, which reacts with DNA at the N7 position of dG, forming N7-(2-carbamoyl-2-hydroxyethyl)-dG (GA7dG). Owing to its chemical lability, the mutagenic potency of GA7dG has not yet been clarified. We found that GA7dG undergoes ring-opening hydrolysis to form N6-(2-deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-[N-(2-carbamoyl-2-hydroxyethyl)formamido]pyrimidine (GA-FAPy-dG), even at neutral pH. Therefore, we aimed to examine the effects of GA-FAPy-dG on the efficiency and fidelity of DNA replication using an oligonucleotide carrying GA-FAPy-9-(2-deoxy-2-fluoro-ß-d-arabinofuranosyl)guanine (dfG), a 2'-fluorine substituted analog of GA-FAPy-dG. GA-FAPy-dfG inhibited primer extension by both human replicative DNA polymerase ε and the translesion DNA synthesis polymerases (Polη, Polι, Polκ, and Polζ) and reduced the replication efficiency by less than half in human cells, with single base substitution at the site of GA-FAPy-dfG. Unlike other formamidopyrimidine derivatives, the most abundant mutation was G:C > A:T transition, which was decreased in Polκ- or REV1-KO cells. Molecular modeling suggested that a 2-carbamoyl-2-hydroxyethyl group at the N5 position of GA-FAPy-dfG can form an additional H-bond with thymidine, thereby contributing to the mutation. Collectively, our results provide further insight into the mechanisms underlying the mutagenic effects of acrylamide.

Fundamentals and Translational Applications of Stem Cells and Biomaterials in Dental, Oral and Craniofacial Regenerative Medicine.

Regenerative dental medicine continuously expands to improve treatments for prevalent clinical problems in dental and oral medicine. Stem cell based translational opportunities include regenerative therapies for tooth restoration, root canal therapy, and inflammatory processes (e.g., periodontitis). The potential of regenerative approaches relies on the biological properties of dental stem cells. These and other multipotent somatic mesenchymal stem cell (MSC) types can in principle be applied as either autologous or allogeneic sources in dental procedures. Dental stem cells have distinct developmental origins and biological markers that determine their translational utility. Dental regenerative medicine is supported by mechanistic knowledge of the molecular pathways that regulate dental stem cell growth and differentiation. Cell fate determination and lineage progression of dental stem cells is regulated by multiple cell signaling pathways (e.g., WNTs, BMPs) and epigenetic mechanisms, including DNA modifications, histone modifications, and non-coding RNAs (e.g., miRNAs and lncRNAs). This review also considers a broad range of novel approaches in which stem cells are applied in combination with biopolymers, ceramics, and composite materials, as well as small molecules (agonistic or anti-agonistic ligands) and natural compounds. Materials that mimic the microenvironment of the stem cell niche are also presented. Promising concepts in bone and dental tissue engineering continue to drive innovation in dental and non-dental restorative procedures.

Natural supplements in antiphospholipid syndrome: A case for further study.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic events and/or pregnancy complications in the presence of persistently positive antiphospholipid antibodies (aPL). Although long-term anticoagulation with vitamin K antagonists is considered standard of care, there is an unmet need for safe therapeutics as primary thromboprophylaxis or adjuncts to standard of care in APS. APS is driven by oxidative stress, procoagulant, proinflammatory and angiogenic pathways. For these reasons there has been an increased interest into the investigation of antithrombotic, anti-inflammatory and anti-oxidant properties of natural supplements in APS. The objective of this review is to summarize the mechanistic, epidemiologic and clinical evidence behind the use of natural supplements in APS, with a specific focus on vitamin D, omega-3 fatty acids, coenzyme Q10, gingerol, and isoquercetin. This review should serve as a compelling argument for the future study of natural supplements in APS.

Diagnostic Performance of Surgical Indication for Branch-duct or Mixed-type Intraductal Papillary Mucinous Neoplasms of the Revised International Association of Pancreatology (IAP) 2023 Guidelines.

OBJECTIVE: To evaluate the diagnostic performance of surgical indications of the revised International Association of Pancreatology (IAP) 2023 guidelines compared to the IAP 2017 and European 2018 guidelines. SUMMARY BACKGROUND DATA: The revised IAP guidelines for surgical indications for branch duct (BD) intraductal papillary mucinous neoplasms (IPMN) include the presence of at least two worrisome features without mandatory endoscopic ultrasound. METHODS: Among 663 patients who underwent resection for pathologically confirmed IPMN in a tertiary hospital between 2013 and 2023, 556 patients with BD or mixed-type IPMN were retrospectively reviewed. Diagnostic performances of the three guidelines for predicting high-grade dysplasia or IPMN with invasive carcinoma were compared. The primary outcome was the malignancy rate. Clinicopathological and radiological imaging data were analyzed. RESULTS: A total of 540, 451, and 490 patients met the surgical indications of the IAP, 2017, 2023, and European guidelines, respectively. Malignant IPMN was observed in 229 (41.2%) patients (high-grade dysplasia, n=99; invasive carcinoma, n=130). Surgical indication by the IAP 2023 guidelines showed higher specificity (29.1 vs. 4.9%, P<0.001), positive predictive value (48.6 vs. 42.4%, P=0.031), and accuracy (55.5 vs. 44.1%, P<0.001) than the IAP 2017 guidelines. It also had higher specificity than the European guidelines (18.7%, P=0.024). The IAP 2023 guidelines showed a superior AUC of surgical indication (0.623 vs. 0.582 for the European guidelines, P<0.001; and 0.524 for the IAP guidelines, P=0.008). CONCLUSIONS: The IAP 2023 guidelines showed better malignancy prediction than the IAP 2017 and European guidelines, potentially reducing unnecessary surgeries.

Piperlongumine inhibits the early stage of adipogenesis in 3T3-L1 cells.

Piperlongumine (PLM), a natural compound isolated from long peppers, has been reported to possess multiple pharmacological roles, including anti-tumor and anti-diabetic. However, the pharmacological role of PLM on adipogenesis is still unknown. In this study, we found that PLM strongly inhibited 3T3-L1 adipocyte differentiation. This inhibition was determined by the accumulation of lipid droplets and intracellular triglycerides. In addition, PLM downregulated both the mRNA and protein expression of adipogenic transcription factors, including CCAAT-enhancer binding proteins ß (C/EBPß), C/EBPα, and peroxisome proliferator-activated receptor γ (PPARγ). Based on the time-course experiment, we found that the inhibitory effect of PLM on adipogenesis was mainly involved in the early stage of adipogenesis. Studying these differential effects could uncover new mechanisms for regulating adipogenesis and new chemicals for treating obesity.

Validation of Diagnostic Thresholds for Compensated Advanced Chronic Liver Disease Using Supersonic Shear Imaging.

Background The Society of Radiologists in Ultrasound (SRU) has proposed thresholds for acoustic radiation force impulse techniques to diagnose compensated advanced chronic liver disease (cACLD). However, the diagnostic performance of these thresholds has not been extensively validated. Purpose To validate the SRU thresholds in patients with chronic liver disease who underwent supersonic shear imaging and, if suboptimal diagnostic performance is observed, to identify optimal values for diagnosing cACLD. Materials and Methods This retrospective single-center study included high-risk patients with chronic liver disease who had liver stiffness (LS) measurements and had undergone endoscopy or liver biopsy between January 2018 and December 2021. Patients were randomly allocated to test and validation sets. cACLD was defined as varices at endoscopy and/or severe fibrosis or cirrhosis at liver biopsy. The diagnostic performance of the SRU guidelines was evaluated, and optimal threshold values were identified using receiver operating characteristic (ROC) curve analysis. Results A total of 1180 patients (median age, 57 years [IQR, 50-64 years]; 761 men), of whom 544 (46%) had cACLD, were included. With the SRU recommended thresholds of less than 9 kPa and greater than 13 kPa in the test set (n = 786), the sensitivity and specificity for ruling out and ruling in cACLD were 81% (303 of 374 patients; 95% CI: 77, 85) and 92% (380 of 412 patients; 95% CI: 89, 94), respectively. In ROC curve analysis, the identified optimal threshold values were less than 7 kPa and greater than 12 kPa, showing 91% sensitivity (340 of 374 patients; 95% CI: 88, 93) for ruling out cACLD and 91% specificity (373 of 412 patients; 95% CI: 87, 93) for ruling in cACLD, respectively. In the validation set (n = 394), the optimal thresholds showed 91% sensitivity (155 of 170 patients; 95% CI: 86, 95) and 92% specificity (206 of 224 patients; 95% CI: 88, 95). Conclusion Compared with the SRU guidelines, the dual LS threshold values of less than 7 kPa and greater than 12 kPa were better for diagnosing cACLD. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Barr in this issue.

Adipocyte-specific disruption of the BBSome causes metabolic and autonomic dysfunction.

Obesity is a major public health issue due to its association with type 2 diabetes, hypertension, and other cardiovascular risks. The BBSome, a complex of eight conserved Bardet-Biedl syndrome (BBS) proteins, has emerged as a key regulator of energy and glucose homeostasis as well as cardiovascular function. However, the importance of adipocyte BBSome in controlling these physiological processes is not clear. Here, we show that adipocyte-specific constitutive disruption of the BBSome through selective deletion of the Bbs1 gene adiponectin (AdipoCre/Bbs1fl/fl mice) does not affect body weight under normal chow or high-fat and high-sucrose diet (HFHSD). However, constitutive BBSome deficiency caused impairment in glucose tolerance and insulin sensitivity. Similar phenotypes were observed after inducible adipocyte-specific disruption of the BBSome (AdipoCreERT2/Bbs1fl/fl mice). Interestingly, a significant increase in renal sympathetic nerve activity, measured using multifiber recording in the conscious state, was observed in AdipoCre/Bbs1fl/fl mice on both chow and HFHSD. A significant increase in tail-cuff arterial pressure was also observed in chow-fed AdipoCre/Bbs1fl/fl mice, but this was not reproduced when arterial pressure was measured by radiotelemetry. Moreover, AdipoCre/Bbs1fl/fl mice had no significant alterations in vascular reactivity. On the other hand, AdipoCre/Bbs1fl/fl mice displayed impaired baroreceptor reflex sensitivity when fed HFHSD, but not on normal chow. Taken together, these data highlight the relevance of the adipocyte BBSome for the regulation of glucose homeostasis and sympathetic traffic. The BBSome also contributes to baroreflex sensitivity under HFHSD, but not normal chow.NEW & NOTEWORTHY The current study show how genetic manipulation of fat cells impacts various functions of the body including sensitivity to the hormone insulin.

Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin.

Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1(hi) monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.

Impact of pod and seed photosynthesis on seed filling and canopy carbon gain in soybean.

There is a limited understanding of the carbon assimilation capacity of nonfoliar green tissues and its impact on yield and seed quality since most photosynthesis research focuses on leaf photosynthesis. In this study, we investigate the photosynthetic efficiency of soybean (Glycine max) pods and seeds in a field setting and evaluate its effect on mature seed weight and composition. We demonstrate that soybean pod and seed photosynthesis contributes 13% to 14% of the mature seed weight. Carbon assimilation by soybean pod and seed photosynthesis can compensate for 81% of carbon loss through the respiration of the same tissues, and our model predicts that soybean pod and seed photosynthesis contributes up to 9% of the total daily carbon gain of the canopy. Chlorophyll fluorescence (CF) shows that the operating efficiency of photosystem II in immature soybean seeds peaks at the 10 to 100 mg seed weight stage, while that of immature pods peaks at the 75 to 100 mg stage. This study provides quantitative information about the efficiency of soybean pod and seed photosynthesis during tissue development and its impact on yield.

In Neoadjuvant FOLFIRINOX Chemotherapy for Pancreatic Ductal Adenocarcinoma, Which Response is the More Reliable Indicator for Prognosis, Radiologic or Biochemical?

BACKGROUND: In this era of increasing neoadjuvant chemotherapy, methods for evaluating responses to neoadjuvant chemotherapy are still diverse among institutions. Additionally, the efficacy of adjuvant chemotherapy for patients undergoing neoadjuvant chemotherapy remains unclear. Therefore, this retrospective study was performed to evaluate the effectiveness of methods for assessing response to neoadjuvant chemotherapy and the need for adjuvant chemotherapy in treating patients with non-metastatic pancreatic ductal adenocarcinoma. METHODS: The study identified 150 patients who underwent neoadjuvant FOLFIRINOX chemotherapy followed by curative-intent pancreatectomy. The patients were stratified by biochemical response based on the normalization of carbohydrate antigen 19-9 and by radiologic response based on size change at imaging. RESULTS: The patients were classified into the following three groups based on their response to neoadjuvant chemotherapy and prognosis: biochemical responders (BR+), radiology-only responders (BR-/RR+), and non-responders (BR-/RR-). The 3-year overall survival rate was higher for BR+ (71.0%) than for BR-/RR+ (53.6%) or BR-/RR- (33.1%) (P < 0.001). Response to neoadjuvant chemotherapy also was identified as a significant risk factor for recurrence in a comparison between BR-/RR+ and BR+ (hazard ratio [HR], 2.15; 95% confidence interval [CI] 1.19-3.88; P = 0.011) and BR-/RR- (HR, 3.82; 95% CI 2.41-6.08; P < 0.001). Additionally, regardless of the response to neoadjuvant chemotherapy, patients who completed adjuvant chemotherapy had a significantly higher 3-year overall survival rate than those who did not. CONCLUSIONS: This response evaluation criterion for neoadjuvant chemotherapy is feasible and can significantly predict prognosis. Additionally, completion of adjuvant chemotherapy could be helpful to patients who undergo neoadjuvant chemotherapy regardless of their response to neoadjuvant chemotherapy.