Coherent feedback enhanced quantum-dense metrology in a lossy environment.

Quantum dense metrology (QDM) performs high-precision measurements by a two-mode entangled state created by an optical parametric amplifier (PA), where one mode is a meter beam and the other is a reference beam. In practical applications, the photon losses of meter beam are unavoidable, resulting in a degradation of the sensitivity. Here, we employ coherent feedback that feeds the reference beam back into the PA by a beam splitter to enhance the sensitivity in a lossy environment. The results show that the sensitivity is enhanced significantly by adjusting the splitting ratio of the beam splitter. This method may find its potential applications in QDM. Furthermore, such a strategy that two non-commuting observables are simultaneous measurements could provide a new way to individually control the noise-induced random drift in phase or amplitude of the light field, which would be significant for stabilizing the system and long-term precision measurement.

Fungal Prenyltransferase AnaPT and Its F265 Mutants Catalyze the Dimethylallylation at the Nonaromatic Carbon of Phloretin.

Phloretin is widely found in fruit and shows various biological activities. Here, we demonstrate the dimethylallylation, geranylation, and farnesylation, particularly the first dimethylallylation at the nonaromatic carbon of phloretin (1) by the fungal prenyltransferase AnaPT and its mutants. F265 was identified as a key amino acid residue related to dimethylallylation at the nonaromatic carbon of phloretin. Mutants AnaPT_F265D, AnaPT_F265G, AnaPT_F265P, AnaPT_F265C, and AnaPT_F265Y were discovered to generally increase prenylation activity toward 1. AnaPT_F265G catalyzes the O-geranylation selectively at the C-2' hydroxyl group, which involves an intramolecular hydrogen bond with the carbonyl group of 1. Seven products, 1D5, 1D7-1D9, 1G2, 1G4, and 1F2, have not been reported prior to this study. Twelve compounds, 1D3-1D9, 1G1-1G3, and 1F1-1F2, exhibited potential inhibitory effects on α-glucosidase with IC50 values ranging from 11.45 ± 0.87 to 193.80 ± 6.52 µg/mL. Among them, 1G1 with an IC50 value of 11.45 ± 0.87 µg/mL was the most potential α-glucosidase inhibitor, which is about 30 times stronger than the positive control acarbose with an IC50 value of 346.63 ± 15.65 µg/mL.

Aloperine-Type Alkaloids with Antiviral and Antifungal Activities from the Seeds of Sophora alopecuroides L.

As a continuous flow investigation of novel pesticides from natural quinolizidine alkaloids, the chemical compositions of the seeds of Sophora alopecuroides were thoroughly researched. Fifteen new aloperine-type alkaloids (1-15) as well as six known aloperine-type alkaloids (16-21) were obtained from the extract of S. alopecuroides. The structures of 1-21 were confirmed via HRESIMS, NMR, UV, IR, ECD calculations, and X-ray diffraction. The antiviral activities of 1-21 against tobacco mosaic virus (TMV) were detected following the improved method of half-leaf. Compared with ningnanmycin (protective: 69.7% and curative: 64.3%), 15 exhibited excellent protective (71.7%) and curative (64.6%) activities against TMV. Further biological studies illustrated that 15 significantly inhibited the transcription of the TMV-CP gene and increased the activities of polyphenol oxidase (PPO), peroxidase (POD), superoxide dismutase (SOD), and phenylalanine ammonia-lyase (PAL). The antifungal activities of 1-21 against Phytophythora capsica, Botrytis cinerea, Alternaria alternata, and Gibberella zeae were screened according to a mycelial inhibition test. Compound 13 displayed excellent antifungal activity against B. cinerea (EC50: 7.38 µg/mL). Moreover, in vitro antifungal mechanism studies displayed that 13 causes accumulation of reactive oxygen species and finally leads to mycelia cell membrane damage and cell death in vitro.

Construction of WS2/NC@C nanoflake composites as performance-enhanced anodes for sodium-ion batteries.

The development of layered metal sulfides with stable structure and accessible active sites is of great importance for sodium-ion batteries (SIBs). Herein, a simple liquid-mixing method is elaborately designed to immobilize WS2 nanoflakes on N-doped carbon (NC), then further coat carbon to produce WS2/NC@C. In the formation process of this composite, the presence of NC not only avoids the overlap and improves the dispersion of WS2 nanoflakes, but also creates a connection network for charge transfer, where the wrapped carbon provides a stable chemical and electrochemical reaction interface. Thus, the composite of WS2/NC@C exhibits the desired Na+ storage capacity as anticipated. The reversible capacity reaches the high value of 369.8 mA h g-1 at 0.2 A g-1 after 200 cycles, while excellent rate performances and cycle life are also acquired in that capacity values of 256.7 and 219.6 mA h g-1 at 1 and 5 A g-1 are preserved after 1000 cycles, respectively. In addition, the assembled sodium-ion hybrid capacitors (SIHCs, AC//WS2/NC@C) exhibit an energy/power density of 68 W h kg-1 at 64 W kg-1, and capacity retention of 82.9% at 1 A g-1 after 2000 cycles. The study provides insight into developing layered metal sulfides with eminent performance of Na+ storage.

Isolating Antipathogenic Fungal Coumarins from Coriaria nepalensis and Determining Their Primary Mechanism In Vitro.

Through bioassay-guided isolation, eight undescribed coumarins (1-8), along with six reported coumarins (9-14), were obtained from Coriaria nepalensis. The new structures were determined by using IR, UV, NMR, HRESIMS, and ECD calculations. The results of the biological activity assays showed that compound 9 exhibited broad spectrum antifungal activities against all tested fungi in vitro and a significant inhibitory effect on Phytophthora nicotianae with an EC50 value of 3.00 µg/mL. Notably, compound 9 demonstrated greater curative and protective effects against tobacco balack shank than those of osthol in vivo. Thus, 9 was structurally modified to obtain new promising antifungal agents, and the novel derivatives (17b, 17j, and 17k) exhibited better effects on Sclerotinia sclerotiorum than did lead compound 9. Preliminary mechanistic exploration illustrated that 9 could enhance cell membrane permeability, destroy the morphology and ultrastructure of cells, and reduce the exopolysaccharide content of P. nicotianae mycelia. Furthermore, the cytotoxicity results revealed that compound 9 exhibited relatively low cytotoxicity against HEK293 cell lines with an inhibition rate of 33.54% at 30 µg/mL. This research is promising for the discovery of new fungicides from natural coumarins with satisfactory ecological compatibility.

Effect of transcutaneous electrical acupoint stimulation based on the theory of "qi ascending and descending movement" on autonomic nervous system and gastrointestinal function in patients after general anesthesia laparoscopic cholecystectomy. / 基于"气机升降"ç†è®ºç»çš®ç©´ä½ç”µåˆºæ¿€å¯¹å ¨éº»è ¹è ”é•œèƒ†å›Šåˆ‡é™¤æœ¯åŽæ‚£è€ è‡ªä¸»ç¥žç»å’Œèƒƒè‚ åŠŸèƒ½çš„å½±å“.

OBJECTIVES: To observe the therapeutic effect of transcutaneous electrical acupoint stimulation (TEAS) based on the theory of "qi ascending and descending movement" in patients after general anesthesia laparoscopic cholecystectomy, so as to explore the impact of TEAS on the autonomic nervous system and gastrointestinal function of patients. METHODS: A total of 204 patients scheduled to undergo general anesthesia laparoscopic cholecystectomy were selected and randomly divided into control, double acupoints and multiple acupoints groups, with 68 cases in each group. For patients in the multiple acupoints group, TEAS was applied at Zusanli (ST36), Tiantu (CV22), Danzhong (CV17), Zhongwan (CV12), Taichong (LR3), and Neiguan (PC6) 30 min before anesthesia induction until the end of the surgery. In the double acupoints group, TEAS was applied only at ST36 and PC6. No electrical stimulation was applied in the control group. The postoperative bloating, bowel sound recovery time, first farting time, first defecation time, length of hospital stay, nausea and vomiting were compared among the three groups. Heart rate variability was monitored by twelve-lead electrocardiogram to evaluate the autonomic nervous function of the patients, including the low frequency power/high frequency power ratio (LF/HF), the standard deviation of all sinus RR intervals (SDNN), and the root mean square of difference between successive normal RR intervals (RMSSD). RESULTS: At 6 h and 24 h after surgery, the symptoms of bloating, nausea and vomiting in the multiple acupoints group and double acupoints group were significantly improved compared to the control group (P<0.05), and the multiple acupoints group was superior to the double acupoints group (P<0.05). Compared with the control group, the bowel sound recovery time, first farting time, first defecation time, and length of hospital stay were significantly shorter (P<0.05) in the multiple acupoints group and double acupoints group, and the multiple acupoints group was superior to the double acupoints group (P<0.05). At 1 d and 2 d after surgery, compared with the control group, LF/HF was decreased (P<0.05) while SDNN and RMSSD were increased (P<0.05) in the multiple acupoints group and double acupoints group, and there was a significant difference between the two groups (P<0.05). CONCLUSIONS: TEAS treatment based on the theory of "qi ascending and descending movement" can relieve gastrointestinal dysfunction, reduce early postoperative sympathetic nerve excitement and maintain parasympathetic nerve tension in patients after general anesthesia laparoscopic cholecystectomy, thereby promoting gastrointestinal function recovery.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

Quinolizidine Alkaloids and Isoflavones from the Herb of Thermopsis lupinoides and Their Antiviral, Antifungal, and Insecticidal Activities.

As part of our ongoing investigation of natural bioactive substances from the genus Thermopsis of the tribe Fabaceae for agricultural protection, the chemical constituents of the herb Thermopsis lupinoides were systematically investigated, which led to the isolation of 39 quinolizidine alkaloids (QAs) (1-39), including 14 new QAs (1-14) and 14 isoflavones (40-53). Their structures were elucidated through comprehensive spectroscopic data analysis (IR, UV, NMR, HRESIMS), ECD calculations, and X-ray crystallography. The antitomato spotted wilt virus (TSWV) and antifungal (against Botrytis cinerea, Gibberella zeae, Phytophythora capsica, and Alternaria alternata) and insecticidal (against Aphis fabae and Tetranychus urticae) activities of the isolated compounds were screened using the lesion counting method, mycelial inhibition assay, and spray method, respectively. The bioassay results showed that 34 exhibited excellent protective activity against TSWV, with an EC50 value of 36.04 µg/mL, which was better than that of the positive control, ningnanmycin (86.03 µg/mL). The preliminary mechanistic exploration illustrated that 34 induced systemic acquired resistance in the host plant by acting on the salicylic acid signaling pathway. Moreover, 1 showed significant antifungal activity against B. cinerea (EC50 value of 20.83 µg/mL), while 2 exhibited good insecticidal activity against A. fabae (LC50 value of 24.97 µg/mL). This research is promising for the invention of novel pesticides from QAs with high efficiency and satisfactory ecological compatibility.

Phytochemistry of Red Ginseng, a Steam-Processed Panax ginseng.

Asian ginseng, the root of Panax ginseng C.A. Meyer, occupies a prominent position in the list of best-selling natural products in the world. There are two major types of ginseng roots: white ginseng and red ginseng, each with numerous preparations. White ginseng is prepared by air-drying fresh Asian ginseng roots after harvest. Red ginseng is prepared by steaming roots in controlled conditions using fresh or raw Asian ginseng. Red ginseng is commonly used in Asian countries due to its unique chemical profile, different therapeutic efficacy, and increased stability. Compared with the widespread research on white ginseng, the study of red ginseng is relatively limited. In this paper, after a botanical feature description, the structures of different types of constituents in red ginseng are systematically described, including naturally occurring compounds and those resulting from the steam processing. In red ginseng phytochemical studies, the number of published reports on ginsenosides is significantly higher than that for other constituents. Up to now, 57 ginsenosides have been isolated and characterized in red ginseng. The structural transformation pathways during steaming have been summarized. In comparison with white ginseng, red ginseng also contains other constituents, including polyacetylenes, Maillard reaction products, other types of glycosides, lignans, amino acids, fatty acids, and polysaccharides, which have also been presented. Appropriate analytical methods are necessary for differentiating between unprocessed white ginseng and processed red ginseng. Specific marker compounds and chemical profiles have been used to discriminate red ginseng from white ginseng and adulterated commercial products. Additionally, a brief phytochemical profile comparison has been made between white ginseng and black ginseng, and the latter is another type of processed ginseng prepared from white or red ginseng by steaming several times. In conclusion, to ensure the safe and effective use of red ginseng, phytochemical and analytical studies of its constituents are necessary and even crucial.

Adaptive spline surface fitting with arbitrary topological control mesh.

Reconstructing a spline surface from a given arbitrary topological triangle mesh is a fundamental and challenging problem in computer-aided design and engineering. This paper introduces a novel surface fitting method utilizing G-NURBS capable of handling control meshes with arbitrary topologies. This method employs adaptive control point adjustment, guided by the geometric attributes of the input model, ensuring precise representation of sharp features such as edges and corners. Two primary strategies are employed: a parameter correspondence approach designed for sharp features and a control mesh iterative refinement technique that incorporates geometrical feature information. The proposed method has been tested and evaluated on various CAD models to demonstrate its effectiveness. This method can achieve higher fitting accuracy while faithfully preserving the geometrical features with fewer control points.

Prediction of bowel necrosis by reduced bowel wall enhancement in closed-loop small bowel obstruction: Quantitative methods.

PURPOSE: To assess diagnostic performance and reproducibility of reduced bowel wall enhancement evaluated by quantitative methods using CT to identify bowel necrosis among closed-loop small bowel obstruction (CL-SBO) patients. METHODS: This retrospective single-center study included patients who diagnosed with CL-SBO caused by adhesion or internal hernia during January 2016 and May 2022. Patients were divided into necrotic group (n = 41) and non-necrotic group (n = 67) according to surgical exploration and postoperative pathology. Two doctors independently measured the attenuation of bowel wall and consensus was reached through panel discussion with a third gastrointestinal radiologist. Reduced bowel wall enhancement was assessed by four quantitative methods. Univariate analyses were used to evaluate the association between each method and bowel necrosis, and kappa/intraclass correlation coefficient values were used to assess interobserver agreement. Diagnostic performance parameters were calculated for each method. RESULTS: Reduced bowel wall enhancement in arterial phase (OR 8.98, P < 0.0001), reduced bowel wall enhancement in portal phase (OR 16.84, P < 0.001), adjusted reduced bowel wall enhancement in arterial phase (OR 29.48, P < 0.001), adjusted reduced bowel wall enhancement in portal phase (OR 145.69, P < 0.001) were significantly associated with bowel necrosis. Adjusted reduced bowel wall enhancement in portal phase had the best diagnostic performance (AUC: 0.92; Youden index: 0.84; specificity: 94.03 %) and interobserver agreement (kappa value of 0.59-0.73) to predict bowel necrosis. CONCLUSION: When assessing reduced bowel enhancement to predict bowel necrosis among CL-SBO patients, using unenhanced CT images and proximal dilated loop as standard references in portal phase is the most accurate quantitative method among those tested.

Increased Attenuation of Intestinal Contents at CT Indicates Bowel Necrosis in Closed-Loop Small Bowel Obstruction.

Background Preoperative recognition of irreversible bowel necrosis is important, as it provides valuable guidance for surgical strategy selection but also may inform perioperative risk assessment and communication. Few studies have focused on the association between CT signs and bowel necrosis. Purpose To assess the diagnostic accuracy of CT signs to predict bowel necrosis in patients with closed-loop small bowel obstruction (CL-SBO). Materials and Methods This retrospective single-center study included patients who were surgically confirmed to have CL-SBO caused by adhesion or internal hernia between January 2016 and May 2022. Necrosis was determined based on surgical exploration and postoperative pathologic examination. Two radiologists independently reviewed CT signs by both subjective visual assessment and objective measurement. Disagreements were resolved in consensus with a third gastrointestinal radiologist. Univariable and multivariable analyses were used to assess the association between CT signs and bowel necrosis, and Cohen κ was used to assess interobserver agreement. Sensitivity and specificity were calculated for each CT sign. Results This study included 145 patients: 61 (42.1%) in the necrotic group (median age, 62 years [IQR, 51-71.5 years]; 37 [60.7%] women) and 84 (57.9%) in the nonnecrotic group (median age, 61.5 years [IQR, 51-68.8 years]; 51 [60.7%] women). Univariable analysis and multivariable analysis showed that increased attenuation of intestinal contents and increased attenuation of intestinal wall were independent predictors for bowel necrosis (odds ratio = 45.3 and 15.1; P = .001 and P < .001, respectively). Increased attenuation of intestinal contents and increased attenuation of intestinal wall had similar sensitivity (64% and 67%, respectively) and specificity (99% and 92%, respectively) for predicting bowel necrosis. However, interobserver agreement was better for assessing the contents than the wall (κ = 0.84 and 0.59, respectively). Conclusion Increased attenuation of intestinal contents was a highly specific CT sign with good reproducibility to predict bowel necrosis in CL-SBO. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Taourel and Zins in this issue.

Management of biofilm by an innovative layer-structured membrane for membrane biofilm reactor (MBfR) to efficient methane oxidation coupled to denitrification (AME-D).

Aerobic methane oxidation coupled with denitrification (AME-D) has garnered significant attention as a promising technology for nitrogen removal from water. Effective biofilm management on the membrane surface is essential to enhance the efficiency of nitrate removal in AME-D systems. In this study, we introduce a novel and scalable layer-structured membrane (LSM) developed using a meticulously designed polyurethane sponge. The application of the LSM in advanced biofilm management for AME-D resulted in a substantial enhancement of denitrification performance. Our experimental results demonstrated remarkable improvements in nitrate-removal flux (92.8 mmol-N m-2 d-1) and methane-oxidation rate (325.6 mmol m-2 d-1) when using an LSM in a membrane biofilm reactor (L-MBfR) compared with a conventional membrane reactor (C-MBfR). The l-MBfR exhibited 12.4-, 6.8- and 3.4-fold increases in nitrate-removal rate, biomass-retention capacity, and methane-oxidation rate, respectively, relative to the control C-MBfR. Notably, the l-MBfR demonstrated a 3.5-fold higher abundance of denitrifying bacteria, including Xanthomonadaceae, Rhodocyclaceae, and Methylophilaceae. In addition, the denitrification-related enzyme activity was twice as high in the l-MBfR than in the C-MBfR. These findings underscore the LSM's ability to create anoxic/anaerobic microenvironments conducive to biofilm formation and denitrification. Furthermore, the LSM exhibited a unique advantage in shaping microbial community structures and facilitating cross-feeding interactions between denitrifying bacteria and aerobic methanotrophs. The results of this study hold great promise for advancing the application of MBfRs in achieving efficient and reliable nitrate removal through the AME-D pathway, facilitated by effective biofilm management.

Ruthenium-dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation.

BACKGROUND: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies. METHODS: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties. RESULTS: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1ß, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.

Associations of Intracranial Artery Length and Branch Number on Time-of-Flight MRA With Cognitive Impairment in Hypertensive Older Males.

BACKGROUND: Hypertension-induced impairment of the cerebral artery network contributes to cognitive impairment. Characterizing the structure and function of cerebral arteries may facilitate the understanding of hypertension-related pathological mechanisms and lead to the development of new indicators for cognitive impairment. PURPOSE: To investigate the associations between morphological features of the intracranial arteries distal to the circle of Willis on time-of-flight MRA (TOF-MRA) and cognitive performance in a hypertensive cohort. STUDY TYPE: Prospective observational study. POPULATION: 189 hypertensive older males (mean age 64.9 ± 7.2 years). FIELD STRENGTH/SEQUENCE: TOF-MRA sequence with a 3D spoiled gradient echo readout and arterial spin labeling perfusion imaging sequence with a 3D stack-of-spirals fast spin echo readout at 3T. ASSESSMENT: The intracranial arteries were segmented from TOF-MRA and the total length of distal arteries (TLoDA) and number of arterial branches (NoB) were calculated. The mean gray matter cerebral blood flow (GM-CBF) was extracted from arterial spin labeling perfusion imaging. The cognitive level was assessed with short-term and long-term delay-recall auditory verbal learning test (AVLT) scores, and with montreal cognitive assessment. STATISTICAL TESTS: Univariable and multivariable linear regression were used to analyze the associations between TLoDA, NoB, GM-CBF and the cognitive assessment scores, with P < 0.05 indicating significance. RESULTS: TLoDA (r = 0.314) and NoB (r = 0.346) were significantly correlated with GM-CBF. Multivariable linear regression analyses showed that TLoDA and NoB, but not GM-CBF (P = 0.272 and 0.141), were significantly associated with short-term and long-term delay-recall AVLT scores. These associations remained significant after adjusting for GM-CBF. DATA CONCLUSION: The TLoDA and NoB of distal intracranial arteries on TOF-MRA are significantly associated with cognitive impairment in hypertensive subjects. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.

OBJECTIVE: To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible. RESULTS: 76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A1c and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A1c concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration. CONCLUSIONS: GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A1c and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022342845.

Carotid Plaque-RADS: A Novel Stroke Risk Classification System.

BACKGROUND: Carotid artery atherosclerosis is highly prevalent in the general population and is a well-established risk factor for acute ischemic stroke. Although the morphological characteristics of vulnerable plaques are well recognized, there is a lack of consensus in reporting and interpreting carotid plaque features. OBJECTIVES: The aim of this paper is to establish a consistent and comprehensive approach for imaging and reporting carotid plaque by introducing the Plaque-RADS (Reporting and Data System) score. METHODS: A panel of experts recognized the necessity to develop a classification system for carotid plaque and its defining characteristics. Using a multimodality analysis approach, the Plaque-RADS categories were established through consensus, drawing on existing published reports. RESULTS: The authors present a universal classification that is applicable to both researchers and clinicians. The Plaque-RADS score offers a morphological assessment in addition to the prevailing quantitative parameter of "stenosis." The Plaque-RADS score spans from grade 1 (indicating complete absence of plaque) to grade 4 (representing complicated plaque). Accompanying visual examples are included to facilitate a clear understanding of the Plaque-RADS categories. CONCLUSIONS: Plaque-RADS is a standardized and reliable system of reporting carotid plaque composition and morphology via different imaging modalities, such as ultrasound, computed tomography, and magnetic resonance imaging. This scoring system has the potential to help in the precise identification of patients who may benefit from exclusive medical intervention and those who require alternative treatments, thereby enhancing patient care. A standardized lexicon and structured reporting promise to enhance communication between radiologists, referring clinicians, and scientists.

Synergistic combination of isogarcinol isolated from edible fruits of Garcinia multiflora and dexamethasone to overcome leukemia glucocorticoid resistance.

Isogarcinol (ISO), a cytotoxic polycyclic polyprenylated acylphloroglucinol isolated from the edible fruits of Garcinia multiflora. However, synergistic combination of ISO and dexamethasone (DEX) to overcome leukemia glucocorticoid resistance has never been investigated. Therefore, in this study, the effects of ISO in combination with DEX was conducted on leukemia in vivo and glucocorticoid resistance in vitro. As a result, the combination of the two compounds could efficiently inhibit leukemia progression in mice and reverse DEX resistance in acute lymphoblastic leukemia (ALL) Jurkat cells. Significantly, our findings indicated that c-Myc may be a potential target of ISO, as it is involved in cell cycle arrest and apoptosis by the combination of ISO and DEX in Jurkat cells. Furthermore, western blot analysis revealed that ISO and DEX inhibits the PI3K/Akt/mTOR signaling pathway and promotes the nuclear translocation of glucocorticoid receptor (GR), which activates target genes NR3C1 and TSC22D3, leading to apoptosis in Jurkat cells. Hence, our results suggest that ISO, as a safe and effective food-derived agent, can enhance the anti-leukemia effects of DEX.

Atherosclerotic plaque characteristics in extracranial carotid artery may indicate closer association with white matter hyperintensities than intracranial arteries: A CARE-II study.

PURPOSE: This study aimed to investigate the associations of atherosclerotic plaque characteristics in intracranial and extracranial carotid arteries with severity of white matter hyperintensities (WMHs) in symptomatic patients using magnetic resonance (MR) imaging. METHOD: Patients with cerebrovascular symptoms and carotid plaque were recruited from the cross-sectional, multicenter study of CARE-II. Luminal stenosis of intracranial and extracranial carotid arteries, carotid plaque compositional features, and WMHs were evaluated by brain structural and vascular MR imaging. The atherosclerotic plaque characteristics in intracranial and extracranial carotid arteries were compared between patients with and without moderate-to-severe WMHs (Fazekas score > 2), and their associations with severity of WMHs were analyzed using logistic regression. RESULTS: Of the recruited 622 patients (mean age, 58.7 ± 10.9 years; 422 males), 221 (35.5 %) had moderate-to-severe WMHs with higher prevalence of moderate-to-severe luminal stenosis (17.0 % vs. 10.4 %), intraplaque hemorrhage (15.7 % vs. 9.0 %), thin/ruptured fibrous cap (30.2 % vs. 20.4 %), calcification (44.4 % vs. 22.2 %) and lipid-rich necrotic core (63.8 % vs. 51.1 %) in carotid artery compared to those without (all P < 0.05). Multivariate logistic regression showed that carotid calcification (OR, 1.854; 95 % CI, 1.187-2.898; P = 0.007) was independently associated with moderate-to-severe WMHs after adjusting for confounding factors. No significant association was found between intracranial atherosclerotic stenosis and moderate-to-severe WMHs (P > 0.05). CONCLUSION: Carotid atherosclerotic plaque features, particularly presence of calcification, were independently associated with severity of WMHs, but such association was not found in intracranial atherosclerotic stenosis, suggesting that carotid atherosclerotic plaque characteristics may have closer association with severity of WMHs compared to intracranial atherosclerosis.

Androgen-induced upregulation of CFTR in pancreatic ß-cell contributes to hyperinsulinemia in PCOS model.

PURPOSE: Polycystic ovarian syndrome (PCOS) is an endocrine-metabolic condition affecting 5-10% of reproductive-aged women and characterized by hyperandrogenism, insulin resistance (IR), and hyperinsulinemia. CFTR is known to be regulated by steroid hormones, and our previous study has demonstrated an essential role of CFTR in ß-cell function. This study aims to investigate the contribution of androgen and CFTR to hypersecretion of insulin in PCOS and the underlying mechanism. METHODS: We established a rat PCOS model by subcutaneously implanting silicon tubing containing Dihydrotestosterone (DHT). Glucose tolerance test with insulin levels was performed at 9 weeks after implantation. A rat ß-cell line RINm5F, a mouse ß-cell line ß-TC-6, and mouse islets were treated with DHT, and with or without the androgen antagonist flutamide for CFTR and insulin secretion-related functional assays or mRNA/protein expression measurement. The effect of CFTR inhibitors on DHT-promoted membrane depolarization, glucose-stimulated intracellular Ca2+ oscillation and insulin secretion were examined by membrane potential imaging, calcium imaging and ELISA, respectively. RESULTS: The DHT-induced PCOS model showed increased body weight, impaired glucose tolerance, and higher blood glucose and insulin levels after glucose stimulation. CFTR was upregulated in islets of PCOS model and DHT-treated cells, which was reversed by flutamide. The androgen receptor (AR) could bind to the CFTR promoter region, which was enhanced by DHT. Furthermore, DHT-induced membrane depolarization, enhanced glucose-stimulated Ca2+ oscillations and insulin secretion, which could be abolished by CFTR inhibitors. CONCLUSIONS: Excessive androgen enhances glucose-stimulating insulin secretion through upregulation of CFTR, which may contribute to hyperinsulinemia in PCOS.