Rose Petal Extract Ameliorates Obesity in High Fat Diet-Induced Obese Mice.

In Asia, Rosa spp. has been used in traditional medicine for the treatment of osteoarthritis, rheumatoid arthritis, and edema. In this study, we investigated the effect of rose petal extract (RPE) on high fat diet (HFD)-induced obesity in mice. C57BL/6J mice were fed with either an AIN-93G diet (normal control), a 60% HFD, or a HFD plus supplementation with RPE at 100 or 200 mg/kg body weight (HFD+R100, HFD+R200) for 14 weeks. The HFD increased the body weight gain, liver and fat weight, lipid profiles (total cholesterol, triglyceride, high density lipoprotein cholesterol, and low density lipoprotein cholesterol), and the serum aspartate aminotransferase and alanine aminotransferase levels of mice, while RPE supplementation significantly decreased these parameters compared with the HFD group. Furthermore, the HFD increased the protein expressions of adipogenesis- and lipogenesis-related factors and decreased the protein expression of lipolysis- and energy metabolism-related factors. Conversely, RPE supplementation significantly decreased the protein expression of adipogenesis- and lipogenesis-related factors and increased the protein expression of lipolysis- and energy metabolism-related factors compared to the HFD group. Taken together, the results provide preliminary evidence for the potential protective effects of the RPE against obesity.

Fluorophore-Labeled Pyrrolones Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR1.

In this study, we describe the structure-based development of the first fluorescent ligands targeting the intracellular allosteric binding site (IABS) of the CC chemokine receptor type 1 (CCR1), a G protein-coupled receptor (GPCR) that has been pursued as a drug target in inflammation and immune diseases. Starting from previously reported intracellular allosteric modulators of CCR1, tetramethylrhodamine (TAMRA)-labeled ligands were designed, synthesized, and tested for their suitability as fluorescent tracers to probe binding to the IABS of CCR1. In the course of these studies, we developed LT166 (12) as a highly versatile fluorescent CCR1 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a nonradioactive and high-throughput manner. Besides the detection of intracellular allosteric ligands by direct competition with 12, we were also able to monitor the binding of extracellular antagonists due to their positive cooperative binding with 12. Thereby, we provide a straightforward and nonradioactive method to easily distinguish between ligands binding to the IABS of CCR1 and extracellular negative modulators. Further, we applied 12 for the identification of novel chemotypes for intracellular CCR1 inhibition that feature high binding selectivity for CCR1 over CCR2. For one of the newly identified intracellular CCR1 ligands (i.e., 23), we were able to show CCR1 over CCR2 selectivity also on a functional level and demonstrated that this compound inhibits basal ß-arrestin recruitment to CCR1, thereby acting as an inverse agonist. Thus, our fluorescent CCR1 ligand 12 represents a highly promising tool for future studies of CCR1-targeted pharmacology and drug discovery.

Lactuca sativa L. Extract Enhances Sleep Duration Through Upregulation of Adenosine A1 Receptor and GABAA Receptors Subunits in Pentobarbital-Injected Mice.

We investigated the effects of Lactuca sativa L. extracts (Lactuc) on pentobarbital-induced sleep in mice to elucidate the mechanisms underlying its impact on sleep quality. Mice were randomly assigned to five groups: control, positive control (diazepam 2 mg/kg b.w.), and three groups orally administered with Lactuc (50, 100, and 200 mg/kg b.w.). After 2 weeks of oral administration and intraperitoneal injections, the mice were killed. We found that the Lactuc-administered groups had significantly reduced sleep latency and increased sleep duration compared with the control group. Furthermore, the oral administration of Lactuc induced a significant increase in mRNA expression and protein expression of adenosine A1 receptor in the brains compared with the expressions in the control group. In addition, the Lactuc-administered groups exhibited significantly higher levels of mRNA expressions of GABAA receptors subunits α2, ß2, γ1, and, γ2 in the brain tissue. Therefore, we suggest that Lactuc could be used to develop natural products that effectively improve sleep quality and duration.

Indian Gooseberry and Barley Sprout Complex Prevent Oxidative Stress and Photoaging of the Skin in Ultraviolet B-Irradiated SHK-I Mice.

This study investigated the protective effects of a complex of Indian gooseberry and barley sprout (IB complex) on oxidative stress and skin damage caused by ultraviolet B irradiation in SHK-I hairless mice. The study examined the impact of IB complex on skin hydration, wrinkle formation, and melanogenesis using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and western blot analysis. The IB complex reduced skin hydration loss and wrinkle formation, while also demonstrating enhanced antioxidant activities. The IB complex maintained skin hydration via upregulation of hyaluronic acid and ceramide synthesis, including the regulation of hyaluronic acid synthase, long-chain ceramide formation, dihydroceramide desaturase 1 activity, and type I collagen production. The IB complex prevented wrinkle formation via downregulating JNK and upregulating TGF-ß pathways. Moreover, IB complex blocked melanin production via inhibition of protein kinase A, cAMP response element-binding protein, and microphthalmia-associated transcription factor pathways. These results suggest that IB complex is a potential agent to protect the skin against photodamage caused by exposure to UVB radiation. The research protocols underwent approval from the Institutional Animal Care and Use Committee of Kyung Hee University (KHGASP-21-577), ensuring compliance with ethical standards.

Extract mixture of plants (OXYLIA) inhibits fat accumulation by blocking FAS-related factors and promoting lipolysis via cAMP-dependent PKA activation.

Background: Obesity is characterized by an imbalance between energy intake and expenditure, leading to the excessive accumulation of triglycerides in adipose tissue. Objective: This study investigated the potential of Oxylia to prevent obesity in mice fed with a high-fat diet (HFD). Design: C57BL/6J mice were fed with one of the following five diets - AIN93G normal diet (normal control), 60% (HFD; control), HFD containing metformin at 40 mg/kg body weight (b.w.) (Met; positive control), HFD containing Oxylia at 30 mg/kg b.w. (O30), or HFD containing Oxylia at 60 mg/kg b.w. (O60) - for 15 weeks. Results: Mice under an HFD supplemented with Oxylia had decreased body weight gain, adipose tissue weight, and adipose tissue mass. In addition, triglyceride (TG), total cholesterol, and VLDL/LDL cholesterol levels were lower in the O60 groups than in the HFD-fed control group. Moreover, Oxylia supplementation decreased the expression of adipogenesis-related mRNAs and lipogenesis-related proteins while increasing the expression of lipolysis-related proteins in white adipose tissue and thermogenesis-related proteins in brown adipose tissue. Conclusions: These findings suggest that Oxylia has potential as a functional food ingredient for the prevention and treatment of obesity and related metabolic disorders.

Curcuma longa L. extract exhibits anti-inflammatory and cytoprotective functions in the articular cartilage of monoiodoacetate-injected rats.

Background: Osteoarthritis (OA), the most prevalent form of arthritis, is a degenerative joint disease marked by the progressive deterioration of articular cartilage, leading to clinical manifestations such as joint pain. Objective: This study investigated the effects of Curcuma longa L. extract (CL) containing curcumin, demethoxycurcumin, and bisdemethoxycurcumin on monosodium iodoacetate (MIA)-induced OA rats. Design: Sprague-Dawley rats with MIA-induced OA received CL supplementation at doses of 5, 25, and 40 mg/kg body weight. Results: CL extract administration suppressed mineralisation parameters and morphological modifications and decreased arachidonate5-lipoxygenase and leukotriene B4 levels in articular cartilage. Additionally, it decreased serum prostaglandin E2, NO, and glycosaminoglycanlevels as well as the protein expression of phosphorylated inhibitor kappa B-alpha, phosphorylated p65, cyclooxygenase-2, and inducible nitric oxide synthase in the cartilage of MIA-injected rats. Furthermore, it also reduced matrix metalloproteinases and elevated SMAD family member 3 phosphorylation, tissue inhibitor of metalloproteinases, aggrecan, collagen type I, and collagen type II levels in the articular cartilage of MIA-induced OA rats. Conclusions: This study's findings suggest that CL supplementation helps prevent OA development and is an effective therapy for OA.

A Robust Platform for the Molecular Design of Potent, Protease-Stable, Long-Acting GIP Analogues.

Glucose-dependent insulinotropic peptide (GIP) is a 42-amino acid peptide hormone that regulates postprandial glucose levels. GIP binds to its cognate receptor, GIPR, and mediates metabolic physiology by improved insulin sensitivity, ß-cell proliferation, increased energy consumption, and stimulated glucagon secretion. Dipeptidyl peptidase-4 (DPP4) catalyzes the rapid inactivation of GIP within 6 min in vivo. Here, we report a molecular platform for the design of GIP analogues that are refractory to DPP4 action and exhibit differential activation of the receptor, thus offering potentially hundreds of GIP-based compounds to fine-tune pharmacology. The lead compound from our studies, which harbored a combination of N-terminal alkylation and side-chain lipidation, was equipotent and retained full efficacy at GIPR as the native peptide, while being completely refractory toward DPP4, and was resistant to trypsin. The GIP analogue identified from these studies was further evaluated in vivo and is one of the longest-acting GIPR agonists to date.

Quantification of enlarged deep medullary vein volumes in Sturge-Weber syndrome.

Background: Enlarged deep medullary veins (EDMVs) in patients with Sturge-Weber syndrome (SWS) may channel venous blood from the surface to the deep vein system in brain regions affected by the leptomeningeal venous malformation. Thus, the quantification of EDMV volume may provide an objective imaging marker for this vascular compensatory process. The present study proposes a novel analytical method to quantify enlarged EDMV volumes in the affected hemisphere of patients with unilateral SWS. Methods: Twenty young subjects, including 10 patients with unilateral SWS and 10 healthy siblings (age 14.5±6.7 and 16.0±7.0 years, respectively) underwent 3T brain MRI scanning using susceptibility-weighted imaging (SWI) and volumetric T1-weighted sequences. The proposed image analytic steps segmented EDMVs in white matter regions, defined on the volumetric T1-weighted images, by statistically associating the likelihood of intensity, location, and tubular shape on SWI. The volumes of the segmented EDMVs, calculated in each hemisphere, were compared between affected and unaffected hemispheres. EDMV volumes were also correlated with visually assessed EDMV scores, hemispheric white matter volumes, and cortical surface areas. Parametric tests including Pearson's correlation, unpaired and paired t-tests, were used. A P value <0.05 was considered statistically significant. Results: It was found that EDMVs were identified well in SWS-affected hemispheres while calcified regions were excluded. Mean EDMV volumes in the SWS-affected hemispheres were 10-12-fold greater than in the unaffected or healthy control hemispheres; while white matter volumes and cortical surface areas were lower. EDMV volumes in the SWS-affected hemispheres showed a strong positive correlation with the visual EDMV scores (r=0.88, P=0.001) and an inverse correlation with cortical surface area ratios (r=-0.65, P=0.04) but no correlation with white matter volume ratios. Conclusions: EDMVs were detected in the SWS-affected atrophic hemispheres reliably while avoiding calcified regions. The approach can be used to quantify enlarged deep cerebral veins in the human brain, which may provide a potential marker of cerebral venous remodeling.

Low-Molecular-Weight Fish Collagen Peptide (Valine-Glycine-Proline-Hydroxyproline-Glycine-Proline-Alanine-Glycine) Prevents Osteoarthritis Symptoms in Chondrocytes and Monoiodoacetate-Injected Rats.

The objective of this study was to investigate the effect of low-molecular-weight fish collagen (valine-glycine-proline-hydroxyproline-glycine-proline-alanine-glycine; LMWCP) on H2O2- or LPS-treated primary chondrocytes and monoiodoacetate (MIA)-induced osteoarthritis rat models. Our findings indicated that LMWCP treatment exhibited protective effects by preventing chondrocyte death and reducing matrix degradation in both H2O2-treated primary chondrocytes and cartilage tissue from MIA-induced osteoarthritis rats. This was achieved by increasing the levels of aggrecan, collagen type I, collagen type II, TIMP-1, and TIMP-3, while simultaneously decreasing catabolic factors such as phosphorylation of Smad, MMP-3, and MMP-13. Additionally, LMWCP treatment effectively suppressed the activation of inflammation and apoptosis pathways in both LPS-treated primary chondrocytes and cartilage tissue from MIA-induced osteoarthritis rats. These results suggest that LMWCP supplementation ameliorates the progression of osteoarthritis through its direct impact on inflammation and apoptosis in chondrocytes.

Unripe Pear Extract Suppresses UVB-Induced Skin Photoaging in Hairless Mice and Keratinocytes.

Our study aimed to investigate whether unripe pear extract (UP) could provide protection against UVB-induced damage to both mouse skin and keratinocytes. We observed that UVB exposure, a common contributor to skin photoaging, led to wrinkle formation, skin dryness, and inflammation in mice. Nevertheless, these effects were mitigated in the groups of UVB-irradiated mice treated with UP. Moreover, UP treatment at 400 µg/mL increased the antioxidant enzyme activities (sodium dodecyl sulfate, 2.22-fold higher; catalase, 2.91-fold higher; GPx, 1.96-fold higher) along with sphingomyelin (1.58-fold higher) and hyaluronic acid (1.31-fold higher) levels in UVB-irradiated keratinocytes. In the keratinocytes irradiated with UVB, UP 400 µg/mL resulted in reduced cytokine production (TNF-α, 33.2%; IL-1ß, 45.3%; IL-6, 33.4%) and the expression of inflammatory pathway-related proteins. The findings indicate that UP has a direct protective effect on UVB-irradiated keratinocytes and is also able to shield against photoaging induced by UVB. Hence, it is suggested that UP could contribute to improved skin health by averting skin photoaging.

Salacia reticulata Extract Suppresses Fat Accumulation by Regulating Lipid Metabolism.

The excessive storage of triglycerides in adipose tissue is a characteristic feature of obesity, which arises from an imbalance between energy intake and expenditure. In this study, we aimed to explore the potential anti-obesity effects of Salacia reticulata extracts (SC) in a high-fat diet (HFD)-induced in obese mice and 3T3-L1 adipocytes, with a specific focus on understanding the underlying lipid mechanisms. Mice were fed with a normal diet (NC; normal control), HFD (60% high-fat diet), Met (HFD containing metformin 250 mg/kg b.w.), SC25 (HFD containing SC 25 mg/kg b.w.), SC50 (HFD containing SC 50 mg/kg b.w.), or SC 100 (HFD containing SC 100 mg/kg b.w.) for 12 weeks. Notably, SC supplementation led to significant reductions in body weight gain, adipose tissue weight, adipose tissue mass, and adipocyte size in HFD-fed mice. Furthermore, SC supplementation exerted inhibitory effects on the adipogenesis and lipogenesis pathways while promoting lipolysis and thermogenesis pathways in the adipose tissues of HFD-fed mice. In vitro experiments using 3T3-L1 cells demonstrated that SC treatment during the differentiation phase suppressed adipogenesis and lipogenesis, whereas SC treatment after differentiation, activated lipolysis and thermogenesis. Collectively, these findings indicate that SC exhibits a direct influence on the lipid metabolism of adipocytes, making it an effective candidate for weight loss interventions.

Lactobacillus reuteri NCIMB 30242 (LRC) Inhibits Cholesterol Synthesis and Stimulates Cholesterol Excretion in Animal and Cell Models.

In this study, we evaluated the effects of Lactobacillus reuteri NCIMB (LRC™) supplementation on hypercholesterolemia by researching its effects on cellular cholesterol metabolism in hypercholesterolemic rats (KHGASP-22-170) and HepG2 cell line. Rats were separated into six groups after adaptation and were then fed a normal control (NC), a high-cholesterol diet (HC), or a HC supplemented with simvastatin 15 mg/kg body weight (positive control [PC]), LRC 1 × 109 colony-forming units (CFU)/rat/day, LRC 4 × 109 CFU/rat/day, or LRC 1 × 1010 CFU/rat/day (1 × 109, 4 × 109, or 1 × 1010). The rats were dissected to study the effects of LRC on cholesterol metabolism and intestinal excretion at the end of experimental period. We discovered that LRC mainly participated in the restraint of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the uptake of low-density lipoprotein (LDL) cholesterol into tissues, partially in the transport of cholesteryl esters into high density lipoprotein for maturation, and intestinal excretion of cholesterol. These results are supported by the expression of transcription factors and enzymes such as HMG-CoA reductase, SREBP2, CYP7A1, CETP, and LCAT in both messenger RNA (mRNA) and protein levels in serum and hepatic tissue. Furthermore, the LRC treatment in HepG2 significantly reduced the mRNA expression of HMG-CoA reductase, SREBP2, and CEPT and significantly increased the mRNA expression of LDL-receptor, LCAT, and CYP7A1 at all doses. Hence, we suggest that LRC supplementation could alleviate the serum cholesterol level by inhibiting the intracellular cholesterol synthesis, and augmenting excretion of intestinal cholesterol.

All-cause and major-cause mortality associated with sleep latency in the Korean Genome and Epidemiology Study (KoGES): a population-based prospective cohort study.

BACKGROUND: The all-cause and cause-specific mortality risk associated with sleep latencies in the general adult population is unknown. We aimed to investigate the association of habitual prolonged sleep latency with long-term all-cause and cause-specific mortality in adults. METHODS: The Korean Genome and Epidemiology Study (KoGES) is a population-based prospective cohort study comprising community-dwelling men and women aged 40-69 years from Ansan, South Korea. The cohort was studied bi-annually from April 17, 2003, to Dec 15, 2020, and the current analysis included all individuals who completed the Pittsburgh Sleep Quality Index (PSQI) questionnaire between April 17, 2003, and Feb 23, 2005. The final study population comprised 3757 participants. Data were analysed from Aug 1, 2021, to May 31, 2022. The main exposure was sleep latency groups based on the PSQI questionnaire: fell asleep in 15 min or less, fell asleep in 16-30 min, occasional prolonged sleep latency (fell asleep in >30 min once or twice a week in the past month) and habitual prolonged sleep latency (fell asleep in >60 min more than once a week or fell asleep in >30 min ≥3 times a week, or both) in the past month at baseline. Outcomes were all-cause and cause-specific (cancer, cardiovascular disease, and other causes) mortality reported during the 18-year study period. Cox proportional hazards regression models were used to examine the prospective relationship between sleep latency and all-cause mortality, and competing risk analyses were done to investigate the association of sleep latency with cause-specific mortality. FINDINGS: During a median follow-up of 16·7 years (IQR 16·3-17·4), 226 deaths were reported. After adjusting for demographic characteristics, physical characteristics, lifestyle factors, chronic conditions, and sleep variables, self-reported habitual prolonged sleep latency was associated with an increased risk of all-cause mortality (hazard ratio [HR] 2·22, 95% CI 1·38-3·57) compared to the reference group (those who fell asleep in 16-30 min). In the fully adjusted model, habitual prolonged sleep latency was associated with a more than doubled risk of dying from cancer compared to the reference group (HR 2·74, 95% CI 1·29-5·82). No significant association was observed between habitual prolonged sleep latency and deaths from cardiovascular disease and other causes. INTERPRETATION: In this population-based prospective cohort study, habitual prolonged sleep latency was independently associated with an increased risk of all-cause and cancer-specific mortality in adults (independently of demographic characteristics, lifestyle factors, chronic morbidities, and other sleep variables). Although further studies are warranted to investigate the causality of the relationship, strategies or interventions to prevent habitual prolonged sleep latencies might enhance longevity in the general adult population. FUNDING: Korea Centers for Disease Control and Prevention.

Antiobesity effect of Kaempferia parviflora accompanied by inhibition of lipogenesis and stimulation of lipolysis.

Background: Obesity occurs when energy intake is excessive compared to energy expenditure, resulting in the excessive storage of triglyceride in adipose tissue. Objective: The present study aimed to investigate the antiobesity effects of Kaempferia parviflora extracts (PF) in high-fat diet (HFD)-induced obese mice and 3T3-L1 adipocytes to demonstrate the lipid mechanisms underlying these effects. Design: Mice were fed with a normal diet (AIN93G normal diet), HFD (60% HFD), Met (HFD containing metformin 250 mg/kg b.w.), PF50 (HFD containing PF 50 mg/kg b.w.), and PF100 (HFD containing PF 100 mg/kg b.w.) for 12 weeks. Results: Body weight gain, adipose tissue weight, adipose tissue mass, and size of adipocytes were significantly decreased by PF supplementation in HFD-fed mice. Moreover, PF supplementation suppressed the adipogenesis and lipogenesis pathways and activated the lipolysis and thermogenesis pathways in the adipose tissues of HFD-fed mice. Conclusions: PF treatment during the differentiation of 3T3-L1 cells suppressed adipogenesis and lipogenesis and PF treatment after differentiation activated lipolysis and thermogenesis. Thus, we suggest that PF is effective for weight loss by directly affecting the lipid metabolism of adipocytes.

Effect of physical activity on the change in carotid intima-media thickness: An 8-year prospective cohort study.

BACKGROUND AND AIMS: There is a demand for longitudinal studies that use both objective and subjective measures of physical activity to investigate the association of physical activity with the change in carotid intima-media thickness (CIMT). In order to investigate such association, we conducted an 8-year follow-up study that used both objective and subjective measures of physical activity. METHODS: This cohort study used subsamples of the ongoing Korean Genome and Epidemiology Study (KoGES). Included participants were between 49 to 79 years of age at baseline. Exclusion criteria included incomplete assessments of pedometer/accelerometer, international physical activity questionnaire (IPAQ), and baseline CIMT. Participants with a history of cardiovascular diseases were further excluded. Linear regression models were used for the main analysis. Age differences were assessed by stratifying the participants into < 60 years and ≥ 60 years. RESULTS: After removing excluded participants, 835 participants were included in the final analysis (age, 59.84 ± 6.53 years; 326 (39.04%) males). 453 participants were < 60 years and 382 participants were ≥ 60 years. The daily total step count was inversely associated with the percent change in overall CIMT over 8-years (ß = -0.015, standard error = 0.007, P = 0.034). This association was present among participants in the < 60-year-old group (ß = -0.026, standard error = 0.010, P = 0.006), but not among participants in the ≥ 60-year-old group (ß = -0.010, standard error = 0.011, P = 0.38). CONCLUSIONS: The findings suggest that taking preemptive actions of increasing physical activity may prevent the incidence of atherosclerosis.

Gly-Pro-Val-Gly-Pro-Ser Peptide Fish Collagen Improves Skin Moisture and Wrinkles with Ameliorated the Oxidative Stress and Pro-inflammatory Factors in Skin Photoaging Mimic Models.

This study aimed to investigate whether low molecular fish collagen peptide (FC) from Oreochromis niloticus had protective effects on skin of photoaging mimic models. We observed that FC supplementation improved antioxidant enzymes activities and regulated the pro-inflammatory cytokines [e.g., tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6] by reducing the protein expressions of pro-inflammatory factors IκBα, p65, and cyclooxygenase-2 in ultraviolet-B (UV-B) irradiated in vitro and in vivo. Furthermore, FC increased hyaluronic acid, sphingomyelin, and skin hydration by reg-ulating the mRNA expression of hyaluronic acid synthases 1∼3, serine palmitoyltransferase 1, delta 4-desaturase, sphingolipid 1, and protein expressions of ceramide synthase 4, matrix metalloproteinase (MMP)-1, -2, and -9. In UV-B irradiated in vitro and in vivo, FC down-regulated the protein expression of the c-Jun N-terminal kinase, c-Fos, c-Jun, and MMP pathways and up-reg-ulated that of the transforming growth factor-ß receptor I, collagen type I, procollagen type I, and small mothers against decapentaplegic homolog pathways. Our results suggest that FC can be effective against UV-B induced skin photoaging by improving skin dryness and wrinkle formation through antioxidant and anti-inflammatory properties.

Obstructive sleep apnoea and long-term risk of incident diabetes in the middle-aged and older general population.

Background: Obstructive sleep apnoea (OSA) is associated with increased risk of type 2 diabetes. However, results from large population-based prospective cohort studies are rare. The main aim of the present study was to investigate the relative risk of 8-year incident type 2 diabetes in relation to OSA severity in a prospective cohort study of middle-aged and older adults. Methods: A total of 2918 participants (mean age 59 years) of the Korean Genome and Epidemiology Study (KoGES), who underwent home-based overnight polysomnography at baseline examination between 2011 and 2014, were followed up 4-yearly between 2015-2018 and 2019-2021. A total of 1697 participants were present in both follow-ups. After excluding participants who had diabetes at baseline (n=481), a total of 1216 participants were eligible for the analyses. Results: OSA at baseline was categorised by apnoea-hypopnoea index levels as non-OSA (0-4.9 events·h-1), mild OSA (5.0-14.9 events·h-1) and moderate-severe OSA (≥15.0 events·h-1). Incident type 2 diabetes was identified at each follow-up. Compared with non-OSA, participants with moderate-severe OSA had 1.5 times higher risk of developing type 2 diabetes at the end of the 8-year follow-up after adjusting for potential covariates (relative risk 1.50, 95% CI 1.02-2.21). In the same analytical models for 4-year relative risk of incident type 2 diabetes, none of the OSA groups were at significantly higher risk compared with the non-OSA group. Conclusion: Moderate-severe OSA, a modifiable risk factor, poses a higher risk of incident type 2 diabetes compared with non-OSA over an 8-year period in general middle-aged and older adults.

Survival Prediction Using Transformer-Based Categorical Feature Representation in the Treatment of Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive subtype of lymphoma, and accurate survival prediction is crucial for treatment decisions. This study aims to develop a robust survival prediction strategy to integrate various risk factors effectively, including clinical risk factors and Deauville scores in positron-emission tomography/computed tomography at different treatment stages using a deep-learning-based approach. We conduct a multi-institutional study on 604 DLBCL patients' clinical data and validate the model on 220 patients from an independent institution. We propose a survival prediction model using transformer architecture and a categorical-feature-embedding technique that can handle high-dimensional and categorical data. Comparison with deep-learning survival models such as DeepSurv, CoxTime, and CoxCC based on the concordance index (C-index) and the mean absolute error (MAE) demonstrates that the categorical features obtained using transformers improved the MAE and the C-index. The proposed model outperforms the best-performing existing method by approximately 185 days in terms of the MAE for survival time estimation on the testing set. Using the Deauville score obtained during treatment resulted in a 0.02 improvement in the C-index and a 53.71-day improvement in the MAE, highlighting its prognostic importance. Our deep-learning model could improve survival prediction accuracy and treatment personalization for DLBCL patients.

Sevoflurane-induced high-frequency oscillations, effective connectivity and intraoperative classification of epileptic brain areas.

OBJECTIVE: To determine how sevoflurane anesthesia modulates intraoperative epilepsy biomarkers on electrocorticography, including high-frequency oscillation (HFO) effective connectivity (EC), and to investigate their relation to epileptogenicity and anatomical white matter. METHODS: We studied eight pediatric drug-resistant focal epilepsy patients who achieved seizure control after invasive monitoring and resective surgery. We visualized spatial distributions of the electrocorticography biomarkers at an oxygen baseline, three time-points while sevoflurane was increasing, and at a plateau of 2 minimum alveolar concentration (MAC) sevoflurane. HFO EC was combined with diffusion-weighted imaging, in dynamic tractography. RESULTS: Intraoperative HFO EC diffusely increased as a function of sevoflurane concentration, although most in epileptogenic sites (defined as those included in the resection); their ability to classify epileptogenicity was optimized at sevoflurane 2 MAC. HFO EC could be visualized on major white matter tracts, as a function of sevoflurane level. CONCLUSIONS: The results strengthened the hypothesis that sevoflurane-activated HFO biomarkers may help intraoperatively localize the epileptogenic zone. SIGNIFICANCE: Our results help characterize how HFOs at non-epileptogenic and epileptogenic networks respond to sevoflurane. It may be warranted to establish a normative HFO atlas incorporating the modifying effects of sevoflurane and major white matter pathways, as critical reference in epilepsy presurgical evaluation.

High-throughput profiling of sequence recognition by tyrosine kinases and SH2 domains using bacterial peptide display.

Tyrosine kinases and SH2 (phosphotyrosine recognition) domains have binding specificities that depend on the amino acid sequence surrounding the target (phospho)tyrosine residue. Although the preferred recognition motifs of many kinases and SH2 domains are known, we lack a quantitative description of sequence specificity that could guide predictions about signaling pathways or be used to design sequences for biomedical applications. Here, we present a platform that combines genetically encoded peptide libraries and deep sequencing to profile sequence recognition by tyrosine kinases and SH2 domains. We screened several tyrosine kinases against a million-peptide random library and used the resulting profiles to design high-activity sequences. We also screened several kinases against a library containing thousands of human proteome-derived peptides and their naturally-occurring variants. These screens recapitulated independently measured phosphorylation rates and revealed hundreds of phosphosite-proximal mutations that impact phosphosite recognition by tyrosine kinases. We extended this platform to the analysis of SH2 domains and showed that screens could predict relative binding affinities. Finally, we expanded our method to assess the impact of non-canonical and post-translationally modified amino acids on sequence recognition. This specificity profiling platform will shed new light on phosphotyrosine signaling and could readily be adapted to other protein modification/recognition domains.