A single-component, light-assisted uncaging switch for endoproteolytic release.

Proteases function as pivotal molecular switches, initiating numerous biological events. Notably, potyviral protease, derived from plant viruses, has emerged as a trusted proteolytic switch in synthetic biological circuits. To harness their capabilities, we have developed a single-component photocleavable switch, termed LAUNCHER (Light-Assisted UNcaging switCH for Endoproteolytic Release), by employing a circularly permutated tobacco etch virus protease and a blue-light-gated substrate, which are connected by fine-tuned intermodular linkers. As a single-component system, LAUNCHER exhibits a superior signal-to-noise ratio compared with multi-component systems, enabling precise and user-controllable release of payloads. This characteristic renders LAUNCHER highly suitable for diverse cellular applications, including transgene expression, tailored subcellular translocation and optochemogenetics. Additionally, the plug-and-play integration of LAUNCHER into existing synthetic circuits facilitates the enhancement of circuit performance. The demonstrated efficacy of LAUNCHER in improving existing circuitry underscores its significant potential for expanding its utilization in various applications.

HPr prevents FruR-mediated facilitation of RNA polymerase binding to the fru promoter in Vibrio cholerae.

Phosphorylation state-dependent interactions of the phosphoenolpyruvate (PEP):carbohydrate phosphotransferase system (PTS) components with transcription factors play a key role in carbon catabolite repression (CCR) by glucose in bacteria. Glucose inhibits the PTS-dependent transport of fructose and is preferred over fructose in Vibrio cholerae, but the mechanism is unknown. We have recently shown that, contrary to Escherichia coli, the fructose-dependent transcriptional regulator FruR acts as an activator of the fru operon in V. cholerae and binding of the FruR-fructose 1-phosphate (F1P) complex to an operator facilitates RNA polymerase (RNAP) binding to the fru promoter. Here we show that, in the presence of glucose, dephosphorylated HPr, a general PTS component, binds to FruR. Whereas HPr does not affect DNA-binding affinity of FruR, regardless of the presence of F1P, it prevents the FruR-F1P complex from facilitating the binding of RNAP to the fru promoter. Structural and biochemical analyses of the FruR-HPr complex identify key residues responsible for the V. cholerae-specific FruR-HPr interaction not observed in E. coli. Finally, we reveal how the dephosphorylated HPr interacts with FruR in V. cholerae, whereas the phosphorylated HPr binds to CcpA, which is a global regulator of CCR in Bacillus subtilis and shows structural similarity to FruR.

Combination of [18F]FDG and [18F]PSMA-1007 PET/CT predicts tumour aggressiveness at staging and biochemical failure postoperatively in patients with prostate cancer.

PURPOSE: [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has limitations in prostate cancer (PCa) detection owing to low glycolysis in the primary tumour. Recently, prostate-specific membrane antigen (PSMA) PET/CT has been useful for biochemical failure detection and radioligand therapy (RLT) guidance. However, few studies have evaluated its use in primary prostate tumours using PSMA and [18F]FDG PET/CT. This study aimed to evaluate [18F]PSMA-1007 and [18F]FDG PET/CT for primary tumour detection and understand the association of metabolic heterogeneity with clinicopathological characteristics at staging and postoperatively. METHOD: This prospective study included 42 index tumours (27 acinar and 15 ductal-dominant) in 42 patients who underwent [18F]PSMA-1007 and [18F]FDG PET/CT and subsequent radical prostatectomy. All patients were followed for a median of 26 mo, and serum prostate-specific antigen levels were measured every 3 mo to evaluate biochemical failure. One-way analysis of variance, Tukey's multiple comparison test, and Fisher's exact test were performed. RESULTS: All 42 index tumours were detected on [18F]PSMA-1007 PET/CT, whereas only 15 were detected on [18F]FDG PET/CT (62.3% vs. 37.7%, p < 0.0001). A high SUVmax for [18F]PSMA-1007 was observed in tumours with high Gleason scores (GS 6-7 vs. GS 8-10; 12.1 vs. 20.1, p < 0.05). Tumours with [18F]FDG uptake were mostly ductal dominant (acinar-dominant 4/27; ductal-dominant; 11/15, p < 0.001), with lower [18F]PSMA-1007 uptake than tumours without [18F]FDG uptake (SUVmax 16.58 vs. 11.19, p < 0.001). There were 16.6% (7/42) of patients with pStage IV in whom the primary tumours were [18F]FDG positive. Biochemical failure was observed in 14.8% (4/27) of patients with [18F]FDG negative tumours but in 53.3% (8/15) of patients with [18F]FDG positive tumours (p = 0.013). CONCLUSIONS: [18F]PSMA-1007 PET/CT was superior to [18F]FDG PET/CT in detecting primary PCa. In contrast, tumours with [18F]FDG uptake are associated with larger size, a ductal-dominant type, and likely to undergo metastasis at staging and biochemical failure postoperatively.

Real-world efficacy and safety of capecitabine with oxaliplatin in patients with advanced adenocarcinoma of the ampulla of Vater.

BACKGROUND: Adenocarcinoma of the ampulla of Vater (AoV) is one of the rare periampullary cancers, and due to its anatomical location, it is categorized into various histologic subtypes. Its rarity and diversity pose challenges in treatment decision-making for patients with advanced AoV carcinoma. This study investigated the efficacy and safety of the combined regimen of capecitabine and oxaliplatin (CAPOX) in a real-world clinical setting. METHODS: This investigation encompassed patients with advanced AoV carcinoma who underwent CAPOX treatment. Histologic phenotypes were identified through a combination of histopathological analysis and protein expression markers, including MUC1, CDX2, CK20, and MUC2. The correlation between histopathological determinants and survival outcomes was explored, in addition to an evaluation of the safety profile of CAPOX therapy. RESULTS: From January 2010 to June 2023, 42 patients received CAPOX. Of these, 14 patients (33.3%) had not received any prior palliative chemotherapy, while 28 patients (66.7%) had undergone one prior line of chemotherapy. At a median follow up of 9.0 months, the median progression-free survival (PFS) was 4.38 months (95% CI, 2.78-5.69) and the median overall survival (OS) was 9.57 months (95% CI 7.56-11.6). The objective response and disease control rates were 38.1% and 61.9%, respectively. Patients who received CAPOX as a second-line treatment had poorer PFS (HR = 2.62; 95% CI, 1.49-4.90, p = 0.003) and OS (HR = 2.82, 95% CI, 1.47-5.38, p = 0.001) compared to those who received CAPOX as a first-line chemotherapy. There were no statistically significant differences in PFS (p = 0.185) and OS (p = 0.097) between groups based on histologic subtypes. Neutropenia (14.3%) emerged as the predominant grade 3-4 toxicity. Notably, treatment cessation occurred in select instances owing to grade 3 fatigue (9.5%) and peripheral neuropathy (9.5%). CONCLUSIONS: This study confirmed the therapeutic efficacy and safety of CAPOX in a real-world setting, consistent with prior phase II trial results. While CAPOX proved feasible for advanced AoV carcinoma regardless of histologic subtype, its reduced effectiveness in second-line settings necessitates further research to determine its optimal palliative use.

Quantitative Comparison of the Hydration Capacity of Surface-Bound Dextran and Polyethylene Glycol.

We have quantified and compared the hydration capacity (i.e., capability to incorporate water molecules) of the two surface-bound hydrophilic polymer chains, dextran (dex) and poly(ethylene glycol) (PEG), in the form of poly(l-lysine)-graft-dextran (PLL-g-dex) and poly(l-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG), respectively. The copolymers were attached to a negatively charged silica-titania surface through the electrostatic interaction between the PLL backbone and the surface in neutral aqueous media. While the molecular weights of PLL and PEG were fixed, that of dex and the grafting density of PEG or dex on the PLL were varied. The hydration capacity of the polymer chains was quantified through the combined experimental approach of optical waveguide lightmode spectroscopy (OWLS) and quartz crystal microbalance with dissipation monitoring (QCM-D) to yield a value for areal solvation (Ψ), i.e., mass of associated solvent molecules within the polymer chains per unit substrate area. For the two series of copolymers with comparable stretched chain lengths of hydrophilic polymers, namely, PLL(20)-g-PEG(5) and PLL(20)-g-dex(10), the Ψ values gradually increased as the initial grafting density on the PLL backbone increased or as g decreased. However, the rate of increase in Ψ was higher for PEG than dextran chains, which was attributed to higher stiffness of the dextran chains. More importantly, the number of water molecules per hydrophilic group was clearly higher for PEG chains. Given that the -CH2CH2O- units that make up the PEG chains form a cage-like structure with 2-3 water molecules, these "strongly bound" water molecules can account for the slightly more favorable behavior of PEG compared to dextran in both aqueous lubrication and antifouling behavior of the copolymers.

A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin.

AIM: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. RESULTS: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: -0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. CONCLUSIONS: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference.

Pharmacokinetics, pharmacodynamics and safety of oral formulation (CG-750) of ivaltinostat, a histone deacetylase inhibitor, compared to IV formulation (CG-745).

AIMS: CG-750 is an oral formulation of ivaltinostat, a newly developing histone deacetylase (HDAC) inhibitor. This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of an oral formulation (CG-750) of ivaltinostat compared to an intravenous (IV) formulation (CG-745). METHODS: A randomized, double-blind, placebo-controlled study was conducted in three cohorts. Subjects received either CG-745 (Cohorts 1 and 3: 125 mg; Cohort 2: 250 mg) or placebo followed by CG-750 (Cohort 1: 125 mg; Cohort 2: 375 mg; Cohort 3: 750 mg) or placebo. Blood samples for PK and PD assessment were collected up to 72 h post-dose. Histone H3 acetylation at sites K9, K9/K14 and K27 was assessed for area under the % acetylation induction versus time curve (AUEC). RESULTS: A total of 25 subjects were randomized, and 23 subjects completed the study (Cohort 1, n = 6; Cohort 2, n = 6; Cohort 3, n = 6; placebo, n = 5). The mean bioavailability of CG-750 was 10.6% (range: 4.18%-21.33%) and displayed linear PK in the dose range of 125-750 mg. The comparison of AUEC between formulations and the evaluation of the dose-AUEC relationship were inconclusive, due to the small sample sizes and significant variability observed in PD markers. All adverse events (AEs) were transient and of mild or moderate intensity. CONCLUSIONS: The oral formulation of ivaltinostat (CG-750) was generally well tolerated after a single dose. CG-750 displayed a mean bioavailability of 10.6%.

Profiling of endogenous metabolites and changes in intestinal microbiota distribution after GEN-001 (Lactococcus lactis) administration.

This study aimed to identify metabolic biomarkers and investigate changes in intestinal microbiota in the feces of healthy participants following administration of Lactococcus lactis GEN-001. GEN-001 is a single-strain L. lactis strain isolated from the gut of a healthy human volunteer. The study was conducted as a parallel, randomized, phase 1, open design trial. Twenty healthy Korean males were divided into five groups according to the GEN-001 dosage and dietary control. Groups A, B, C, and D1 received 1, 3, 6, and 9 GEN-001 capsules (1 × 1011 colony forming units), respectively, without dietary adjustment, whereas group D2 received 9 GEN-001 capsules with dietary adjustment. All groups received a single dose. Fecal samples were collected 2 days before GEN-001 administration to 7 days after for untargeted metabolomics and gut microbial metagenomic analyses; blood samples were collected simultaneously for immunogenicity analysis. Levels of phenylalanine, tyrosine, cholic acid, deoxycholic acid, and tryptophan were significantly increased at 5-6 days after GEN-001 administration when compared with predose levels. Compared with predose, the relative abundance (%) of Parabacteroides and Alistipes significantly decreased, whereas that of Lactobacillus and Lactococcus increased; Lactobacillus and tryptophan levels were negatively correlated. A single administration of GEN-001 shifted the gut microbiota in healthy volunteers to a more balanced state as evidenced by an increased abundance of beneficial bacteria, including Lactobacillus, and higher levels of the metabolites that have immunogenic properties.

Revisiting the phylogeny of the family Miridae (Heteroptera: Cimicomorpha), with updated insights into its origin and life history evolution.

Heteroptera is one of the most successfully adapted groups on Earth and can be observed in almost every environment. Within the evolution of heteropteran insects, Miridae show remarkable diversity (>11,700 spp.), accounting for a quarter of all Heteroptera. However, their phylogeny is still unclear, and no plausible theory for the driving force of their diversification has been established. In this work, we provide new suggestions for the phylogeny of Miridae using a larger dataset than previous studies. In addition, we suggest an alternative evolutionary history based on newly calibrated divergence dates for Miridae and its subordinate groups, and present probable factors of the family's success in terms of species diversity. The entire dataset comprises 16 outgroups and 188 ingroup taxa including all seven known subfamilies and 37 out of 45 known tribes. Each species is aligned as 3,577 bp with six molecular loci (COI, 16S rRNA, 18S rRNA, 28S rRNA D3 region, H2A, and H3A). Among the molecular markers, we are the first to test histone genes (H2A, H3A) in Miridae. Our results raise the following points about phylogenetic relationships: i) The earliest group to diverge from Miridae was Monaloniini (Bryocorinae). ii) Bryocorinae and Cylapinae are polyphyletic, Deraeocorinae and Orthotylinae also rendered as non-monophyletic group. iii) Termatophylini and Coridromiini separated from Deraeocorinae and Orthotylinae respectively. iv) Four large tribes, Orthotylini, Phylini, Deraeocorini and Mirini are non-monophyletic. The results from our ancestral state reconstruction and divergence date estimation suggest the following: i) Miridae first diverged during the Late Jurassic (approx. 163.4 Mya), and the divergence dates of most subfamilies and tribes overlap with angiosperm radiation, which perhaps synergized their diversification. ii) Ancestral reconstruction results for Miridae reveal it to be predominantly phytophagous and diverge to oligophagy mainly in plant-tissue habitats, which could have allowed the mirids to select optimal tactics as plant-dwellers. iii) The common ancestor of Miridae originated among plant-dwellers mainly on Eudicots, and that tendency was largely maintained, but sporadic host shifts also occurred.

Diabetes severity is strongly associated with the risk of active tuberculosis in people with type 2 diabetes: a nationwide cohort study with a 6-year follow-up.

BACKGROUND: Many have the rising coincidence of diabetes mellitus (DM) and endemic tuberculosis (TB). We evaluated whether the severity of diabetes is associated with an increased risk of active TB infection. METHODS:  Using a nationally representative database from the Korean National Health Insurance System, 2, 489, 718 people with type 2 DM who underwent a regular health checkup during 2009-2012 were followed up until the end of 2018. The diabetes severity score parameters included the number of oral hypoglycemic agents (≥ 3), insulin use, diabetes duration (≥ 5 years), and the presence of chronic kidney disease (CKD) or cardiovascular disease. Each of these characteristics was scored as one point, and their sum (0-5) was used as the diabetes severity score. RESULTS: We identified 21, 231 cases of active TB during a median follow-up of 6.8 years. Each parameter of the diabetes severity score was associated with an increased risk of active TB (all P < 0.001). Insulin use was the most significant factor related to the risk of TB, followed by CKD. The risk of TB increased progressively with increasing diabetes severity score. After adjusting for possible confounding factors, the hazard ratio (95% confidence interval) for TB were 1.23 (1.19-1.27) in participants with one parameter, 1.39 (1.33-1.44) in those with two parameters, 1.65 (1.56-1.73) in those with three parameters, 2.05 (1.88-2.23) in those with four parameters, and 2.62 (2.10-3.27) in those with five parameters compared with participants with no parameters. CONCLUSION: Diabetes severity was strongly associated in a dose-dependent manner with the occurrence of active TB. People with a higher diabetes severity score may be a targeted group for active TB screening.

Effect of haemodialysis on the pharmacokinetics and pharmacodynamics of evogliptin.

AIM: To investigate the possible effect of haemodialysis (HD) on the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of evogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. METHODS: A single-dose, open-label, parallel-group study of eight end-stage renal disease (ESRD) patients and eight matched healthy subjects was conducted. ESRD patients received a single oral dose of evogliptin 5 mg after and before HD with a 2-week washout between each dose, and healthy subjects received a single oral dose of evogliptin 5 mg. Serial blood, dialysate, and urine samples were collected to assess the PK and PD profiles of evogliptin. To compare PK parameters before and after HD, geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were calculated. RESULTS: The GMRs for the maximum concentration and area under the concentration-time curve from time 0 to the last measurable timepoint (AUClast ) of evogliptin when administered before HD compared with after HD were 0.7293 (90% CI 0.6171-0.8620) and 0.9480 (90% CI 0.8162-1.1010), respectively. The maximum DPP-4 inhibitory effect, area under the DPP-4 inhibitory effect-time curve, and time duration of more than 80% DPP-4 inhibition were comparable when evogliptin was administered before and after HD. Compared with healthy subjects, the mean AUClast of evogliptin was approximately 1.4-fold greater in ESRD patients, but the difference is unlikely to affect the safety and efficacy of evogliptin. CONCLUSION: The effect of HD on the PK and PD characteristics of evogliptin was not clinically significant; therefore, dose adjustment according to HD status is not necessary.

Pharmacokinetic and pharmacodynamic interaction of DWP16001, a sodium-glucose cotransporter 2 inhibitor, with gemigliptin and metformin in healthy adults.

AIMS: DWP16001, a novel sodium-glucose cotransporter 2 inhibitor, is under clinical development for the treatment of type 2 diabetes mellitus. This study aimed to explore the pharmacokinetics (PK) and pharmacodynamics interaction of DWP16001 with gemigliptin and metformin. METHODS: A randomized, open-label, 2-sequence, 2-period crossover study was conducted in 34 healthy male subjects. All subjects received a single oral dose of DWP16001 2 mg with and without gemigliptin and metformin (8 days of 50 mg once-daily dose and 1000 mg twice daily dose for gemigliptin and metformin, respectively). Serial blood samples were collected for PK and serum glucose analysis, and timed urine samples were collected to analyse urine glucose excretion (UGE). The PK and pharmacodynamic parameters were analysed by the noncompartmental method. RESULTS: The PK interactions of DWP16001, gemigliptin and metformin were not clinically significant. The geometric mean ratios (with 90% confidence intervals) of coadministration to separate administration for area under the time-concentration curves were 1.04 (1.02-1.06), 1.03 (0.98-1.09) and 1.17 (1.12-1.22), for gemigliptin, metformin and DWP16001 respectively. The UGE induced by DWP16001 was not affected by the coadministration of gemigliptin and metformin. CONCLUSION: The results suggest that the DWP16001 could be added to metformin and gemigliptin combination therapy without dose adjustment.

Pharmacokinetic and pharmacodynamic interaction between DWP16001, an sodium-glucose cotransporter 2 inhibitor and metformin in healthy subjects.

AIMS: DWP16001 is a novel sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes with selective and sustained sodium-glucose cotransporter 2 inhibition. We aimed to evaluate whether the coadministration of DWP16001 and metformin causes any changes in pharmacokinetics (PK) or pharmacodynamics (PD). METHODS: A randomized, open-label, single- and multiple-dose, 2-sequence, crossover study was conducted in healthy male subjects. Subjects received the following treatments: a single oral dose of DWP16001 (DWP) 2 mg, metformin immediate release 1000 mg (MET) twice daily for 7 days and a single oral dose of DWP and MET at steady-state for metformin (DWP+MET). Serial blood and interval urine were collected for PK and PD analyses. Safety and tolerability profiles were assessed throughout the study. RESULTS: DWP+MET displayed increased peak concentration and area under the concentration-time curve from time 0 to time of the last quantifiable concentration compared with DWP (per standard bioequivalence boundaries, 0.8-1.25); the geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were 1.22 (1.13-1.31) and 1.09 (1.05-1.14), respectively. DWP+MET and MET showed similar peak concentration and area under the concentration-time curve within a dosing interval at steady state for metformin; the GMRs and 90% CIs were 0.98 (0.90-1.06) and 1.05 (0.98-1.13), respectively. The amount of urinary glucose excretion from time 0 to 144 h was also comparable between DWP+MET and DWP (GMR and 90% CI; 0.99, 0.94-1.05). CONCLUSION: The results suggest that DWP16001 and metformin could be coadministered without clinically relevant PK and PD interactions.

Automatic Depression Detection Using Smartphone-Based Text-Dependent Speech Signals: Deep Convolutional Neural Network Approach.

BACKGROUND: Automatic diagnosis of depression based on speech can complement mental health treatment methods in the future. Previous studies have reported that acoustic properties can be used to identify depression. However, few studies have attempted a large-scale differential diagnosis of patients with depressive disorders using acoustic characteristics of non-English speakers. OBJECTIVE: This study proposes a framework for automatic depression detection using large-scale acoustic characteristics based on the Korean language. METHODS: We recruited 153 patients who met the criteria for major depressive disorder and 165 healthy controls without current or past mental illness. Participants' voices were recorded on a smartphone while performing the task of reading predefined text-based sentences. Three approaches were evaluated and compared to detect depression using data sets with text-dependent read speech tasks: conventional machine learning models based on acoustic features, a proposed model that trains and classifies log-Mel spectrograms by applying a deep convolutional neural network (CNN) with a relatively small number of parameters, and models that train and classify log-Mel spectrograms by applying well-known pretrained networks. RESULTS: The acoustic characteristics of the predefined text-based sentence reading automatically detected depression using the proposed CNN model. The highest accuracy achieved with the proposed CNN on the speech data was 78.14%. Our results show that the deep-learned acoustic characteristics lead to better performance than those obtained using the conventional approach and pretrained models. CONCLUSIONS: Checking the mood of patients with major depressive disorder and detecting the consistency of objective descriptions are very important research topics. This study suggests that the analysis of speech data recorded while reading text-dependent sentences could help predict depression status automatically by capturing the characteristics of depression. Our method is smartphone based, is easily accessible, and can contribute to the automatic identification of depressive states.

Long-Term Risk of Cardiovascular Disease Among Type 2 Diabetes Patients According to Average and Visit-to-Visit Variations of HbA1c Levels During the First 3 Years of Diabetes Diagnosis.

BACKGROUND: It remains unclear whether a combination of glycemic variability and glycated hemoglobin (HbA1c) status leads to a higher incidence of cardiovascular disease (CVD). Therefore, to investigate CVD risk according to the glucose control status during early diabetes, we examined visit-to-visit HbA1c variability among patients with type 2 diabetes (T2DM). METHODS: In this 9-year retrospective study, we measured HbA1c levels at each visit and tracked the change in HbA1c levels for 3 years after the first presentation (observation window) in newly diagnosed T2DM patients. We later assessed the occurrence of CVD in the last 3 years (target outcome window) of the study period after allowing a 3-year buffering window. The HbA1c variability score (HVS; divided into quartiles, HVS_Q1-4) was used to determine visit-to-visit HbA1c variability. RESULTS: Among 4,817 enrolled T2DM patients, the mean HbA1c level was < 7% for the first 3 years. The group with the lowest HVS had the lowest rate of CVD (9.4%; 104/1,109 patients). The highest incidence of CVD of 26.7% (8/30 patients) was found in HVS [≥ 9.0%]_Q3, which was significantly higher than that in HVS [6.0-6.9%]_Q1 (P = 0.006), HVS [6.0-6.9%]_Q2 (P = 0.013), HVS [6.0-6.9%]_Q3 (P = 0.018), and HVS [7.0-7.9%]_Q3 (P = 0.040). CONCLUSION: To our knowledge, this is the first long-term study to analyze the importance of both HbA1c change and visit-to-visit HbA1c variability during outpatient visits within the first 3 years. Lowering glucose levels during early diabetes may be more critical than reducing visit-to-visit HbA1c variability.

Hierarchical Area-Based and Path-Based Heuristic Approaches for Multirobot Coverage Path Planning with Performance Analysis in Surveillance Systems.

In this study, we present a systematic exploration of hierarchical designs for multirobot coverage path planning (MCPP) with a special focus on surveillance applications. Unlike conventional studies centered on cleaning tasks, our investigation delves into the realm of surveillance problems, specifically incorporating the sensing range (SR) factor equipped on the robots. Conventional path-based MCPP strategies considering SR, primarily rely on naive approaches, generating nodes (viewpoints) to be visited and a global path based on these nodes. Therefore, our study proposes a general MCPP framework for surveillance by dealing with path-based and area-based structures comprehensively. As the traveling salesman problem (TSP) solvers, our approach incorporates not the naive approach but renowned and powerful algorithms such as genetic algorithms (GAs), and ant colony optimization (ACO) to enhance the planning process. We devise six distinct methods within the proposed MCPP framework. Two methods adopt area-based approaches which segments areas via a hierarchical max-flow routing algorithm based on SR and the number of robots. TSP challenges within each area are tackled using a GA or ACO, and the result paths are allocated to individual robots. The remaining four methods are categorized by the path-based approaches with global-local structures such as GA-GA, GA-ACO, ACO-GA, and ACO-ACO. Unlike conventional methods which requires a global path, we further incorporate ACO- or GA-based local planning. This supplementary step at the local level enhances the quality of the path-planning results, particularly when dealing with a large number of nodes, by preventing any degradation in global path-planning outcomes. An extensive comparative analysis is conducted to evaluate the proposed framework based on execution time, total path length, and idle time. The area-based approaches tend to show a better execution time and overall path length performance compared to the path-based approaches. However, the path-based MCPP methods have the advantage of having a smaller idle time than the area-based MCPP methods. Our study finds that the proposed area-based MCPP method excels in path planning, while the proposed path-based MCPP method demonstrates superior coverage balance performance. By selecting an appropriate MCPP structure based on the specific application requirements, leveraging the strengths of both methodologies, efficient MCPP execution becomes attainable. Looking forward, our future work will focus on tailoring these MCPP structures to diverse real-world conditions, aiming to propose the most suitable approach for specific applications.

Artificial-Neural-Network-Driven Innovations in Time-Varying Process Diagnosis of Low-K Oxide Deposition.

To address the challenges in real-time process diagnosis within the semiconductor manufacturing industry, this paper presents a novel machine learning approach for analyzing the time-varying 10th harmonics during the deposition of low-k oxide (SiOF) on a 600 Å undoped silicate glass thin liner using a high-density plasma chemical vapor deposition system. The 10th harmonics, which are high-frequency components 10 times the fundamental frequency, are generated in the plasma sheath because of their nonlinear nature. An artificial neural network with a three-hidden-layer architecture was applied and optimized using k-fold cross-validation to analyze the harmonics generated in the plasma sheath during the deposition process. The model exhibited a binary cross-entropy loss of 0.1277 and achieved an accuracy of 0.9461. This approach enables the accurate prediction of process performance, resulting in significant cost reduction and enhancement of semiconductor manufacturing processes. This model has the potential to improve defect control and yield, thereby benefiting the semiconductor industry. Despite the limitations imposed by the limited dataset, the model demonstrated promising results, and further performance improvements are anticipated with the inclusion of additional data in future studies.

Diagnosing Time-Varying Harmonics in Low-k Oxide Thin Film (SiOF) Deposition by Using HDP CVD.

This study identified time-varying harmonic characteristics in a high-density plasma (HDP) chemical vapor deposition (CVD) chamber by depositing low-k oxide (SiOF). The characteristics of harmonics are caused by the nonlinear Lorentz force and the nonlinear nature of the sheath. In this study, a noninvasive directional coupler was used to collect harmonic power in the forward and reverse directions, which were low frequency (LF) and high bias radio frequency (RF). The intensity of the 2nd and 3rd harmonics responded to the LF power, pressure, and gas flow rate introduced for plasma generation. Meanwhile, the intensity of the 6th harmonic responded to the oxygen fraction in the transition step. The intensity of the 7th (forward) and 10th (in reverse) harmonic of the bias RF power depended on the underlying layers (silicon rich oxide (SRO) and undoped silicate glass (USG)) and the deposition of the SiOF layer. In particular, the 10th (reverse) harmonic of the bias RF power was identified using electrodynamics in a double capacitor model of the plasma sheath and the deposited dielectric material. The plasma-induced electronic charging effect on the deposited film resulted in the time-varying characteristic of the 10th harmonic (in reverse) of the bias RF power. The wafer-to-wafer consistency and stability of the time-varying characteristic were investigated. The findings of this study can be applied to in situ diagnosis of SiOF thin film deposition and optimization of the deposition process.

Role of mTORC2 in biphasic regulation of brown fat metabolism in response to mild and severe cold.

Nonshivering thermogenesis is essential for mammals to maintain body temperature. According to the canonical view, temperature is sensed by cutaneous thermoreceptors and nerve impulses transmitted to the hypothalamus, which generates sympathetic signals to ß-adrenergic receptors in brown adipocytes. The energy for heat generation is primarily provided by the oxidation of fatty acids derived from triglyceride hydrolysis and cellular uptake. Fatty acids also activate the uncoupling protein, UCP1, which creates a proton leak that uncouples mitochondrial oxidative phosphorylation from ATP production, resulting in energy dissipation as heat. Recent evidence supports the idea that in response to mild cold, ß-adrenergic signals stimulate not only lipolysis and fatty acid oxidation, but also act through the mTORC2-Akt signaling module to stimulate de novo lipogenesis. This opposing anabolic effect is thought to maintain lipid fuel stores during increased catabolism. We show here, using brown fat-specific Gs-alpha knockout mice and cultured adipocytes that, unlike mild cold, severe cold directly cools brown fat and bypasses ß-adrenergic signaling to inhibit mTORC2. This cell-autonomous effect both inhibits lipogenesis and augments UCP1 expression to enhance thermogenesis. These findings suggest a novel mechanism for overriding ß-adrenergic-stimulated anabolic activities while augmenting catabolic activities to resolve the homeostatic crisis presented by severe cold.

A Phase 1 Study To Evaluate Safety and Pharmacokinetics following Administration of Single and Multiple Doses of the Antistaphylococcal Lysin LSVT-1701 in Healthy Adult Subjects.

Thirty-two healthy male subjects (8 per cohort) were randomized 6:2 to active:placebo. LSVT-1701, an antistaphylococcal lysin, was administered intravenously as a 6-mg/kg single dose and as 1.5, 3, and 4.5 mg/kg twice daily for 4 days. LSVT-1701 exposure increased in a greater than dose proportional manner and did not accumulate. Treatment-emergent adverse events (TEAEs) were predominantly of mild intensity. The most common TEAEs were chills, pyrexia, headache, infusion site events, cough, rhinorrhea, and increases in C-reactive protein. (This study has been registered at ClinicalTrials.gov under identifier NCT03446053.).