Direct Synthesis of Aliphatic Polyesters with Pendant Hydroxyl Groups from Bio-Renewable Monomers: A Reactive Precursor for Functionalized Biomaterials.

Introducing desired functionalities into biomaterials is an effective way to obtain functionalized biomaterials. A versatile platform with the possibility of postsynthesis functionalization is highly desired but challenging in biomedical engineering. In this work, linear aliphatic polyesters with pendant hydroxyl (PEOH) groups were directly synthesized using renewable malic acid/tartaric acid as raw materials under mild conditions through the polyesterification reaction promoted by 1,1,3,3-tetramethylguanidine (TMG). The hydroxyl groups on PEOH provide an active stepping stone for the fabrication of demanded functionalized polyesters. We demonstrated the possibility of the PEOH as a reactive precursor for functional group transformation, coupling of bioactive molecules, and formation of crosslinking networks. Moreover, a theranostic nanoplatform (mPEG-b-(P7-asp&TPV)-b-mPEG NPs) was synthesized using PEOH as a reactive stepping stone by the programmable combination of the above functionalization methods. Overall, these hydroxyl-containing polyesters have great potential in biological applications.

The combination of body mass index and fasting plasma glucose is associated with type 2 diabetes mellitus in Japan: a secondary retrospective analysis.

Background: Body mass index (BMI) and fasting plasma glucose (FPG) are known risk factors for type 2 diabetes mellitus (T2DM), but data on the prospective association of the combination of BMI and FPG with T2DM are limited. This study sought to characterize the association of the combination of BMI and FPG (ByG) with T2DM. Methods: The current study used the NAGALA database. We categorized participants by tertiles of ByG. The association of ByG with T2DM was expressed with hazard ratios (HRs) with 95% confidence intervals (CIs) after adjustment for potential risk factors. Results: During a median follow-up of 6.19 years in the normoglycemia cohort and 5.58 years in the prediabetes cohort, the incidence of T2DM was 0.75% and 7.79%, respectively. Following multivariable adjustments, there were stepwise increases in T2DM with increasing tertiles of ByG. After a similar multivariable adjustment, the risk of T2DM was 2.57 (95% CI 2.26 - 2.92), 1.97 (95% CI 1.53 - 2.54) and 1.50 (95% CI 1.30 - 1.74) for a per-SD change in ByG in all populations, the normoglycemia cohort and the prediabetes cohort, respectively. Conclusion: ByG was associated with an increased risk of T2DM in Japan. The result reinforced the importance of the combination of BMI and FPG in assessing T2DM risk.

Emerging insights into cuproptosis and copper metabolism: implications for age-related diseases and potential therapeutic strategies.

The expanding geriatric population, whose predisposition toward disabling morbidities and age-related diseases (ARD) is well-documented, has become a paramount social issue, exerting an onerous burden on both the healthcare industry and wider society. ARD manifest as the progressive deterioration of bodily tissues and organs, eventually resulting in the failure of these vital components. At present, no efficacious measures exist to hinder the onset of ARD. Copper, an essential trace element, is involved in a wide range of physiological processes across different cell types. In recent research, a novel variant of copper-dependent cell death, termed cuproptosis, has been identified. This mode of cellular demise stands apart from previously recognized types of cell death. Cuproptosis occurs when copper binds with acyl-CoA synthetase in the tricarboxylic acid (TCA) cycle, resulting in protein aggregation and protein toxicity stress, ultimately leading to cell death. In this paper, we provide a concise overview of the current understanding concerning the metabolism of copper, copper-related diseases, the hallmarks of copper toxicity, and the mechanisms that regulate copper toxicity. Additionally, we discuss the implications of cuproptosis mutations in the development of ARD, as well as the potential for targeting cuproptosis as a treatment for ARD.

What Strengthens Protein-Protein Interactions: Analysis and Applications of Residue Correlation Networks.

Identifying critical residues in protein-protein binding and efficiently designing stable and specific protein binders to target another protein is challenging. In addition to direct contacts in a protein-protein binding interface, our study employs computation modeling to reveal the essential network of residue interaction and dihedral angle correlation critical in protein-protein recognition. We propose that mutating residues regions exhibited highly correlated motions within the interaction network can efficiently optimize protein-protein interactions to create tight and selective protein binders. We validated our strategy using ubiquitin (Ub) and MERS coronaviral papain-like protease (PLpro) complexes, where Ub is one central player in many cellular functions and PLpro is an antiviral drug target. Molecular dynamics simulations and experimental assays were used to predict and verify our designed Ub variant (UbV) binders. Our designed UbV with 3 mutated residues resulted in a ~3,500-fold increase in functional inhibition, compared with the wild-type Ub. Further optimization by incorporating 2 more residues within the network, the 5-point mutant achieved a KD of 1.5 nM and IC50 of 9.7 nM. The modification led to a 27,500-fold and 5,500-fold enhancements in affinity and potency, respectively, as well as improved selectivity, without destabilizing the UbV structure. Our study illustrates the importance of residue correlation and interaction networks in protein-protein interaction and introduces a new approach that can effectively design high affinity protein binder for cell biology studies and future therapeutic solution.

Relationship between lipid accumulation product and new-onset diabetes in the Japanese population: a retrospective cohort study.

Background: Diabetes has become a global public health problem. Obesity has been established as a risk factor for diabetes. However, it remains unclear which of the obesity indicators (BMI, WC, WhtR, ABSI, BRI, LAP, VAI) is more appropriate for monitoring diabetes. Therefore, the objective of this investigation is to compare the strength of the association of these indicators and diabetes and reveal the relationship between LAP and diabetes. Methods: 15,252 people took part in this research. LAP was quartered and COX proportional risk model was applied to explore the relationship between LAP and new-onset diabetes. Smooth curve fitting was employed to investigate the non-linear link between LAP and diabetes mellitus. Finally, the receiver operating characteristic (ROC) curve was used to evaluate the predictive ability of the aforementioned indicators for diabetes. Results: After adjusting for confounding factors, multiple linear regression analysis showed that each unit increase in LAP was associated with a 76.8% increase in the risk of developing diabetes (HR=1.768, 95% CI: 1.139 to 2.746, P=0.011). In addition, LAP predicted new-onset diabetes better than other indicators, and the AUC was the largest [HR: 0.713, 95% CI: 0.6806-0.7454, P<0.001, in women; HR: 0.7922, 95% CI: 0.7396-0.8447; P<0.001, in men]. When LAP was used as a lone predictor, its AUC area was largest both men and women. However, after adding classical predictors (FPG, HbA1c, SBP, exercise, age) to the model, the LAP is better than the ABSI, but not better than the other indicators when compared in pairs. Conclusions: High levels of LAP correlate very strongly with diabetes and are an important risk factor for diabetes, especially in women, those with fatty liver and current smokers. LAP was superior to other indicators when screening for diabetes susceptibility using a single indicator of obesity, both in men and in women. However, when obesity indicators were added to the model together with classical predictors, LAP did not show a significant advantage over other indicators, except ABSI.

What Strengthens Protein-Protein Interactions: Analysis and Applications of Residue Correlation Networks.

Identifying critical residues in protein-protein binding and efficiently designing stable and specific protein binders is challenging. In addition to direct contacts in a protein-protein binding interface, our study employs computation modeling to reveal the essential network of residue interaction and dihedral angle correlation critical in protein-protein recognition. We propose that mutating residues regions exhibited highly correlated motions within the interaction network can efficiently optimize protein-protein interactions to create tight and selective protein binders. We validated our strategy using ubiquitin (Ub) and MERS coronaviral papain-like protease (PLpro) complexes, where Ub is one central player in many cellular functions and PLpro is an antiviral drug target. Our designed UbV with 3 mutated residues resulted in a ~3,500-fold increase in functional inhibition, compared with the wild-type Ub. Further optimization by incorporating 2 more residues within the network, the 5-point mutant achieved a KD of 1.5 nM and IC50 of 9.7 nM. The modification led to a 27,500-fold and 5,500-fold enhancements in affinity and potency, respectively, as well as improved selectivity, without destabilizing the UbV structure. Our study highlights residue correlation and interaction networks in protein-protein interaction, introduces an effective approach to design high affinity protein binders for cell biology and future therapeutics solutions.

What Strengthens Protein-Protein Interactions: Analysis and Applications of Residue Correlation Networks.

Identifying residues critical to protein-protein binding and efficient design of stable and specific protein binders are challenging tasks. Extending beyond the direct contacts in a protein-protein binding interface, our study employs computational modeling to reveal the essential network of residue interactions and dihedral angle correlations critical in protein-protein recognition. We hypothesized that mutating residues exhibiting highly correlated dynamic motion within the interaction network could efficiently optimize protein-protein interactions to create tight and selective protein binders. We tested this hypothesis using the ubiquitin (Ub) and MERS coronaviral papain-like protease (PLpro) complex, since Ub is a central player in multiple cellular functions and PLpro is an antiviral drug target. Our designed ubiquitin variant (UbV) hosting three mutated residues displayed a ∼3,500-fold increase in functional inhibition relative to wild-type Ub. Further optimization of two C-terminal residues within the Ub network resulted in a KD of 1.5 nM and IC50 of 9.7 nM for the five-point Ub mutant, eliciting 27,500-fold and 5,500-fold enhancements in affinity and potency, respectively, as well as improved selectivity, without destabilizing the UbV structure. Our study highlights residue correlation and interaction networks in protein-protein interactions, and introduces an effective approach to design high-affinity protein binders for cell biology research and future therapeutics.

Non-invasive auditory and visual stimulation attenuates α-Synuclein deposition and improves motor and non-motor symptoms in PD mice.

Parkinson's disease (PD) is characterized by dopaminergic neuron loss and α-synuclein (α-Syn) aggregates, but lacks effective treatments for the disease progression and non-motor symptoms. Recently, combined 40 Hz auditory and visual stimulation is emerging as a promising non-invasive method to decrease amyloid and improve cognition in Alzheimer's disease (AD), but whether this treatment can modify α-Syn-induced PD pathology remains unclear. Here we evaluated the effects of chronic exposure to 40 Hz and 80 Hz auditory and visual stimulation on α-Syn accumulation and the functional effects of 40 Hz stimulation on motor, cognitive and mood dysfunctions in PD mice. We found that 40 Hz and 80 Hz auditory and visual stimulation activated multiple cortical regions, entrained gamma oscillations and markedly attenuated p-α-Syn deposition in neurons, but not astrocytes, microglial cells in the primary and secondary motor cortex (M1, M2), medial prefrontal cortex (mPFC) and the striatum. Moreover, 40 Hz stimulation significantly reduced cell apoptosis in M1, increased the neuromuscular strength selectively in PD mice, which correlated with p-α-Syn reduction in the motor cortex. In addition, 40 Hz stimulation improved spatial working memory and decreased depressive-like behaviors specifically in PD mice, which correlated with p-α-Syn reduction in mPFC, but promoted anxiety-like behaviors and increased stress-related adreno-cortico-tropic-hormone (ACTH), corticosterone levels in the plasma of normal mice. Collectively, we demonstrated that chronic multisensory gamma stimulation (40 Hz and 80 Hz) significantly attenuates α-Syn deposition in neurons of the interconnected cortex and 40 Hz stimulation improved neuromuscular strength, spatial working memory, and reduced depressive behaviors, which support its non-invasive therapeutic potential for modifying PD progression and treating non-motor symptoms.

A U-shaped association between the triglyceride to high-density lipoprotein cholesterol ratio and the risk of incident type 2 diabetes mellitus in Japanese men with normal glycemic levels: a population-based longitudinal cohort study.

Background: Several studies have verified that a high baseline TG/HDL-C ratio is a risk factor for incident type 2 diabetes mellitus (T2DM). However, for low baseline TG/HDL-C levels, the findings were inconsistent with ours. In addition, the association between baseline TG/HDL-C ratio and the risk of incident T2DM in Japanese men with normal glycemic levels is unclear. As a result, our study further investigated the relationship between baseline TG/HDL-C and the risk of incident T2DM in Japanese men with normal glycemic levels. Methods: This was a secondary longitudinal cohort study. We selected 7,684 male participants between 2004 and 2015 from the NAGALA database. A standardized Cox regression model and two piecewise Cox regression models were used to explore the relationship between the baseline high-density lipoprotein cholesterol ratio (TG/HDL-C) and incident T2DM. Results: During a median follow-up of 2,282 days, 162 men developed incident T2DM. In the adjusted model, the baseline TG/HDL-C ratio was strongly associated with the risk of incident T2DM, and no dose-dependent positive association was observed between the baseline TG/HDL-C ratio and incidence of T2DM throughout the baseline TG/HDL-C quartiles. Two-piecewise linear regression analysis showed a U-shaped association between baseline TG/HDL-C ratio and incidence of incident T2DM. A baseline TG/HDL-C ratio below 1.188 was negatively associated with incident T2DM (H.R. = 0.105, 95% CI = 0.025, 0.451; P = 0.002). In contrast, a baseline TG/HDL-C ratio >1.188 was positively associated with incident T2DM (H.R. = 1.248, 95% CI = 1.113, 1.399; P<0.001). The best TG/HDL-C threshold for predicting incident T2DM was 1.8115 (area under the curve, 0.6837). Conclusion: A U-shaped relationship between baseline TG/HDL-C ratio and incident T2DM in Japanese men with normal glycemic levels was found.

Robust Design of Effective Allosteric Activators for Rsp5 E3 Ligase Using the Machine Learning Tool ProteinMPNN.

We used the deep learning tool ProteinMPNN to redesign ubiquitin (Ub) as a specific and functionally stimulating/enhancing binder of the Rsp5 E3 ligase. We generated 20 extensively mutated─up to 37 of 76 residues─recombinant Ub variants (UbVs), named R1 to R20, displaying well-folded structures and high thermal stabilities. These UbVs can also form stable complexes with Rsp5, as predicted using AlphaFold2. Three of the UbVs bound to Rsp5 with low micromolar affinity, with R4 and R12 effectively enhancing the Rsp5 activity six folds. AlphaFold2 predicts that R4 and R12 bind to Rsp5's exosite in an identical manner to the Rsp5-Ub template, thereby allosterically activating Rsp5-Ub thioester formation. Thus, we present a virtual solution for rapidly and cost-effectively designing UbVs as functional modulators of Ub-related enzymes.

Triglyceride Glucose-Body Mass Index and Risk of Incident Type 2 Diabetes Mellitus in Japanese People With Normal Glycemic Level: A Population-Based Longitudinal Cohort Study.

Background: It has been proved that triglyceride glucose-body mass index (TyG-BMI) is a readily available and clinically significant indicator of insulin resistance (IR). Nevertheless, the association between TyG-BMI and incident Type 2 diabetes mellitus (T2DM) remains uncertain. This study aimed to study the relationship between TyG-BMI and T2DM and explore the predictive characteristics of TyG-BMI. Methods: Our study was conducted as a longitudinal cohort study. 8,430 men and 7,034 women were enrolled and analyzed. They were both non-diabetic subjects with normal glycemic levels. Follow-up lasted for 13 years, from 1994 to 2016. To make the number of TyG-BMI in each group similar, the subjects were divided into four groups with 3866 subjects in each group. Results: During the 13-year follow-up period, 373 subjects were diagnosed with incident T2DM. Our multivariate Cox regression analysis revealed that TyG-BMI was an independent predictor of incident T2DM. In addition, our research identified four specific groups, young people (18-44 years old), women, the non-hypertensive population and non-drinkers were at significantly higher risk of developing TyG-BMI-related diabetes (P-interaction< 0.05). The best threshold TyG-BMI for predicting incident T2DM was 197.2987 (area under the curve 0.7738). Conclusions: Our longitudinal cohort study demonstrated the positive correlation between baseline TyG-BMI and risk of incident T2DM in Japanese with normal glycemic levels, and this risk was significantly higher in the young people, women, the non-hypertensive population and non-drinkers.

Biodegradable and Light-Responsive Polymeric Nanoparticles for Environmentally Safe Herbicide Delivery.

The low utilization efficiency of pesticides exerts an adverse impact on the environment and human health. Polymer-related controlled-release nanosized pesticide systems provide a promising and efficient way to overcome the problem. In this work, a biodegradable and light-responsive amphiphilic polymer was synthesized via 1,1,3,3-tetramethylguanidine-promoted polyesterification under mild conditions (low temperature, no vacuum, and no inert gas protection). We used this polymer to fabricate a light-triggered controlled-release nanosized pesticide system. The herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), was selected as a model drug to show its potential as a controlled-release pesticide system. It was found that the 2,4-D-loaded polymeric nanoparticles were stable without the treatment of UV, while the release rate of 2,4-D from the nanoparticles gradually increased after treatment with UV light. Pot trial showed that the 2,4-D-loaded polymer nanoparticles showed a good herbicidal effect. Finally, toxicity studies suggested that the polymer can reduce toxicity to nontarget organisms.

Residual Risk of Coronary Atherosclerotic Heart Disease and Severity of Coronary Atherosclerosis Assessed by ApoB and LDL-C in Participants With Statin Treatment: A Retrospective Cohort Study.

Background: Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipid-lowering therapy on the management of hypercholesterolemia in the United States and European guidelines, while apolipoprotein B (apoB) is the secondary target. The objective was to determine if elevated levels of apoB is superior to LDL-C in assessing residual risk of coronary atherosclerotic heart disease and severity of coronary atherosclerosis in participants with statin treatment. Methods: This study included 131 participants with statin treatment. The generalized linear model and relative risk regression (generalized linear Poisson model with robust error variance) were used to analyze the association of the levels of apoB and LDL-C with the severity of coronary atherosclerosis and residual risk of coronary atherosclerotic heart disease. Results: Categorizing apoB and LDL-C based on tertiles, higher levels of apoB were significantly associated with the severity of coronary atherosclerosis (Ptrend = 0.012), whereas no such associations were found for elevated levels of LDL-C (Ptrend = 0.585). After multivariate adjustment, higher levels of apoB were significantly associated with residual risk of coronary atherosclerotic heart disease. When compared with low-level apoB (≤0.66 g/L), the multivariate adjusted RR and 95% CI of intermediate-level apoB (0.67-0.89 g/L) and high-level apoB (≥0.90 g/L) were 1.16 (1.01, 1.33) and 1.31 (1.08, 1.60), respectively (Ptrend = 0.011). There was a 45% increased residual risk of coronary atherosclerotic heart disease per unit increment in natural log-transformed apoB (Ptrend <0.05). However, higher levels of LDL-C were not significantly associated with residual risk of coronary atherosclerotic heart disease. When compared with low-level LDL-C (≤1.56 mmol/L), the multivariate adjusted RR and 95% CI of intermediate-level LDL-C (1.57-2.30 mmol/L) and high-level LDL-C (≥2.31 mmol/L) were 0.99 (0.84, 1.15) and 1.10 (0.86, 1.42), respectively (Ptrend = 0.437). Similar results were observed in the stratified analyses and sensitivity analyses. No significant interactions were detected for both apoB and LDL-C (all Pinteraction>0.05). Conclusions: Elevated apoB are superior in assessing the residual risk of coronary atherosclerotic heart disease and severity of coronary atherosclerosis in participants with statin treatment.

Direct reprogramming of hepatocytes into insulin-producing cells for anti-diabetic treatment by ultrasound-targeted microbubble destruction enhanced hydrodynamic gene delivery.

In animal models, hepatocytes can be reprogrammed into insulin-producing cells (IPCs) for a novel antidiabetic treatment. However, the potential for an immunologic reaction and issues with gene integration of the viral vehicle hamper system efficacy. Here, we adopted an Ultrasound Targeted Microbubble Destruction (UTMD) enhanced hydrodynamic gene delivery system in a streptozotocin induced mouse diabetic model to examine its treatment effect. After transfection by combining UTMD and hydrodynamic injection, accumulated luciferase signal was only found in the liver with optimal signal intensity. Liver function tests showed an increase in alanine aminotransferase level followed by a decrease to normal levels. Then this new gene delivery system was used to deliver Pdx1, Neurog3, and MafA plasmids into diabetic mice. We found that glucose levels gradually decreased, and insulin levels increased in transfected diabetic mice compared to controls. Glucose intolerance in transfected mice was alleviated. Gene expression assay confirmed the reprogramming of hepatocytes. We demonstrated the feasibility of repeated plasmid transfection in vivo by UTMD enhanced hydrodynamic gene delivery system.

Capsular adhesion to intraocular lens in highly myopic eyes evaluated in vivo using ultralong-scan-depth optical coherence tomography.

PURPOSE: To evaluate the in vivo capsular apposition to the intraocular lens (IOL) in subjects with high myopia by ultralong-scan-depth optical coherence tomography (OCT). DESIGN: Prospective observational case series. METHODS: Forty eyes from 40 cataract patients scheduled for phacoemulsification surgery at the Affiliated Eye Hospital, Wenzhou Medical College were studied, of which 20 eyes were highly myopic (axial length >26 mm) and 20 eyes were emmetropic (22 mm < axial length <24.5 mm). All eyes were examined with a custom-built ultralong-scan-depth OCT at 4 hours, 1 day, 7 days, 14 days, and 28 days after surgery. RESULTS: Anterior capsule contact with the IOL was significantly delayed in highly myopic eyes. Complete apposition of the posterior capsule with the IOL was significantly less common among highly myopic eyes than in emmetropic eyes (4 vs 16 eyes; P = .001). Posterior capsule adhesion to the IOL was inversely correlated with axial length (r = -0.494, P < .001, nonparametric Spearman test). The 3 types of complete adhesive capsular bend configurations observed were classified as anterior adhesion, middle adhesion, and posterior adhesion. Incomplete adhesion patterns were classified as funnel adhesion, parallel adhesion, and furcate adhesion. Five highly myopic eyes had slight posterior capsule opacification (PCO) at the last follow-up, as did 1 emmetropic eye. CONCLUSIONS: Ultralong-scan-depth OCT revealed weak capsular adhesion and incompletely adhesive types of capsular bend in highly myopic eyes. These features presumably increase the likelihood of PCO during the early postoperative period.