Hydrogel Rivet with Unidirectional Shape Morphing for Flexible Mechanical Assembly.

Integrating diverse materials and functions into highly additive produce has piqued global interest due to the increasing demands of intelligent soft robotics. Nevertheless, existing assembly techniques, especially supramolecular assembly which heavily rely on precise chemical design and specific recognition, may prove inadequate when confronted with diverse external demands. Inspired by the traditional mechanical assembly, rivet connection, herein, a thermo-responsive hydrogel with unidirectional shape-morphing is fabricated and a stable mechanical assembly is constructed by emulating the rivet connection mechanism. This system employed poly(acrylamide-co-acrylic acid) [P(AAm-co-AAc)] to induce continuous swelling and hexylamine-modified polyvinyl alcohol (PVA-C6) as a molecular switch to control the swelling process. The hydrogel rivet, initially threaded through pre-fabricated hollows in two components. Subsequently, upon the disassociation of alkane chains the molecular switch would activate, inducing swelling and stable mechanical assembly via anchor structures. Moreover, to enhance the assembly strength, knots are introduced to enhance assembly strength, guiding localized stress release for programmed deformations. Additionally, the system can be remotely controlled using near-infrared light (NIR) by incorporating photo-thermal nanoparticles. This work presents a universal and efficient strategy for constructing stable mechanical assemblies without compromising overall softness, offering significant potential for the fabrication of integrated soft robots.

Causal effect of atrial fibrillation on pulmonary embolism: a mendelian randomization study.

Atrial fibrillation (AF) can increase thrombosis, especially arterial thrombosis, and some studies show that AF patients have a higher risk of developing pulmonary embolism (PE). The objective of our study is to investigate whether there is a direct causal effect of AF on PE. A two-sample Mendelian randomization (MR) approach was utilized to determine whether there is a causal relationship between AF and PE. European population-based consortia provided statistical data on the associations between Single Nucleotide Polymorphisms (SNPs) and relevant traits. The AF dataset was obtained from genome-wide association studies (GWAS) comprising 60,620 cases and 970,216 controls, while a GWAS of 1846 cases and 461,164 controls identified genetic variations associated with PE. Estimation of the causal effect was mainly performed using the random effects inverse-variance weighted method (IVW). Additionally, other tests such as MR-Egger intercept, MR-PRESSO, Cochran's Q test, "Leave-one-out," and funnel plots were conducted to assess the extent of pleiotropy and heterogeneity. Using 70 SNPs, there was no evidence to suggest an association between genetically predicted AF and risk of PE with multiplicative random-effects IVW MR analysis (odds ratio = 1.0003, 95% confidence interval: 0.9998-1.0008, P = 0.20). A null association was also observed in other methods. MR-Egger regression and MR-PRESSO respectively showed no evidence of directional (intercept, - 2.25; P = 0.94) and horizontal(P-value in the global heterogeneity test = 0.99) pleiotropic effect across the genetic variants. No substantial evidence was found to support the causal role of AF in the development of PE.

Comparison of the clinical outcomes between proximal femoral nail anti-rotation with cement enhancement and hemiarthroplasty among elderly osteoporotic patients with intertrochanteric fracture.

BACKGROUND: The proximal femoral nail anti-rotation (PFNA) with cement enhancement enhances the anchorage ability of internal fixation in elderly with osteoporotic intertrochanteric fracture. However, whether it is superior to hemiarthroplasty is still controversial. The present study aimed to determine which treatment has better clinical outcomes among older patients. METHODS: We retrospectively analyzed 102 elderly patients with osteoporosis who developed intertrochanteric fractures and underwent PFNA combined with cement-enhanced internal fixation (n = 52, CE group), and hemiarthroplasty (n = 50, HA group) from September 2012 to October 2018. All the intertrochanteric fractures were classified according to the AO/OTA classification. Additionally, the operative time, intraoperative blood loss, intraoperative and postoperative blood transfusion rates, postoperative weight-bearing time, hospitalization time, Barthel Index of Activities Daily Living, Harris score of hip function, visual analog (VAS) pain score, and postoperative complications were compared between the two groups. RESULTS: The CE group had significantly shorter operative time, lesser intraoperative blood loss, lower blood transfusion rate, and longer postoperative weight-bearing time than the HA group. The CE group had lower Barthel's Index of Activities of Daily Living, lower Harris' score, and higher VAS scores in the first and third months after surgery than the HA group, but no difference was observed between the two groups from 6 months to 12 months. There was no significant difference in the total post-operative complications between the two groups. CONCLUSION: The use of PFNA combined with a cement-enhanced internal fixation technique led to shorter operative time and lesser intraoperative blood loss and trauma in elderly patients as compared to HA.

Fluorophore position of headgroup-labeled Gb3 glycosphingolipids in lipid bilayers.

Fluorescent lipid probes are an invaluable tool for investigating lipid membranes. In particular, localizing certain receptor lipids such as glycosphingolipids within phase-separated membranes is of pivotal interest to understanding the influence of protein-receptor lipid binding on membrane organization. However, fluorescent labeling can readily alter the phase behavior of a lipid membrane because of the interaction of the fluorescent moiety with the membrane interface. Here, we investigated Gb3 glycosphingolipids, serving as receptor lipids for the protein Shiga toxin, with a headgroup attached BODIPY fluorophore separated by a polyethylene glycol (PEG) spacer of different lengths. We found that the diffusion coefficients of the fluorescently labeled Gb3 species in 1,2-dioleoyl-sn-glycero-3-phosphocholine/Gb3 (98:2, n/n) supported lipid bilayers are unaltered by the PEG spacer length. However, quenching as well as graphene-induced energy transfer experiments indicated that the length of the PEG spacer (n = 3 and n = 13) alters the position of the BODIPY fluorophore. In particular, the graphene-induced energy transfer technique provided accurate end-to-end distances between the fluorophores in the two leaflets of the bilayer thus enabling us to quantify the distance between the membrane interface and the fluorophore with sub-nanometer resolution. The spacer with three oligo ethylene glycol groups positioned the BODIPY fluorophore directly at the membrane interface favoring its interaction with the bilayer and thus may disturb lipid packing. However, the longer PEG spacer (n = 13) separated the BODIPY moiety from the membrane surface by 1.5 nm.

Mimicking Color-Changing Organisms to Enable the Multicolors and Multifunctions of Smart Fluorescent Polymeric Hydrogels.

Fluorescent polymer hydrogels (FPHs) are of significant interest for diverse emerging applications such as visualized sensing, smart display, camouflaging skins, soft actuators/robots, because they can synergize the features of classic fluorescent polymers and hydrogels. With great efforts in the past decades, the major challenge in this field has been believed to be not whether a given FPH of interest can be prepared but how to fabricate robust FPHs with multicolor tunability and multifunctional synergy. Such materials will conceptually minimize the contribution of passive materials to the mass and size of the final system, holding great potential to facilitate multiple applications. To this end, one promising way is to learn from the Nature that has superb capability to forge delicate or sometimes beyond-imagination materials. Chameleons and cephalopods serve as typical examples, which are famous for not only diverse skin color adaptability under changing environmental demands, but also synergistic skin color and body gesture changes to communicate, warn, camouflage, etc. Biological studies revealed their structural color-changing capacity derives from different types of skin chromatophores and their rational multilayer arrangement in under-skin tissues. Besides, their superb ability to heterogeneously integrate soft tissues with disparate functions into topology-optimized architectures has led to various multifunctional performances. Such natural strategies, if replicated and implemented in artificial systems, would significantly benefit and advance the development of robust FPHs for various applications.In this Account, we summarizes the key advances of smart FPHs mainly achieved by our groups. We start by introducing the unique hierarchical multilayer structures of skin chromatophores in structural color-changing reptiles, followed by an in-depth discussion on how a rational integration of bioinspiration and man-made design makes it possible to largely expand the fluorescence color-changing range of smart FPHs to almost cover the whole visible spectrum. Then, to closely mimic the multifunctional behaviors of chameleons and cephalopods, we further develop efficient strategies to introduce supramolecular interactions or heterogeneously integrating smart FPHs with other soft materials with disparate functions, producing a number of multifunctional fluorescent polymeric hydrogel systems. These robust FPHs can find many frontier applications, including bioinspired synergistic color/shape switchable hydrogel actuators/robots, smart systems with on-demand fluorescent patterning capacities for displaying or information encryption, as well as robust chemosensors for important food or environmental analytes. We expect that the discussion presented in this Account would promote better understanding of the discoloration systems in nature, and advance the development of bioinspired color-changing materials.

Development of an Amorphous Solid Dispersion Formulation for Mitigating Mechanical Instability of Crystalline Form and Improving Bioavailability for Early Phase Clinical Studies.

In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by in vitro and in vivo evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.

Fabrication of Dual pH/Reduction-Responsive P(CL-co-ACL)-Based Cross-Linked Polymeric Micelles for PTX Delivery.

To enhance the stability of the polymeric micelles and optimize their drug-controlled release ability, three disulfide-linked polyethylene glycol methyl ether methacrylate-disulfide-poly(ε-caprolactone-co-γ-amine-ε-caprolactone) (PPEGMA-SS-P(CL-co-ACL)) polymers were synthesized and characterized by 1H NMR, GPC, and FT-IR successfully, and their dual pH/reduction-responsive cross-linked polymeric micelles were prepared for paclitaxel (PTX) delivery by using 2,3-dimethylmaleic anhydride (DMMA) as the cross-linking agent. The PTX loading capacity (LC) and encapsulation efficiency (EE) values of the cross-linked micelles formed by PPEGMA8-SS-P(CL47-co-ACL15) achieved were 23.96% and 71.58%, slightly higher than those of un-cross-linked micelles. Both particle sizes of blank micelles and in vitro drug release of PTX-loaded micelles confirmed that compared with those un-cross-linked micelles, the cross-linked micelles were more stable at pH 7.4 + 0 mM DTT, with a PTX cumulative release of 13% at 120 h, while the PTX cumulative release of the cross-linked micelles at pH 5.0 + 10 mM DTT were close to that of un-cross-linked micelles after 60 h, indicating the successful reversible cross-linking and smooth drug release of the cross-linked micelles. The cytotoxicity assay showed that PPEGMA8-SS-P(CL47-co-ACL15) and its cross-linked micelles had low cell cytotoxicity, and both PTX-loaded micelles revealed a certain inhibitory effect on HepG2 cells. These results revealed that the dual pH/reduction-responsive cross-linked polymeric micelles prepared from PPEGMA8-SS-P(CL47-co-DCL15) were a promising candidate for PTX delivery.

Enhancing Thermal Conductivity of hBN/SiC/PTFE Composites with Low Dielectric Properties via Pulse Vibration Molding.

In order to enhance the thermal conductivity of polytetrafluoroethylene (PTFE)-based composites, while maintaining relatively low dielectric constant and dielectric loss for high-frequency and high-speed applications, hexagonal boron nitride (hBN) and silicon carbide (SiC) compounded fillers are filled into the PTFE matrix. The hBN/SiC/PTFE composites are prepared by pulse vibration molding (PVM), and their subsequent thermal conductivities are comparatively investigated. The PVM process with controlled fluctuation in pressure (1 Hz square wave force, 0-20 MPa, at 150 °C) can reduce the sample porosity and surface defects, improve the orientation of hBN, and increase the thermal conductivity by 44.6% compared with that obtained by compression molding. When hBN:SiC (vol) is 3:1, the in-plane thermal conductivity of the composite with 40 vol% filler content is ≈4.83 W m-1  K-1 , which is 40.3% higher than that of hBN/PTFE. Regarding the dielectric properties, hBN/SiC/PTFE maintains a low dielectric constant of 3.27 and a low dielectric loss of 0.0058. The dielectric constants of hBN/SiC/PTFE ternary composites are predicted by using different prediction models, among which the effective medium theory (EMT), is in good agreement with the experimental results. PVM shows great potential in the large-scale preparation of thermal conductive composites for high-frequency and high-speed applications.

Zero-Carbon Emission Chemical Method to Remove Formaldehyde without Catalyst by Highly Porous Polymer Composites at Room Temperature.

Herein, the fabrication of reduced graphene oxide (RGO)-templated polymer composites for chemical removal of gaseous formaldehyde under ambient conditions is presented. The chemical removal of formaldehyde is achieved by a nucleophilic addition reaction between formaldehyde and aminooxy groups on the polymer chain ends to form the oxime bonds with the only byproduct of H2 O. RGO is essential since it not only has an ultralarge surface area but also can act as a perfect template for immobilizing pyrene-terminated and aminooxy-functionalized polymers via strong π-π stacking interactions, while melamine foam provides a three-dimensional skeleton for loading RGO/polymer composites to afford a porous 3D structure for efficient formaldehyde removal. Since the oxime bond can be cleaved into aminooxy group in acidic media, the RGO/polymer composite can be regenerated for repeatable usage, which shows an excellent performance of adsorbing 14 mg of formaldehyde by 100 mg of the polymer at ambient condition.

Application of three-dimensional printing individualized titanium mesh in alveolar bone defects with different Terheyden classifications: A retrospective case series study.

OBJECTIVE: To present the results of guided bone regeneration (GBR) with three-dimensional printing individualized titanium mesh (3D-PITM) applied to alveolar bone defects with different Terheyden classifications and the factors affecting the osteogenic outcome. MATERIALS AND METHODS: Fifty-nine patients, presenting with 61 defect sites, were enrolled between 2018 and 2021. GBR+3D-PITM was obtained with simultaneous or second stage implant placement. The complication rate, the success rate of the bone grafting procedure and the survival rate of the implant were documented. Bone gain, thickness of pseudo-periosteum and peri-implant marginal bone loss (MBL) were measured through digital methods by imaging data (CBCT and X-ray). RESULTS: Out of 61 sites, 20 were exposed (exposure rate: 32.8%). The width, height, and volume bone gain at P3 (mesh removal) were 5.22 ± 3.19 mm, 5.01 ± 2.83 mm, and 588.91 ± 361.23 mm3 , respectively. From P2 (3D-PITM+GBR) to P3 , changes in bone gain were not statistically different in the different Terheyden classifications, the occurrence of exposure (p < .001 for all dimensions) and the different type of pseudo-periosteum (p = .030 for width and p = .002 for height) were significantly correlated with the reduction of bone gain. Terheyden classification of the defect sites was significantly associated with the occurrence of exposure (p = .014) and types of the pseudo-periosteum (p = .015). CONCLUSION: The 3D-PITM can be used in alveolar bone defects with different Terheyden classification, but cases with severe vertical bone defects have a greater chance of the 3D-PITM exposure and the exposure can affect the outcome of bone augmentation.

Flexible and Stretchable Enzymatic Biofuel Cell with High Performance Enabled by Textile Electrodes and Polymer Hydrogel Electrolyte.

Biofuel cells with good biocompatibility are promising to be used as the power source for flexible and wearable bioelectronics. We here report a type of highly flexible and stretchable biofuel cells, which are enabled by textile electrodes of graphene/carbon nanotubes (G/CNTs) composite and polymer hydrogel electrolyte. The CNT array covalently grown from a graphene layer not only can be served as a conducting substrate to immobilize enzyme molecules but also can provide efficient charge transport channels between the enzyme and graphene electrode. As a result, the developed biofuel cells deliver a high open-circuit voltage of 0.65 V and output power density of 64.2 µW cm-2, which are much higher than previously reported results. Benefiting from the unique textile structure of electrodes and the polymer hydrogel electrolyte, the biofuel cells exhibit high retention of power density after 400 bending cycles and even stretched to a high strain of 60%.

Engineering Biomimetic Nanostructured "Melanosome" Textiles for Advanced Solar-to-Thermal Devices.

In nature, deep-sea fish featured with close-packed melanosomes can remarkably lower light reflection, which have inspired us to design ultrablack coatings for enhanced solar-to-thermal conversion. Herein, a biomimetic ultrablack textile is developed enabled by the formation of hierarchical polypyrrole (Ppy) nanospheres. The fabricated textile exhibits prominently suppressed reflectance of lower than 4% and highly enhanced absorption of up to 96%. Further experimental results and molecular dynamics (MD) simulation evidence the formation process of hierarchical nanospheres. Based on high-efficient solar-to-thermal conversion, the biomimetic textile with desirable conductivity allows the development of a salt-free solar evaporator, enabling a sustainable seawater evaporation rate of up to 1.54 kg m-2 h-1 under 1 sun. Furthermore, the biomimetic hierarchical textile exhibits good superhydrophobicity, enhanced photothermal property, and high electrothermal conversion, demonstrating significant potential in wearable thermal management (rescue vests) in water conditions.

Spectroscopy-Based Local Modeling Method for High-Throughput Quantification of Nucleic Acid Loading in Lipid Nanoparticles.

Lipid nanoparticles (LNPs) are the most widely investigated delivery systems for nucleic acid-based therapeutics and vaccines. Loading efficiency of nucleic acids may vary with formulation conditions, and it is considered one of the critical quality attributes of LNP products. Current analytical methods for quantification of cargo loading in LNPs often require external standard preparations and preseparation of unloaded nucleic acids from LNPs; therefore, they are subject to tedious and lengthy procedures, LNP stability, and unpredictable recovery rates of the separated analytes. Here, we developed a modeling approach, which was based on locally weighted regression (LWR) of ultraviolet (UV) spectra of unpurified samples, to quantify the loading of nucleic acid cargos in LNPs in-situ. We trained the model to automatically tune the training library space according to the spectral features of a query sample so as to robustly predict the nucleic acid cargo concentration and rank loading capacity with similar performance as the more complicated experimental approaches. Furthermore, we successfully applied the model to a wide range of nucleic acid cargo species, including antisense oligonucleotides, single-guided RNA, and messenger RNA, in varied lipid matrices. The LWR modeling approach significantly saved analytical time and efforts by facile UV scans of 96-well sample plates within a few minutes and with minimal sample preprocessing. Our proof-of-concept study presented the very first data mining and modeling strategy to quantify nucleic acid loading in LNPs and is expected to better serve high-throughput screening workflows, thereby facilitates early-stage optimization and development of LNP formulations.

A Multiple Remotely Controlled Platform from Recyclable Polyurethane Composite Network with Shape-Memory Effect and Self-Healing Ability.

Stimuli-responsive materials can transform from temporary to permanent shapes by specific external triggers. However, the damage might inevitably occur to them when exposed to complex environments, causing a significant reduction in their lifetime and quality. In this study, recyclable remotely controlled shape-changing polyurethane composite with self-healing compacity is developed from polyethylene glycol, polytetrahydrofuran diol using isophorone diisocyanate as crosslinker. After the incorporation of magnetite nanoparticles (MNPs), remote heating could be generated by near-infrared irradiation and alternating magnetic fields. The results show that MNPs are uniformly distributed in the smart networks, resulting in tunable temperature changes of the polymer composite material under various direct/indirect triggering in bending experiments, presenting different shape recovery rates. Moreover, to enhance the self-healing capability, a disulfide bond is introduced into the polymer networks, and the results show that highly efficient and rapid healing could be achieved from tensile tests, scanning electron microscopy as well as optical microscopy. Additionally, the synergistic effect of transesterification and the dynamic exchange of disulfide bonds brin the networks reproducibility for recycling use. The obtained material is promising to be an alternative material for soft robots and smart sensors.

Forming a Double-Helix Phase of Single Polymer Chains by the Cooperation between Local Structure and Nonlocal Attraction.

Double-helix structures, such as DNA, are formed in nature to realize many unique functions. Inspired by this, researchers are pursuing strategies to design such structures from polymers. A key question is whether the double helix can be formed from the self-folding of a single polymer chain without specific interactions. Here, using Langevin dynamics simulation and theoretical analysis, we find that a stable double-helix phase can be achieved by the self-folding of single semiflexible polymers as a result of the cooperation between local structure and nonlocal attraction. The critical temperature of double-helix formation approximately follows T^{cri}∼ln(k_{θ}) and T^{cri}∼ln(k_{τ}), where k_{θ} and k_{τ} are the polymer bending and torsion stiffness, respectively. Furthermore, the double helix can exhibit major and minor grooves due to symmetric break for better packing. Our results provide a novel guide to the experimental design of the double helix.

Flexible and adhesive liquid-free ionic conductive elastomers toward human-machine interaction.

Based on the demand for flexible human-machine interaction devices, it is urgent to develop high-performance stretchable ionic conductive materials. However, most gel-based ionic conductive materials are composed of crosslinked polymer networks that contain liquids, and suffer from limitations of solvent volatilization and leakage, and the cross-linking restricts the movement and diffusion of polymer chains, making it difficult for them to achieve adhesion. Here, we introduce flexible and adhesive liquid-free ionic conductive elastomers (ICE) with salt using a non-crosslinked polymer strategy. The ICE show a transparency of 89.5%, Tg of -51.2 °C, negligible weight loss at 200 °C, a tensile fracture strain of 289.5%, and an initial modulus of 45.7 kPa, and is adhesive to various solid surfaces with an interfacial toughness of 11.4 to 41.4 J m-2. Moreover, the ICE exhibit stable electrical conductivity under ambient conditions. Triboelectric nanogenerators (TENGs) were assembled on an electrical shell surface with the adhesive ICE as an electrostatic induction layer and were displayed for use as human-machine interactive keyboards. This approach opens a route to making adhesive and stable polymer ionic conductors for human-machine interaction.

Cationic Conjugated Polyelectrolytes with Aggregation-Induced Ratiometric Fluorescence.

The molecular diversity of aggregation-induced emission remains a challenge due to the limitation of conventional synthesis methods. Here, a series of novel neutral and cationic conjugated polymers composed of various ratios of tetraarylethylene (TAE) containing a bridged oxygen (O) and fluorene (F) units is designed and synthesized via the geminal cross-coupling (GCC) of 1,1-dibromoolefins. The incorporation of TAE segments into the conjugated backbone of polyfluorene produces pronounced aggregation-induced ratiometric fluorescence, i.e., aggregation-induced emission (AIE) at 520-600 nm and grows synergistically with aggregations-caused quenching (ACQ) at 400-450 nm. The content of fluorene unit in the polymer backbones determines the intensity of the initial fluorescence in the blue light region. The huge distinction (about 150 nm) in dual emission wavelengths caused by the environment change makes these conjugated polyelectrolytes particularly suitable for ratiometric fluorescence sensing. Based on electrostatic interaction mechanism, the gradual addition of heparin into the cationic conjugated polymers aqueous solutions can induce dual-color fluorescence changes with a detection limit of 9 × 10-9 m. This work exhibits the great facility of using GCC reaction to synthesis the conjugated TAE polymers with superior AIE properties and special functions.

Development of a rat model for type 2 diabetes mellitus peri-implantitis: A preliminary study.

OBJECTIVE: To develop an in vivo model to simulate the complex internal environment of diabetic peri-implantitis (T2DM-PI) model for a better understanding of peri-implantitis in type 2 diabetic patients. MATERIALS AND METHODS: Maxillary first molars were extracted in Sprague-Dawley (SD) rats, and customized cone-shaped titanium implants were installed in the extraction sites. Thereafter, implants were uncovered and customized abutments were screwed into implants. A high-fat diet and a low-dose injection of streptozotocin were utilized to induce T2DM. Finally, LPS was locally injected in implant sulcus to induce peri-implantitis. RESULTS: In the present study, T2DM-PI model has been successfully established. Imaging analysis revealed that abundant inflammatory cells infiltrated in the soft tissue in T2DM-PI group with concomitant excessive secretion of inflammatory cytokines. Moreover, higher expression of MMP and increased number of osteoclasts led to collagen disintegration and bone resorption in T2DM-PI group. CONCLUSIONS: These results describe a novel rat model which stimulate T2DM-PI in vivo, characterized by overwhelming inflammatory response and bone resorption. This model has a potential to be used for investigation of initiation, progression and interventional therapy of T2DM-PI.

Adaptive Laboratory Evolution of Halomonas bluephagenesis Enhances Acetate Tolerance and Utilization to Produce Poly(3-hydroxybutyrate).

Acetate is a promising economical and sustainable carbon source for bioproduction, but it is also a known cell-growth inhibitor. In this study, adaptive laboratory evolution (ALE) with acetate as selective pressure was applied to Halomonas bluephagenesis TD1.0, a fast-growing and contamination-resistant halophilic bacterium that naturally accumulates poly(3-hydroxybutyrate) (PHB). After 71 transfers, the evolved strain, B71, was isolated, which not only showed better fitness (in terms of tolerance and utilization rate) to high concentrations of acetate but also produced a higher PHB titer compared with the parental strain TD1.0. Subsequently, overexpression of acetyl-CoA synthetase (ACS) in B71 resulted in a further increase in acetate utilization but a decrease in PHB production. Through whole-genome resequencing, it was speculated that genetic mutations (single-nucleotide variation (SNV) in phaB, mdh, and the upstream of OmpA, and insertion of TolA) in B71 might contribute to its improved acetate adaptability and PHB production. Finally, in a 5 L bioreactor with intermittent feeding of acetic acid, B71 was able to produce 49.79 g/L PHB and 70.01 g/L dry cell mass, which were 147.2% and 82.32% higher than those of TD1.0, respectively. These results highlight that ALE provides a reliable method to harness H. bluephagenesis to metabolize acetate for the production of PHB or other high-value chemicals more efficiently.

Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) such as exenatide are used as monotherapy and add-on therapy for maintaining glycaemic control in patients with type 2 diabetes mellitus. The current study investigated the safety and efficacy of once-weekly PB-119, a PEGylated exenatide injection, in treatment-naive patients with type 2 diabetes. METHODS: In this Phase II, randomised, placebo-controlled, double-blind study, we randomly assigned treatment-naive Chinese patients with type 2 diabetes in a 1:1:1:1 ratio to receive subcutaneous placebo or one of three subcutaneous doses of PB-119 (75, 150, and 200 µg) for 12 weeks. The primary endpoint was the change in HbA1c from baseline to week 12, and other endpoints were fasting plasma glucose, 2 h postprandial glucose (PPG), and proportion of patients with HbA1c < 53 mmol/mol (<7.0%) and ≤48 mmol/mol (≤6.5%) at 2, 4, 8 and 12 weeks of treatment. Safety was assessed in all patients who received at least one dose of study drug. RESULTS: We randomly assigned 251 patients to one of the four treatment groups (n = 62 in placebo and 63 each in PB-119 75 µg, 150 µg and 200 µg groups). At the end of 12 weeks, mean differences in HbA1c in the treatment groups were -7.76 mmol/mol (95% CI -9.23, -4.63, p < 0.001) (-0.72%, 95% CI -1.01, -0.43), -12.89 mmol/mol (95% CI -16.05, -9.72, p < 0.001) (-1.18%, 95% CI -1.47, -0.89) and -11.14 mmol/mol (95% CI -14.19, -7.97, p <0 .001) (-1.02%, 95% CI -1.30, -0.73) in the 75 µg, 150 µg and 200 µg PB-119 groups, respectively, compared with that in the placebo group after adjusting for baseline HbA1c. Similar results were also observed for other efficacy endpoints across different time points. There was no incidence of treatment-emergent serious adverse event, severe hypoglycaemia or death. CONCLUSIONS/INTERPRETATION: All tested PB-119 doses had superior efficacy compared with placebo and were safe and well tolerated over 12 weeks in treatment-naive Chinese patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03520972 FUNDING: The study was funded by National Major Scientific and Technological Special Project for Significant New Drugs Development and PegBio.