Catalytic Regio- and Enantioselective Remote Hydrocarboxylation of Unactivated Alkenes with CO2.

The catalytic regio- and enantioselective hydrocarboxylation of alkenes with carbon dioxide is a straightforward strategy to construct enantioenriched α-chiral carboxylic acids but remains a big challenge. Herein we report the first example of catalytic highly enantio- and site-selective remote hydrocarboxylation of a wide range of readily available unactivated alkenes with abundant and renewable CO2 under mild conditions enabled by the SaBOX/Ni catalyst. The key to this success is utilizing the chiral SaBOX ligand, which combines with nickel to simultaneously control both chain-walking and the enantioselectivity of carboxylation. This process directly furnishes a range of different alkyl-chain-substituted or benzo-fused α-chiral carboxylic acids bearing various functional groups in high yields and regio- and enantioselectivities. Furthermore, the synthetic utility of this methodology was demonstrated by the concise synthesis of the antiplatelet aggregation drug (R)-indobufen from commercial starting materials.

Novel Multitarget ACE Inhibitory Peptides from Bovine Colostrum Immunoglobulin G: Cellular Transport, Efficacy in Regulating Endothelial Dysfunction, and Network Pharmacology Studies.

In this study, we used traditional laboratory methods, bioinformatics, and cellular models to screen novel ACE inhibitory (ACEI) peptides with strong ACEI activity, moderate absorption rates, and multiple targets from bovine colostrum immunoglobulin G (IgG). The purified fraction of the compound proteinase hydrolysate of IgG showed good ACEI activity. After nano-UPLC-MS/MS identification and in silico analysis, eight peptides were synthesized and verified. Among them, SFYPDY, TSFYPDY, FSWF, WYQQVPGSGL, and GVHTFP were identified as ACEI peptides, as they exhibited strong ACEI activity (with IC50 values of 104.7, 80.0, 121.2, 39.8, and 86.3 µM, respectively). They displayed good stability in an in vitro simulated gastrointestinal digestion assay. In a Caco-2 monolayer model, SFYPDY, FSWF, and WYQQVPGSGL exhibited better absorption rates and lower IC50 values than the other peptides and were thereby identified as novel ACEI peptides. Subsequently, in a H2O2-induced endothelial dysfunction (ED) model based on HUVECs, SFYPDY, FSWF, and WYQQVPGSGL regulated ED by reducing apoptosis and ROS accumulation while upregulating NOS3 mRNA expression. Network pharmacology analysis and RT-qPCR confirmed that they regulated multiple targets. Overall, our results suggest that SFYPDY, FSWF, and WYQQVPGSGL can serve as novel multitarget ACEI peptides.

Rapid Volumetric Bioprinting of Decellularized Extracellular Matrix Bioinks.

Decellularized extracellular matrix (dECM)-based hydrogels are widely applied to additive biomanufacturing strategies for relevant applications. The extracellular matrix components and growth factors of dECM play crucial roles in cell adhesion, growth, and differentiation. However, the generally poor mechanical properties and printability have remained as major limitations for dECM-based materials. In this study, heart-derived dECM (h-dECM) and meniscus-derived dECM (Ms-dECM) bioinks in their pristine, unmodified state supplemented with the photoinitiator system of tris(2,2-bipyridyl) dichlororuthenium(II) hexahydrate and sodium persulfate, demonstrate cytocompatibility with volumetric bioprinting processes. This recently developed bioprinting modality illuminates a dynamically evolving light pattern into a rotating volume of the bioink, and thus decouples the requirement of mechanical strengths of bioprinted hydrogel constructs with printability, allowing for the fabrication of sophisticated shapes and architectures with low-concentration dECM materials that set within tens of seconds. As exemplary applications, cardiac tissues are volumetrically bioprinted using the cardiomyocyte-laden h-dECM bioink showing favorable cell proliferation, expansion, spreading, biomarker expressions, and synchronized contractions; whereas the volumetrically bioprinted Ms-dECM meniscus structures embedded with human mesenchymal stem cells present appropriate chondrogenic differentiation outcomes. This study supplies expanded bioink libraries for volumetric bioprinting and broadens utilities of dECM toward tissue engineering and regenerative medicine.

Self-enhancing sono-inks enable deep-penetration acoustic volumetric printing.

Volumetric printing, an emerging additive manufacturing technique, builds objects with enhanced printing speed and surface quality by forgoing the stepwise ink-renewal step. Existing volumetric printing techniques almost exclusively rely on light energy to trigger photopolymerization in transparent inks, limiting material choices and build sizes. We report a self-enhancing sonicated ink (or sono-ink) design and corresponding focused-ultrasound writing technique for deep-penetration acoustic volumetric printing (DAVP). We used experiments and acoustic modeling to study the frequency and scanning rate-dependent acoustic printing behaviors. DAVP achieves the key features of low acoustic streaming, rapid sonothermal polymerization, and large printing depth, enabling the printing of volumetric hydrogels and nanocomposites with various shapes regardless of their optical properties. DAVP also allows printing at centimeter depths through biological tissues, paving the way toward minimally invasive medicine.

Triggerable Prodrug Nanocoating Enables On-Demand Activation of Microbial and Small-Molecular Therapeutics for Combination Treatment.

The synergy of living microbial and small-molecular therapeutics has been widely explored for treating a variety of diseases, while current combination strategies often suffer from low bioavailability, heterogeneous spatiotemporal distribution, and premature drug release. Here, the use of a triggerable prodrug nanocoating is reported to enable the on-demand activation of microbial and small-molecular therapeutics for combination treatment. As a proof-of-concept study, a reactive oxygen species-responsive aromatic thioacetal linker is employed to prepare cationic chitosan-drug conjugates, which can form a nanocoating on the surface of living bacteria via electrostatic interaction. Following administration, the wrapped bacteria can be prevented from in vivo insults by the shielding effect of the nanocoating and be co-delivered with the conjugated drug in a spatiotemporally synchronous manner. Upon reaching the lesion site, the upgraded reactive oxygen species trigger in situ cleavage of the thioacetal linker, resulting in the release of the conjugated drug and a linker-derived therapeutic cinnamaldehyde. Meanwhile, a charge reversal achieved by the generation of negatively charged thiolated chitosan induces the dissociation of the nanocoating, leading to synchronous release of the living bacteria. The adequate activation of the combined therapeutics at the lesion site exhibits superior synergistic treatment efficacy, as demonstrated by an in vivo assessment using a mouse model of colitis. This work presents an appealing approach to combine living microbial and small-molecular therapeutics for advanced therapy of diseases.

The causal relationship between physical activity, sedentary time and idiopathic pulmonary fibrosis risk: a Mendelian randomization study.

BACKGROUND: Several observational studies have found that physical inactivity and sedentary time are associated with idiopathic pulmonary fibrosis (IPF) risk. However, the causality between them still requires further investigation. Therefore, our study aimed to investigate the causal effect of physical activity (PA) and sedentary time on the risk of IPF via two-sample Mendelian randomization (MR) analysis. METHODS: Multiple genome-wide association study (GWAS) data involving individuals of European ancestry were analyzed. The datasets encompassed published UK Biobank data (91,105-377,234 participants) and IPF data (2018 cases and 373,064 controls) from FinnGen Biobank. The inverse variance weighting (IVW) method was the primary approach for our analysis. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger regression, MR-PRESSO global test, and leave-one-out analysis. RESULTS: Genetically predicted self-reported PA was associated with lower IPF risk [OR = 0.27; 95% CI 0.09-0.82; P = 0.02]. No causal effects of accelerometry-based PA or sedentary time on the risk of IPF were observed. CONCLUSIONS: Our findings supported a protective relationship between self-reported PA and the risk for IPF. The results suggested that enhancing PA may be an effective preventive strategy for IPF.

The Effect of Filler Dimensionality and Content on Resistive Viscoelasticity of Conductive Polymer Composites for Soft Strain Sensors.

Soft strain sensors based on conductive polymer composites (CPCs) provide a simple and feasible detection tool in wearable electronics, soft machines, electronic skin, etc. However, the CPCs-based soft strain sensors exhibit resistive viscoelasticity (or time-dependent properties) that hinder the intuitive reflection of the accurate strain and a simple calibration process. In this paper, CPCs with different carbon nanotubes (CNTs) and carbon black (CB) contents were prepared, and electro-mechanical experiments were conducted to study the effect of filler dimensionality and content on the resistive viscoelasticity of CPCs, aimed at guiding the fabrication of CPCs with low resistive viscoelasticity. Furthermore, resistive viscoelasticity and mechanical viscoelasticity were compared to study the origin of the resistive viscoelasticity of CPCs. We found that, at the vicinity of their percolation threshold, the CPCs exhibit high resistive viscoelasticity despite their high sensitivity. In addition, the secondary peaks for CB/SR composite were negligible when the CB concentration was low. Generally, compared with one-dimensional CNT-filled CPCs, the zero-dimensional CB-filled CPCs show higher sensitivity, lower resistive hysteresis, lower resistance relaxation ratio, and better cyclic performance, so they are more suitable for sensor usage. By comparing the resistive viscoelasticity and mechanical viscoelasticity of CPCs, it is indicated that, when the concentration of nanoparticles (NPs) approaches the percolation thresholds, the resistive viscoelasticity is mainly derived from the change of conductive network, while when the concentration of NPs is higher, it is primarily due to the unrecoverable deformations inside the material.

BaLa5V2O3N7: a novel anti-perovskite oxynitride for electrode applications.

The exploration of transition metal oxynitrides has garnered significant interest due to their intriguing property diversity. Herein, we present a promising new transition metal oxynitride BaLa5V2O3N7, which features an anti-perovskite structure type. This unique structural configuration endows the material with remarkable conductivity, particularly at low temperatures, paving the way for the material to be used in a wide range of technological applications.

Transcriptomic and metabolomic analysis of liver cirrhosis.

BACKGROUND: Liver cirrhosis is one of the leading causes of decreased life expectancy worldwide. However, the molecular mechanisms underlying liver cirrhosis remain unclear. In this study, we performed a comprehensive analysis using transcriptome and metabolome sequencing to explore the genes, pathways, and interactions associated with liver cirrhosis. METHODS: We performed transcriptome and metabolome sequencing of blood samples from patients with cirrhosis and healthy controls (1:1 matched for sex and age). We validated the differentially expressed microRNA (miRNA) and mRNAs using real-time quantitative polymerase chain reaction. RESULTS: For transcriptome analysis, we screened for differentially expressed miRNAs and mRNAs, analyzed mRNAs to identify possible core genes and pathways, and performed co-analysis of miRNA and mRNA sequencing results. In terms of the metabolome, we screened five pathways that were substantially enriched in the differential metabolites. Next, we identified the metabolites with the most pronounced differences among these five metabolic pathways. We performed receiver operating characteristic (ROC) curve analysis of these five metabolites to determine their diagnostic efficacy for cirrhosis. Finally, we explored possible links between the transcriptome and metabolome. CONCLUSION: Based on sequencing and bioinformatics, we identified miRNAs and genes that were differentially expressed in the blood of patients with liver cirrhosis. By exploring pathways and disease-specific networks, we identified unique biological mechanisms. In terms of metabolomes, we identified novel biomarkers and explored their diagnostic efficacy. We identified possible common pathways in the transcriptome and metabolome that could serve as candidates for further studies.

Blood typing and transfusion therapy in a patient with A2 subtype acute myeloid leukemia M2: A case report.

BACKGROUND: Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults. However, AML is relatively rare in the population overall, accounting for only about 1 percent of all cancers. Treatment for AML can be very effective for some patients, yet it leaves others with serious and even life-threatening side effects. Chemotherapy is still the primary treatment for most AML, but over time, leukemia cells become resistant to chemotherapy drugs. In addition, stem cell transplantation, targeted therapy, and immunotherapy are currently available. At the same time, with the progression of the disease, the patient may have corresponding complications, such as coagulation dysfunction, anemia, granulocytopenia, and repeated infection, so transfusion supportive therapy will be involved in the overall treatment regime. To date, few articles have reported on blood transfusion treatment options for patients with ABO subtypes AML-M2. Blood transfusion therapy is an important supportive treatment for AML-M2, and accurate determination of patients' blood type is one of the most important steps in the treatment process. In this study, we explored blood typing and supportive treatment strategies for a patient with A2 subtype AML-M2 to provide the basis for treatment for all patients. CASE SUMMARY: In order to determine the blood type of the patient, serological and molecular biological methods were used for reference tests, and the genetic background was studied to determine the patient's final blood type and select the appropriate blood products for infusion treatment. According to the results obtained by serological and molecular biological methods, the blood type of the patient was A2 subtype; the genotype was A02/001; the irregular antibody screening was negative, and anti-A1 was found in the plasma. According to the overall treatment plan, active anti-infection, elevated cells, component blood transfusion support, and other rescue and supportive treatments were given, and the patient successfully passed the stage of myelosuppression after chemotherapy. Re-examination of bone marrow smears showed that AL was in complete remission of bone marrow signs, and minimal residual leukemia lesions suggested no cells with obvious abnormal immunophenotype (residual leukemia cells < 10-4). CONCLUSION: The infusion of patients with A2 subtype AML-M2 with A irradiated platelets and O washing red blood cells can meet the needs of clinical treatment.

[Adsorption Mechanism for Phosphate in Aqueous Solutions of Calcium/Aluminum-rich Sludge Biochar Composite].

Excess sludge is rich in organic matter but also contains heavy metals, pathogens, and harmful substances. In this study, hydroaluminite and excess sludge were used as raw materials to reduce the risk of heavy metals leaching from sludge by coagulation and co-pyrolysis, and its phosphate adsorption characteristics were studied. The results showed that the leaching amount of Zn, Cu, Cd, and Ni in sludge biochar decreased with the increase in the hydroaluminite dosage. The sludge biochar composite (1:1HB800), prepared by co-pyrolysis of hydroaluminite and excess sludge with a mass ratio of 1:1 as well as rich in calcium and aluminum, had lowest leaching risk of heavy metals and showed the high adsorption capacity for phosphate. The process could be fitted by the Langmuir adsorption isotherm (R2=0.93), and the maximum phosphate adsorption capacity at 25℃ was 51.38 mg·g-1. The pseudo second-order kinetic model could well describe the adsorption process of 1:1HB800 for high concentration phosphate, and its adsorption rate was controlled by both surface adsorption and particle diffusion. Compared with that in the neutral solution, 1:1HB800 had better phosphate capacity in the acidic and alkaline aqueous solutions, which was related to the leaching amount of calcium/aluminum in 1:1HB800 and the existence form of aluminum under the different pH conditions. FTIR, XRD, SEM, zero potential point, and Ca2+/Al3+ leaching experiments indicated that the main adsorption mechanisms for phosphate by 1:1HB800 were co-precipitation (interaction between Ca2+/Al3+ and phosphate), ligand exchange (hydroxyl), and electrostatic interaction. Therefore, 1:1HB800 can provide a feasible alternative for the removal of phosphate in aqueous solutions and also provide a potential new method for the resource utilization and harmless treatment of excess sludge.

Liquid-embedded (bio)printing of alginate-free, standalone, ultrafine, and ultrathin-walled cannular structures.

While there has been considerable success in the three-dimensional bioprinting of relatively large standalone filamentous tissues, the fabrication of solid fibers with ultrafine diameters or those cannular featuring ultrathin walls remains a particular challenge. Here, an enabling strategy for (bio)printing of solid and hollow fibers whose size ranges could be facilely adjusted across a broad spectrum, is reported, using an aqueous two-phase embedded (bio)printing approach combined with specially designed cross-linking and extrusion methods. The generation of standalone, alginate-free aqueous architectures using this aqueous two-phase strategy allowed freeform patterning of aqueous bioinks, such as those composed of gelatin methacryloyl, within the immiscible aqueous support bath of poly(ethylene oxide). Our (bio)printing strategy revealed the fabrication of standalone solid or cannular structures with diameters as small as approximately 3 or 40 µm, respectively, and wall thicknesses of hollow conduits down to as thin as <5 µm. With cellular functions also demonstrated, we anticipate the methodology to serve as a platform that may satisfy the needs for the different types of potential biomedical and other applications in the future, especially those pertaining to cannular tissues of ultrasmall diameters and ultrathin walls used toward regenerative medicine and tissue model engineering.

O-GlcNAc transferase in astrocytes modulates depression-related stress susceptibility through glutamatergic synaptic transmission.

Major depressive disorder is a common and devastating psychiatric disease, and the prevalence and burden are substantially increasing worldwide. Multiple studies of depression patients have implicated glucose metabolic dysfunction in the pathophysiology of depression. However, the molecular mechanisms by which glucose and related metabolic pathways modulate depressive-like behaviors are largely uncharacterized. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is a glucose metabolite with pivotal functions as a donor molecule for O-GlcNAcylation. O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, catalyzes protein posttranslational modification by O-GlcNAc and acts as a stress sensor. Here, we show that Ogt mRNA was increased in depression patients and that astroglial OGT expression was specifically upregulated in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social-defeat stress. The selective deletion of astrocytic OGT resulted in antidepressant-like effects, and moreover, astrocytic OGT in the mPFC bidirectionally regulated vulnerability to social stress. Furthermore, OGT modulated glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1) in astrocytes. OGT astrocyte-specific knockout preserved the neuronal morphology atrophy and Ca2+ activity deficits caused by chronic stress and resulted in antidepressant effects. Our study reveals that astrocytic OGT in the mPFC regulates depressive-like behaviors through the O-GlcNAcylation of GLT-1 and could be a potential target for antidepressants.

Multiscale photoacoustic tomography using reversibly switchable thermochromics.

Significance: Based on acoustic detection of optical absorption, photoacoustic tomography (PAT) allows functional and molecular imaging beyond the optical diffusion limit with high spatial resolution. However, multispectral functional and molecular PAT is often limited by decreased spectroscopic accuracy and reduced detection sensitivity in deep tissues, mainly due to wavelength-dependent optical attenuation and inaccurate acoustic inversion. Aim: Previous work has demonstrated that reversible color-shifting can drastically improve the detection sensitivity of PAT by suppressing nonswitching background signals. We aim to develop a new color switching-based PAT method using reversibly switchable thermochromics (ReST). Approach: We developed a family of ReST with excellent water dispersion, biostability, and temperature-controlled color changes by surface modification of commercial thermochromic microcapsules with the hydrophilic polysaccharide alginate. Results: The optical absorbance of the ReST was switched on and off repeatedly by modulating the surrounding temperature, allowing differential photoacoustic detection that effectively suppressed the nonswitching background signal and substantially improved image contrast and detection sensitivity. We demonstrate reversible thermal-switching imaging of ReST in vitro and in vivo using three PAT modes at different length scales. Conclusions: ReST-enabled PAT is a promising technology for high-sensitivity deep tissue imaging of molecular activity in temperature-related biomedical applications, such as cancer thermotherapy.

Modeling the resistive viscoelasticity of conductive polymer composites for sensor usage.

With the development of fully printed electronics, soft sensors are in demand in various fields, such as wearable electronics, soft machines, etc. Most soft resistive sensors are made of conductive elements dispersed in a viscoelastic polymer binder, exhibiting resistive viscoelastic behavior. The resistance of soft resistive sensors is time-dependent due to the viscoelastic response of polymer binder and structural rearrangement of the conductive pathway. In this paper, experiments and theoretical modeling are used to study the resistive viscoelastic behavior of printed silver wires. The printed silver wire belongs to conductive polymer composites (CPCs) consisting of conductive silver-nanoparticle pathways in an elastic polymer binder. Based on tunneling theory, a multi-branch model is developed to capture the resistance variation of the printed silver wire under mechanical loading. Our experiment-validated model uses only a single set of parameters to predict the resistive relaxation behaviors of CPCs under different strain and different loading rates. Moreover, we demonstrated this numerical model could describe the resistance response under complex loading conditions, such as cyclic loading, similar to the sensor's working condition. The multi-branch model can be extended to any other soft resistive sensor, such as a strain sensor, and provide a new avenue to calibrate these soft sensors.

Volumetric additive manufacturing of pristine silk-based (bio)inks.

Volumetric additive manufacturing (VAM) enables fast photopolymerization of three-dimensional constructs by illuminating dynamically evolving light patterns in the entire build volume. However, the lack of bioinks suitable for VAM is a critical limitation. This study reports rapid volumetric (bio)printing of pristine, unmodified silk-based (silk sericin (SS) and silk fibroin (SF)) (bio)inks to form sophisticated shapes and architectures. Of interest, combined with post-fabrication processing, the (bio)printed SS constructs reveal properties including reversible as well as repeated shrinkage and expansion, or shape-memory; whereas the (bio)printed SF constructs exhibit tunable mechanical performances ranging from a few hundred Pa to hundreds of MPa. Both types of silk-based (bio)inks are cytocompatible. This work supplies expanded bioink libraries for VAM and provides a path forward for rapid volumetric manufacturing of silk constructs, towards broadened biomedical applications.

An Adhesive Bioink toward Biofabrication under Wet Conditions.

Three-dimensional (3D) bioprinting is driving significant innovations in biomedicine over recent years. Under certain scenarios such as in intraoperative bioprinting, the bioinks used should exhibit not only cyto/biocompatibility but also adhesiveness in wet conditions. Herein, an adhesive bioink composed of gelatin methacryloyl, gelatin, methacrylated hyaluronic acid, and skin secretion of Andrias davidianus is designed. The bioink exhibits favorable cohesion to allow faithful extrusion bioprinting in wet conditions, while simultaneously showing good adhesion to a variety of surfaces of different chemical properties, possibly achieved through the diverse bonds presented in the bioink formulation. As such, this bioink is able to fabricate sophisticated planar and volumetric constructs using extrusion bioprinting, where the dexterity is further enhanced using ergonomic handheld bioprinters to realize in situ bioprinting. In vitro experiments reveal that cells maintain high viability; further in vivo studies demonstrate good integration and immediate injury sealing. The characteristics of the bioink indicate its potential widespread utility in extrusion bioprinting and will likely broaden the applications of bioprinting toward situations such as in situ dressing and minimally invasive tissue regeneration.

Chemical reaction-mediated covalent localization of bacteria.

Methods capable of manipulating bacterial colonization are of great significance for modulating host-microbiota relationships. Here, we describe a strategy of in-situ chemical reaction-mediated covalent localization of bacteria. Through a simple one-step imidoester reaction, primary amino groups on bacterial surface can be converted to free thiols under cytocompatible conditions. Surface thiolation is applicable to modify diverse strains and the number of introduced thiols per bacterium can be easily tuned by varying feed ratios. These chemically reactive bacteria are able to spontaneously bond with mucous layer by catalyst-free thiol-disulfide exchange between mucin-associated disulfides and newly converted thiols on bacterial surface and show thiolation level-dependent attachment. Bacteria optimized with 9.3 × 107 thiols per cell achieve 170-fold higher attachment in mucin-enriched jejunum, a challenging location for gut microbiota to colonize. As a proof-of-concept application for microbiota transplantation, covalent bonding-assisted localization of an oral probiotic in the jejunum generates an improved remission of jejunal mucositis. Our findings demonstrate that transforming bacteria with a reactive surface provides an approach to chemically control bacterial localization, which is highly desirable for developing next-generation bacterial living bioagents.

Microfluidic bioprinting of tough hydrogel-based vascular conduits for functional blood vessels.

Three-dimensional (3D) bioprinting of vascular tissues that are mechanically and functionally comparable to their native counterparts is an unmet challenge. Here, we developed a tough double-network hydrogel (bio)ink for microfluidic (bio)printing of mono- and dual-layered hollow conduits to recreate vein- and artery-like tissues, respectively. The tough hydrogel consisted of energy-dissipative ionically cross-linked alginate and elastic enzyme-cross-linked gelatin. The 3D bioprinted venous and arterial conduits exhibited key functionalities of respective vessels including relevant mechanical properties, perfusability, barrier performance, expressions of specific markers, and susceptibility to severe acute respiratory syndrome coronavirus 2 pseudo-viral infection. Notably, the arterial conduits revealed physiological vasoconstriction and vasodilatation responses. We further explored the feasibility of these conduits for vascular anastomosis. Together, our study presents biofabrication of mechanically and functionally relevant vascular conduits, showcasing their potentials as vascular models for disease studies in vitro and as grafts for vascular surgeries in vivo, possibly serving broad biomedical applications in the future.