Acoustofluidics-enhanced biosensing with simultaneously high sensitivity and speed.

Simultaneously achieving high sensitivity and detection speed with traditional solid-state biosensors is usually limited since the target molecules must passively diffuse to the sensor surface before they can be detected. Microfluidic techniques have been applied to shorten the diffusion time by continuously moving molecules through the biosensing regions. However, the binding efficiencies of the biomolecules are still limited by the inherent laminar flow inside microscale channels. In this study, focused traveling surface acoustic waves were directed into an acoustic microfluidic chip, which could continuously enrich the target molecules into a constriction zone for immediate detection of the immune reactions, thus significantly improving the detection sensitivity and speed. To demonstrate the enhancement of biosensing, we first developed an acoustic microfluidic chip integrated with a focused interdigital transducer; this transducer had the ability to capture more than 91% of passed microbeads. Subsequently, polystyrene microbeads were pre-captured with human IgG molecules at different concentrations and loaded for detection on the chip. As representative results, ~0.63, 2.62, 11.78, and 19.75 seconds were needed to accumulate significant numbers of microbeads pre-captured with human IgG molecules at concentrations of 100, 10, 1, and 0.1 ng/mL (~0.7 pM), respectively; this process was faster than the other methods at the hour level and more sensitive than the other methods at the nanomolar level. Our results indicated that the proposed method could significantly improve both the sensitivity and speed, revealing the importance of selective enrichment strategies for rapid biosensing of rare molecules.

TNF-α-licensed exosome-integrated titaniumaccelerated T2D osseointegration by promoting autophagy-regulated M2 macrophage polarization.

Type 2 diabetes (T2D) is on a notable rise worldwide, which leads to unfavorable outcomes during implant treatments. Surface modification of implants and exosome treatment have been utilized to enhance osseointegration. However, there has been insufficient approach to improve adverse osseointegration in T2D conditions. In this study, we successfully loaded TNF-α-treated mesenchymal stem cell (MSC)-derived exosomes onto micro/nano-network titanium (Ti) surfaces. TNF-α-licensed exosome-integrated titanium (TNF-exo-Ti) effectively enhanced M2 macrophage polarization in hyperglycemic conditions, with increased secretion of anti-inflammatory cytokines and decreased secretion of pro-inflammatory cytokines. In addition, TNF-exo-Ti pretreated macrophage further enhanced angiogenesis and osteogenesis of endothelial cells and bone marrow MSCs. More importantly, TNF-exo-Ti markedly promoted osseointegration in T2D mice. Mechanistically, TNF-exo-Ti activated macrophage autophagy to promote M2 polarization through inhibition of the PI3K/AKT/mTOR pathway, which could be abolished by PI3K agonist. Thus, this study established TNF-α-licensed exosome-immobilized titanium surfaces that could rectify macrophage immune states and accelerate osseointegration in T2D conditions.

A modified glycosylase base editor without predictable DNA off-target effects.

Glycosylase base editor (GBE) can induce C-to-G transversion in mammalian cells, showing great promise for the treatment of human genetic disorders. However, the limited efficiency of transversion and the possibility of off-target effects caused by Cas9 restrict its potential clinical applications. In our recent study, we have successfully developed TaC9-CBE and TaC9-ABE by separating nCas9 and deaminase, which eliminates the Cas9-dependent DNA off-target effects without compromising editing efficiency. We developed a novel GBE called TaC9-GBEYE1, which utilizes the deaminase and UNG-nCas9 guided by TALE and sgRNA, respectively. TaC9-GBEYE1 showed comparable levels of on-target editing efficiency to traditional GBE at 19 target sites, without any off-target effects caused by Cas9 or TALE. The TaC9-GBEYE1 is a safe tool for gene therapy.

Axial O Atom-Modulated Fe(III)-N4 Sites for Enhanced Cascade Catalytic 1O2-Induced Tumor Therapy.

The rational construction of efficient hypoxia-tolerant nanocatalysts capable of generating singlet oxygen (1O2) without external stimuli is of great importance for tumor therapy. Herein, uniformly dispersed and favorable biosafety profile graphitic carbon nitride quantum dots immobilized with Fe-N4 moieties modulated by axial O atom (denoted as O-Fe-N4) are developed for converting H2O2 into 1O2 via Russell reaction, without introducing external energy. Notably, O-Fe-N4 performs two interconnected catalytic properties: glutathione oxidase-mimic activity to provide substrate for subsequent 1O2 generation, avoiding the blunting anticancer efficacy by glutathione. The O-Fe-N4 catalyst demonstrates a specific activity of 79.58 U mg-1 at pH 6.2, outperforming the most reported Fe-N4 catalysts. Density functional theory calculations demonstrate that the axial O atom can effectively modulate the relative position and electron affinity between Fe and N, lowering the activation energy, strengthening the selectivity, and thus facilitating the Russell-type reaction. The gratifying enzymatic activity stemming from the well-defined Fe-N/O structure can inhibit tumor proliferation by efficiently downregulating glutathione peroxidase 4 activity and inducing lipid peroxidation. Altogether, the O-Fe-N4 catalyst not only represents an efficient platform for self-cascaded catalysis to address the limitations of 1O2-involved cancer treatment but also provides a paradigm to enhance the performance of the Fe-N4 catalyst.

Chemoenzymatic synthesis of sialyl-α2,3-lactoside-functionalized BSA conjugate inhibits influenza infection.

Influenza remains a global public health threat, and the development of new antivirals is crucial to combat emerging drug-resistant influenza strains. In this study, we report the synthesis and evaluation of a sialyl lactosyl (TS)-bovine serum albumin (BSA) conjugate as a potential multivalent inhibitor of the influenza virus. The key trisaccharide component, TS, was efficiently prepared via a chemoenzymatic approach, followed by conjugation to dibenzocyclooctyne-modified BSA via a strain-promoted azide-alkyne cycloaddition reaction. Biophysical and biochemical assays, including surface plasmon resonance, isothermal titration calorimetry, hemagglutination inhibition, and neuraminidase inhibition, demonstrated the strong binding affinity of TS-BSA to the hemagglutinin (HA) and neuraminidase (NA) proteins of the influenza virus as well as intact virion particles. Notably, TS-BSA exhibited potent inhibitory activity against viral entry and release, preventing cytopathic effects in cell culture. This multivalent presentation strategy highlights the potential of glycocluster-based antivirals for combating influenza and other drug-resistant viral strains.

Eggplant NAC domain transcription factor SmNST1 as an activator promotes secondary cell wall thickening.

NAC-domain transcription factors (TFs) are plant-specific transcriptional regulators playing crucial roles in plant secondary cell wall (SCW) biosynthesis. SCW is important for plant growth and development, maintaining plant morphology, providing rigid support, ensuring material transportation and participating in plant stress responses as a protective barrier. However, the molecular mechanisms underlying SCW in eggplant have not been thoroughly explored. In this study, the NAC domain TFs SmNST1 and SmNST2 were cloned from the eggplant line 'Sanyue qie'. SmNST1 and SmNST2 expression levels were the highest in the roots and stems. Subcellular localization analysis showed that they were localized in the cell membrane and nucleus. Their overexpression in transgenic tobacco showed that SmNST1 promotes SCW thickening. The expression of a set of SCW biosynthetic genes for cellulose, xylan and lignin, which regulate SCW formation, was increased in transgenic tobacco. Bimolecular fluorescence and luciferase complementation assays showed that SmNST1 interacted with SmNST2 in vivo. Yeast one-hybrid, electrophoretic mobility shift assay (EMSA) and Dual-luciferase reporter assays showed that SmMYB26 directly bound to the SmNST1 promoter and acted as an activator. SmNST1 and SmNST2 interact with the SmMYB108 promoter and repress SmMYB108 expression. Altogether, we showed that SmNST1 positively regulates SCW formation, improving our understanding of SCW biosynthesis transcriptional regulation.

AI-based digital pathology provides newer insights into lifestyle intervention-induced fibrosis regression in MASLD: An exploratory study.

BACKGROUND AND AIMS: Lifestyle intervention is the mainstay of therapy for metabolic dysfunction-associated steatohepatitis (MASH), and liver fibrosis is a key consequence of MASH that predicts adverse clinical outcomes. The placebo response plays a pivotal role in the outcome of MASH clinical trials. Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence analyses can provide an automated quantitative assessment of fibrosis features on a continuous scale called qFibrosis. In this exploratory study, we used this approach to gain insight into the effect of lifestyle intervention-induced fibrosis changes in MASH. METHODS: We examined unstained sections from paired liver biopsies (baseline and end-of-intervention) from MASH individuals who had received either routine lifestyle intervention (RLI) (n = 35) or strengthened lifestyle intervention (SLI) (n = 17). We quantified liver fibrosis with qFibrosis in the portal tract, periportal, transitional, pericentral, and central vein regions. RESULTS: About 20% (7/35) and 65% (11/17) of patients had fibrosis regression in the RLI and SLI groups, respectively. Liver fibrosis tended towards no change or regression after each lifestyle intervention, and this phenomenon was more prominent in the SLI group. SLI-induced liver fibrosis regression was concentrated in the periportal region. CONCLUSION: Using digital pathology, we could detect a more pronounced fibrosis regression with SLI, mainly in the periportal region. With changes in fibrosis area in the periportal region, we could differentiate RLI and SLI patients in the placebo group in the MASH clinical trial. Digital pathology provides new insight into lifestyle-induced fibrosis regression and placebo responses, which is not captured by conventional histological staging.

Multicentre randomized clinical trial on robot-assisted versus video-assisted thoracoscopic oesophagectomy (REVATE trial).

BACKGROUND: Surgery for oesophageal squamous cell carcinoma involves dissecting lymph nodes along the recurrent laryngeal nerve. This is technically challenging and injury to the recurrent laryngeal nerve may lead to vocal cord palsy, which increases the risk of pulmonary complications. The aim of this study was to compare the efficacy and safety of robot-assisted oesophagectomy (RAO) versus video-assisted thoracoscopic oesophagectomy (VAO) for dissection of lymph nodes along the left RLN. METHODS: Patients with oesophageal squamous cell carcinoma who were scheduled for minimally invasive McKeown oesophagectomy were allocated randomly to RAO or VAO, stratified by centre. The primary endpoint was the success rate of left recurrent laryngeal nerve lymph node dissection. Success was defined as the removal of at least one lymph node without causing nerve damage lasting longer than 6 months. Secondary endpoints were perioperative and oncological outcomes. RESULTS: From June 2018 to March 2022, 212 patients from 3 centres in Asia were randomized, and 203 were included in the analysis (RAO group 103; VAO group 100). Successful left recurrent laryngeal nerve lymph node dissection was achieved in 88.3% of the RAO group and 69% of the VAO group (P < 0.001). The rate of removal of at least one lymph node according to pathology was 94.2% for the RAO and 86% for the VAO group (P = 0.051). At 1 week after surgery, the RAO group had a lower incidence of left recurrent laryngeal nerve palsy than the VAO group (20.4 versus 34%; P = 0.029); permanent recurrent laryngeal nerve palsy rates at 6 months were 5.8 and 20% respectively (P = 0.003). More mediastinal lymph nodes were dissected in the RAO group (median 16 (i.q.r. 12-22) versus 14 (10-20); P = 0.035). Postoperative complication rates were comparable between the two groups and there were no in-hospital deaths. CONCLUSION: In patients with oesophageal squamous cell carcinoma, RAO leads to more successful left recurrent laryngeal nerve lymph node dissection than VAO, including a lower rate of short- and long-term recurrent laryngeal nerve injury. Registration number: NCT03713749 (http://www.clinicaltrials.gov).

Oesophageal cancer often requires complex surgery. Recently, minimally invasive techniques like robot- and video-assisted surgery have emerged to improve outcomes. This study compared robot- and video-assisted surgery for oesophageal cancer, focusing on removing lymph nodes near a critical nerve. Patients with a specific oesophageal cancer type were assigned randomly to robot- or video-assisted surgery at three Asian hospitals. Robot-assisted surgery had a higher success rate in removing lymph nodes near the important nerve without permanent damage. It also had shorter operating times, more lymph nodes removed, and faster drain removal after surgery. In summary, for oesophageal cancer surgery, the robotic approach may provide better lymph node removal and less nerve injury than video-assisted techniques.

CRISPR-Cas3 and type I restriction-modification team up against blaKPC-IncF plasmid transfer in Klebsiella pneumoniae.

OBJECTIVE: We explored whether the Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas and restriction-modification (R-M) systems are compatible and act together to resist plasmid attacks. METHODS: 932 global whole-genome sequences from GenBank, and 459 K. pneumoniae isolates from six provinces of China, were collected to investigate the co-distribution of CRISPR-Cas, R-M systems, and blaKPC plasmid. Conjugation and transformation assays were applied to explore the anti-plasmid function of CRISPR and R-M systems. RESULTS: We found a significant inverse correlation between the presence of CRISPR and R-M systems and blaKPC plasmids in K. pneumoniae, especially when both systems cohabited in one host. The multiple matched recognition sequences of both systems in blaKPC-IncF plasmids (97%) revealed that they were good targets for both systems. Furthermore, the results of conjugation assay demonstrated that CRISPR-Cas and R-M systems in K. pneumoniae could effectively hinder blaKPC plasmid invasion. Notably, CRISPR-Cas and R-M worked together to confer a 4-log reduction in the acquisition of blaKPC plasmid in conjugative events, exhibiting robust synergistic anti-plasmid immunity. CONCLUSIONS: Our results indicate the synergistic role of CRISPR and R-M in regulating horizontal gene transfer in K. pneumoniae and rationalize the development of antimicrobial strategies that capitalize on the immunocompromised status of KPC-KP.

Obesity is associated with lower levels of negative emotions in polycystic ovary syndrome in clinical and animal studies.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in women of reproductive age. It is frequently comorbid with obesity and negative emotions. Currently, there are few reports on the relationship between obesity and negative emotions in patients with PCOS. Here we performed both basic and clinical studies to study the relationship between obesity and negative emotions in PCOS. METHODS: We performed a cross-sectional study including 608 patients with PCOS and 184 healthy participants to assess the mental health status of people with different body mass indices (BMI). Self-rated anxiety, depression, and perceived stress scales were used for subjective mood evaluations. Rat PCOS models fed 45 and 60% high-fat diets were used to confirm the results of the clinical study. Elevated plus maze and open field tests were used to assess anxiety- and depression-like behaviors in rats. RESULTS: We observed overweight/obesity, increased depression, anxiety, and perceived stress in women with PCOS, and found that anxiety and depression were negatively correlated with BMI in patients with severe obesity and PCOS. Similar results were confirmed in the animal study; the elevated plus maze test and open field test demonstrated that only 60% of high fat diet-induced obesity partly reversed anxiety- and depression-like behaviors in PCOS rats. A high-fat diet also modulated rat hypothalamic and hippocampal luteinizing hormone and testosterone levels. CONCLUSION: These results reveal a potential relationship between obesity and negative emotions in PCOS and prompt further investigation. The interactions between various symptoms of PCOS may be targeted to improve the overall well-being of patients.

Obesity was negatively correlated with negative emotions in patients with PCOS.Obesity may affect the downregulation of LH and testosterone and participate in the regulation of emotions.Increased BMI may be beneficial for patients with PCOS in terms of the psychological aspects.

Brain-targeting redox-sensitive micelles for codelivery of TMZ and ß-lapachone for glioblastoma therapy.

Glioblastoma (GBM) is a central nervous system cancer with high incidence and poor survival rates. Enhancing drug penetration of the blood-brain barrier (BBB) and targeting efficacy is crucial for improving treatment outcomes. In this study, we developed a redox-sensitive targeted nano-delivery system (HCA-A2) for temozolomide (TMZ) and ß-lapachone (ß-Lapa). This system used hyaluronic acid (HA) as the hydrophilic group, arachidonic acid (CA) as the hydrophobic group, and angiopep-2 (A2) as the targeting group. Control systems included non-redox sensitive (HDA-A2) and non-targeting (HCA) versions. In vitro, HCA-TMZ-Lapa micelles released 100 % of their payload in a simulated tumor microenvironment within 24 h, compared to 43.97 % under normal conditions. HCA-A2 micelles, internalized via clathrin-mediated endocytosis, showed stronger cytotoxicity and better BBB penetration and cellular uptake than controls. In vivo studies demonstrated superior tumor growth inhibition with HCA-A2 micelles, indicating their potential for GBM treatment.

Enantiopure trigonal bipyramidal coordination cages templated by in situ self-organized D2h-symmetric anions.

The control of a molecule's geometry, chirality, and physical properties has long been a challenging pursuit. Our study introduces a dependable method for assembling D3-symmetric trigonal bipyramidal coordination cages. Specifically, D2h-symmetric anions, like oxalate and chloranilic anions, self-organize around a metal ion to form chiral-at-metal anionic complexes, which template the formation of D3-symmetric trigonal bipyramidal coordination cages. The chirality of the trigonal bipyramid is determined by the point chirality of chiral amines used in forming the ligands. Additionally, these cages exhibit chiral selectivity for the included chiral-at-metal anionic template. Our method is broadly applicable to various ligand systems, enabling the construction of larger cages when larger D2h-symmetric anions, like chloranilic anions, are employed. Furthermore, we successfully produce enantiopure trigonal bipyramidal cages with anthracene-containing backbones using this approach, which would be otherwise infeasible. These cages exhibit circularly polarized luminescence, which is modulable through the reversible photo-oxygenation of the anthracenes.

Protective effects of Lactococcus lactis subsp. lactis HFY14 supplementation on the brain, intestines, and motor function of antibiotic-treated mice.

Introduction: This study aimed to explore the anti-oxidative and anti-inflammatory properties of Lactococcus lactis subsp. lactis HFY14 (LLSLHFY14) and investigate its effects on the intestinal barrier, cranial nerve, and motor function in mice treated with antibiotics. Methods: Mice were administered an antibiotic mixture (neomycin 5 mg/mL, vancomycin 25 mg/mL, amphotericin B 0.1 mg/mL, ampicillin 10 mg/mL, metronidazole file 5 mg/mL, and lipopolysaccharide 1.5 µg/mL) intraperitoneally, and oxidative stress and inflammatory markers in the serum and brain tissues, and liver index were measured. H&E staining was performed to detect pathological alterations in brain tissues. The expression of intestinal-barrier-related genes and that of genes involved in inflammatory pathways in the brain were detected using polymerase chain reaction (PCR). Results: LLSLHFY14 administration extended the weight-loaded swimming and running times of mice and decreased the liver index. Moreover, the levels of malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the serum and brain tissue were reduced, whereas those of superoxide dismutase (SOD), glutathione (GSH), and interleukin-10 (IL-10) were elevated. Elevated brain expression of the protein kinase B (AKT)/cAMP-response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase 1 (ERK1) pathway, decreased brain expression of the IL-6 gene, and elevated cecum expression of zonula occludens-1 (ZO-1), occludin-1, and claudin-1 genes were noted. LLSLHFY14 supplementation significantly increased Bacteroidetes expression but decreased Firmicutes expression, thus increasing the Bacteroidetes/Firmicutes ratio. Discussion: Overall, LLSLHFY14 supplementation ameliorated antibiotic-induced oxidative stress and inflammation in the mouse central nervous system, intestinal barrier dysfunction, and increased motor function, thus confirming its potential application as probiotics.

Facile fabrication of linezolid/strontium coated hydroxyapatite/graphene oxide nanocomposite for osteoporotic bone defect.

Hydroxyapatite (HAp) coatings currently have limited therapeutic applications because they lack anti-infection, osteoinductivity, and poor mechanical characteristics. On the titanium substrate, electrochemical deposition (ECD) was used to construct the strontium (Sr)-featuring hydroxyapatite (HAp)/graphene oxides (GO)/linezolid (LZ) nanomaterial coated with antibacterial and drug delivery properties. The newly fabricated nanomaterials were confirmed by X-ray diffraction analysis (XRD), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS) analysis and morphological features were examined by scanning electron microscope (SEM) analysis. The results reveal multiple nucleation sites for SrHAp/GO/LZ composite coatings due to oxygen-comprising moieties on the 2D surface of GO. It was shown to be favorable for osteoblast proliferation and differentiation. The elastic modulus and hardness of LZ nanocomposite with SrHAp/GO/LZ coatings were increased by 67 % and 121 %, respectively. An initial 5 h burst of LZ release from the SrHAp/GO/LZ coating was followed by 14 h of gradual release, owing to LZ's physical and chemical adsorption. The SrHAp/GO/LZ coating effectively inhibited both S. epidermidis and S. aureus, and the inhibition lasted for three days, as demonstrated by the inhibition zone and colony count assays. When MG-63 cells are coated with SrHAp/GO/LZ composite coating, their adhesion, proliferation, and differentiation greatly improve when coated with pure titanium. A novel surface engineering nanomaterial for treating and preventing osteoporotic bone defects, SrHAp/GO/LZ, was shown to have high mechanical characteristics, superior antibacterial abilities, and osteoinductivity.

LCGNet: Local Sequential Feature Coupling Global Representation Learning for Functional Connectivity Network Analysis with fMRI.

Analysis of functional connectivity networks (FCNs) derived from resting-state functional magnetic resonance imaging (rs-fMRI) has greatly advanced our understanding of brain diseases, including Alzheimer's disease (AD) and attention deficit hyperactivity disorder (ADHD). Advanced machine learning techniques, such as convolutional neural networks (CNNs), have been used to learn high-level feature representations of FCNs for automated brain disease classification. Even though convolution operations in CNNs are good at extracting local properties of FCNs, they generally cannot well capture global temporal representations of FCNs. Recently, the transformer technique has demonstrated remarkable performance in various tasks, which is attributed to its effective self-attention mechanism in capturing the global temporal feature representations. However, it cannot effectively model the local network characteristics of FCNs. To this end, in this paper, we propose a novel network structure for Local sequential feature Coupling Global representation learning (LCGNet) to take advantage of convolutional operations and self-attention mechanisms for enhanced FCN representation learning. Specifically, we first build a dynamic FCN for each subject using an overlapped sliding window approach. We then construct three sequential components (i.e., edge-to-vertex layer, vertex-to-network layer, and network-to-temporality layer) with a dual backbone branch of CNN and transformer to extract and couple from local to global topological information of brain networks. Experimental results on two real datasets (i.e., ADNI and ADHD-200) with rs-fMRI data show the superiority of our LCGNet.

Perioperative outcomes of transvaginal specimen extraction laparoscopic total gastrectomy and conventional laparoscopic-assisted total gastrectomy.

BACKGROUND: Natural orifice specimen extraction surgery (NOSES) has emerged as a promising alternative compared to conventional laparoscopic-assisted total gastrectomy (LATG) for treating gastric cancer (GC). However, evidence regarding the efficacy and safety of NOSES for GC surgery is limited. This study aimed to compare the safety and feasibility, in addition to postoperative complications of NOSES and LATG. AIM: To discuss the postoperative effects of two different surgical methods in patients with GC. METHODS: Dual circular staplers were used in Roux-en-Y digestive tract reconstruction for transvaginal specimen extraction LATG, and its outcomes were compared with LATG in a cohort of 51 GC patients with tumor size ≤ 5 cm. The study was conducted from May 2018 to September 2020, and patients were categorized into the NOSES group (n = 22) and LATG group (n = 29). Perioperative parameters were compared and analyzed, including patient and tumor characteristics, postoperative outcomes, and anastomosis-related complications, postoperative hospital stay, the length of abdominal incision, difference in tumor type, postoperative complications, and postoperative survival. RESULTS: Postoperative exhaust time, operation duration, mean postoperative hospital stay, length of abdominal incision, number of specific staplers used, and Brief Illness Perception Questionnaire score were significant in both groups (P < 0.01). In the NOSES group, the postoperative time to first flatus, mean postoperative hospital stay, and length of abdominal incision were significantly shorter than those in the LATG group. Patients in the NOSES group had faster postoperative recovery, and achieved abdominal minimally invasive incision that met aesthetic requirements. There were no significant differences in gender, age, tumor type, postoperative complications, and postoperative survival between the two groups. CONCLUSION: The application of dual circular staplers in Roux-en-Y digestive tract reconstruction combined with NOSES gastrectomy is safe and convenient. This approach offers better short-term outcomes compared to LATG, while long-term survival rates are comparable to those of conventional laparoscopic surgery.

Threonine Aldolase-Catalyzed Enantioselective α-Alkylation of Amino Acids through Unconventional Photoinduced Radical Initiation.

Visible light-driven pyridoxal radical biocatalysis has emerged as a promising strategy for the stereoselective synthesis of valuable noncanonical amino acids (ncAAs). Previously, the use of well-tailored photoredox catalysts represented the key to enable efficient pyridoxal phosphate (PLP) enzyme-catalyzed radical reactions. Here, we report a PLP-dependent threonine aldolase-catalyzed asymmetric α-C-H alkylation of abundant amino acids using Katritzky pyridinium salts as alkylating agents. The use of engineered threonine aldolases allowed for this redox-neutral radical alkylation to proceed efficiently, giving rise to challenging α-trisubstituted and -tetrasubstituted ncAA products in a protecting-group-free fashion with excellent enantiocontrol. Mechanistically, this enantioselective α-alkylation capitalizes on the unique reactivity of the persistent enzymatic quinonoid intermediate derived from the PLP cofactor and the amino acid substrate to allow for novel radical C-C coupling. Surprisingly, this photobiocatalytic process does not require the use of well-established photoredox catalysts and operates through an unconventional photoinduced radical generation involving a PLP-derived aldimine. The ability to develop photobiocatalytic reactions without relying on classic photocatalysts or photoenzymes opens up new avenues for advancing stereoselective intermolecular radical reactions that are not known in either organic chemistry or enzymology.

Glycogen synthase kinase-3ß: A multifaceted player in ischemia-reperfusion injury and its therapeutic prospects.

Ischemia-reperfusion injury (IRI) results in irreversible metabolic dysfunction and structural damage to tissues or organs, posing a formidable challenge in the field of organ implantation, cardiothoracic surgery, and general surgery. Glycogen synthase kinase-3ß (GSK-3ß) a multifunctional serine/threonine kinase, is involved in a variety of biological processes, including cell proliferation, apoptosis, and immune response. Phosphorylation of its tyrosine 216 and serine 9 sites positively and negatively regulates the activation and inactivation of the enzyme. Significantly, inhibition or inactivation of GSK-3ß provides protection against IRI, making it a viable target for drug development. Though numerous GSK-3ß inhibitors have been identified to date, the development of therapeutic treatments remains a considerable distance away. In light of this, this review summarizes the complicated network of GSK-3ß roles in IRI. First, we provide an overview of GSK-3ß's basic background. Subsequently, we briefly review the pathological mechanisms of GSK-3ß in accelerating IRI, and highlight the latest progress of GSK-3ß in multiorgan IRI, encompassing heart, brain, kidney, liver, and intestine. Finally, we discuss the current development of GSK-3ß inhibitors in various organ IRI, offering a thorough and insightful reference for GSK-3ß as a potential target for future IRI therapy.

Recent advances in CO2 reduction with renewable reductants under hydrothermal conditions: towards efficient and net carbon benefit CO2 conversion.

The ever-growing atmospheric CO2 concentration threatening the environmental sustainability of humankind makes the reduction of CO2 to chemicals or fuels an ideal solution. Two priorities are anticipated for the conversion technology, high efficiency and net carbon benefit, to ensure the mitigation of the CO2 problem both promptly and sustainably. Until now, catalytic hydrogenation or solar/electro-chemical CO2 conversion have achieved CO2 reduction promisingly while, to some extent, compromising to fulfill the two rules, and thus alternative approaches for CO2 reduction are necessary. Natural geochemical processes as abiotic CO2 reductions give hints for efficient CO2 reduction by building hydrothermal reaction systems, and this type of reaction atmosphere provides room for introducing renewable substances as reductants, which offers the possibility to achieve CO2 reduction with net carbon benefit. While the progress in CO2 reduction has been abundantly summarized, reviews on hydrothermal CO2 reduction are relatively scarce and, more importantly, few have focused on CO2 reduction with renewable reductants with the consideration of both scale of efficiency and sustainability. This review provides a fundamental and critical review of metal, biomass and polymer waste as reducing agents for hydrothermal CO2 reduction. Various products including formic acid, methanol, methane and multi-carbon chemicals can be formed, and effects of operational parameters such as temperature, batch holding time, pH value and water filing as well as detailed reaction mechanisms are illustrated. Particularly, the critical roles of high temperature and pressure water as reaction promotor and catalyst in hydrothermal CO2 conversion are discussed at the mechanistic level. More importantly, this review compares hydrothermal CO2 reduction with other methods such as catalytic hydrogenation and photo/electrocatalysis, evaluating their efficiency and potential for net carbon benefit. The aim of this review is to promote the understanding of CO2 activation under a hydrothermal environment and provide insights into the efficient and sustainable strategy of hydrothermal CO2 conversion for future fundamental research and industrial applications.