Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

A multi-iron enzyme installs copper-binding oxazolone/thioamide pairs on a nontypeable Haemophilus influenzae virulence factor.

The multinuclear nonheme iron-dependent oxidases (MNIOs) are a rapidly growing family of enzymes involved in the biosynthesis of ribosomally synthesized, posttranslationally modified peptide natural products (RiPPs). Recently, a secreted virulence factor from nontypeable Haemophilus influenzae (NTHi) was found to be expressed from an operon, which we designate the hvf operon, that also encodes an MNIO. Here, we show by Mössbauer spectroscopy that the MNIO HvfB contains a triiron cofactor. We demonstrate that HvfB works together with HvfC [a RiPP recognition element (RRE)-containing partner protein] to perform six posttranslational modifications of cysteine residues on the virulence factor precursor peptide HvfA. Structural characterization by tandem mass spectrometry and NMR shows that these six cysteine residues are converted to oxazolone and thioamide pairs, similar to those found in the RiPP methanobactin. Like methanobactin, the mature virulence factor, which we name oxazolin, uses these modified residues to coordinate Cu(I) ions. Considering the necessity of oxazolin for host cell invasion by NTHi, these findings point to a key role for copper during NTHi infection. Furthermore, oxazolin and its biosynthetic pathway represent a potential therapeutic target for NTHi.

Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO.

Excessive activation of dendritic cells (DCs) leads to the development of autoimmune and inflammatory diseases, which has prompted a search for regulators of DC activation. Here we report that Rhbdd3, a member of the rhomboid family of proteases, suppressed the activation of DCs and production of interleukin 6 (IL-6) triggered by Toll-like receptors (TLRs). Rhbdd3-deficient mice spontaneously developed autoimmune diseases characterized by an increased abundance of the TH17 subset of helper T cells and decreased number of regulatory T cells due to the increase in IL-6 from DCs. Rhbdd3 directly bound to Lys27 (K27)-linked polyubiquitin chains on Lys302 of the modulator NEMO (IKKγ) via the ubiquitin-binding-association (UBA) domain in endosomes. Rhbdd3 further recruited the deubiquitinase A20 via K27-linked polyubiquitin chains on Lys268 to inhibit K63-linked polyubiquitination of NEMO and thus suppressed activation of the transcription factor NF-κB in DCs. Our data identify Rhbdd3 as a critical regulator of DC activation and indicate K27-linked polyubiquitination is a potent ubiquitin-linked pattern involved in the control of autoimmunity.

EphB2-dependent prefrontal cortex activation promotes long-range social approach and partner responsiveness.

Social behavior starts with dynamic approach prior to the final consummation. The flexible processes ensure mutual feedback across social brains to transmit signals. However, how the brain responds to the initial social stimuli precisely to elicit timed behaviors remains elusive. Here, by using real-time calcium recording, we identify the abnormalities of EphB2 mutant with autism-associated Q858X mutation in processing long-range approach and accurate activity of prefrontal cortex (dmPFC). The EphB2-dependent dmPFC activation precedes the behavioral onset and is actively associated with subsequent social action with the partner. Furthermore, we find that partner dmPFC activity is responsive coordinately to the approaching WT mouse rather than Q858X mutant mouse, and the social defects caused by the mutation are rescued by synchro-optogenetic activation in dmPFC of paired social partners. These results thus reveal that EphB2 sustains neuronal activation in the dmPFC that is essential for the proactive modulation of social approach to initial social interaction.

Pyroptosis and the fight against lung cancer.

Pyroptosis, a newly characterized type of inflammatory programmed cell death (PCD), is usually triggered by multiple inflammasomes which can recognize different danger or damage-associated molecular patterns (DAMPs), leading to the activation of caspase-1 and the cleavage of gasdermin D (GSDMD). Gasdermin family pore-forming proteins are the executers of pyroptosis and are normally maintained in an inactive state through auto-inhibition. Upon caspases mediated cleavage of gasdermins, the pro-pyroptotic N-terminal fragment is released from the auto-inhibition of C-terminal fragment and oligomerizes, forming pores in the plasma membrane. This results in the secretion of interleukin (IL)-1ß, IL-18, and high-mobility group box 1 (HMGB1), generating osmotic swelling and lysis. Current therapeutic approaches including chemotherapy, radiotherapy, molecularly targeted therapy and immunotherapy for lung cancer treatment efficiently force the cancer cells to undergo pyroptosis, which then generates local and systemic antitumor immunity. Thus, pyroptosis is recognized as a new therapeutic regimen for the treatment of lung cancer. In this review, we briefly describe the signaling pathways involved in pyroptosis, and endeavor to discuss the antitumor effects of pyroptosis and its potential application in lung cancer therapy, focusing on the contribution of pyroptosis to microenvironmental reprogramming and evocation of antitumor immune response.

Solvation Structure Regulation for Highly Reversible Aqueous Al Metal Batteries.

Metallic Al has been deemed an ideal electrode material for aqueous batteries by virtue of its abundance and high theoretical capacity (8056 mAh cm-3). However, the development of aqueous Al metal batteries has been hindered by several side reactions, including water decomposition, Al corrosion, and passivation, which arise from the solvation reaction of Al and H2O in conventional aqueous electrolytes. In this work, we report that water activity in electrolyte can be suppressed by optimizing the Al3+ solvation structure through intercalation of polar pyridine-3-carboxylic acid in an aluminum trifluoromethanesulfonate aqueous environment. Furthermore, the pyridine-3-carboxylic acid molecules are inclined to alter the surface energy of Al, thus suppressing the random deposition of Al. As a result, the Al corrosion in the hybrid electrolyte is restrained, and the long-term electrochemical stability of the electrolyte is tremendously improved. These merits bring remarkable reversibility to aqueous Al batteries using Al-preintercalated MnO2 cathodes, delivering a retaining energy density of >250 Wh kg-1 at 0.2 A g-1 after 600 cycles.

Recent advances (2019-2021) of capillary electrophoresis-mass spectrometry for multilevel proteomics.

Multilevel proteomics aims to delineate proteins at the peptide (bottom-up proteomics), proteoform (top-down proteomics), and protein complex (native proteomics) levels. Capillary electrophoresis-mass spectrometry (CE-MS) can achieve highly efficient separation and highly sensitive detection of complex mixtures of peptides, proteoforms, and even protein complexes because of its substantial technical progress. CE-MS has become a valuable alternative to the routinely used liquid chromatography-mass spectrometry for multilevel proteomics. This review summarizes the most recent (2019-2021) advances of CE-MS for multilevel proteomics regarding technological progress and biological applications. We also provide brief perspectives on CE-MS for multilevel proteomics at the end, highlighting some future directions and potential challenges.

Alpha-kinase 1 (ALPK1) agonist DF-006 demonstrates potent efficacy in mouse and primary human hepatocyte (PHH) models of hepatitis B.

BACKGROUND AND AIMS: In the treatment of chronic hepatitis B (CHB) infection, stimulation of innate immunity may lead to hepatitis B virus (HBV) cure. Alpha-kinase 1 (ALPK1) is a pattern recognition receptor (PRR) that activates the NF-κB pathway and stimulates innate immunity. Here we characterized the preclinical anti-HBV efficacy of DF-006, an orally active agonist of ALPK1 currently in clinical development for CHB. APPROACH AND RESULTS: In adeno-associated virus (AAV)-HBV mouse models and primary human hepatocytes (PHHs) infected with HBV, we evaluated the antiviral efficacy of DF-006. In the mouse models, DF-006 rapidly reduced serum HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen levels using doses as low as 0.08 µg/kg, 1 µg/kg, and 5 µg/kg, respectively. DF-006 in combination with the HBV nucleoside reverse transcriptase inhibitor, entecavir, further reduced HBV DNA. Antiviral efficacy in mice was associated with an increase in immune cell infiltration and decrease of hepatitis B core antigen, encapsidated pregenomic RNA, and covalently closed circular DNA in liver. At subnanomolar concentrations, DF-006 also showed anti-HBV efficacy in PHH with significant reductions of HBV DNA. Following dosing with DF-006, there was upregulation of NF-κB-targeted genes that are involved in innate immunity. CONCLUSION: DF-006 was efficacious in mouse and PHH models of HBV without any indications of overt toxicity. In mice, DF-006 localized primarily to the liver where it potently activated innate immunity. The transcriptional response in mouse liver provides insights into mechanisms that mediate anti-HBV efficacy by DF-006.

CircSKA3 is Associated With the Risk of Extracranial Artery Stenosis and Plaque Instability Among Ischemic Stroke Patients.

Circular RNA circSKA3 (spindle and kinetochore-related complex subunit 3) has been identified as a prognostic factor in ischemic stroke. The objective of this study was to investigate the association of circSKA3 with the risk of extracranial artery stenosis (ECAS) and plaque instability in patients with ischemic stroke. We constructed a competing endogenous RNA (ceRNA) network regulated by circSKA3 based on differentially expressed circRNAs and mRNAs between five patients and five controls. Gene Ontology (GO) analysis was performed on the 65 mRNAs within the network, revealing their primary involvement in inflammatory biological processes. A total of 284 ischemic stroke patients who underwent various imaging examinations were included for further analyses. Each 1 standard deviation increase in the log-transformed blood circSKA3 level was associated with a 56.3% increased risk of ECAS (P = 0.005) and a 142.1% increased risk of plaque instability (P = 0.005). Patients in the top tertile of circSKA3 had a 2.418-fold (P < 0.05) risk of ECAS compared to the reference group (P for trend = 0.02). CircSKA3 demonstrated a significant but limited ability to discriminate the presence of ECAS (AUC = 0.594, P = 0.015) and unstable carotid plaques (AUC = 0.647, P = 0.034). CircSKA3 improved the reclassification power for ECAS (NRI: 9.86%, P = 0.012; IDI: 2.97%, P = 0.007) and plaque instability (NRI: 36.73%, P = 0.008; IDI: 7.05%, P = 0.04) beyond conventional risk factors. CircSKA3 played an important role in the pathogenesis of ischemic stroke by influencing inflammatory biological processes. Increased circSKA3 was positively associated with the risk of ECAS and plaque instability among ischemic stroke patients.

Blood Pressure Fluctuation During 72 Hours After Endovascular Therapy and Prognosis in Acute Ischemic Stroke Patients.

PURPOSE: Our study aimed to investigate the relationship between fluctuations in different blood pressure (BP) components within 72 hours following endovascular therapy (EVT) and the prognosis of acute ischemic stroke (AIS) patients. METHODS: This prospective multicenter study included 283 AIS patients who underwent EVT and had available BP data. The primary outcome was the ordinal modified Rankin Scale (mRS) score evaluated at 90 days. The secondary outcome was a combination of death and major disability, defined as an mRS score of 3 to 6 within 3 months. RESULTS: After adjusting for imbalanced variables, the highest tertile of systolic blood pressure (SBP) fluctuation had an odds ratio (OR) of 1.747 (95% confidence interval [CI]=1.031-2.961; p for trend=0.035) for the primary outcome and 1.889 (95% CI=1.015-3.516; p for trend=0.039) for the secondary outcome, respectively. Fluctuations in diastolic blood pressure (DBP) (OR=1.914, 95% CI=1.134-3.230, p for trend=0.015) and mean arterial pressure (MAP) (OR=1.759, 95% CI=1.026-3.015, p for trend=0.039) were only associated with the primary outcome. The multivariate-adjusted restricted cubic spline analyses supported these findings. Furthermore, the fluctuations in both SBP and MAP exhibited the significant discriminatory capability in predicting the prognosis, comparable to their mean values. CONCLUSION: Our study revealed that larger fluctuations in SBP, DBP, and MAP within 72 hours after EVT were associated with a higher risk of poor clinical outcomes within 3 months in AIS patients. Controlling BP fluctuations may be valuable for improving the prognosis in patients undergoing EVT. CLINICAL IMPACT: How will this change clinical practice?It provides physicians a new approach to directly monitor BP fluctuations over an extended observation period in AIS patients after EVT in routine clinical practice.What does it mean for the clinicians?These results underscore the importance of giving equal attention to controlling long-term BP fluctuations, in addition to managing mean BP, as a means to improve the prognosis of AIS patients after EVT.What is the innovation behind the study?This study systematically evaluated the association between fluctuations in different blood pressure components and clinical outcomes in AIS patients over an extended period following EVT.

Ceftazidime/avibactam versus polymyxin B in carbapenem-resistant Klebsiella pneumoniae infections: a propensity score-matched multicenter real-world study.

OBJECTIVES: In this retrospective observational multicenter study, we aimed to assess efficacy and mortality between ceftazidime/avibactam (CAZ/AVI) or polymyxin B (PMB)-based regimens for the treatment of Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, as well as identify potential risk factors. METHODS: A total of 276 CRKP-infected patients were enrolled in our study. Binary logistic and Cox regression analysis with a propensity score-matched (PSM) model were performed to identify risk factors for efficacy and mortality. RESULTS: The patient cohort was divided into PMB-based regimen group (n = 98, 35.5%) and CAZ/AVI-based regimen group (n = 178, 64.5%). Compared to the PMB group, the CAZ/AVI group exhibited significantly higher rates of clinical efficacy (71.3% vs. 56.1%; p = 0.011), microbiological clearance (74.7% vs. 41.4%; p < 0.001), and a lower incidence of acute kidney injury (AKI) (13.5% vs. 33.7%; p < 0.001). Binary logistic regression revealed that the treatment duration independently influenced both clinical efficacy and microbiological clearance. Vasoactive drugs, sepsis/septic shock, APACHE II score, and treatment duration were identified as risk factors associated with 30-day all-cause mortality. The CAZ/AVI-based regimen was an independent factor for good clinical efficacy, microbiological clearance, and lower AKI incidence. CONCLUSIONS: For patients with CRKP infection, the CAZ/AVI-based regimen was superior to the PMB-based regimen.

Recycled Cathodes in Rechargeable Aqueous Batteries as Ready-Made Electrodes for Oxygen Evolution Catalysis.

The development of a low-cost and efficient oxygen evolution reaction (OER) electrode is of critical importance for water electrolysis technologies. The general approach to achieving a high-efficiency OER electrode is to regulate catalytic material structures by synthetic control. Here we reported an orthogonal approach to obtaining the OER electrode without intentional design and synthesis, namely, recycling MnO2 cathodes from failed rechargeable aqueous batteries and investigating them as ready-made catalytic electrodes. The recycled MnO2 cathode showed very little Zn2+ storage capacity but surprisingly high OER activity with a low overpotential of 307 mV at 10 mA cm-2 and a small Tafel slope of 77.9 mV dec-1, comparable to the state-of-the-art RuO2 catalyst (310 mV, 86.9 mV dec-1). In situ electrochemical and theoretical studies jointly revealed that the accelerated OER kinetics of the recycled MnO2 electrode was attributed to the enlarged active surface area of MnO2 and optimized electronic structure of Mn sites. This work suggests failed battery cathodes as successful catalysis electrodes for sustainable energy development.

Nanoporous Nickel Cathode with an Electrostatic Chlorine-Resistant Surface for Industrial Seawater Electrolysis Hydrogen Production.

Seawater electrolysis presents a promising avenue for green hydrogen production toward a carbon-free society. However, the electrode materials face significant challenges including severe chlorine-induced corrosion and high reaction overpotential, resulting in low energy conversion efficiency and low current density operation. Herein, we put forward a nanoporous nickel (npNi) cathode with high chlorine corrosion resistance for energy-efficient seawater electrolysis at industrial current densities (0.4-1 A cm-2). With the merits of an electrostatic chlorine-resistant surface, modulated Ni active sites, and a robust three-dimensional open structure, the npNi electrode showed a low hydrogen evolution reaction overpotential of 310 mV and a high electricity-hydrogen conversion efficiency of 59.7% at 400 mA cm-2 in real seawater and outperformed most Ni-based seawater electrolysis cathodes in recent publications and the commercial Ni foam electrode (459 mV, 46.4%) under the same test condition. In situ electrochemical impedance spectroscopy, high-frame-rate optical microscopy, and first-principles calculation revealed that the improved corrosion resistance, enhanced intrinsic activity, and mass transfer were responsible for the lowered electrocatalytic overpotential and enhanced energy efficiency.

The Key Phytochemical Cue Camphor Is a Promising Lure for Traps Monitoring the New Monophagous Camphor Tree Borer Pagiophloeus tsushimanus (Coleoptera: Curculionidae).

The landscape plant, Cinnamomum camphora, is a broad-spectrum insect-repelling tree species, mainly due to a diversity of terpenoids, such as camphor. Despite its formidable chemical defenses, C. camphora is easily attacked and invaded by a monophagous weevil pest, Pagiophloeus tsushimanus. Deciphering the key olfactory signal components regulating host preference could facilitate monitoring and control strategies for this pest. Herein, two host volatiles, camphor and ocimene, induced GC-EAD/EAG reactions in both male and female adult antennae. Correspondingly, Y-tube olfactometer assays showed that the two compounds were attractive to both male and female adults. In field assays, a self-made trap device baited with 5 mg dose d(+)-camphor captured significantly more P. tsushimanus adults than isopropanol solvent controls without sexual bias. The trunk gluing trap device baited with bait can capture adults, but the number was significantly less than that of the self-made trap device and adults often fell after struggling. The cross baffle trap device never trapped adults. Neither ocimene nor isopropanol solvent control captured adults. When used in combination, ocimene did not enhance the attraction of d(+)-camphor to both female and male adults. These results indicate that d(+)-camphor is a key active compound of P. tsushimanus adults for host location. The combination of the host-volatile lure based on d(+)-camphor and the self-made trapping device is promising to monitor and provide an eco-friendly control strategy for this novel pest P. tsushimanus in C. camphora plantations.

Constrained motion of self-propelling eccentric disks linked by a spring.

It has been supposed that the interplay of elasticity and activity plays a key role in triggering the non-equilibrium behaviors in biological systems. However, the experimental model system is missing to investigate the spatiotemporally dynamical phenomena. Here, a model system of an active chain, where active eccentric-disks are linked by a spring, is designed to study the interplay of activity, elasticity, and friction. Individual active chain exhibits longitudinal and transverse motions; however, it starts to self-rotate when pinning one end and self-beat when clamping one end. In addition, our eccentric-disk model can qualitatively reproduce such behaviors and explain the unusual self-rotation of the first disk around its geometric center. Furthermore, the structure and dynamics of long chains were studied via simulations without steric interactions. It was found that a hairpin conformation emerges in free motion, while in the constrained motions, the rotational and beating frequencies scale with the flexure number (the ratio of self-propelling force to bending rigidity), χ, as ∼(χ)4/3. Scaling analysis suggests that it results from the balance between activity and energy dissipation. Our findings show that topological constraints play a vital role in non-equilibrium synergy behaviors.

Polystyrene nano-plastics impede skeletal muscle development and induce lipid accumulation via the PPARγ/LXRß pathway in vivo and in vitro in mice.

Nano-plastics (NPs) have emerged as a significant environmental pollutant, widely existing in water environment, and pose a serious threat to health and safety with the intake of animals. Skeletal muscle, a vital organ for complex life activities and functional demands, has received limited attention regarding the effects of NPs. In this study, the effects of polystyrene NPs (PS-NPs) on skeletal muscle development were studied by oral administration of different sizes (1 mg/kg) of PS-NPs in mice. The findings revealed that PS-NPs resulted in skeletal muscle damage and significantly hindered muscle differentiation, exhibiting an inverse correlation with PS-NPs particle size. Morphological analysis demonstrated PS-NPs caused partial disruption of muscle fibers, increased spacing between fibers, and lipid accumulation. RT-qPCR and western blots analyses indicated that PS-NPs exposure downregulated the expression of myogenic differentiation-related factors (Myod, Myog and Myh2), activated PPARγ/LXRß pathway, and upregulated the expressions of lipid differentiation-related factors (SREBP1C, SCD-1, FAS, ACC1, CD36/FAT, ADIPOQ, C/EBPα and UCP-1). In vitro experiments, C2C12 cells were used to confirm cellular penetration of PS-NPs (0, 100, 200, 400 µg/mL) through cell membranes along with activation of PPARγ expression. Furthermore, to verify LXRß as a key signaling molecule, silencing RNA transfection experiments were conducted, resulting in no increase in the expressions of PPARγ, LXRß, SREBP1C, FAS, CD36/FAT, ADIPOQ, C/EBPα and UCP-1 even after exposure to PS-NPs. However, the expressions of SCD-1and ACC1 remained unaffected. The present study evidenced that exposure to PS-NPs induced lipid accumulation via the PPARγ/LXRß pathway thereby influencing skeletal muscle development.

A green leaf volatile, (Z)-3-hexenyl-acetate, mediates differential oviposition by Spodoptera frugiperda on maize and rice.

BACKGROUND: Insects rely on chemosensory perception, mainly olfaction, for the location of mates, food sources, and oviposition sites. Plant-released volatile compounds guide herbivorous insects to search for and locate their host plants, further helping them to identify suitable positions for oviposition. The fall armyworm Spodoptera frugiperda (S. frugiperda) was found to invade China in 2019 and has since seriously threatened multiple crops, particularly maize and rice. However, the chemical and molecular mechanisms underlying oviposition preference in this pest are not fully understood. Here, the oviposition preference of S. frugiperda on maize and rice plants was investigated. RESULTS: GC-EAD and GC-MS/MS techniques were used to identify the antennally active volatiles from maize and rice plants. The attraction and oviposition stimulation of identified components to female adults were tested in both laboratory and field settings. The odorant receptors (ORs) on female antennae were expressed in Xenopus oocytes, and their functions evaluated by RNAi. Ten and eleven compounds of maize and rice plants, respectively, were identified to possess electrophysiological activity from headspace volatiles. Among these compounds, (Z)-3-hexenyl-acetate specifically presented in maize volatiles was found to play a critical role in attracting females and stimulating oviposition compared to rice volatiles. Among the cloned ORs on the antennae of both sexes, SfruOR23 with highly female-biased expression mediated the responses of females to (Z)-3-hexenyl-acetate. Knockdown of SfruOR23 using RNAi markedly reduced the electrophysiological response of female antennae and oviposition preference to the compound. CONCLUSIONS: (Z)-3-Hexenyl-acetate is a key volatile mediating the host and oviposition preference of S. frugiperda on maize. The olfactory receptor of (Z)-3-hexenyl-acetate was identified to be SfruOR23, which is mainly expressed in the antennae of S. frugiperda.

Enhanced tyrosine sulfation is associated with chronic kidney disease-related atherosclerosis.

BACKGROUND: Chronic kidney disease (CKD) accelerates atherosclerosis, but the mechanisms remain unclear. Tyrosine sulfation has been recognized as a key post-translational modification (PTM) in regulation of various cellular processes, and the sulfated adhesion molecules and chemokine receptors have been shown to participate in the pathogenesis of atherosclerosis via enhancement of monocyte/macrophage function. The levels of inorganic sulfate, the essential substrate for the sulfation reaction, are dramatically increased in patients with CKD, which indicates a change of sulfation status in CKD patients. Thus, in the present study, we detected the sulfation status in CKD patients and probed into the impact of sulfation on CKD-related atherosclerosis by targeting tyrosine sulfation function. RESULTS: PBMCs from individuals with CKD showed higher amounts of total sulfotyrosine and tyrosylprotein sulfotransferase (TPST) type 1 and 2 protein levels. The plasma level of O-sulfotyrosine, the metabolic end product of tyrosine sulfation, increased significantly in CKD patients. Statistically, O-sulfotyrosine and the coronary atherosclerosis severity SYNTAX score positively correlated. Mechanically, more sulfate-positive nucleated cells in peripheral blood and more abundant infiltration of sulfated macrophages in deteriorated vascular plaques in CKD ApoE null mice were noted. Knockout of TPST1 and TPST2 decreased atherosclerosis and peritoneal macrophage adherence and migration in CKD condition. The sulfation of the chemokine receptors, CCR2 and CCR5, was increased in PBMCs from CKD patients. CONCLUSIONS: CKD is associated with increased sulfation status. Increased sulfation contributes to monocyte/macrophage activation and might be involved in CKD-related atherosclerosis. Inhibition of sulfation may suppress CKD-related atherosclerosis and is worthy of further study.

Meta-analysis of robotic-assisted NOSE versus traditional TWSR in colorectal cancer surgery: postoperative outcomes and efficacy.

BACKGROUND: This meta-analysis aimed to assess the safety and efficacy of robotic-assisted natural orifice specimen extraction surgery (NOSE) compared to traditional robotic transabdominal wall specimen retrieval surgery (TWSR) for colorectal cancer. METHODS: A systematic search was conducted in three electronic databases (PubMed, Web of Science and Embase) from inception to August 2023. Primary outcomes included postoperative complications, the number of lymph nodes harvested, overall survival and disease-free survival. Secondary outcomes included the postoperative visual analog scale (VAS) score, the additional use of analgesics, the restoration of gastrointestinal function, blood loss, the mean operation time, and length of postoperative hospital stay. RESULTS: In this meta-analysis, a total of 717 patients from 6 observational studies met the inclusion criteria. Compared with the TWSR group, the NOSE group had greater benefits in terms of overall postoperative complications [odds ratios (OR) 0.55; 95% confidence intervals (CI) = 0.34 to 0.89; P = 0.01, I2 = 0%)], the number of lymph nodes harvested [weighted mean differences (WMD) = 1.18; 95% CI = 0.15 to 2.21; P = 0.02, I2 = 0%)], the rate of wound infection (OR 0.17; 95% CI = 0.04 to 0.80; P = 0.02, I2 = 0%), the passed flatus time (WMD = - 0.35 days; 95% CI = - 0.60 to - 0.10; P = 0.007, I2 = 73%), the additional use of analgesics (OR 0.25; 95% CI = 0.15 to 0.40; P < 0.001, I2 = 0%), the diet recovery time (WMD = - 0.56; 95% CI = - 1.00 to - 0.11; P = 0.01, I2 = 78%) and the postoperative VAS score (WMD = - 1.23; 95% CI = - 1.63 to - 0.83; P < 0.001, I2 = 65%). There were no significant differences in the blood loss (WMD = - 5.78 ml; 95% CI = - 17.57 to 6.00; P = 0.34, I2 = 90%), mean operation time (WMD = 14.10 min; 95% CI = - 3.76 to 31.96; P = 0.12) (I2 = 93%), length of postoperative hospital stay (WMD = - 0.47 day; 95% CI = - 0.98 to 0.03; P = 0.07, I2 = 51%), incidences of postoperative ileus (OR 1.0; 95% CI = 0.22 to 4.46; P = 1.00, I2 = 0%), anastomotic leakage (OR 0.73; 95% CI = 0.33 to 1.60; P = 0.43, I2 = 0%), and intra-abdominal abscess (OR 1.59; 95% CI = 0.47 to 5.40; P = 0.46, I2 = 0%), or 3-year overall survival [hazard ratio (HR) = 1.07, 95% CI = 0.60 to 1.94; P = 0.81)] or disease-free survival (HR = 0.94, 95% CI = 0.54 to 1.63; P = 0.82, I2 = 0%). CONCLUSION: This meta-analysis showed that the NOSE group had better postoperative outcomes than did the TWSR group and that NOSE was a safe and viable alternative to TWSR. More large-sample reviews and further randomized trials are warranted.

Ectopic Activation of Fgf8 in Dental Mesenchyme Causes Incisor Agenesis and Molar Microdontia.

Putatively, tooth agenesis was attributed to the initiation failure of tooth germs, though little is known about the histological and molecular alterations. To address if constitutively active FGF signaling is associated with tooth agenesis, we activated Fgf8 in dental mesenchyme with Osr-cre knock-in allele in mice (Osr2-creKI; Rosa26R-Fgf8) and found incisor agenesis and molar microdontia. The cell survival assay showed tremendous apoptosis in both the Osr2-creKI; Rosa26R-Fgf8 incisor epithelium and mesenchyme, which initiated incisor regression from cap stage. In situ hybridization displayed vanished Shh transcription, and immunostaining exhibited reduced Runx2 expression and enlarged mesenchymal Lef1 domain in Osr2-creKI; Rosa26R-Fgf8 incisors, both of which were suggested to enhance apoptosis. In contrast, Osr2-creKI; Rosa26R-Fgf8 molar germs displayed mildly suppressed Shh transcription, and the increased expression of Ectodin, Runx2 and Lef1. Although mildly smaller than WT controls prenatally, the Osr2-creKI; Rosa26R-Fgf8 molar germs produced a miniature tooth with impaired mineralization after a 6-week sub-renal culture. Intriguingly, the implanted Osr2-creKI; Rosa26R-Fgf8 molar germs exhibited delayed odontoblast differentiation and accelerated ameloblast maturation. Collectively, the ectopically activated Fgf8 in dental mesenchyme caused incisor agenesis by triggering incisor regression and postnatal molar microdontia. Our findings reported tooth agenesis resulting from the regression from the early bell stage and implicated a correlation between tooth agenesis and microdontia.