Comparative Study on Enzymatic Characteristics of Two κ-Carrageenases from Carrageenan-Degrading Bacterium Catenovulum agarivorans DS2.

κ-Carrageenase plays an important role in achieving the high-value utilization of carrageenan. Factors such as the reaction temperature, thermal stability, catalytic efficiency, and product composition are key considerations for its large-scale application. Previous studies have shown that the C-terminal noncatalytic domains (nonCDs) could influence the enzymatic properties, of κ-carrageenases, providing a strategy for exploring κ-carrageenases with different properties, especially catalytic products. Accordingly, two κ-carrageenases (CaKC16A and CaKC16B), from the Catenovulum agarivorans DS2, were selected and further characterized. Bioinformatics analysis suggested that CaKC16A contained a nonCD but CaKC16B did not. CaKC16A exhibited better enzymatic properties than CaKC16B, including thermal stability, substrate affinity, and catalytic efficiency. After truncation of the nonCD of CaKC16A, its thermal stability, substrate affinity, and catalytic efficiency have significantly decreased, indicating the vital role of nonCD in maintaining a good enzymatic property. Moreover, CaKC16A degraded κ-carrageenan to produce a highly single κ-neocarratetrose, while CaKC16B produced a single κ-neocarrabiose. CaKC16A could degrade ß/κ-carrageenan to produce a highly single desulfated κ-neocarrahexaose, while CaKC16B produced κ-neocarrabiose and desulfated κ-neocarratetrose. Furthermore, it was proposed that CaKC16A and CaKC16B participate in the B/KC metabolic pathway and serve different roles, providing new insight into obtaining κ-carrageenases with different properties.

Cell-free Nucleic Acid as Promising Diagnostic Biomarkers for Gastric Cancer: a Systematic Review.

Background: Gastric cancer (GC) is a common malignancy with early detection being crucial for survival. Liquid biopsy analysis using cell-free nucleic acid is a preferred method for detection. Hence, we conducted a systematic review to assess the diagnostic efficacy of cell-free nucleic acid markers for GC. Methods: We searched PubMed and ISI Web of Science databases for articles that conformed to our inclusion and exclusion criteria from 2012 to 2022. The following information was abstracted: first author, year of publication, country/region, age, male proportion, tumor stage for cases, specimen type, measurement method, targeted markers and diagnostic related indicators (including sensitivity, specificity, AUC, P-value). Results: Fifty-eight studies examined cell-free RNAs (cfRNAs) with a total of 62 individual circulating markers and 7 panels in serum or plasma, while 21 studies evaluated cell-free DNAs (cfDNAs) with 29 individual circulating markers and 7 panels. For individual cfRNAs, the median (range) sensitivity and specificity were 80% (21% - 98%) and 80% (54% - 99%), respectively. The median (range) sensitivity and specificity for cfRNA panels were 86% (83% - 90%) and 75% (60% - 98%), respectively. In comparison, the median (range) sensitivity and specificity reported for individual cfDNAs were 50% (18% - 96%) and 93% (57% - 100%), respectively, while cfDNA panels had a median (range) sensitivity and specificity of 85% (41% - 92%) and 73.5% (38% - 90%), respectively. The meta results indicate that cfRNA markers exhibit high sensitivity (80%) and low specificity (80%) for detecting GC, while cfDNA markers have lower sensitivity (59%) but higher specificity (92%). Conclusions: This review has demonstrated that cell-free nucleic acids have the potential to serve as useful diagnostic markers for GC. Given that both cfRNA and cfDNA markers have shown promising diagnostic performance for GC, the combination of the two may potentially enhance diagnostic efficiency.

High-definition transcranial direct current stimulation (HD-tDCS) in major depressive disorder with anxious distress-a study protocol for a double-blinded randomized sham-controlled trial.

BACKGROUND: Comorbid anxiety disorders and anxious distress are highly prevalent among individuals with major depressive disorder (MDD). The presence of the DSM-5 anxious distress specifier (ADS) has been associated with worse treatment outcomes and chronic disease course. Few studies have evaluated the therapeutic effects of High-definition transcranial direct current stimulation (HD-tDCS) on depressive and anxiety symptoms among MDD patients with ADS. The current randomized controlled trial aims to assess the efficacy of HD-tDCS as an augmentation therapy with antidepressants compared to sham-control in subjects of MDD with ADS. METHODS: MDD patients with ADS will be recruited and randomly assigned to the active HD-tDCS or sham HD-tDCS group. In both groups, patients will receive the active or sham intervention in addition to their pre-existing antidepressant therapy, for 2 weeks with 5 sessions per week, each lasting 30 min. The primary outcome measures will be the change of depressive symptoms, clinical response, and the remission rate as measured with the 17-item Hamilton Depression Rating Scale (HDRS-17) before and after the intervention and at the 2nd and 6th week after the completed intervention. Secondary outcome measures include anxiety symptoms, cognitive symptoms, disability assessment, and adverse effects. DISCUSSION: The HD-tDCS applied in this trial may have treatment effects on MDD with ADS and have minimal side effects. TRIAL REGISTRATION: The trial protocol is registered with www.chictr.org.cn under protocol registration number ChiCTR2300071726. Registered 23 May 2023.

KinomeMETA: a web platform for kinome-wide polypharmacology profiling with meta-learning.

Kinase-targeted inhibitors hold promise for new therapeutic options, with multi-target inhibitors offering the potential for broader efficacy while minimizing polypharmacology risks. However, comprehensive experimental profiling of kinome-wide activity is expensive, and existing computational approaches often lack scalability or accuracy for understudied kinases. We introduce KinomeMETA, an artificial intelligence (AI)-powered web platform that significantly expands the predictive range with scalability for predicting the polypharmacological effects of small molecules across the kinome. By leveraging a novel meta-learning algorithm, KinomeMETA efficiently utilizes sparse activity data, enabling rapid generalization to new kinase tasks even with limited information. This significantly expands the repertoire of accurately predictable kinases to 661 wild-type and clinically-relevant mutant kinases, far exceeding existing methods. Additionally, KinomeMETA empowers users to customize models with their proprietary data for specific research needs. Case studies demonstrate its ability to discover new active compounds by quickly adapting to small dataset. Overall, KinomeMETA offers enhanced kinome virtual profiling capabilities and is positioned as a powerful tool for developing new kinase inhibitors and advancing kinase research. The KinomeMETA server is freely accessible without registration at https://kinomemeta.alphama.com.cn/.

Long non-coding RNA LIP interacts with PARP-1 influencing the efficiency of base excision repair.

In recent years, various long non-coding RNAs (lncRNAs) involved in DNA damage response (DDR) have been identified and studied to deepen our understanding. However, there are rare reports on the association between lncRNAs and base excision repair (BER). Our designed DNA microarray identified dozens of functionally unknown lncRNAs, and their transcription levels significantly increased upon exposure to DNA damage inducers. One of them, named LIP (Long noncoding RNA Interacts with PARP-1), exhibited a significant alteration in transcription in response to methyl methanesulfonate (MMS) and temozolomide (TMZ) treatments. LIP knockdown or knockout cell lines are sensitive to MMS and TMZ, indicating that LIP plays a crucial role in DDR. The loss or insufficiency of LIP significantly influences the efficiency of BER in human cells, and it suggests that LIP participates in the BER pathway. The interaction between LIP and a key factor in BER, poly (ADP-ribose) polymerase 1 (PARP-1), has been confirmed. We identified and characterized LIP, a lncRNA, which is involved in DDR, significantly influences BER efficiency, and interacts with the BER key factor PARP-1. This advances our understanding of the connection between lncRNAs and BER, presenting the potential for the discovery of new drug targets.

ß-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer's disease.

Introduction: The study of the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular -amyloid (A) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. Methods: The humanized APPNL-G-F knock-in mouse line was crossed to the PS19 MAPTP301S, over-expression mouse line to create the dual APPNL-G-F/PS19 MAPTP301S line. The resulting pathologies were characterized by immunochemical methods and PCR. Results: We now report on a double transgenic APPNL-G-F/PS19 MAPTP301S mouse that at 6 months of age exhibits robust A plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of A pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. MAPT pathology neither changed levels of amyloid precursor protein nor potentiated A accumulation. Interestingly, study of immunofluorescence in cleared brains indicates that microglial inflammation was generally stronger in the hippocampus, dentate gyrus and entorhinal cortex, which are regions with predominant MAPT pathology. The APPNL-G-F/MAPTP301S mouse model also showed strong accumulation of N6-methyladenosine (m6A), which was recently shown to be elevated in the AD brain. m6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively. Discussion: Our understanding of the pathophysiology of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular -amyloid (A) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. The APPNL-G-F/MAPTP301S mouse recapitulates many features of AD pathology beginning at 6 months of aging, and thus represents a useful new mouse model for the field.

Systematic review on carrageenolytic enzymes: From metabolic pathways to applications in biotechnology.

Carrageenan, the major carbohydrate component of some red algae, is an important renewable bioresource with very large annual outputs. Different types of carrageenolytic enzymes in the carrageenan metabolic pathway are potentially valuable for the production of carrageenan oligosaccharides, biofuel, and other chemicals obtained from carrageenan. However, these enzymes are not well-developed for oligosaccharide or biofuel production. For further application, comprehensive knowledge of carrageenolytic enzymes is essential. Therefore, in this review, we first summarize various carrageenolytic enzymes, including the recently discovered ß-carrageenase, carrageenan-specific sulfatase, exo-α-3,6-anhydro-D-galactosidase (D-ADAGase), and exo-ß-galactosidase (BGase), and describe their enzymatic characteristics. Subsequently, the carrageenan metabolic pathways are systematically presented and applications of carrageenases and carrageenan oligosaccharides are illustrated with examples. Finally, this paper discusses critical aspects that can aid researchers in constructing cascade catalytic systems and engineered microorganisms to efficiently produce carrageenan oligosaccharides or other value-added chemicals through the degradation of carrageenan. Overall, this paper offers a comprehensive overview of carrageenolytic enzymes, providing valuable insights for further exploration and application of these enzymes.

Preparation of Ultrafine Co- and Ni-Coated (Ti,W,Mo,Ta)(C,N) Powders and Their Influence on the Microstructure of Ti(C,N)-Based Cermets.

The use of metal-coated ceramic powders not only effectively enhances the wettability of the metal-ceramic interface but also promotes a more uniform microstructure in Ti(C,N)-based cermets, which is advantageous for improving their mechanical properties. In this study, ultrafine Co- and Ni-coated (Ti,W,Mo,Ta)(C,N) powders were synthesized via the spray-drying-in-situ carbothermal reduction method. Subsequently, Ti(C,N)-based cermets were effectively fabricated using the as-prepared ultrafine Co- and Ni-coated (Ti,W,Mo,Ta)(C,N) powders. The impact of reaction temperature, heating rate, and isothermal time on the phase and microstructure of prepared powders was analyzed using X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Additionally, the microstructure of the as-sintered cermets was experimentally investigated. The findings reveal that the complete reduction of Co and Ni metal salts, pre-coated on the surface of (Ti,W,Mo,Ta)(C,N) particles, can be achieved through rapid heating (10 °C/min) in a specific temperature range (600-1000 °C) with an isothermal time of 3 h at a lower reduction temperature (1000 °C). The synthesized powders have only two phases: the (Ti,W,Mo,Ta)(C,N) phase and Co/Ni phase, and no other heterogeneous phases were observed with an oxygen content of 0.261 wt.%. Notably, the conventional core-rim structure was not dominant in the cermets obtained from the prepared Co- and Ni-coated (Ti,W,Mo,Ta)(C,N) powders. Moreover, the heterogeneous segregation effect of the Co/Ni coating on the ultrafine powder particles resulted in a finer microstructure than the traditional cermets with the same composition. However, the grain size is mainly in the range of 0.5-0.8 µm. The weaker residual stresses at the core and rim interfaces and the finer particle distributions could theoretically enhance the toughness of Ti(C,N)-based cermets, simultaneously.

Effect of intraoperative dexmedetomidine on recovery of gastrointestinal function after caesarean section undergoing spinal and epidural anesthesia: A randomized, double blind, placebo-controlled clinical trial.

OBJECTIVE: Gastrointestinal dysfunction after cesarean section negatively affects postoperative recovery. Dexmedetomidine has been shown to improve postoperative gastrointestinal function in patients undergoing lumbar spinal fusion surgery and laparoscopic gastrectomy, but its role in cesarean section has not been fully elucidated. The study aimed to investigate the effect of dexmedetomidine on gastrointestinal function after cesarean section. STUDY DESIGN: 220 pregnant women who underwent elective cesarean section were randomized into group D and group S. Group D patients received a loading dose of 0.5 µg/kg of dexmedetomidine for 10 mins followed by a maintenance dose of 0.5 µg/kg/h intravenously immediately after the umbilical cord was cut intraoperatively, whereas the other group (group S) received an equivalent quantity of normal saline as loading and maintenance dose IV by infusion pump. The primary outcome was time to first flatus after surgery (hours). Secondary outcomes included time to first feces and first bowel sounds (hours), incidence rates of postoperative gastrointestinal complications, and the length of postoperative hospital stay (days). RESULTS: Modified intention-to-treat analysis showed that patients in Group D had a significantly shorter time to first flatus (21 [16 to 28.25] vs. 25 [18 to 32.25] h; P = 0.014), time to first feces (45.5 [35.75 to 55.25] vs. 53 [40 to 60] h; P = 0.019), and time to first bowel sounds (P = 0.010), a lower incidence of abdominal distension (21[20.6 %] vs. 36[34.3 %], P = 0.027), shorter length of postoperative hospital stay (P = 0.010) compared to patients in Group S. CONCLUSION: Intraoperative dexmedetomidine infusion reduces the time to first flatus, the incidence of abdominal distension, and shortens the length of hospital stay, promoting gastrointestinal function after cesarean section.

Two sequential gene expression programs bridged by cell division support long-distance collective cell migration.

The precise assembly of tissues and organs relies on spatiotemporal regulation of gene expression to coordinate the collective behavior of cells. In Drosophila embryos, the midgut musculature is formed through collective migration of caudal visceral mesoderm (CVM) cells, but how gene expression changes as cells migrate is not well understood. Here, we have focused on ten genes expressed in the CVM and the cis-regulatory sequences controlling their expression. Although some genes are continuously expressed, others are expressed only early or late during migration. Late expression relates to cell cycle progression, as driving string/Cdc25 causes earlier division of CVM cells and accelerates the transition to late gene expression. In particular, we found that the cell cycle effector transcription factor E2F1 is a required input for the late gene CG5080. Furthermore, whereas late genes are broadly expressed in all CVM cells, early gene transcripts are polarized to the anterior or posterior ends of the migrating collective. We show this polarization requires transcription factors Snail, Zfh1 and Dorsocross. Collectively, these results identify two sequential gene expression programs bridged by cell division that support long-distance directional migration of CVM cells.

Enhancing endometrial receptivity: the roles of human chorionic gonadotropin in autophagy and apoptosis regulation in endometrial stromal cells.

Inadequate endometrial receptivity often results in embryo implantation failure and miscarriage. Human chorionic gonadotropin (hCG) is a key signaling molecule secreted during early embryonic development, which regulates embryonic maternal interface signaling and promotes embryo implantation. This study aimed to examine the impact of hCG on endometrial receptivity and its underlying mechanisms. An exploratory study was designed, and endometrial samples were obtained from women diagnosed with simple tubal infertility or male factor infertile (n = 12) and recurrent implantation failure (RIF, n = 10). Using reverse transcription-quantitative PCR and western blotting, luteinizing hormone (LH)/hCG receptor (LHCGR) levels and autophagy were detected in the endometrial tissues. Subsequently, primary endometrial stromal cells (ESCs) were isolated from these control groups and treated with hCG to examine the presence of LHCGR and markers of endometrial receptivity (HOXA10, ITGB3, FOXO1, LIF, and L-selectin ligand) and autophagy-related factors (Beclin1, LC3, and P62). The findings revealed that the expressions of receptivity factors, LHCGR, and LC3 were reduced in the endometrial tissues of women with RIF compared with the control group, whereas the expression of P62 was elevated. The administration of hCG to ESCs specifically activated LHCGR, stimulating an increase in the endometrial production of HOXA10, ITGB3, FOXO1, LIF and L-selectin ligands. Furthermore, when ESCs were exposed to 0.1 IU/mL hCG for 72 h, the autophagy factors Beclin1 and LC3 increased within the cells and P62 decreased. Moreover, the apoptotic factor Bax increased and Bcl-2 declined. However, when small interfering RNA was used to knock down LHCGR, hCG was less capable of controlling endometrial receptivity and autophagy molecules in ESCs. In addition, hCG stimulation enhanced the phosphorylation of ERK1/2 and mTOR proteins. These results suggest that women with RIF exhibit lower levels of LHCGR and compromised autophagy function in their endometrial tissues. Thus, hCG/LHCGR could potentially improve endometrial receptivity by modulating autophagy and apoptosis.

Effect of intravenous lidocaine on the ED50 of propofol induction dose in elderly patients undergoing painless gastroscopy: a prospective, randomized, double-blinded, controlled study.

BACKGROUND: Intravenous lidocaine could be a potential alternative adjuvant to propofol-based sedation for gastroscopy in elderly patients. This study aimed to evaluate the effect of intravenous lidocaine on the median effective dose (ED50) of propofol induction dose in elderly patients undergoing painless gastroscopy. METHODS: The study included 70 patients aged ≥ 60 years undergoing painless gastroscopy with 64 randomly assigned to either group L (2% lidocaine 1.5 mg/kg, n = 31) or group N (equal volume normal saline, n = 33). All patients received propofol induction following 0.1 µg/kg intravenous sufentanil. The Dixon "up-and-down" sequential method was used, with a 1.5 mg/kg initial induction dose of propofol followed by a 0.1 mg/kg sequential variable dose. The primary endpoint was the ED50 of the propofol induction dose. The total propofol dose, recovery time, adverse events, and local anesthetic intoxication reactions were also recorded. RESULTS: The ED50 of propofol induction dose was 0.670 (95% confidence interval [CI] 0.216-0.827) mg/kg in group L and 1.118 (95% CI 0.803-1.232) mg/kg in group N. There was a statistically significant difference between the two groups (p < 0.001). The incidence of hypotension and propofol injection pain were lower in group L than in group N (p < 0.05). Furthermore, the orientation recovery time in group L was shorter compared to group N (p < 0.05). None of the participants in group L observed local anesthetic intoxication reactions after receiving lidocaine. CONCLUSIONS: The administration of intravenous lidocaine to elderly patients undergoing painless gastroscopy resulted in a significant 40% reduction in the ED50 of propofol induction dose, which may be related to the decreased incidence of hypotension and injection pain, as well as the improved post-gastroscopy orientation recovery. TRIAL REGISTRATION: ChiCTR, ChiCTR2200065530. Registered on 08 November 2022.

Telo boxes within the AGAMOUS second intron recruit histone 3 lysine 27 methylation to increase petal number in rose (Rosa chinensis) in response to low temperatures.

The petals of rose (Rosa sp.) flowers determine the ornamental and industrial worth of this species. The number of petals in roses was previously shown to be subject to fluctuations in ambient temperature. However, the mechanisms by which rose detects and responds to temperature changes are not entirely understood. In this study, we identified short interstitial telomere motifs (telo boxes) in the second intron of AGAMOUS (RcAG) from China rose (Rosa chinensis) that play an essential role in precise temperature perception. The second intron of RcAG harbors two telo boxes that recruit telomere repeat binding factors (RcTRBs), which interact with CURLY LEAF (RcCLF) to compose a repressor complex. We show that this complex suppresses RcAG expression when plants are subjected to low temperatures via depositing H3K27me3 marks (trimethylation of lysine 27 on histone H3) over the RcAG gene body. This regulatory mechanism explains the low-temperature-dependent decrease in RcAG transcript levels, leading to the production of more petals under these conditions. Our results underscore an interesting intron-mediated regulatory mechanism governing RcAG expression, enabling rose plants to perceive temperature cues and establish petal numbers.

Mapping the tRNA modification landscape of Bartonella henselae Houston I and Bartonella quintana Toulouse.

Transfer RNA (tRNA) modifications play a crucial role in maintaining translational fidelity and efficiency, and they may function as regulatory elements in stress response and virulence. Despite their pivotal roles, a comprehensive mapping of tRNA modifications and their associated synthesis genes is still limited, with a predominant focus on free-living bacteria. In this study, we employed a multidisciplinary approach, incorporating comparative genomics, mass spectrometry, and next-generation sequencing, to predict the set of tRNA modification genes responsible for tRNA maturation in two intracellular pathogens-Bartonella henselae Houston I and Bartonella quintana Toulouse, which are causative agents of cat-scratch disease and trench fever, respectively. This analysis presented challenges, particularly because of host RNA contamination, which served as a potential source of error. However, our approach predicted 26 genes responsible for synthesizing 23 distinct tRNA modifications in B. henselae and 22 genes associated with 23 modifications in B. quintana. Notably, akin to other intracellular and symbiotic bacteria, both Bartonella species have undergone substantial reductions in tRNA modification genes, mostly by simplifying the hypermodifications present at positions 34 and 37. Bartonella quintana exhibited the additional loss of four modifications and these were linked to examples of gene decay, providing snapshots of reductive evolution.

A rapid one-step affinity purification of C-phycocyanin from Spirulina platensis.

The high-purity phycocyanin has a high commercial value. Most current purification methods of C-phycocyanin involve multiple steps, which are complicated and time-consuming. To solve the problem, this research was studied, and an efficient affinity chromatography purification for C-phycocyanin from Spirulina platensis was developed. Through molecular docking simulation, virtual screening of ligands was performed, and ursolic acid was identified as the specific affinity ligand, which coupled to Affi-Gel 102 gel via 1-ethyl (3-dimethylaminopropyl)-3-carbodiimide, hydrochloride as coupling agent. With this customized and synthesized resin, a high-efficiency one-step purification procedure for C-phycocyanin was developed and optimized, the purity was determined to be 4.53, and the yield was 69 %. This one-step purification protocol provides a new approach for purifying other phycobilin proteins.

FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression.

SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression. Aberrant glycosylation has been intricately linked with immune escape and tumor growth. SEMA7A is a highly glycosylated protein with five glycosylated sites. The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear. Here, we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma, and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides (Asn 105, 157, 258, 330, and 602) via a direct protein‒protein interaction. A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane. Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8, whereas TGF-ß1 promotes abnormal glycosylation of SEMA7A via induction of epithelial-mesenchymal transition. Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8+ T cells along a trajectory toward an exhausted state, thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death. Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy. Finally, we also define RBM4, a splice regulator, as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing. These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

Nanosphere-reinforced polysaccharide self-healing hydrogels for infected wound healing.

Bacterial infection remarkably impedes wound healing, with antibiotics traditionally serving as the primary therapeutic intervention. However, the escalating misuse of antibiotics and the emergence of bacterial resistance present substantial treatment challenges for infected wounds. Consequently, the development of antibiotic-free antimicrobial dressings holds pertinent research and clinical relevance. To this end, this study aimed to introduce an all-natural hydrogel dressing, amalgamating polyphenols and polysaccharides, exhibiting pronounced antibacterial and antioxidant properties without relying on antibiotics. First, we constructed curcumin-tannic acid­zinc ion nanospheres (CTZN) through self-assembly. Our experimental results showed that the nanospheres had excellent biocompatibility, antioxidant, and antimicrobial abilities. Subsequently, we prepared carboxymethylated chitosan/oxidized sodium alginate hydrogels via Schiff base reactions. Incorporation of CTZN into the hydrogel system not only improves the inherent qualities of the hydrogel but also confers multifunctional properties, including antimicrobial, antioxidant, and anti-inflammatory abilities. In this study, we enhanced the physicochemical properties and biological activity of hydrogels by introducing natural material nanospheres, offering a novel approach that could pave the way for the development of purely natural biomaterial dressings.

Dimeric eremophilane-type sesquiterpenoids from the peeled stems of Syringa pinnatifolia.

A continued phytochemical investigation guided by 1H NMR and LC-MS data on the ethanol extract from the peeled stems of Syringa pinnatifolia Hemsl. led to the isolation of 16 undescribed dimeric eremophilane sesquiterpenoids, namely syringenes R-Z (1-9) and A1-G1 (10-16). These structures were elucidated by extensive analysis of spectroscopic data, including HRESIMS, NMR, quantum-mechanics-based computational analysis of NMR chemical shifts, and single-crystal X-ray diffraction analyses, and a concise rule for determination of relative configuration of angular methyl was proposed. The results of the cardioprotective assay demonstrated that 3 exhibits a protective effect against hypoxia-induced injuries in H9c2 cells. This effect was observed at a concentration of 10 µM, with a protective rate of 28.43 ± 11.80%.

Alternate routes to mnm5s2U synthesis in Gram-positive bacteria.

The wobble bases of tRNAs that decode split codons are often heavily modified. In bacteria, tRNAGlu, Gln, Asp contains a variety of xnm5s2U derivatives. The synthesis pathway for these modifications is complex and fully elucidated only in a handful of organisms, including the Gram-negative Escherichia coli K12 model. Despite the ubiquitous presence of mnm5s2U modification, genomic analysis shows the absence of mnmC orthologous genes, suggesting the occurrence of alternate biosynthetic schemes for the conversion of cmnm5s2U to mnm5s2U. Using a combination of comparative genomics and genetic studies, a member of the YtqA subgroup of the radical Sam superfamily was found to be involved in the synthesis of mnm5s2U in both Bacillus subtilis and Streptococcus mutans. This protein, renamed MnmL, is encoded in an operon with the recently discovered MnmM methylase involved in the methylation of the pathway intermediate nm5s2U into mnm5s2U in B. subtilis. Analysis of tRNA modifications of both S. mutans and Streptococcus pneumoniae shows that growth conditions and genetic backgrounds influence the ratios of pathway intermediates owing to regulatory loops that are not yet understood. The MnmLM pathway is widespread along the bacterial tree, with some phyla, such as Bacilli, relying exclusively on these two enzymes. Although mechanistic details of these newly discovered components are not fully resolved, the occurrence of fusion proteins, alternate arrangements of biosynthetic components, and loss of biosynthetic branches provide examples of biosynthetic diversity to retain a conserved tRNA modification in Nature.IMPORTANCEThe xnm5s2U modifications found in several tRNAs at the wobble base position are widespread in bacteria where they have an important role in decoding efficiency and accuracy. This work identifies a novel enzyme (MnmL) that is a member of a subgroup of the very versatile radical SAM superfamily and is involved in the synthesis of mnm5s2U in several Gram-positive bacteria, including human pathogens. This is another novel example of a non-orthologous displacement in the field of tRNA modification synthesis, showing how different solutions evolve to retain U34 tRNA modifications.

In Situ Formation of Fibronectin-Enriched Protein Corona on Epigenetic Nanocarrier for Enhanced Synthetic Lethal Therapy.

PARP inhibitors (PARPi)-based synthetic lethal therapy demonstrates limited efficacy for most cancer types that are homologous recombination (HR) proficient. To potentiate the PARPi application, a nanocarrier based on 5-azacytidine (AZA)-conjugated polymer (PAZA) for the codelivery of AZA and a PARP inhibitor, BMN673 (BMN) is developed. AZA conjugation significantly decreased the nanoparticle (NP) size and increased BMN loading. Molecular dynamics simulation and experimental validations shed mechanistic insights into the self-assembly of effective NPs. The small PAZA NPs demonstrated higher efficiency of tumor targeting and penetration than larger NPs, which is mediated by a new mechanism of active targeting that involves the recruitment of fibronectin from serum proteins following systemic administration of PAZA NPs. Furthermore, it is found that PAZA carrier sensitize the HR-proficient nonsmall cell lung cancer (NSCLC) to BMN, a combination therapy that is more effective at a lower AZA/BMN dosage. To investigate the underlying mechanism, the tumor immune microenvironment and various gene expressions by RNAseq are explored. Moreover, the BMN/PAZA combination increased the immunogenicity and synergized with PD-1 antibody in improving the overall therapeutic effect in an orthotopic model of lung cancer (LLC).