Study on the Synergistic Suppression Effect and Mechanism of N2/Ultrafine Water Mist on Liquefied Petroleum Gas Explosion.

Liquefied petroleum gas (LPG) is widely used for its cleanliness and high efficiency in industry and city life. In order to improve the suppression effect on LPG explosion, a constant volume combustion bomb was used to investigate the synergistic influence of N2/ultrafine water mist on the explosion and combustion characteristics of 6% premixed LPG/air gas. The results showed that (1) the effect of a single ultrafine water mist on suppressing LPG explosion is unstable. When the concentration of ultrafine water mist is low, the flame acceleration in the initial stage of explosion is promoted, and when the ultrafine water mist with a mass fraction of 420 g/m3 is introduced, the maximum pressure rise rate increases. (2) The combination of N2/ultrafine water mist has a synergistic effect on LPG explosion. Compared to the individual suppression effects, the combination of N2/ultrafine water mist showed more effective suppression on the explosion pressure, flame propagation, and flame instability of LPG explosion. (3) Through the mechanism analysis, it is found that the combined action of N2/ ultrafine water mist can better reduce the mole fraction and ROP peak of active free radicals such as H, O, and OH by inhibiting the main reaction of generating H, O, and OH radicals during the explosion of LPG, resulting in the reduction of flame free radicals in the explosion system, thus effectively inhibiting the chain reaction of ignition and explosion of LPG. This research can provide guidance for a better understanding and implementation of gas-liquid two-phase suppression technology for LPG explosion.

Balancing mechanical property and swelling behavior of bacterial cellulose film by in-situ adding chitosan oligosaccharide and covalent crosslinking with γ-PGA.

Bacterial cellulose (BC) is an ideal candidate material for drug delivery, but the disbalance between the swelling behavior and mechanical properties limits its application. In this work, covalent crosslinking of γ-polyglutamic acid (γ-PGA) with the chitosan oligosaccharide (COS) embedded in BC was designed to remove the limitation. As a result, the dosage, time, and batch of COS addition significantly affected the mechanical properties and the yield of bacterial cellulose complex film (BCCF). The addition of 2.25 % COS at the incubation time of 0.5, 1.5, and 2 d increased the Young's modulus and the yield by 5.65 and 1.42 times, respectively, but decreased the swelling behavior to 1774 %, 46 % of that of native BC. Covalent γ-PGA transformed the dendritic structure of BCCF into a spider network, decreasing the porosity and increasing the swelling behavior by 3.46 times. The strategy balanced the swelling behavior and mechanical properties through tunning hydrogen bond, electrostatic interaction, and amido bond. The modified BCCF exhibited a desired behavior of benzalkonium chlorides transport, competent for drug delivery. Thereby, the strategy will be a competent candidate to modify BC for such potential applications as wound dressing, artificial skin, scar-inhibiting patch, and so on.

Effect of dexmedetomidine infusion on post-operative sleep disturbances in women with breast cancer: A monocentric randomized-controlled double-blind trial.

BACKGROUND: Most women with breast cancer are prone to post-operative sleep disturbances (POSD). Little is known about the differences between sevoflurane and propofol combined with dexmedetomidine on POSD in the same context. We investigated the effect of intra-operative sevoflurane or propofol combined with intravenous dexmedetomidine on the incidence of POSD and post-operative sleep structures. METHODS: A monocentric, randomized-controlled, double-blind trial. Female patients undergoing radical surgery for breast cancer were randomly assigned to receive sevoflurane and placebo, sevoflurane and dexmedetomidine, propofol and placebo, or propofol and dexmedetomidine. Dexmedetomidine was administered at 1.0 µg kg-1 infusion 15 min before induction, then infused at 0.4 µg kg-1 h-1 until the surgical drain started to be placed. The primary outcome was the incidence of POSD within the postoperative first three days (defined as an Athens Insomnia Scale score ≥ 6 points on at least one day of post-operative first three days). The secondary outcome was the duration of sleep structures, collected from the Fitbit Charge 2® smart bracelet (Fitbit, Inc., San Francisco, CA, USA). RESULTS: There were 188 women analyzed with the modified intention-to-treat method. The incidences of POSD in the dexmedetomidine and placebo groups were similar (P = 0.649). In the sevoflurane sedation strategy, dexmedetomidine decreased nocturnal wakefulness on post-operative first day (P = 0.001). In the propofol sedation strategy, dexmedetomidine increased nocturnal deep sleep on post-operative first (P < 0.001) and third (P < 0.001) days. CONCLUSION: Intra-operative infusion of dexmedetomidine had no significant effect on POSD but decreased nocturnal wakefulness in the sevoflurane group and increased nocturnal deep sleep in the propofol group. TRIAL REGISTRATION: Registered at www.chictr.org.cn (ChiCTR2300070136).

Butyrate Prevents the Pathogenic Anemia-Inflammation Circuit by Facilitating Macrophage Iron Export.

Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron-mediated, pathogenic anemia-inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short-chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis-induced anemia but also reduces TNF-α production in macrophages. Consistently, macrophage-conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti-TNF-α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation.

A NIR-driven green affording-oxygen microrobot for targeted photodynamic therapy of tumors.

Photodynamic therapy (PDT) is a light-activated local treatment modality that has promising potential in cancer therapy. However, ineffective delivery of photosensitizers and hypoxia in the tumor microenvironment severely restrict the therapeutic efficacy of PDT. Herein, phototactic Chlorella (C) is utilized to carry photosensitizer-encapsulated nanoparticles to develop a near-infrared (NIR) driven green affording-oxygen microrobot system (CurNPs-C) for enhanced PDT. Photosensitizer (curcumin, Cur) loaded nanoparticles are first synthesized and then covalently attached to C through amide bonds. An in vitro study demonstrates that the developed CurNPs-C exhibits continuous oxygen generation and desirable phototaxis under NIR treatment. After intravenous injection, the initial 660 nm laser irradiation successfully induces the active migration of CurNPs-C to tumor sites for higher accumulation. Upon the second 660 nm laser treatment, CurNPs-C produces abundant oxygen, which in turn induces the natural product Cur to generate more reactive oxygen species (ROS) that significantly inhibit the growth of tumors in 4T1 tumor-bearing mice. This contribution showcases the ability of a light-driven green affording-oxygen microrobot to exhibit targeting capacity and O2 generation for enhancing photodynamic therapy.

A Bioorthogonal Decaging Chemistry of N-Oxide and Silylborane for Prodrug Activation both In Vitro and In Vivo.

Bioorthogonal decaging chemistry with both fast kinetics and high efficiency is highly demanded for in vivo applications but remains very sporadic. Herein, we describe a new bioorthogonal decaging chemistry between N-oxide and silylborane. A simple replacement of "C" in boronic acid with "Si" was able to substantially accelerate the N-oxide decaging kinetics by 106 fold (k2: up to 103 M-1 s-1). Moreover, a new N-oxide-masked self-immolative spacer was developed for the traceless release of various payloads upon clicking with silylborane with fast kinetics and high efficiency (>90%). Impressively, one such N-oxide-based self-assembled bioorthogonal nano-prodrug in combination with silylborane led to significantly enhanced tumor suppression effects as compared to the parent drug in a 4T1 mouse breast tumor model. In aggregate, this new bioorthogonal click-and-release chemistry is featured with fast kinetics and high efficiency and is perceived to find widespread applications in chemical biology and drug delivery.

Design, synthesis, and structure-activity relationships of a novel class of quinazoline derivatives as coronavirus inhibitors.

There remain great unmet needs to treat coronavirus infections in clinic, and the development of novel antiviral agents is highly demanded. In this work, a phenotypic screening against our in-house compound library identified several cajanine derivatives with moderate antiviral activity against HCoV-OC43. Based on the scaffold of cajanine, a series of quinazoline derivatives were designed employing a scaffold-hopping strategy. After an iterative structural optimization campaign, several quinazoline derivatives with potent antiviral efficacy (EC50: ∼0.1 µM) and high selectivity (SI > 1000) were successfully identified. The preliminary mechanism of action study indicated that such quinazoline derivatives functioned at the early stage of infection. In aggregate, this work delivered a new chemical type of coronavirus inhibitors, which could be employed not only for further development of antiviral drugs but also as important chemical tools to delineate the target of action.

Biochemical and Structural Insights into a Thiamine Diphosphate-Dependent α-Ketoglutarate Decarboxylase from Cyanobacterium Microcystis aeruginosa NIES-843.

α-Ketoglutarate decarboxylase is a crucial enzyme in the tricarboxylic acid cycle of cyanobacteria, catalyzing the non-oxidative decarboxylation of α-ketoglutarate to produce succinate semialdehyde and CO2. The decarboxylation process is reliant on the cofactor of thiamine diphosphate. However, this enzyme's biochemical and structural properties have not been well characterized. In this work, two α-ketoglutarate decarboxylases encoded by MAE_06010 and MiAbw_01735 genes from Microcystis aeruginosa NIES-843 (MaKGD) and NIES-4325 (MiKGD), respectively, were overexpressed and purified by using an Escherichia coli expression system. It was found that MaKGD exhibited 9.2-fold higher catalytic efficiency than MiKGD, which may be attributed to the absence of glutamate decarboxylase in Microcystis aeruginosa NIES-843. Further biochemical investigation of MaKGD demonstrated that it displayed optimum activity at pH 6.5-7.0 and was most activated by Mg2+. Additionally, MaKGD showed substrate specificity towards α-ketoglutarate. Structural modeling and autodocking results revealed that the active site of MaKGD contained a distinct binding pocket where α-ketoglutarate and thiamine diphosphate interacted with specific amino acid residues via hydrophobic interactions, hydrogen bonds and salt bridges. Furthermore, the mutagenesis study provided strong evidence supporting the importance of certain residues in the catalysis of MaKGD. These findings provide new insights into the structure-function relationships of α-ketoglutarate decarboxylases from cyanobacteria.

Near-Infrared Bodipy-Based Molecular Rotors for ß-Amyloid Imaging In Vivo.

ß-amyloid (Aß) is one of the important biomarkers for diagnosing Alzheimer's disease (AD). Many near-infrared probes based on the donor-π-acceptor structure have been developed to detect Aß. Most reported Aß probes are based on the N,N-dimethylamino group as the ideal donor, which is a widely accepted binding unit. As such, the development of fluorescent probes with improved binding units to detect Aß is urgently required. Therefore, with this research three anchoring molecular rotor electron donors consisting of cyclic amines of different ring sizes are developed, namely five-membered ring (TPyr), six-membered ring (TPip), and seven-membered ring (THAI). These new anchored molecular rotors are connected to a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) and named TPyrBDP, TPipBDP, and THAIBDP. These probes exhibit high affinities (from 28 to 54 nm) for Aß1-42 aggregates. The six-membered ring dye TPipBDP exhibits the highest signal-to-noise (75.5-fold) and higher affinity (28.30 ± 5.94 nm). TPipBDP can cross the blood-brain barrier and exhibits higher fluorescence enhancement with APP/PS1 (AD) double transgenic (Tg) mice than with wild-type (WT) mice.

Design, Synthesis, and Structure-Activity Relationships of Biaryl Anilines as Subtype-Selective PPAR-alpha Agonists.

The role of peroxisome proliferator-activated receptor alpha (PPARα) in retinal biology is clarifying, and evidence demonstrates that novel PPARα agonists hold promising therapeutic utility for diseases like diabetic retinopathy and age-related macular degeneration. Herein, we disclose the design and initial structure-activity relationships for a new biaryl aniline PPARα agonistic chemotype. Notably, this series exhibits subtype selectivity for PPARα over other isoforms, a phenomenon postulated to be due to the unique benzoic acid headgroup. This biphenyl aniline series is sensitive to B-ring functionalization but allows isosteric replacement, and provides an opportunity for C-ring extension. From this series, 3g, 6j, and 6d were identified as leads with <90 nM potency in a cell-based luciferase assay cell and exhibited efficacy in various disease-relevant cell contexts, thereby setting the stage for further characterization in more advanced in vitro and in vivo models.

Delivery of AntagomiR-7 through polymer nanoparticles for assisting B Cell to alleviate systemic lupus erythematosus.

An autoimmune condition known as systemic lupus erythematosus (SLE) is characterized by B cell hyperresponsiveness and persistent generation of pathogenic autoantibodies that cause damage to various organs and tissues. The treatments available today are either ineffective or have adverse effects. The dysregulation of B cell activation is crucial for the emergence of SLE. MiR-7 explicitly targeted PTEN mRNA in B cells. Treatment with antagomiR-7 reduced B cell hyperresponsiveness and prevented the onset of lupus. As a result, inhibiting miR-7 may be used therapeutically to treat SLE. We developed a SA (sialic acid)-poly (D, L-lactide-co-glycolide) (SA-PLGA) nano delivery system to deliver antagomiR-7 into splenic B cells since the stability and targeted delivery of miRNA remain significant challenges in vivo. Results show that SA-PLGA nanoparticles (SA-PLGA@antagomiR-7) loaded with antagomiR-7 display good biocompatibility and shield antagomiR-7 from degradation, extending the miRNA's duration in circulation in vivo. Additionally, in MRL/Ipr lupus mice, SA-PLGA@antagomiR-7 is successfully delivered to the splenic B cells and preferentially enriched in the diseased spleen in MRL/Ipr lupus mice. The SA-PLGA@antagomiR-7 NPs therapy effectively decreases immunological abnormalities, normalizes splenic B cell subtypes, and suppresses B cell activation. The antagomiR-7 NPs exhibit excellent therapeutic efficiency and high biosafety collectively, which may result in a more effective treatment for SLE.

Dichloromethanol but not difluoromethanol as a viable surrogate of carbon monoxide for prodrug design.

Herein, we demonstrate that dichloromethanol but not difluoromethanol is a viable surrogate of carbon monoxide for prodrug design. A proof of concept was established by the successful development of a ROS-responsive carbon monoxide prodrug, presenting specific CO release in response to endogenous ROS in cells.

Structural basis for the assembly of the DNA polymerase holoenzyme from a monkeypox virus variant.

The ongoing global pandemic caused by a variant of the monkeypox (or mpox) virus (MPXV) has prompted widespread concern. The MPXV DNA polymerase holoenzyme, consisting of F8, A22, and E4, is vital for replicating the viral genome and represents a crucial target for the development of antiviral drugs. However, the assembly and working mechanism for the DNA polymerase holoenzyme of MPXV remains elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the DNA polymerase holoenzyme at an overall resolution of 3.5 Å. Unexpectedly, the holoenzyme is assembled as a dimer of heterotrimers, of which the extra interface between the thumb domain of F8 and A22 shows a clash between A22 and substrate DNA, suggesting an autoinhibition state. Addition of exogenous double-stranded DNA shifts the hexamer into trimer exposing DNA binding sites, potentially representing a more active state. Our findings provide crucial steps toward developing targeted antiviral therapies for MPXV and related viruses.

Using less annotation workload to establish a pathological auxiliary diagnosis system for gastric cancer.

Pathological diagnosis of gastric cancer requires pathologists to have extensive clinical experience. To help pathologists improve diagnostic accuracy and efficiency, we collected 1,514 cases of stomach H&E-stained specimens with complete diagnostic information to establish a pathological auxiliary diagnosis system based on deep learning. At the slide level, our system achieves a specificity of 0.8878 while maintaining a high sensitivity close to 1.0 on 269 biopsy specimens (147 malignancies) and 163 surgical specimens (80 malignancies). The classified accuracy of our system is 0.9034 at the slide level for 352 biopsy specimens (201 malignancies) from 50 medical centers. With the help of our system, the pathologists' average false-negative rate and average false-positive rate on 100 biopsy specimens (50 malignancies) are reduced to 1/5 and 1/2 of the original rates, respectively. At the same time, the average uncertainty rate and the average diagnosis time are reduced by approximately 22% and 20%, respectively.

Banxia Xiexin decoction alleviates AS co-depression disease by regulating the gut microbiome-lipid metabolic axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Xiexin decoction (BXD) is a classic Chinese herbal formulation consisting of 7 herbs including Pinelliae Rhizoma, Scutellariae Radix, Zingiberis Rhizoma, Ginseng Radix, Glycyrrhizae Radix, Coptidis Rhizoma, and Jujubae Fructus, which can exert effects on lowering lipids and alleviating depressive mood disorders via affecting gastrointestinal tract. AIM OF THE STUDY: The pathogenesis of atherosclerosis (AS) co-depression disease has not been well studied, and the current clinical treatment strategies are not satisfactory. As a result, it is critical to find novel methods of treatment. Based on the hypothesis that the gut microbiome may promote the development of AS co-depression disease by regulating host lipid metabolism, this study sought to evaluate the effectiveness and action mechanism of BXD in regulation of the gut microbiome via an intervention in AS co-depression mice. MATERIALS AND METHODS: To determine the primary constituents of BXD, UPLC-Q/TOF-MS analysis was carried out. Sixteen C56BL/6 mice were fed normal chow as a control group; 64 ApoE-/- mice were randomized into four groups (model group and three treatment groups) and fed high-fat chow combined with daily bind stimulation for sixteen weeks to develop the AS co-depression mouse model and were administered saline or low, medium or high concentrations of BXD during the experimental modeling period. The antidepressant efficacy of BXD was examined by weighing, a sucrose preference test, an open field test, and a tail suspension experiment. The effectiveness of BXD as an anti-AS treatment was evaluated by means of biochemical indices, the HE staining method, and the Oil red O staining method. The impacts of BXD on the gut microbiome structure and brain (hippocampus and prefrontal cortex tissue) lipids in mice with the AS co-depression model were examined by 16S rDNA sequencing combined with lipidomics analysis. RESULTS: The main components of BXD include baicalin, berberine, ginsenoside Rb1, and 18 other substances. BXD could improve depression-like behavioral characteristics and AS-related indices in AS co-depression mice; BXD could regulate the abundance of some flora (phylum level: reduced abundance of Proteobacteria and Deferribacteres; genus level: reduced abundance of Clostridium_IV, Helicobacter, and Pseudoflavonifractor, Acetatifactor, Oscillibacter, which were significantly different). The lipidomics analysis showed that the differential lipids between the model and gavaged high-dose BXD (BXH) groups were enriched in glycerophospholipid metabolism, and lysophosphatidylcholine (LPC(20:3)(rep)(rep)) in the hippocampus and LPC(20:4)(rep) in the prefrontal cortex both showed downregulation in BXH. The correlation analysis illustrated that the screened differential lipids were mainly linked to Deferribacteres and Actinobacteria. CONCLUSION: BXD may exert an anti-AS co-depression therapeutic effect by modulating the abundance of some flora and thus intervening in peripheral lipid and brain lipid metabolism (via downregulation of LPC levels).

Genetic liability to mental disorders in relation to the risk of hypertension.

Background: Observational studies have indicated that psychosocial factors contribute to hypertension; however, the causality of these associations remains unclear due to reverse causality and confounders. We aim to assess the causal associations of mental health disorders with hypertension. Methods: Instrumental variables of anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, depression, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, and subjective well-being measure were obtained from the corresponding largest genome-wide association studies. Summary statistics for the association of essential hypertension were obtained from the FinnGen Study (42,857 cases and 162,837 controls) and UK Biobank cohort (54,358 cases and 408,652 controls). The multiplicative random-effects inverse-variance weighted method was utilized as the primary analysis and three other statistical methods were conducted in the supplementary analyses. The results were combined using the fixed-effects method. Results: In the pooled analyses, genetic liability to depression was associated with higher risk of hypertension (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.17-1.35; p < 0.001). Besides, a suggestive association was found between genetically predicted higher weighted neuroticism sum-score and increased risk of hypertension (OR, 1.16; 95% CI, 1.02-1.33; p < 0.05). No associations were found for other mental health disorders. Sensitivity analyses revealed consistent evidence as the main results. Conclusion: We provide consistent evidence for the causal effect of genetic liability to depression on hypertension, which highlights the importance of blood pressure measurement and monitoring in patients with depression.

ß-Alanine enhancing the crosslink of chitosan/poly-(γ-glutamic acid) hydrogel for a potential alkaline-adapted wound dressing.

Tiny crosslink in chitosan (CS)/poly-(γ-glutamic acid) (γ-PGA) hydrogel leads to some disadvantages including low mechanical strength and high swelling. To enhance the crosslink of CS/γ-PGA hydrogel, amino acid (AA) was introduced to remove the drawbacks. The results indicated that AA can dramatically increase the crosslink and mechanical properties of CS/γ-PGA hydrogel, and AA chain length and concentration have a drastic effect on them. Particularly, 0.5 % ß-Alanine (ß-Ala) decreased the hydrogel by 70 % in porosity, 52 % in water solubility, and 30 % in swelling, but increased by 2.2-fold in elastic modulus, 2.08-fold in stress, and 1.53-fold in water retention. The porosity of the hydrogel correlates positively with the elastic modulus but negatively with the crosslinking degree. The effect of pH on CS/ß-Ala/γ-PGA hydrogel was investigated in the load and release of benzalkonium chlorides (BAC). ß-Ala strengthened pH response of the hydrogel in BAC load and release. The loading capacity increased with pH value, and 0.5 % ß-Ala increased the hydrogel by 1.25-fold in the release capacity in alkaline environment, suggesting a good buffering effect of ß-Ala on pH variation to accelerate the transportation of BAC. CS/ß-Ala/γ-PGA hydrogel will be competently applied as a potential material for wound dressing in alkaline environment.