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Intervertebral disc degeneration (IVDD) is commonly associated with many spinal problems, such as low back pain, and significantly impacts a patient’s quality of life. However, current treatments for IVDD, which include conservative and surgical methods, are limited in their ability to fully address degeneration. To combat IVDD, delivery-system-based therapy has received extensive attention from researchers. These delivery systems can effectively deliver therapeutic agents for IVDD, overcoming the limitations of these agents, reducing leakage and increasing local concentration to inhibit IVDD or promote intervertebral disc (IVD) regeneration. This review first briefly introduces the structure and function of the IVD, and the related pathophysiology of IVDD. Subsequently, the roles of drug-based and bioactive-substance-based delivery systems in IVDD are highlighted. The former includes natural source drugs, nonsteroidal anti-inflammatory drugs, steroid medications, and other small molecular drugs. The latter includes chemokines, growth factors, interleukin, and platelet-rich plasma. Additionally, gene-based and cell-based delivery systems are briefly involved. Finally, the limitations and future development of the combination of therapeutic agents and delivery systems in the treatment of IVDD are discussed, providing insights for future research.

ABSTRACTMacroautophagy/autophagy has been recognized as a central antiviral defense mechanism in plant, which involves complex interactions between viral proteins and host factors. Rhabdoviruses are single-stranded RNA viruses, and the infection causes serious harm to public health, livestock, and crop production. However, little is known about the role of autophagy in the defense against rhabdovirus infection by plant. In this work, we showed that Rice stripe mosaic cytorhabdovirus(RSMV) activated autophagy in plants and that autophagy served as an indispensable defense mechanism during RSMV infection. We identified RSMV glycoprotein as an autophagy inducer that interacted with OsSnRK1B and promoted the kinase activity of OsSnRK1B on OsATG6b. RSMV glycoprotein was toxic to rice cells and its targeted degradation by OsATG6b-mediated autophagy was essential to restrict the viral titer in plants. Importantly, SnRK1-glycoprotein and ATG6-glycoprotein interactions were well-conserved between several other rhabdoviruses and plants. Together, our data support a model that SnRK1 senses rhabdovirus glycoprotein for autophagy initiation, while ATG6 mediates targeted degradation of viral glycoprotein. This conserved mechanism ensures compatible infection by limiting the toxicity of viral glycoprotein and restricting the infection of rhabdoviruses.Abbreviations:AMPK: adenosine 5‘-monophosphate (AMP)-activated protein kinase; ANOVA: analysis of variance; ATG: autophagy related; AZD: AZD8055; BiFC: bimolecular fluorescence complementation; BYSMV: barley yellow striate mosaic virus; Co-IP: co-immunoprecipitation; ConA: concanamycin A; CTD: C-terminal domain; DEX: dexamethasone; DMSO: dimethyl sulfoxide; G: glycoprotein; GFP: green fluorescent protein; MD: middle domain; MDC: monodansylcadaverine; NTD: N-terminal domain; OE: over expression; Os: Oryza sativa; PBS: phosphate-buffered saline; PtdIns3K: class III phosphatidylinositol-3-kinase; qRT-PCR: quantitative real-time reverse-transcription PCR; RFP: red fluorescent protein; RSMV: rice stripe mosaic virus; RSV: rice stripe virus; SGS3: suppressor of gene silencing 3; SnRK1: sucrose nonfermenting1-related protein kinase1; SYNV: sonchus yellow net virus; TEM: transmission electron microscopy; TM: transmembrane region; TOR: target of rapamycin; TRV: tobacco rattle virus; TYMaV: tomato yellow mottle-associated virus; VSV: vesicular stomatitis virus; WT: wild type; Y2H: yeast two-hybrid; YFP: yellow fluorescent protein.

Invasive listeriosis is a rare but serious foodborne disease that causes maternal–neonatal, central nervous system, and bloodstream infections. The aim of this study was to assess the whole-genome sequencing (WGS)-based genetic diversity of clinical Listeria monocytogenesisolates over a 7-year period and prove the effect of WGS application in food vehicle investigation. A total of 360 isolates were recovered during 2013 and 2019 through the national listeriosis special surveillance program. Two hundred twenty-six isolates (62.8%) were associated with pregnancy. All isolates belonged to lineage I (214 isolates) or lineage II (146 isolates), with 4 serogroups (46.9% IIb, 39.7% IIa, 12.5% IVb, and 0.8% IIc). All isolates were in 25 clonal complexes (CCs) and 3 singletons, with CC87, CC8, and CC5 being the most common causes of human listeriosis. All clinical isolates were positive for Listeriapathogenicity island 1 (LIPI-1), LIPI-3 was present in 21.4% of isolates and LIPI-4 was detected in 29.2% of isolates. LIPI-4-positive isolates, including CC87, sequence type (ST)619, ST382, CC4, and CC2, have been shown to confer hypervirulence. Fifteen isolates harbored at least one antimicrobial encoding gene, including tet(M), mef(A), msr(D), and dfr(G). The sublineage designations were consistent with CC designations, and 215 distinct cgMLST types (CTs) were classified, the most abundant being CT58 and CT750. In summary, there is a high level of genetic diversity among the clinical isolates. WGS has strengthened listeriosis surveillance and will be implemented for other foodborne bacteria in the National Molecular Tracing Network for Foodborne Disease.

Calcium carbonate (CaCO3) nanoparticles are highly regarded for their excellent biocompatibility and distinctive pH responsiveness, making them an ideal nanocarrier system for anti-tumor therapy. The incorporation of additives during the preparation of CaCO3can significantly influence its morphology, particle size, and tumor inhibitory effects, necessitating a systematic study of these impacts. This study utilized the gas diffusion method to prepare CaCO3nanoparticles, introducing various additives such as hyaluronic acid, polyacrylic acid, polyvinyl pyrrolidone, fucoidan, and polyethyleneimine. Different additives were found to have diverse effects on the morphology, particle size, zeta potential, and pH responsiveness of CaCO3. Methotrexate was employed as a model drug to evaluate the cytotoxicity of CaCO3nanoparticles with different additives. Among them, hyaluronic acid-modified CaCO3nanoparticles exhibited ideal morphology, particle size, significant pH responsiveness, and tumor-targeting capabilities. In vitroand in vivoexperiments demonstrated their remarkable antitumor effects.

Poor oral health may be a significant risk factor for gastric cancer (GC); however, previous results are not consistent. Here, we investigated the effect of oral health on GC and effect modification by other factors. We conducted a population‐based case‐control study in Taixing, China. Participants aged between 40 and 85 years and who had lived in Taixing for at least 5 years were included. The GC cases were confirmed by endoscopy and pathological diagnosis, and the controls were randomly selected using the frequency‐matching method. Unconditional logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals (CIs) of oral health for GC risk after adjusting for confounders and risk factors. Overall, 901 GC cases and 1972 controls were included. Tooth loss was not significantly associated with an increased risk of GC (yes vs. no, OR = 1.08, 95% CI 0.88 to 1.33). Compared with toothbrushing at least twice per day, toothbrushing once per day or less was associated with an increased risk of GC (OR = 2.39, 95% CI 1.94 to 2.94), and was more pronounced in esophagogastric junction cancer and intestinal‐type GC. There was no significant interaction between the indicators of oral health and age, sex, tobacco smoking, alcohol drinking, and Helicobacter pyloriseropositivity. Poor oral hygiene behavior is associated with an increased risk of GC, and this positive association is consistent across all GC subgroups classified by anatomy and histology. Further studies are needed to explore the possible mechanisms behind this association.

The emergence of mobilized colistin resistance (mcr) genes has raised significant concerns as they pose a public health issue. The prevalence of mcrgenes, particularly the newly discovered mcr-9gene, in non-typhoidal Salmonella(NTS) isolates remains unclear. We characterized mcr-9.1-producing NTS isolates from China. Among 7,106 NTS isolates from diarrhea cases in 32 provinces during 2010–2020, 11 mcr-9.1-producing isolates were identified and were all not resistant to colistin. Five isolates belonged to SalmonellaThompson and sequence type (ST) 26, two belonged to SalmonellaTyphimurium and ST34, two belonged to SalmonellaTyphimurium and ST36, and two belonged to Salmonella1,4,[5],12:i:- and ST34. Plasmids harboring mcr-9.1tended to possess the IncHI2 backbone and were ~ 300 kb long. All mcr-9.1genes shared the same flanking sequence, rcnR-rcnA-pcoS-IS903-mcr-9.1-wbuC. According to the NCBI data, we found that NTS serves as the primary host of mcr-9.1, although the prevalence of specific serotypes differed between domestic and international settings. Notably, most data came from developed countries, such as the USA. mcr-9.1tended to be transferred as a gene cassette or to be mobilized by a conjugational plasmid in multiple bacteria across humans, animals, and the environment. Furthermore, mcr-9.1frequently co-existed and was co-transferred with various genes encoding resistance to first-line drugs, reducing the effectiveness of available therapeutic options. In summary, although mcr-9does not mediate colistin resistance, it can silently spread with some genes encoding resistance to first-line drugs, and therefore warrants research attention.

ABSTRACTLow-grade cervical squamous intraepithelial lesion is a precancerous neoplasia that has appreciable probability to evolve into malignancy. To explore the prognostic value of HPV 16/18 genotyping and geminin mRNA quantification in predicting the progressiveness of LSIL. We recruited 212 participants who were negative for intraepithelial lesion or malignancy (NILM 76), low-grade squamous intraepithelial lesion (LSIL 85), high-grade squamous intraepithelial lesion (HSIL 36) and cervical intraepithelial neoplasia grade cervical cancer grade 3, (CIN3 15) patients. Tissues were obtained during excisional treatment. HPV 16/18 genotyping and geminin mRNA qRT-PCR were performed. HPV 16/18 positivity rate and geminin mRNA level were integrated with the clinical parameters into a multivariate logistic model. Area under curve was yielded based on receiver operation curve derived from this multivariate logistic model. Follow-up visits were performed to LSIL patients with progression. HSIL patients have higher HPV 16/18 positivity rate and geminin mRNA levels than LSIL. Among HSIL, CIN3 have higher HPV 16/18 positivity rate and geminin mRNA levels. Multivariate logistic analysis showed that HPV 16/18 positivity and geminin mRNA expression status are independent factors for differentiating HSIL and LSIL. The baseline HPV 16/18 positivity rate and geminin mRNA levels of 18 LSIL patients who developed HSIL are significantly higher than non-progressive LSIL patients. The values examined at follow-up timepoints were also higher than baseline. These results suggest that geminin is implicated in the progression of LSIL and combining HPV 16/18 genotyping and geminin mRNA qRT-PCR could potentially differentiating the progressive LSIL and improve the efficacy of clinical intervention.

Due to the short length and differences in abundance of microRNAs, microRNA profile screening and quantification is challenging. In this study, we found that size selection magnetic beads could be employed to easily and efficiently remove long RNA transcripts. After removing the long transcripts, the remaining small RNAs could be concentrated and then reverse-transcribed using universal stem-loop primers (USLP), with six randomized nucleotides at the 3′ end region. The efficiency of reverse transcription decreased when the number of randomized nucleotides was reduced. In addition, we found that touchdown qPCR improved microRNA profile detection, with lower CTvalues and better detection efficiency than the regular qPCR protocol, especially for those low-abundance microRNAs. Finally, we incorporated these observations to create a new protocol we named long transcripts minus touchdown qPCR (LTMT-qPCR). We performed a side-by-side comparison of LTMT with USLP and traditional stem-loop primer (TSLP) protocols. We found that LTMT has higher detection efficiency than USLP, especially for the detection of low-abundance microRNAs. Although LTMT was equivalent to TSLP in terms of microRNA profile detection, LTMT is more convenient, user-friendly, and cost-effective. Taken together, the present data indicate that LTMT is a simple, rapid, and user-friendly approach that has higher precision, accuracy, and sensitivity than the previously described methods, making it more suitable for microRNA profile screening and quantification.

AbstractLaccases are multi-copper oxidases (MCOs) that catalyze the oxidation of various organic and inorganic compounds with concomitant reduction of dioxygen to water, and are considered to be green catalysts. Previous studies revealed that in MCOs, the structure of substrate-binding pocket was closely related to the substrate specificity. The amino acids on the pocket-constructing loops were involved in the identification of substrate and affected the catalytic properties of the enzyme. In the Thermus thermophilusSG0.5JP17-16 laccase (lacTT), the Lys428 residue is on pocket-constructing loops, to explore the role of the K428 residue and obtain mutants with enhanced catalytic activity, it was mutated to leucine, glutamic acid, arginine and methionine by site-directed mutagenesis. Structural data revealed that the K428 residue identified the conformation of the substrate by the steric hindrance and interactions with the substrate. Kinetic data indicated that the replacement of K428 by methionine resulted in a mutant with enhanced catalytic activity. The K428M mutant could decolorize the synthetic dyes more efficiently than the wild type enzyme. Altogether, this study provided a strategy to find the mutant with the enhanced catalytic activity. Communicated by Ramaswamy H. Sarma

Stimuli-responsive silica nanoparticles are an attractive therapeutic agent for effective tumor ablation, but the responsiveness of silica nanoagents is limited by intrastimulation level and silica framework structure. Herein, a biodegradable hollow SiO2-based nanosystem (Ag2S-GOx@BHS NYs) is developed by a novel one-step dual-template (bovine serum albumin (BSA) and cetyltrimethylammonium bromide (CTAB)) synthetic strategy for image-guided therapy. The Ag2S-GOx@BHS NYs can be specifically activated in the tumor microenvironment via a self-feedback mechanism to achieve reactive oxygen species (ROS)-induced multistep therapy. In response to the inherent acidity and H2O2at the tumor sites, Ag2S-GOx@BHS would accelerate the structural degradation while releasing glucose oxidase (GOx), which could efficiently deplete intratumoral glucose to copious amounts of gluconic acid and H2O2. More importantly, the sufficient H2O2not only acts as a reactant to generate Ag+from Ag2S for metal-ion therapy and improves the oxidative stress but also combines with gluconic acid results in the self-accelerating degradation process. Moreover, the released Ag2S nanoparticles can help the Ag2S-GOx@BHS NYs realize the second near-infrared window fluorescence (NIR-II FL) and photoacoustic (PA) imaging-guided precise photothermal therapy (PTT). Taken together, the development of a self-feedback nanosystem may open up a new dimension for a highly effective multistep tumor therapy.

A direct aerobic oxidative dehydrogenative coupling reaction of glycine esters with β-naphthols has been achieved via the synergistic combination of photoredox catalysis and Lewis acid catalysis. A wide range of glycine esters and β-naphthols are suitable substrates for this reaction. A variety of 1,3-benzoxazines were obtained in good yields with excellent diastereoselectivities under mild reaction conditions. Moreover, this protocol could be performed on a gram-scale without considerable loss in activity.

A photoredox catalyst free, visible-light-induced aerobic oxidative [2 + 3] cycloaddition reaction between glycine derivatives and styrene oxides has been disclosed that provides an efficient approach for the rapid synthesis of 1,3-oxazolidines under mild conditions. This photoinduced process is enabled by the formation of an electron donor–acceptor complex between glycine derivatives and benzyl iodides.

The conserved structural motif D is an important determinant of the speed and fidelity of viral RNA-dependent RNA polymerases (RdRps). Structural and computational studies have suggested that conformational changes in the motif-D loop that help to reposition the catalytic lysine represent critical steps in nucleotide selection and incorporation. Conformations of the motif-D loop in the poliovirus RdRp are likely controlled in part by noncovalent interactions involving the motif-D residue Glu364. This residue swivels between making interactions with Lys228 and Asn370 to stabilize the open and closed loop conformations, respectively. We show here that we can rationally control the motif-D loop conformation by breaking these interactions. The K228A variant favors a more active closed conformation, leading to increased nucleotide incorporation rates and decreased nucleotide selectivity, and the N370A variant favors a less active open conformation, leading to decreased nucleotide incorporation rates and increased nucleotide selectivity. Similar competing interactions likely control nucleotide incorporation rates and fidelity in other viral RdRps. Rational engineering of these interactions may be important in the generation of live, attenuated vaccine strains, considering the established relationships between RdRp function and viral pathogenesis.

Salmonellais widely known as one of the most common foodborne pathogens, and antibiotics remain effective in clinical therapies against its infections. To guide better clinical antibiotic treatment, we analyzed the antimicrobial resistance (AMR) profiles of a nation-wide collection of 36,822 Salmonellaisolates derived from sporadic diarrhea cases in China from 2014 to 2021. A panel of 15 antibiotics, including 10 critically important and 5 highly important antimicrobial agents for human medicine based on the WHO CIA List, was selected for AMR surveillance. Salmonella entericaserovar Typhimurium, Enteritidis, I 4,[5],12:i:-, London, and Stanley were turns to be the top five serotypes from human diarrhea cases in China. Antimicrobial susceptibility testing revealed that the majority of the isolates (87.2%) were resistant to at least one antimicrobial agent, and 66.5% were multidrug resistant (MDR). Salmonellaisolates were found to be highly resistant to ampicillin (73.4%) while sensitive to imipenem (98.73%). Over the eight years, the isolates were demonstrated generally an increase in resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and azithromycin, but displayed varied resistance profiles in terms of serotypes. Stanley (0.66–27.18%) and Agona (0.78–45.30%) had lower resistance rates compared to Typhimurium (1.11–85.6%), Enteritidis (1.55–91.29%), and I 4,[5],12:i:- (1.02–94.28%). In conclusion, our results provide systematic data on the resistance characteristics of Salmonellaisolates from human diarrhea cases in China. Furthermore, this data identifies priorities for the clinical treatments of antibiotics.

Background: Cuproptosis, as a copper-induced mitochondrial cell death, has attracted extensive attention recently, especially in cancer. Although some key regulatory genes have been identified in cuproptosis, the related lncRNAs have not been further studied. Exploring the prognostic and diagnostic value of cuproptosis-related lncRNAs (CRLs) in colon adenocarcinoma and providing guidance for individualized immunotherapy for patients are of great significance. Results: A total of 2003 lncRNAs were correlated with cuproptosis genes and considered as CRLs. We screened 33 survival-associated CRLs and established a prognostic signature base on 7 CRLs in the training group. The patients in the low-risk group had better outcomes in both training group (P< 0.001) and test group (P= 0.016). More exciting, our model showed good prognosis prediction in both stage I–II (P= 0.020) and stage III–IV (P= 0.001). The nomogram model could further improve the accuracy of prognosis prediction. Interestingly, glucose-related metabolic pathways, which were closely related to cuproptosis, were enriched in the low-risk group. Meanwhile, the immune infiltration scores were lower in the high-risk group. The high-risk group was more sensitive to OSI.906 and ABT.888, while low-risk group was more sensitive to Sorafenib. Three lncRNAs, FALEC, AC083967.1 and AC010997.4, were highly expressed in serum of COAD patients, and the AUC was 0.772, 0.726 and 0.714, respectively, indicating their valuable diagnostic value. Conclusions: Our research constructed a prognostic signature based on 7 CRLs and found three promising diagnostic markers for COAD patients. Our results provided a reference to the personalized immunotherapy strategies.

This paper provides a computational model for calculating three-directional ball spinning force in accordance with the theory of space analytic geometry. The contact boundary equation of the ball and tube is obtained. By projection, the two-dimensional curve in each coordinate plane is acquired. The projected area of the contact zone in the coordinate plane is calculated through the curve integral. It is assumed that the average pressure of the forming region is nearly equal to that when the steel ball is pressed into the tube. Hence, the unit pressure of the deformation zone is obtained. Then, the spinning component force and total spinning force are calculated. Using a Tu1 thin-walled tube of oxygen-free copper as experimental object, a ball spinning experiment is conducted, the axial spinning components force are tested and the ball spinning force calculation model is verified. Based on deformation rate, backward sliding accumulation and extension and frictional heating, the factors influencing calculation error are analysed at the end of this paper.

Studies have reported alcohol consumption and genetic variants as major contributing factors for esophageal squamous cell carcinoma (ESCC). However, the complicated interactions between alcohol and genetic factors involved in alcohol metabolism have not been well elucidated with respect to augmented risk of ESCC.

In 2019, transferable plasmid-borne tet(X3)/tet(X4) genes conferring high-level tigecycline resistance were identified in Enterobacteriaceaeand Acinetobacter. These transferable tet(X) variants are associated with different plasmids and could further spread and disseminate through associated mobile plasmids, raising public concern. In this study, we report the identification and characterization of two novel plasmids carrying tet(X4) in Escherichia coliisolated from retail chicken meat. We believe that our study contributes to our understanding of the genetic environment of tet(X4) and their transferability and capability of recombination and integration with other resistance genes in plasmids.

AbstractMethicillin-resistant Staphylococcus aureus(MRSA) is a major multidrug-resistant (MDR) opportunistic pathogen that is responsible for nosocomial infections worldwide. The emergence of MRSA in food-producing animals has heightened concerns regarding the presence of MRSA in foods having an animal origin. The objectives of this study were to determine the prevalence of MRSA in different sources, including retail food, food-producing animals, and food handlers in Sichuan province. During 2007–2015, S. aureuswas isolated from samples having different origins. Susceptibilities of MRSA to a panel of 12 antimicrobial agents were determined according to Clinical and Laboratory Standards Institute (CSLI) procedures. Pulsed-field gel electrophoresis, spatyping, staphylococcalchromosomal cassette (SCC) mectyping, and multilocus sequence typing (MLST) were used to characterize the relationship between these isolates. A total of 756 S. aureuswere isolated from 11,067 samples. Of these, 52 isolates were classified as MRSA based on the presence of mecAgenes. An antimicrobial susceptibility assay indicated that CHL-CLI-ERY-FOX-OXA-PEN-TET (n= 10) and CHL-CIP-CLI-ERY-FOX-OXA-PEN-TET (n= 8) were the two predominant MDR profiles in the isolates. Using 60% genetic similarity as a cutoff, the 52 MRSA isolates were grouped into 6 clusters having 34 pulsotypes. MLST typing showed seven multilocus sequence types (STs) with ST59 and ST9 being the most common. Six SCCmectypes were identified in all MRSA isolates. The MRSA isolates had relatively low prevalence in Sichuan province. Clonal expansion is not involved in the dissemination of MRSA from food origins. Considering the threat of MRSA to public health, further surveillance is required to monitor the prevalence of food-related MRSA.

ABSTRACTIn this study, the histological changes in the sciatic nerves of rats after exposure to different doses of focused ultrasound (FU) were investigated in order to provide an experimental basis for the application of FU to peripheral nerve disorders. Forty-eight healthy male SD rats were randomly divided into six groups. Each group was subjected to different FU exposure times, including 10 s, 30 s, 1 min, 2 min, 3 min and 4 min of exposure. The irradiated target area was centered 0.5 cm behind the greater trochanter of the left femur with a 1-cm radius. A 1-cm-long segment of the sciatic nerve within the irradiated target area of each rat was selected for observation. The corresponding region of the right sciatic nerve of each rat was used as the control group. The results indicated that the degree of nerval injury is positively related to the dosage of FU exposure, i.e. a higher dosage leads to a greater degree of injury. Thus, FU is expected to become a new method for treating chronic neuropathic pain. Furthermore, different dosages of FU could be selected to irradiate nerves so as to cause different degrees of blockage in nerve conduction function, thus meeting the requirements of different patients suffering from pain.

The current treatment therapies for chyluria are often invasive and recurrent. Here, we investigated a novel noninvasive treatment of chyluria with high-intensity focused ultrasound (HIFU) and evaluated its clinical efficacy. 155 patients with chyluria were treated with HIFU ablation and followed up over a period of 15 years from May 2000 to December 2015. Routine examinations including urine color observation, color Doppler ultrasound examination, blood serum test of Cr, BUN, and albumin, and detection of urinary chyle were performed before and after the treatment, 1 week, 1 and 6 months post-treatment, and followed up via telephone and other forms. We lost contact with 54 patients during the course of the study. In the 101 complete cases, the serum levels of Cr and BUN and the color Doppler ultrasound examination did not reveal significant differences before and after the treatment. However, there was a significant increase in the hemoglobin and albumin levels, as well as the body weight after the HIFU treatment. The other 54 patients also showed an improvement of the symptoms after the HIFU treatment before losing contact. Our results suggest that the HIFU ablation therapy is a feasible, effective, and noninvasive method for the treatment of chyluria.

There is accumulating evidence that cysteine sulfenation (cys-SOH) in proteins plays an important role in cellular response to oxidative stress. The purpose of the present study was to identify mitochondrial proteins that undergo changes in cys-SOH during aging. Studies were conducted in rats when they were 5 or 30 months of age. Following blocking of free protein thiols with N-ethylmaleimide, protein sulfenic acids were reduced by arsenite to free thiol groups that were subsequently labeled with biotin-maleimide. Samples were then comparatively analyzed by two-dimensional Western blots, and proteins showing changes in sulfenation were selectively identified by mass spectrometry peptide sequencing. As a result, five proteins were identified. Proteins showing an age-related decrease in sulfenation include pyruvate carboxylase and pyruvate dehydrogenase; while those showing an age-related increase in sulfenation include aconitase, mitofilin, and tubulin (α-1). Results of the present study provide a general picture of mitochondrial protein sulfenation in brain oxidative stress and implicate the involvement of protein sulfenation in overall decline of mitochondrial function during brain aging.

ABSTRACTAntimicrobial proteins possess a broad spectrum of bactericidal activity and play an important role in shaping the composition of gut microbiota, which is related to multiple diseases such as metabolic syndrome. However, it is incompletely known for the regulation of defensin expression in the gut Paneth cells. Here, we found that FABP4 in the Paneth cells of gut epithelial cells and organoids can downregulate the expression of defensins. FABP4fl/flpvillinCreTmice were highly resistance to SalmonellaTyphimurium (S.T) infection and had increased bactericidal ability to pathogens. The FABP4-mediated downregulation of defensins is through degrading PPARγ after K48 ubiquitination. We also demonstrate that high-fat diet (HFD)-mediated downregulation of defensins is through inducing a robust FABP4 in Paneth cells. Firmicutes/Bacteroidetes(F/B) ratio in FABP4fl/flpvillinCreTmice is lower than control mice, which is opposite to that in mice fed HFD, indicating that FABP4 in the Paneth cells could reprogram gut microbiota. Interestingly, FABP4-mediated downregulation of defensins in Paneth cells not only happens in mice but also in human. A better understanding of the regulation of defensins, especially HFD-mediated downregulation of defensin in Paneth cells will provide insights into factor(s) underlying modern diseases.Abbreviations: FABP4: Fatty acid binding protein 4; S. T: SalmonellaTyphimurium; HFD: High-fat diet; Defa: α-defensin; 930HD5: Human α-defensin 5; HD6: Human α-defensin 6;F/B: Firmicutes/Bacteroidetes; SFB: Segmental filamentousbacteria; AMPs: Antimicrobial peptides; PPARγ:Peroxisome proliferator-activated receptor γ; P-PPAR:Phosphorylated PPAR; Dhx15: DEAD-box helicase 15; 935EGF: Epidermal growth factor; ENR: Noggin andR-spondin 1; CFU: Colony forming unit; Lyz1: Lysozyme1; Saa1: Serum amyoid A 1; Pla2g2a: Phospholipase A2,group IIA; MMP-7: Matrix metalloproteinase; AU-PAGE:Acid-urea polyacrylamide gel electrophoresis; PA: Palmitic 940acid; GPR40: G-protein-coupled receptor; GF: Germ-free;EGF: Epidermal growth factor; LP: Lamina propria; KO:Knock out; WT: Wild-type.

In this paper, the Hoffmann-Jørgensen inequality for negatively associated (NA) random variables is derived. As an important tool, it will be applied to the establishing for the logarithm law of NA arrays, and the results of Su, Hu and Liang {xc[15]} are extended.

AbstractAimsAutism spectrum disorder (ASD) is a neurodevelopmental condition, with symptoms appearing in the early developmental period. Little is known about its current burden at the global, regional and national levels. This systematic analysis aims to summarise the latest magnitudes and temporal trends of ASD burden, which is essential to facilitate more detailed development of prevention and intervention strategies.MethodsThe data on ASD incidence, prevalence, disability-adjusted life years (DALYs) in 204 countries and territories between 1990 and 2019 came from the Global Burden of Disease Study 2019. The average annual percentage change was calculated to quantify the secular trends in age-standardised rates (ASRs) of ASD burden by region, sex and age.ResultsIn 2019, there were an estimated 60.38 × 104[95% uncertainty interval (UI) 50.17–72.01] incident cases of ASD, 283.25 × 105(95% UI 235.01–338.11) prevalent cases and 43.07 × 105(95% UI 28.22–62.32) DALYs globally. The ASR of incidence slightly increased by around 0.06% annually over the past three decades, while the ASRs of prevalence and DALYs both remained stable over the past three decades. In 2019, the highest burden of ASD was observed in high-income regions, especially in high-income North America, high-income Asia Pacific and Western Europe, where a significant growth in ASRs was also observed. The ASR of ASD burden in males was around three times that of females, but the gender difference was shrunk with the pronounced increase among females. Of note, among the population aged over 65 years, the burden of ASD presented increasing trends globally.ConclusionsThe global burden of ASD continues to increase and remains a major mental health concern. These substantial heterogeneities in ASD burden worldwide highlight the need for making suitable mental-related policies and providing special social and health services.

Introduction Oral health and genetic factors can independently influence the risk of developing esophageal squamous cell carcinoma (ESCC).Objectives The primary objective of this study was to investigate the interactive effects of oral health and genetic factors on ESCC risk.Methods This was a matched case-control study with 927 ESCC patients and 1701 matched controls. We selected 101 candidate single nucleotide polymorphisms (SNPs) from 59 genes that were associated with ESCC. Oral health was assessed based on tooth-brushing frequency, tooth loss, and age at the time of first tooth loss. An unconditional logistic regression model was employed in which SNP–oral health interactions were assessed as risk factors for ESCC, after adjusting for age and sex. A genetic risk score (GRS) analysis was conducted.Results The association between GRS and ESCC and the synergistic effect of GRS and oral health on ESCC were examined. Daily frequency of tooth-brushing was found to interact with 5 SNPs, rs3765524, rs753724, rs994771, rs3781264, and rs11187842, to increase the risk of ESCC. In particular, individuals with genotype TT of rs3765524 who brushed their teeth less than twice a day had a 5.13-times higher risk of ESCC than those with genotype CC who brushed their teeth at least twice a day. Furthermore, tooth loss interacted with two SNPs: rs1159918 from ADH1B and rs3813867 from CYP2E1.Conclusion Oral health may interact with genetic factors increasing ESCC risk, which provides new insights into the relationship between ESCC and gene–lifestyle interactions which can be used for disease prevention.

This study investigated the microbial contamination of ice cream in China. A total of 2887 ice cream samples were collected from different regions of China. Contamination by the aerobic plate count (APC), coliforms, and three foodborne pathogens, Listeria monocytogenes(L. monocytogenes), Staphylococcus aureus(S. aureus), and Salmonellaspp., was detected in the samples. L. monocytogenesisolates were further analyzed for antibiotic susceptibility and multi-locus sequence typing (MLST). The results showed that APC was more than 105colony forming units (CFU)/g in 6.10% (176/2887) and coliform was more than 102CFU/g in 15.69% (453/2887) of all samples. The positive rates of S. aureus, L. monocytogenes, and Salmonellaspp. were 0.66%, 0.62%, and 0.10%, respectively. Among these, S. aureuscontamination was more than 102CFU/g in two samples, and L. monocytogenesin the positive sample was in the range of 0.3–240 most probable number (MPN)/g, with a median of 4.3 MPN/g. The hygienic status of the packaged samples was much better than that of the bulk samples (P<0.05). Catering samples were more frequently and heavily contaminated than samples from retail and wholesale outlets (P<0.05). No significant differences were observed in samples bought from urban and rural areas (P>0.05). For 18 L. monocytogenesstrains isolated from ice cream, the resistance rate of nine antibiotics was 5.56% (1/18). By MLST, the L. monocytogenesstrains were classified into nine sequence types (STs), of which ST8 was the most common (six isolates). These results indicate that a potential health risk to the public may be caused by ice cream, particularly in susceptible populations.

AbstractAimsAnxiety disorders are widespread across the world. A systematic understanding of the disease burden, temporal trend and risk factors of anxiety disorders provides the essential foundation for targeted public policies on mental health at the national, regional, and global levels.MethodsThe estimation of anxiety disorders in the Global Burden of Disease Study 2019 using systematic review was conducted to describe incidence, prevalence and disability-adjusted life years (DALYs) in 204 countries and regions from 1990 to 2019. We calculated the estimated annual percentage change (EAPC) to quantify the temporal trends in anxiety disorders burden by sex, region and age over the past 30 years and analysed the impact of epidemiological and demographic changes on anxiety disorders.ResultsGlobally, 45.82 [95% uncertainty interval (UI): 37.14, 55.62] million incident cases of anxiety disorders, 301.39 million (95% UI: 252.63, 356.00) prevalent cases and 28.68 (95% UI: 19.86, 39.32) million DALYs were estimated in 2019. Although the overall age-standardised burden rate of anxiety disorders remained stable over the past three decades, the latest absolute number of anxiety disorders increased by 50% from 1990. We observed huge disparities in both age-standardised burden rate and changing trend of anxiety disorders in sex, country and age. In 2019, 7.07% of the global DALYs due to anxiety disorders were attributable to bullying victimisation, mainly among the population aged 5–39 years, and the proportion increased in almost all countries and territories compared with 1990.ConclusionAnxiety disorder is still the most common mental illness in the world and has a striking impact on the global burden of disease. Controlling potential risk factors, such as bullying, establishing effective mental health knowledge dissemination and diversifying intervention strategies adapted to specific characteristics will reduce the burden of anxiety disorders.

Neoadjuvant chemotherapy (NAC) is the standard therapeutic regimen for locally advanced breast cancer. However, clinical physical examination and imaging results fail to accurately assess the treatment response, and postoperative pathological examination has a time lag in response to therapeutic effect which is not conducive to the timely adjustment of treatment strategies. A previous study has shown that miR-301a was associated with invasion and metastasis in breast cancer, and was found to be involved in endocrine therapy resistance; however, evidence regarding the correlation between miR-301a expression and NAC efficacy remains scarce. In this study, 101 patients with locally advanced breast cancer were included. All patients received anthracycline based chemotherapy. The expression level of miR-301a in pretreatment core needle biopsy tissues was determined by real-time polymerase chain reaction analysis. Relevant clinicopathological data were collected, and the correlation between miR-301a expression and NAC efficacy was assessed. Based on our data, miR-301a cannot be used to identify whether breast cancer benefits from NAC, and no correlation was observed between miR-301a expression and clinicopathological characteristics. In conclusion, miR-301a may not be a potential prognostic biomarker of NAC efficacy in breast cancer.

AbstractA new type of bulk acoustic wave sensing device based on a conductivity-bulk acoustic wave frequency response is applied in ion chromatography to determine nitrate and other inorganic ions in vegetables. The present method has the advantages in its rapidity, simplicity, sensitivity and accuracy. Detection limits (peak=3[sgrave]) are obtained for NO3−, Cl−, NO2−, H2PO4−and SO42−at concentrations of 1, 0.6, 1, 7 and 3 ng (on column), respectively. Neither derivatization nor a clean-up step is necessary besides filtration. For the IC analysis, the analytical column is a Shim-pack IC AI column, and the eluent is 2.0 mM phthalic acid solution with pH 4.0. A comparison of IC-SBAW with conventional IC is made. The method allows the simultaneous determination of nitrate and other inorganic ion levels in vegetables.

A feasible chromatographic method for the determination of iodide using ion chromatography (IC) with series bulk acoustic wave (SBAW) detection has been developed. The advantages of the good selectivity of ion chromatography and the highly sensitive response of SBAW have been combined to improve detection limit, linearity, and reproducibility. The detection limit has been estimated to be 5 ng/ml. For the IC analysis a 12.5-μm polymethacrylate resin column incorporating a quaternary base was used, with the mobile phase being 5.0 mMphthalic acid. The method has been applied to the determination of iodide in some dairy products and table salt.Copyright 1998 Academic Press.

Obstructive sleep apnea (OSA) is characterized by repetitive intermittent oxygen desaturation during sleep. Carbon monoxide poisoning (COP) is the second most common cause of death among non-medicinal poisonings, and oxygen therapy is the current standard of treatment for COP. We herein report a case of a 50-year-old woman diagnosed with severe OSA associated with COP. Both the OSA and COP gradually resolved by automatic continuous positive airway pressure (CPAP) therapy. New OSA symptoms appeared following the development of delayed encephalopathy after acute COP (DEACMP) 3 weeks later. Severe OSA was diagnosed 76 days after COP with an apnea–hypopnea index of 66 events/hour, and CPAP therapy was immediately administered. The patient’s DEACMP symptoms and OSA both improved with CPAP therapy (her apnea–hypopnea index decreased to 32.4 and 16.5 events/hour at 161 and 204 days after COP, respectively). To our knowledge, this is the first case report of OSA caused by COP based on the occurrence and disappearance of OSA symptoms and laboratory findings associated with the emergence and improvement of DEACMP.

ABSTRACTTriple-negative breast cancer (TNBC) is characterized by broad genomic and transcriptional heterogeneity and results in a worse prognosis than other breast cancer types. Here, we integrated genomic and transcriptomic data combined with clinicopathologic information from 538 patients with TNBC and identified four novel significantly mutated genes (SMGs), namely, KDM6A, CD86, RBM47, and IFNGR1. A mutational signature (known as age-related signature 1) featured by enrichment of C > T mutations at NpCpG trinucleotides was associated with worse survival in TNBC (HR, 1.76 [95% CI, 1.07–2.90]; P= .025). We also analyzed gene transcriptomic profiles of TNBC samples and identified immune regulation-related gene pathways (e.g., antigen processing presentation and interferon signaling), and the cell cycle was significantly altered in samples with different signature 1 activity groups. The analysis further revealed that signature 1 was associated with decreased tumor immunogenicity and immunocyte infiltration in TNBC. This negative correlation was also observed in lung adenocarcinoma and prostate cancer samples. Furthermore, we found that patients with mutational signature 1 were markedly associated with decreased tumor mutation burden, even after controlling for age, grade, histological type, lymph node status, mutations in BRCA1/2and ATR, and APOBECand homologous recombination repair deficiency signatures (OR, 0.19 [95% CI, 0.11–0.32]; P< .001). Overall, this study identified previously unreported SMGs and re-annotated that age-related signature 1 was associated with a weakened immune microenvironment and predictive of poor survival in TNBC, offering opportunities to stratify patients into optimal treatment plans based on genomic subtyping.

By integrating full‐duplex (FD) and nonorthogonal multiple‐access (NOMA) techniques for wireless self‐backhaul at small‐cell base stations (SBSs), a novel multitier heterogeneous network (HetNet) is proposed. In the HetNet, NOMA is used at SBSs for combing backhaul and downlink (DL) signals. As a result, at each SBS, the backhaul, uplink transmission, and DL transmission are executed simultaneously, whereas the FD macro base stations (MBSs) communicate with mobile users (MUs) and transceive backhaul signals from associated SBSs by using massive‐MIMO antennas. The simple time‐division duplex is performed for the communications between MBSs and MUs so that a round of communications consists of MBS‐MU‐DL and MBS‐MU‐UL phases. This work particularly focuses on the MBS‐MU‐DL phase. By assuming the HetNet to be fully loaded, this paper first models the distribution of active SBSs and those of the interference received at the different types of receivers. Then, by formulating the received signal‐to‐interference ratios, this paper obtains the coverage probabilities of the MU‐SBS‐MBS uplink backhaul and MU DLs as well as the spectrum and energy efficiencies. The presented simulations and numerical results show that the integration of FD and NOMA at SBSs is an effective solution for creating the backhaul between FD‐SBS and FD‐MBS. It is obtained that when the power‐sharing coefficient allocated for a small‐cell DL is small, the coverage probability of SBS DL transmission increases; otherwise, it decreases. However, the coverage probabilities of the MBS DL and MU‐SBS‐MBS backhaul link monotonically vary with the power‐sharing coefficient. It is also achieved that the power‐sharing coefficient imposes the effect on the energy efficiencies of the MU‐SBS‐MBS backhaul link and MU DL in inverse directions. At the same time, it is found that the achieved energy efficiency gain depends greatly on the resolution of massive‐MIMO antennas. By integrating full‐duplex (FD) and non‐orthogonal multiple access (NOMA) techniques, a novel in‐band wireless self‐backhaul scheme is proposed for co‐channel deployed multitier massive MIMO heterogeneous networks, where the NOMA is used at small‐cell base stations (SBSs) for combing backhaul and downlink (DL) signals. At each SBS the backhaul, uplink transmission, and DL transmission are executed simultaneously, while the FD macro base stations communicate with mobile users and tranceive backhaul signals from associated SBSs by using massive MIMO antennas.

C14H15N5O2, orthorhombic, Pbca (no. 61), a = 7.1378(3) Å, b = 12.0046(4) Å, c = 32.1450(13) Å, V = 2754.4 Å3, Z = 8, Rgt(F) = 0.0452, wRref(F2) = 0.1009, T = 120 K.

A study was conducted to evaluate the surface roughness levels of fruits and vegetables by a novel tactile sensor. Firstly, the effective areas of the sensor were determined through the mechanical analysis with the ANSYS software, and the sensitive elements of polyvinylidene fluoride piezoelectric films and strain gauges were randomly arranged in these areas. When the sensor contacted with the surfaces of the fruits and vegetables, the signals produced by the sensitive elements were output and tactile features were obtained. Secondly, the D-score criterion was applied to evaluate the contribution of every tactile feature component in expressing the surface roughness levels. According to the value of D-score, the strategies of the sequential forward selection and equential forward floating selection were used to guide the optimization of feature components selection. Back propagation neural network model was applied to evaluate the performance of the optimal features. Finally, the experimental results revealed that the identification accuracy of the algorithm was up to 93.737%, which demonstrated that the optimal feature subsets possessed fewer dimensions while maintaining a high performance in expressing the surface roughness characteristics of the fruits and vegetables. The results also provided a basis for the optimized design of the tactile sensor.

The determination of histamine in fish using an unsuppressed ion chromatographic (IC) method with series bulk acoustic wave (SBAW) detection is developed. The advantages of the good selectivity of IC and the highly sensitive response of SBAW are combined to improve detection limit, accuracy and reproducibility. The detection limit is 8 ng, recoveries are 98–106%, and the relative standard deviation is 1.6%. For the IC analysis, the analytical column is a Shim-pack IC C1 column, and the mobile phase is a 2.5mM HNO3 solution. The fish samples are treated with trichloroacetic acid and purified with either n-pentanol or n-hexanol. Histamine is finally isolated with a 0.2M HCI solution. The method is applied for the determination of histamine levels in black carp.

Quantile regression neural network (QRNN) model has recently become popular in solving complex nonlinear problems, but the quantile curves achieved by QRNN model may cross each other, leading to unreliable results. To remedy this defect, monotone composite quantile regression neural network (MCQRNN) model is more attractive with non-crossing quantile predictions. However, few works have been involved in the literature to apply MCQRNN model for censoring issues. Based on the data augmentation algorithm, this study presents an iterative estimation method, which is a three-step alternating process, for censored MCQRNN model. Step 1 imputes the censored data through a data augmentation procedure. Step 2 updates the MCQRNN model with the imputed data. Step 3 makes predictions by the updated MCQRNN model. Simulation studies and real data application demonstrate that our proposed method is not only superior to the available censored methods with respect to quantile loss and C-index, but also yields very close prediction results to those obtained by full uncensored data. Avoiding the quantile crossing problem, the proposed method is more flexible to cope with different types of censoring, overcoming the limitation that the existing censored methods only work for single censoring type with unbelievable predictions caused by the crossing phenomenon. • An iterative estimation method is first proposed for censored MCQRNN model. • The proposed method works for any censoring type that simultaneously exists in the model. • The proposed method can effectively avoid the quantile crossing problem to yield reliable prediction results. • The proposed method outperforms the existing methods in terms of quantile loss and C-index. [ABSTRACT FROM AUTHOR]