Legumain-deficient macrophages regulate inflammation and lipid metabolism in adipose tissues to protect against diet-induced obesity.

Adipose tissue macrophages (ATMs) are key players in the development of obesity and associated metabolic inflammation, which contributes to systemic metabolic dysfunction, and understanding the interaction between macrophages and adipocytes is crucial for developing novel macrophage-based strategies against obesity. Here, we found that Legumain (Lgmn), a well-known lysosomal cysteine protease, is expressed mainly in the ATMs of obese mice. To further define the potential role of Lgmn-expressing macrophages in the generation of an aberrant metabolic state, LgmnF/F; LysMCre mice, which do not express Lgmn in macrophages, were maintained on a high-fat diet (HFD), and metabolic parameters were assessed. Macrophage-specific Lgmn deficiency protects mice against diet-induced obesity, diminishes the quantity of proinflammatory macrophages in obese adipose tissues, and alleviates hepatic steatosis and insulin resistance. By analysing the transcriptome and proteome of murine visceral white adipose tissue (vWAT) after HFD feeding, we determined that macrophage Lgmn deficiency causes changes in lipid metabolism and the inflammatory response. Furthermore, the reciprocity of macrophage-derived Lgmn with integrin α5ß1 in adipocytes was tested via colocalization analyses. It is further demonstrated in macrophage and adipocyte coculture system that macrophage derived Lgmn bound to integrin α5ß1 in adipocytes, therefore attenuating PKA activation, downregulating lipolysis-related proteins and eventually exacerbating obesity development. Overall, our study identified Lgmn as a previously unrecognized regulator involved in the interaction between ATMs and adipocytes contributing to diet-induced obesity and suggested that Lgmn is a potential target for treating metabolic disorders.

A Strain-Promoted Divergent Chemical Steroidation Unveils Potent Anti-Inflammatory Pseudo-Steroidal Glycosides.

The development of novel agents with immunoregulatory effects is a keen way to combat the growing threat of inflammatory storms to global health. To synthesize pseudo-steroidal glycosides tethered by ether bonds with promising immunomodulatory potential, we develop herein a highly effective deoxygenative functionalization of a novel steroidal donor (steroidation) facilitated by strain-release, leveraging cost-effective and readily available Sc(OTf)3 catalysis. This transformation produces a transient steroid-3-yl carbocation which readily reacts with O-, C-, N-, S-, and P-nucleophiles to generate structurally diverse steroid derivatives. DFT calculations were performed to shed light on the mechanistic details of the regioselectivity, underlying an acceptor-dependent steroidation mode. This approach can be readily extended to the etherification of sugar alcohols to enable the achievement of a diversity-oriented, pipeline-like synthesis of pseudo-steroidal glycosides in good to excellent yields with complete stereo- and regiospecific control for anti-inflammatory agent discovery. Immunological studies have demonstrated that a meticulously designed cholesteryl disaccharide can significantly suppress interleukin-6 secretion in macrophages, exhibiting up to 99% inhibition rates compared to the negative control. These findings affirm the potential of pseudo-steroidal glycosides as a prospective category of lead agents for the development of novel anti-inflammatory drugs.

Anus preservation in low rectal adenocarcinoma based on MMR/MSI status (APRAM): a study protocol for a randomised, controlled, open-label, multicentre phase III trial.

BACKGROUND: Anus preservation has been a challenge in the treatment of patients with low rectal adenocarcinoma (within 5 cm from the anal verge) because it is difficult to spare the anus with its functioning sphincter complex under the safe margin of tumour resection. Patients with dMMR/MSI-H can achieve a favourable complete response (CR) rate by using a single immune checkpoint inhibitor. For patients with pMMR/MSS/MSI-L, intensified neoadjuvant three-drug chemotherapy may be the preferred option for anal preservation. In addition, the watch and wait (W&W) strategy has been proven safe and feasible for patients with rectal cancer who achieve a clinical complete response (cCR). Therefore, we initiated this clinical trial to explore the optimal neoadjuvant treatment pattern for patients with low locally advanced rectal cancer (LARC) with different MMR/MSI statuses, aiming to achieve a higher cCR rate with the W&W strategy and ultimately provide more patients with a chance of anus preservation. METHODS: This is a randomised, controlled, open-label, multicentre phase III trial. Patients with clinical stage T2-4 and/or N + tumours located within 5 cm from the anal verge are considered eligible. Based on the results of pathological biopsy, the patients are divided into two groups: dMMR/MSI-H and pMMR/MSS. Patients in the dMMR/MSI-H group will be randomly allocated in a 1:1 ratio to either arm A (monoimmunotherapy) or arm B (short-course radiotherapy followed by monoimmunotherapy). Patients in the pMMR/MSS group will be initially treated with long-term pelvic radiation with concurrent capecitabine combined with irinotecan. Two weeks after the completion of chemoradiotherapy (CRT), the patients will be randomly allocated in a 1:1 ratio to arm C (XELIRI six cycle regime) or arm D (FOLFIRINOX nine cycle regime). The irinotecan dose will be adjusted according to the UGT1A1-genotype. After treatment, a comprehensive assessment will be performed to determine whether a cCR has been achieved. If achieved, the W&W strategy will be adopted; otherwise, total mesorectal excision (TME) will be performed. The primary endpoint is cCR with the maintenance of 12 months at least, determined using digital rectal examination, endoscopy, and rectal MRI or PET/CT as a supplementary method. DISCUSSION: APRAM will explore the best anus preservation model for low LARC, combining the strategies of consolidation chemotherapy, immunotherapy, and short-course radiotherapy, and aims to preserve the anus of more patients using W&W. Our study provides an accurate individual treatment mode based on the MMR/MSI status for patients with low LARC, and more patients will receive the opportunity for anus preservation under our therapeutic strategy, which would transform into long-term benefits. TRIAL REGISTRATION: Clinicaltrials.gov NCT05669092 (Registered 28th Nov 2022).

Efficacy of Serratus Anterior Plane Block Versus Paravertebral and Intercostal Blocks for Pain Control After Surgery:: A Systematic Review and Meta-analysis.

OBJECTIVE: Our study aimed to compare the analgesic efficacy of serratus anterior plane block (SAB) with the paravertebral block (PVB) and intercostal block (ICB) for patients undergoing surgical procedures. MATERIALS AND METHODS: A literature search was performed on the databases of ScienceDirect, Google Scholar, PubMed, and Embase from inception to October 24, 2021. Only randomized controlled trials comparing SAB with either PVB or ICB and reporting pain outcomes were included. RESULTS: A total of 16 randomized controlled trials were included. Thirteen compared SAB with PVB and 3 with ICB. Comparing SAB with PVB, we noted no difference in 24-hour morphine consumption between the groups (mean difference: 1.37; 95% CI: -0.33, 3.08; I2 = 96%; P = 0.11). However, the exclusion of 1 study indicated significantly increased analgesic consumption with the SAB. No difference was found in pain scores between SAB and PVB at 2, 4, 6, 8, 12, and 24 hours. Meta-analysis failed to demonstrate any statistically significant difference in time to the first analgesic request between the two groups (mean difference: -0.79; 95% CI: -0.17, 1.75; I2 = 94%; P = 0.11). We also noted no statistically significant difference in the incidence of nausea/vomiting with SAB or PVB (odds ratio: 0.79; 95% CI: 0.41, 1.51; I2 = 0%; P = 0.47). CONCLUSIONS: Evidence on the analgesic efficacy of the SAB versus the PVB is conflicting. Twenty-four-hour total analgesic consumption may be higher with the SAB as compared with PVB but with no difference in pain scores and time to the first analgesic request. Data on the comparison of the SAB with the ICB is insufficient to draw strong conclusions.

Unraveling Colorectal Cancer and Pan-cancer Immune Heterogeneity and Synthetic Therapy Response Using Cuproptosis and Hypoxia Regulators by Multi-omic Analysis and Experimental Validation.

Cuproptosis, a new type of programmed cell death (PCD), is closely related to cellular tricarboxylic acid cycle and cellular respiration, while hypoxia can modulate PCD. However, their combined contribution to tumor subtyping remains unexplored. Here, we applied a multi-omics approach to classify TCGA_COADREAD based on cuproptosis and hypoxia. The classification was validated in three colorectal cancer (CRC) cohorts and extended to a pan-cancer analysis. The results demonstrated that pan-cancers, including CRC, could be divided into three distinct subgroups (cuproptosis-hypoxia subtypes, CHSs): CHS1 had active metabolism and poor immune infiltration but low fibrosis; CHS3 had contrasting characteristics with CHS1; CHS2 was intermediate. CHS1 may respond well to cuproptosis inducers, and CHS3 may benefit from a combination of immunotherapy and anti-fibrosis/anti-hypoxia therapies. In CRC, the CHSs also showed a significant difference in prognosis and sensitivity to classic drugs. Organoid-based drug sensitivity assays validated the results of transcriptomics. Cell-based assays indicated that masitinib and simvastatin had specific effects on CHS1 and CHS3, respectively. A user-friendly website based on the classifier was developed (https://fan-app.shinyapps.io/chs_classifier/) for accessibility. Overall, the classifier based on cuproptosis and hypoxia was applicable to most pan-cancers and could aid in personalized cancer therapy.

Foot-and-Mouth Disease Virus Induces Porcine Gasdermin E-Mediated Pyroptosis through the Protease Activity of 3Cpro.

Foot-and-mouth disease (FMD) is an acute, highly contagious disease of cloven-hoofed animals caused by FMD virus (FMDV). Currently, the molecular pathogenesis of FMDV infection remains poorly understood. Here, we demonstrated that FMDV infection induced gasdermin E (GSDME)-mediated pyroptosis independent of caspase-3 activity. Further studies showed that FMDV 3Cpro cleaved porcine GSDME (pGSDME) at the Q271-G272 junction adjacent to the cleavage site (D268-A269) of porcine caspase-3 (pCASP3). The inhibition of enzyme activity of 3Cpro failed to cleave pGSDME and induce pyroptosis. Furthermore, overexpression of pCASP3 or 3Cpro-mediated cleavage fragment pGSDME-NT was sufficient to induce pyroptosis. Moreover, the knockdown of GSDME attenuated the pyroptosis caused by FMDV infection. Our study reveals a novel mechanism of pyroptosis induced by FMDV infection and might provide new insights into the pathogenesis of FMDV and the design of antiviral drugs. IMPORTANCE Although FMDV is an important virulent infectious disease virus, few reports have addressed its relationship with pyroptosis or pyroptosis factors, and most studies focus on the immune escape mechanism of FMDV. GSDME (DFNA5) was initially identified as being associated with deafness disorders. Accumulating evidence indicates that GSDME is a key executioner for pyroptosis. Here, we first demonstrate that pGSDME is a novel cleavage substrate of FMDV 3Cpro and can induce pyroptosis. Thus, this study reveals a previously unrecognized novel mechanism of pyroptosis induced by FMDV infection and might provide new insights into the design of anti-FMDV therapies and the mechanisms of pyroptosis induced by other picornavirus infections.

Exploiting Broad-Spectrum Chimeric Lysin to Cooperate with Mupirocin against Staphylococcus aureus-Induced Skin Infections and Delay the Development of Mupirocin Resistance.

Staphylococcus aureus often leads to severe skin infections. However, S. aureus is facing a crisis of antibiotic resistance. The combination of phage and antibiotics is effective for drug-resistant S. aureus infections. Therefore, it is worth exploiting novel antibacterial agents to cooperate with antibiotics against S. aureus infections. Herein, a novel chimeric lysin ClyQ was constructed, which was composed of a cysteine- and histidine-dependent amidohydrolase/peptidase (CHAP) catalytic domain from S. aureus phage lysin LysGH15 and cell wall-binding domain (CBD) from Enterococcus faecalis phage lysin PlyV12. ClyQ had an exceptionally broad host range targeting streptococci, staphylococci, E. faecalis, and E. rhusiopathiae. ClyQ combined with mupirocin (2.64 log reduction) was more effective at treating S. aureus skin infections than ClyQ (0.46 log reduction) and mupirocin (2.23 log reduction) alone. Of equal importance, none of S. aureus ATCC 29213 or S3 exposed to ClyQ developed resistance, and the combination of ClyQ and mupirocin delayed the development of mupirocin resistance. Collectively, chimeric lysin ClyQ enriches the reservoirs for treating S. aureus infections. Our findings may provide a way to alleviate the current antibiotic resistance crisis. IMPORTANCE Staphylococcus aureus, as an Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) pathogen, can escape the elimination of existing antibiotics. At present, phages and phage lysins against S. aureus infections are considered alternative antibacterial agents. However, the development of broad-spectrum chimeric phage lysins to cooperate with antibiotics against S. aureus infections remains at its initial stage. In this study, we found that the broad-host-range chimeric lysin ClyQ can synergize with mupirocin to treat S. aureus skin infections. Furthermore, the development of S. aureus resistance to mupirocin is delayed by the combination of ClyQ and mupirocin in vitro. Our results bring research attention toward the development of chimeric lysin that cooperates with antibiotics to overcome bacterial infections.

m6A-dependent mevalonate kinase in juvenile hormone synthesis pathway regulates the diapause process of bivoltine silkworm (Bombyx mori).

BACKGROUND: Research has shown that epigenetic modification are involved the regulation of diapause in bivoltine silkworms (Bombyx mori), but it remains unclear how epigenetic modification in response to environmental signals precisely to regulate the diapause processing of bivoltine B. mori. METHODS AND RESULTS: In this study, the diapause terminated eggs of bivoltine B. mori, Qiufeng (QF) were divided into two groups: a QFHT group incubated at 25 °C with a natural day/night cycle to produce diapause eggs, and a QFLT group incubated at 16.5 °C in darkness to produce non-diapause eggs. On the 3rd day of the pupal stage, the total RNAs of the eggs were extracted and their N6-adenosine methylation (m6A) abundances were analyzed to explore the effects of m6A methylation on diapause in the silkworm. The results showed that 1984 m6A peaks are shared, 1563 in QFLT and 659 in QFHT. The m6A methylation level of the QFLT group was higher than that of the QFHT one in various signaling pathways. The m6A methylation rate of mevalonate kinase (MK) in the insect hormone synthesis pathway was significantly different between the two groups. The knockdown of MK by RNA interference in the pupae of QFLT resulted in females laying diapause eggs rather than non-diapause eggs after mating. CONCLUSIONS: m6A methylation involves in the diapause regulation of bivoltine B. mori by changing the expression levels of MK. This result provides a clearer image of the environmental signals on the regulation of diapause in bivoltine silkworms.

A Structure-Guided Genetic Modification Strategy: Developing Seneca Valley Virus Therapy against Nonsensitive Nonsmall Cell Lung Carcinoma.

Numerous studies have illustrated that the Seneca Valley virus (SVV) shows sufficient oncolytic efficacy targeting small cell lung cancer (SCLC). However, the therapeutics of nonsmall cell lung carcinoma (NSCLC, accounts for 85% of lung cancer cases) using oncolytic virus have been resisting due to the filtration of neutralizing antibody and limited reproduction capacity. Here, we employed structural biology and reverse genetics to optimize novel oncolytic SVV mutants (viral receptor-associated mutant SVV-S177A and viral antigenic peptide-related variant SVV-S177A/P60S) with increased infectivity and lower immunogenicity. The results of the NSCLC-bearing athymic mouse model demonstrated that wild-type (wt) SVV-HB extended the median overall survival (mOS) from 11 days in the PBS group to 19 days. Notably, the newly discovered mutations significantly (P < 0.001) prolonged the mOS from 11 days in the control cohort to 23 days in the SVV-S177A cohort and the SVV-S177A/P60S cohort. Taken together, we present a structure-guided genetic modification strategy for oncolytic SVV optimization and provide a candidate for developing oncolytic viral therapy against nonsensitive NSCLC. IMPORTANCE Nonsmall cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases (more than 1.85 million cases with 1.48 million deaths in 2020). In the present study, two novel oncolytic SVV mutants modified based on structural biology and reverse genetics (viral receptor-associated mutant SVV-S177A and viral antigenic peptide-related mutant SVV-S177A/P60S) with increased infectivity or lower immunogenicity significantly (P < 0.001) prolonged the mOS from 11 days in the control cohort to 23 days in the SVV-S177A cohort and the SVV-S177A/P60S cohort in the NSCLC-bearing athymic mouse model, which may provide the direction for modifying SVV to improve the effect of oncolysis.

Seneca Valley virus enters cells through multiple pathways and traffics intracellularly via the endolysosomal pathway.

Seneca Valley virus (SVV, also known as Senecavirus A), an oncolytic virus, is a nonenveloped, positive-strand RNA virus and the sole member of the genus Senecavirus within the family Picornaviridae. The mechanisms of SVV entry into cells are currently almost unknown. In the present study, we found that SVV entry into HEK293T cells is acidic pH-dependent by using ammonium chloride (NH4Cl) and chloroquine, both of which could inhibit SVV infection. We confirmed that dynamin II is required for SVV entry by using dynasore, silencing the dynamin II protein, or expressing the dominant-negative (DN) K44A mutant of dynamin II. Then, we discovered that chlorpromazine (CPZ) treatment or knockdown of the clathrin heavy chain (CLTC) protein significantly inhibited SVV infection. In addition, overexpression of CLTC promoted SVV infection. Caveolin-1 and membrane cholesterol were also required for SVV endocytosis. Notably, utilizing genistein, EIPA or nocodazole, we observed that macropinocytosis and microtubules are not involved in SVV entry. Furthermore, overexpression of the Rab7 and Rab9 proteins but not the Rab5 or Rab11 proteins promoted SVV infection. The findings were further validated by the knockdown of four Rabs and Lamp1 proteins, indicating that after internalization, SVV is transported from late endosomes to the trans-Golgi network (TGN) or lysosomes, respectively, eventually releasing its RNA into the cytosol from the lysosomes. Our findings concretely revealed SVV endocytosis mechanisms in HEK293T cells and provided an insightful theoretical foundation for further research into SVV oncolytic mechanisms.

Perioperative safety assessment of patients undergoing unilateral or bilateral hip replacements.

Introduction: Due to the aging of the world population and the increase of obesity rate, it is expected that the number of joint replacement surgery will continue to increase in the next few years. This study evaluated the safety differences between unilateral and bilateral hip replacement surgeries. Methods: The data for patients who underwent hip arthroplasty in 2021 and 2022 were examined. The data set included 68 patients who were grouped according to the type of hip replacement needed, sex, age, and body mass index. Total blood loss and operative time were the safety-related indicators used to compare the groups. Results: Regardless of whether the unilateral replacement group was compared with the overall bilateral replacement group or separately with the staged and simultaneous bilateral replacement groups, simultaneous bilateral replacement surgeries were equally safe as the other types of hip replacements. The total blood loss and operative time for the simultaneous bilateral replacement group were not significantly different from those in the unilateral and staged bilateral replacement groups. For overweight patients, the operative time for simultaneous bilateral replacements was significantly shorter than that for unilateral replacements. Conclusions: These findings suggest that for patients requiring bilateral hip replacements, the blood loss risk for patients undergoing simultaneous bilateral hip replacements was similar to that for patients undergoing either unilateral or staged bilateral hip replacements. Thus, simultaneous bilateral total hip replacement (THR) are safe and should be considered for candidate patients.

Structural and Energetic Origin of Different Product Specificities and Activities for SETD3 and Its Mutants on the Methylation of the ß-Actin H73K Peptide: Insights from a QM/MM Study.

The methylation of the lysine residue can affect some fundamental biological processes, and specific biological effects of the methylations are often related to product specificity of methyltransferases. The question remains concerning how active-site structural features and dynamics control the activity as well as the number (1, 2, or 3) of methyl groups on methyl lysine products. SET domain containing protein 3 (SETD3) has been identified recently as the ß-actin histidine73-N3 methyltransferase, and also, it has a weak methylation activity on the H73K ß-actin peptide for which the target H73 residue is mutated into K73. Interestingly, the K73 methylation activity of SETD3 increases significantly as a result of the N255 → A or N255 → F/W273 → A mutation, and the N255A product specificity also differs from that of wild-type. Here, we performed QM/MM molecular dynamics and potential of mean force (PMF) simulations for SETD3 and its mutants (N255A and N255F/W273A) to study how SETD3 and its mutants could have different product specificities and activities for the K73 methylation. The PMF simulations show that the barrier for the first methylation of K73 is higher compared to the barrier of the H73 methylation in SETD3. Moreover, the second methylation of K73 has been found to have a barrier from the free energy simulation that is higher by 2.2 kcal/mol compared to the barrier of the first methyl transfer to K73, agreeing with the suggestion that SETD3 is a monomethylase. For the first, second, and third methylations of K73 in the N255A mutant, the barriers obtained from the PMF simulations for transferring the second and third methyl groups are found to be lower relative to the barrier for the first methyl transfer. Thus, N255A can be considered as a trimethyl lysine methyltransferase. In addition, for the first K73 methylation, the activities from the PMF simulations follow the order of N255F/W273A > N255A > WT, in agreement with experiments. The examination of the structural and dynamic results at the active sites provides better understanding of different product specificities and activities for the K73 methylations in SETD3 and its mutants. It is demonstrated that the existence of well-balanced interactions at the active site leading to the near attack conformation is of crucial importance for the efficient methyl transfers. Moreover, the presence of potential interactions (e.g., the C-H···O and cation-π interactions) that are strengthening at the transition state can also be important. Furthermore, the activity as well as product specificity of the K73 methylation also seems to be controlled by certain active-site water molecules which may be released to provide extra space for the addition of more methyl groups on K73.

[Combined use of prefabricated rib-locking titanium plate with ultrasound-guided thoracic paravertebral nerve blockade in the treatment of multiple rib fractures among the elderly].

OBJECTIVE: This paper is aimed at investigating the efficacy of combining internal fixation using prefabricated rib-locking titanium plate with ultrasound-guided thoracic paravertebral nerve blockade in treating multiple rib fractures among the elderly. METHODS: Retrospective analysis of 221 elderly patients with multiple rib fractures treated from February 2016 to November 2020. According to whether surgery was performed, they were divided into the plate-blockage combination group (surgical group, 102 cases) and conservative treatment group (non-surgical group, 119 cases). The surgical group consisted of 58 males and 44 females aged from 60 to 85 years old, with an average of (67.2±3.6 ) years old, who suffered from 3 to 12 rib fractures with an average of (5.3±2.1) fractures. The non-surgical group consisted of 66 males and 53 females aged from 60 to 84 years old with an average of (66.8±3.2) years old, who suffered from 2 to 11 rib fractures with an average of(6.1±2.3) fractures. The clinical data, efficacies observed, and complications associated with both groups were compared and analyzed. RESULTS: There was no significant difference in preoperative clinical data between two groups (P>0.05), and all patients were discharged smoothly. Pulmonary infection (P=0.028), atelectasis (P=0.032), respiratory failure (P=0.026), time to get out of bed (P=0.040), time to fracture healing (P=0.035), length of hospital stay in the operation group (P=0.043), visual analogue scale (VAS) at 3 days (P=0.028), 5 days(P=0.032), and 7 days(P=0.019), maximal voluntary ventilation (MVV) at 3 months after surgery (P=0.042), forced expiratory volume in one second (FEV1)(P=0.035), and maximal voluntary ventilation at 6 months, the maximal voluntary ventilation(MVV)(P=0.021) and forced FEV1(P=0.026) were all significantly better than those in non-surgical treatment group. CONCLUSION: For elderly patients with severe multiple rib fractures, the proposed plate-blockade combination can timely and effectively relieve pain, restore thoracic stability, shorten hospital stay, and reduce the incidence of complications such as pulmonary infections and acute respiratory distress syndrome(ARDS) compared with non-surgical treatments. Prefabricated rib-locking titanium plates have proved to demonstrate high clinical efficacy in treating multiple rib fractures among the elderly.

Advances in the functions of CTRP6 in the development and progression of the malignancy.

CTRP6, a member of the C1q/TNF-related protein (CTRP) family, has gained increasing scientific interest because of its regulatory role in tumor progression. Previous studies have shown that CTRP6 is closely involved in regulating various pathophysiological processes, including glucose and lipid metabolism, cell proliferation, apoptosis, and inflammation. To date, CTRP6 has been identified as related to eight different malignancies, including lung cancer, oral cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, renal cancer, and ovarian cancer. CTRP6 is reported to be associated with tumor progression by activating a series of related signal networks. This review article mainly discusses the biochemistry and pleiotropic pathophysiological functions of CTRP6 as a new molecular mediator in carcinogenesis, hoping that the information summarized herein could make a modest contribution to the development of novel cancer treatments in the future.

Porcine Sapelovirus 3Cpro Inhibits the Production of Type I Interferon.

Porcine sapelovirus (PSV) is the causative pathogen of reproductive obstacles, acute diarrhea, respiratory distress, or severe polioencephalomyelitis in swine. Nevertheless, the pathogenicity and pathogenic mechanism of PSV infection are not fully understood, which hinders disease prevention and control. In this study, we found that PSV was sensitive to type I interferon (IFN-ß). However, PSV could not activate the IFN-ß promoter and induce IFN-ß mRNA expression, indicating that PSV has evolved an effective mechanism to block IFN-ß production. Further study showed that PSV inhibited the production of IFN-ß by cleaving mitochondrial antiviral signaling (MAVS) and degrading melanoma differentiation-associated gene 5 (MDA5) and TANK-binding kinase 1 (TBK1) through viral 3Cpro. In addition, our study demonstrated that PSV 3Cpro degrades MDA5 and TBK1 through its protease activity and cleaves MAVS through the caspase pathway. Collectively, our results revealed that PSV inhibits the production of type I interferon to escape host antiviral immunity through cleaving and degrading the adaptor molecules.

Fatal left atrial air embolism as a complication of percutaneous transthoracic lung biopsy: A case report.

BACKGROUND: Computed tomography (CT)-guided percutaneous lung biopsy is a common protocol in the context of diagnostic thoracic oncology, but entails a risk of complications including systematic air embolism (SAE). While SAE is often well tolerated, it can be difficult to treat and may result in rapid mortality in some cases. CASE SUMMARY: We report a rare case of left atrial SAE in a 71-year-old woman who underwent a CT-guided lung biopsy of a pulmonary nodule in the posterior basal segment of the right lower lobe. Shortly following needle extraction, she experienced a mild cough, hemoptysis, rapid-onset unconsciousness, and cardiopulmonary arrest. Cardiopulmonary resuscitation was immediately performed, but the patient died 40 min after the procedure. A closer review of collected CT scans revealed the presence of a large volume of air within the left atrium. CONCLUSION: Although SAE is generally well tolerated and asymptomatic, interventional radiologists must be aware of the risk of fatal outcomes and establish appropriate emergency management protocols. In this report, the characteristics, mechanisms, and treatment recommendations associated with SAE are discussed in an effort to improve the survival of affected patients.

The Function Improved of the Newly Designed Magnetic-End Ureteric Stenting Retrieval Device: A Clinical Prospective Randomized and Control Trial in a Multicenter Study.

Objective: To demonstrate the advantage of our newly designed magnetic ureteric stenting retrieval device over traditional nonmagnetic ureteric stents and other retrieval devices without cystoscopy intervention on clinical application and cost-related outcomes. Patients and Methods. A total of 333 patients were recruited into two study groups: magnetic-end ureteral stent (Group A) and conventional ureteral stent (Group B). The effects were evaluated by Ureteral Stent Symptom Questionnaire (USSQ) scores, complications of the indwelling stent, visual analog scale (VAS) pain scores at stent removal, and cost-analysis outcomes between the magnetic ureteric stenting retrieval device and traditional double-J ureteral stent (DJUS) removed by cystoscopy. Results: The VAS of the pain score of patients undergoing magnetic stent removal with the retrieval device was 2 ± 0.97, whereas that of patients undergoing conventional ureteral stent removal with cystoscopy was 5.76 ± 1.53 (p < 0.001). The removal of magnetic stents by a retrieval device proved to be less painful than cystoscopy-mediated stent removal (p < 0.001). Obviously, the total cost for the magnetic stent removal was much lower than the conventional ureteral stent removal, although the magnetic stent costs more than the conventional ureteral stent. The improved magnetic stent used in our study showed a remarkable cost saving of 705/111 USD Chinese Yuan (CNY) per patient when compared with the conventional ureteral stent. Conclusion: We reported the integrated design features of the improved magnetic stent in the world, which was granted a patent in China. USSQ scores and rate of complications in the magnetic stent were as equally acceptable as a conventional stent. Furthermore, successful stent insertion rate reached 100% by both the antegrade and retrograde approaches, and no failure case of magnetic stent removal was reported in our study.

Computational Study of Methionine Methylation Process Catalyzed by SETD3.

The SETD3 enzyme has been identified as the methyltransferase for the His73 methylation in ß-actin, and such methylation plays an important role in regulating the actin's biochemical properties and fine-tuning the protein's cellular roles. Further studies have demonstrated that SETD3 may be able to methylase some other residues, including lysine and methionine, that substitute His73 in the ß-actin peptide. The activity of SETD3 on the Met73 peptide is low without turnover. Interestingly, it has been shown that the N255V and N255A mutations of SETD3 can increase the activity by about 3-fold for the methionine methylation, while such mutations lead to a significant reduction of kcat for the His73 methylation. The detailed mechanism that leads to such increase of the activity for the Met73 methylation as a result of the mutations has not been understood. In this work, QM/MM molecular dynamics (MD) and potential of mean force (PMF) free energy simulations are undertaken for investigating structural, dynamic, and energetic properties involving the complex of SETD3 and Met73 peptide and to study the SETD3-catalyzed methionine methylation and the effects of the N255V mutation. It is demonstrated that the free energy barrier in the case of the methionine methylation in SETD3 is about 10 kcal/mol higher than that for the histidine methylation. Moreover, the free energy barrier for the methionine methylation in the N255V mutant is about 1 kcal/mol lower than that in the wild-type enzyme. These results agree with previous experimental observation. The origin of the free-energy barrier changes as a result of the H to M substitution on the ß-actin peptide and the N255V mutation of SETD3 is discussed based on the data obtained from the simulations.

Identification of a conserved neutralizing epitope in Seneca Valley virus VP2 protein: new insight for epitope vaccine designment.

BACKGROUND: Seneca Valley virus (SVV) is a picornavirus that causes vesicular disease in swine. Clinical characteristics of the disease are similar to common viral diseases such as foot-and-mouth disease virus, porcine vesicular disease virus, and vesicular stomatitis virus, which can cause vesicles in the nose or hoof of pigs. Therefore, developing tools for detecting SVV infection is critical and urgent. METHODS: The neutralizing antibodies were produced to detect the neutralizing epitope. RESULTS: Five SVV neutralizing monoclonal antibodies (mAb), named 2C8, 3E4, 4C3, 6D7, and 7C11, were generated by immunizing mouses with ultra-purified SVV-LNSY01-2017. All five monoclonal antibodies exhibited high neutralizing titers to SVV. The epitopes targeted by these mAbs were further identified by peptide scanning using GST fusion peptides. The peptide 153QELNEE158 is defined as the smallest linear neutralizing epitope. The antibodies showed no reactivity to VP2 single mutants E157A. Furthermore, the antibodies showed no neutralizing activity with the recombinant virus (SVV-E157A). CONCLUSIONS: The five monoclonal antibodies and identified epitopes may contribute to further research on the structure and function of VP2 and the development of diagnostic methods for detecting different SVV strains. Additionally, the epitope recognized by monoclonal antibodies against VP2 protein may provide insights for novel SVV vaccines and oncolytic viruses development.

TRIM67 Suppresses TNFalpha-Triggered NF-kB Activation by Competitively Binding Beta-TrCP to IkBa.

The transcription factor NF-κB plays an important role in modulation of inflammatory pathways, which are associated with inflammatory diseases, neurodegeneration, apoptosis, immune responses, and cancer. Increasing evidence indicates that TRIM proteins are crucial role in the regulation of NF-κB signaling pathways. In this study, we identified TRIM67 as a negative regulator of TNFα-triggered NF-κB activation. Ectopic expression of TRIM67 significantly represses TNFα-induced NF-κB activation and the expression of pro-inflammatory cytokines TNFα and IL-6. In contrast, Trim67 depletion promotes TNFα-induced expression of TNFα, IL-6, and Mcp-1 in primary mouse embryonic fibroblasts. Mechanistically, we found that TRIM67 competitively binding ß-transducin repeat-containing protein (ß-TrCP) to IκBα results inhibition of ß-TrCP-mediated degradation of IκBα, which finally caused inhibition of TNFα-triggered NF-κB activation. In summary, our findings revealed that TRIM67 function as a novel negative regulator of NF-κB signaling pathway, implying TRIM67 might exert an important role in regulation of inflammation disease and pathogen infection caused inflammation.