Mycobacterium bovis BCG Given at Birth Followed by Inactivated Respiratory Syncytial Virus Vaccine Prevents Vaccine-Enhanced Disease by Promoting Trained Macrophages and Resident Memory T Cells.

Respiratory syncytial virus (RSV) infects more than 60% of infants in their first year of life. Since an experimental formalin-inactivated (FI) RSV vaccine tested in the 1960s caused enhanced respiratory disease (ERD), few attempts have been made to vaccinate infants. ERD is characterized by Th2-biased responses, lung inflammation, and poor protective immune memory. Innate immune memory displays an increased nonspecific effector function upon restimulation, a process called trained immunity, or a repressed effector function upon restimulation, a process called tolerance, which participates in host defense and inflammatory disease. Mycobacterium bovis bacillus Calmette-Guérin (BCG) given at birth can induce trained immunity as well as heterologous Th1 responses. We speculate that BCG given at birth followed by FI-RSV may alleviate ERD and enhance protection through promoting trained immunity and balanced Th immune memory. Neonatal mice were given BCG at birth and then vaccinated with FI-RSV+Al(OH)3. BCG/FI-RSV+Al(OH)3 induced trained macrophages, tissue-resident memory T cells (TRM), and specific cytotoxic T lymphocytes (CTL) in lungs and inhibited Th2 and Th17 cell immune memory, all of which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented the innate tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. Therefore, BCG given at birth to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants. IMPORTANCE RSV is the leading cause of severe lower respiratory tract infection of infants. ERD, characterized by Th2-biased responses, inflammation, and poor immune memory, has been an obstacle to the development of safe and effective killed RSV vaccines. Innate immune memory participates in host defense and inflammatory disease. BCG given at birth can induce trained immunity as well as heterologous Th1 responses. Our results showed that BCG/FI-RSV+Al(OH)3 induced trained macrophages, TRM, specific CTL, and balanced Th cell immune memory, which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. BCG at birth as an adjuvant to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants.

Phase retrieval based on deep learning with bandpass filtering in holographic data storage.

A phase retrieval method based on deep learning with bandpass filtering in holographic data storage is proposed. The relationship between the known encoded data pages and their near-field diffraction intensity patterns is established by an end-to-end convolutional neural network, which is used to predict the unknown phase data page. We found the training efficiency of phase retrieval by deep learning is mainly determined by the edge details of the adjacent phase codes, which are the high-frequency components of the phase code. Therefore, we can attenuate the low-frequency components to reduce material consumption. Besides, we also filter out the high-order frequency over twice Nyquist size, which is redundant information with poor anti-noise performance. Compared with full-frequency recording, the consumption of storage media is reduced by 2.94 times, thus improving the storage density.

Polysorbate 80 as a possible allergenic component in cross-allergy to docetaxel and fosaprepitant: A literature review.

OBJECTIVE: Patients had allergies to both fosaprepitant and docetaxel with similar signs and symptoms. To explore the possible causes of allergy and whether there is cross-allergy between fosaprepitant and docetaxel, we conducted a literature review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. METHODS: A systematic search of the following databases was performed: Pubmed, Embase, Cochrane Library, CINAHL, Scopus, Web of Science and Taylor & Francis. The final search was on 12 November 2022. Two investigators independently selected eligible studies and extracted data according to inclusion and exclusion criteria and assessed the methodological quality of included studies. Any disagreement was resolved by a third researcher. RESULTS: The main cause of fosaprepitant and docetaxel allergy is polysorbate 80. Fosaprepitant and docetaxel have similar allergic symptoms, mainly facial flushing (19.0%, 18.5%); erythema/dermatitis (17.2%, 1.9%); fluid retention (17.2%, 22.2%); and dyspnea, bronchospasm, shortness of breath and coughing (15.5%, 16.7%). Hypotension (1.7%, 7.4%) and decreased oxygen saturation (1.7%, 1.9%) are rare. The treatments for both allergies are similar: stop injection, oxygen, glucocorticoid, antihistamines and symptomatic treatments. CONCLUSION: Polysorbate 80 is the same allergenic component of docetaxel and fosaprepitant. The symptoms and treatments caused by the two drugs are similar. Most allergic reactions are not serious. Medications containing the same allergy ingredient need to be used with caution for patients with severe allergies to polysorbate 80.

Electrophysiological evidence of diabetes' impacts on central conduction recoveries in degenerative cervical myelopathy after surgery.

OBJECTIVES: To assess the impact of diabetes mellitus (DM) on the postoperative motor and somatosensory functional recoveries of degenerative cervical myelopathy (DCM) patients. METHODS: Motor and somatosensory evoked potentials (MEP and SSEPs) and modified Japanese Orthopedic Association (mJOA) scores were recorded in 27 diabetic (DCM-DM group) and 38 non-diabetic DCM patients (DCM group) before and 1 year after surgery. The central motor (CMCT) and somatosensory (CSCT) conduction time were recorded to evaluate the conductive functions of the spinal cord. RESULTS: The mJOA scores, CMCT and CSCT improved (t test, p < 0.05) in both of the DCM-DM and DCM groups 1 year after surgery. The mJOA recovery rate (RR) and CSCT recovery ratio were significantly worse (t test, p < 0.05) in the DCM-DM group compared to the DCM group. DM proved to be a significant independent risk factor for poor CSCT recovery (OR = 4.52, 95% CI 2.32-7.12) after adjusting for possible confounding factors. In DCM-DM group, CSCT recovery ratio was also correlated with preoperative HbA1 level (R = - 0.55, p = 0.003). Furthermore, DM duration longer than 10 years and insulin dependence were risk factors for lower mJOA, CMCT and CSCT recoveries among all DCM-DM patients (t test, p < 0.05). CONCLUSIONS: DM may directly hinders spinal cord conduction recovery in DCM patients after surgery. Corticospinal tract impairments are similar between DCM and DCM-DM patients, but significantly worsened in chronic or insulin-dependent DM patients. The dorsal column is more sensitively affected in all DCM-DM patients. Deeper investigation into the mechanisms and neural regeneration strategies is needed.

Few-Shot Fault Diagnosis Based on an Attention-Weighted Relation Network.

As energy conversion systems continue to grow in complexity, pneumatic control valves may exhibit unexpected anomalies or trigger system shutdowns, leading to a decrease in system reliability. Consequently, the analysis of time-domain signals and the utilization of artificial intelligence, including deep learning methods, have emerged as pivotal approaches for addressing these challenges. Although deep learning is widely used for pneumatic valve fault diagnosis, the success of most deep learning methods depends on a large amount of labeled training data, which is often difficult to obtain. To address this problem, a novel fault diagnosis method based on the attention-weighted relation network (AWRN) is proposed to achieve fault detection and classification with small sample data. In the proposed method, fault diagnosis is performed through the relation network in few-shot learning, and in order to enhance the representativeness of feature extraction, the attention-weighted mechanism is introduced into the relation network. Finally, in order to verify the effectiveness of the method, a DA valve fault dataset is constructed, and experimental validation is performed on this dataset and another benchmark PU rolling bearing fault dataset. The results show that the accuracy of the network on DA is 99.15%, and the average accuracy on PU is 98.37%. Compared with the state-of-the-art diagnosis methods, the proposed method achieves higher accuracy while significantly reducing the amount of training data.

Optimized Sieving Effect for Ethanol/Water Separation by Ultramicroporous MOFs.

High-purity ethanol is a promising renewable energy resource, however separating ethanol from trace amount of water is extremely challenging. Herein, two ultramicroporous MOFs (UTSA-280 and Co-squarate) were used as adsorbents. A prominent water adsorption and a negligible ethanol adsorption identify perfect sieving effect on both MOFs. Co-squarate exhibits a surprising water adsorption capacity at low pressure that surpassing the reported MOFs. Single crystal X-ray diffraction and theoretical calculations reveal that such prominent performance of Co-squarate derives from the optimized sieving effect through pore structure adjustment. Co-squarate with larger rhombohedral channel is suitable for zigzag water location, resulting in reinforced guest-guest and guest-framework interactions. Ultrapure ethanol (99.9 %) can be obtained directly by ethanol/water mixed vapor breaking through the columns packed with Co-squarate, contributing to a potential for fuel-grade ethanol purification.

Comparison of blood loss between tranexamic acid-soaked absorbable Gelfoam and topical retrograde injection via drainage catheter plus clamping in cervical laminoplasty surgery.

BACKGROUND: To compare the safety and efficacy of tranexamic acid (TXA)-soaked absorbable Gelfoam and the retrograde injection of TXA through a drain with drain-clamping in degenerative cervical laminoplasty patients. METHODS: Patients were assigned into either TXA retrograde injection (TXA-RI), TXA-soaked absorbable Gelfoam (TXA-Gel), or control groups. The demographics, operative measurements, volume and length of drainage, length of hospital stay, complete blood cell count, coagulopathy, postoperative complications, and blood transfusion were recorded. RESULTS: We enrolled 133 patients, with 44, 44, and 45 in the TXA-RI, TXA-Gel, and control groups, respectively. The baseline characteristics did not differ significantly among the three groups. The TXA-RI group exhibited a lower volume and length of postoperative drainage compared to the TXA-Gel and control groups (126.60 ± 31.27 vs. 156.60 ± 38.63 and 275.45 ± 75.27 mL; 49.45 ± 9.70 vs 58.70 ± 10.46 and 89.31 ± 8.50 hours, all P < 0.01). The TXA-RI group also had significantly shorter hospital stays compared to the control group (5.31 ± 1.18 vs 7.50 ± 1.25 days, P < 0.05) and higher hemoglobin and hematocrit levels (12.58 ± 1.67 vs 11.28 ± 1.76 g/dL; 36.62 ± 3.66% vs 33.82 ± 3.57%, both P < 0.05) at hospital discharge. In the TXA-RI and TXA-Gel groups, the D-dimmer (DD) and fibrinogen (FIB) were significantly lower than those in the control group after surgery (P < 0.05). None of the patients required blood transfusion. No complications, including thromboembolic events, were reported. CONCLUSION: Topical retrograde injection of TXA through a drain with drain-clamping at the conclusion of unilateral posterior cervical expansive open-door laminoplasty may effectively reduce postoperative blood loss and the length of hospital stays without increasing postoperative complications.

Comparison of Bazaz scale, Dysphagia Short Questionnaire, and Hospital for Special Surgery-Dysphagia and Dysphonia Inventory for Assessing Dysphagia Symptoms After Anterior Cervical Spine Surgery in Chinese Population.

Dysphagia is one of the most common complaints after anterior cervical spine surgery. The Bazaz scale, the Dysphagia Short Questionnaire (DSQ), and the Hospital for Special Surgery-Dysphagia and Dysphonia Inventory (HSS-DDI) were patient-reported outcome measures assessing the patients' perceptions of their swallowing functions after surgery. This prospective diagnostic test study aimed to compare these surveys' psychometric properties in the Chinese population. We evaluated 150 consecutive patients after anterior cervical spine surgery with the Bazaz scale, DSQ, HSS-DDI, and M.D. Anderson Dysphagia Inventory (MDADI). The reliability and validity of the Bazaz scale, DSQ, and HSS-DDI were compared. Receiver operating characteristic (ROC) curves of the DSQ, Bazaz scale, and HSS-DDI were constructed using the MDADI as a reference criterion. Their areas under the curve (AUCs) were further analyzed. In total, 132 participants completed all of the surveys. The results showed that all surveys were significantly correlated with each other. The HSS-DDI and HSS-Dysphagia subscale showed near-perfect reliability (Cronbach α = 0.969 and 0.957, respectively). ROC curves showed both HSS-DDI and HSS-Dysphagia subscale had greater accuracy (AUCs > 0.9) in detecting mild dysphagia and moderate/severe dysphagia. The HSS-Dysphagia subscale achieved higher accuracy in assessing the dysphagia symptoms after anterior cervical spine surgery. The Bazaz scale was considered less accurate than other scales. Our results provided guidance for selecting the appropriate measuring tool during clinical and research practices.

An Approach for Time Synchronization of Wireless Accelerometer Sensors Using Frequency-Squeezing-Based Operational Modal Analysis.

Wireless sensor networks usually suffer from the issue of time synchronization discrepancy due to environmental effects or clock management collapse. This will result in time delays between the dynamic responses collected by wireless sensors. If non-synchronized dynamic response data are directly used for structural modal identification, it leads to the misestimation of modal parameters. To overcome the non-synchronization issue, this study proposes a time synchronization approach to detect and correct asynchronous dynamic responses based on frequency domain decomposition (FDD) with frequency-squeezing processing (FSP). By imposing the expected relationship between modal phase angles extracted from the first-order singular value spectrum, the time lags between different sensors can be estimated, and synchronization can be achieved. The effectiveness of the proposed approach is fully demonstrated by numerical and experimental studies, as well as field measurement of a large-span spatial structure. The results verify that the proposed approach is effective for the time synchronization of wireless accelerometer sensors.

Acyltransferase AniI, a Tailoring Enzyme with Broad Substrate Tolerance for High-Level Production of Anisomycin.

Anisomycin (compound 1), a pyrrolidine antibiotic, exhibits diverse biological and pharmacologic activities. The biosynthetic gene cluster of compound 1 has been identified previously, and the multistep assembly of the core benzylpyrrolidine scaffold was characterized. However, enzymatic modifications, such as acylation, involved in compound 1 biosynthesis are unknown. In this study, the genetic manipulation of aniI proved that it encoded an indispensable acetyltransferase for compound 1 biosynthesis. Bioinformatics analysis suggested AniI as a member of maltose (MAT) and galactoside O-acetyltransferases (GAT) with C-terminal left-handed parallel beta-helix (LbH) subdomain, which were referred to as LbH-MAT-GAT sugar O-acetyltransferases. However, the biochemical assay identified that its target site was the hydroxyl group of the pyrrolidine ring. AniI was found to be tolerant of acyl donors with different chain lengths for the biosynthesis of compound 1 and derivatives 12 and 13 with butyryl and isovaleryl groups, respectively. Meanwhile, it showed comparable activity toward biosynthetic intermediates and synthesized analogues, suggesting promiscuity to the pyrrolidine ring structure of compound 1. These data may inspire new viable synthetic routes for the construction of more complex pyrrolidine ring scaffolds in compound 1. Finally, the overexpression of aniI under the control of strong promoters contributed to the higher productivities of compound 1 and its analogues. These findings reported here not only improve the understanding of anisomycin biosynthesis but also expand the substrate scope of O-acetyltransferase working on the pyrrolidine ring and pave the way for future metabolic engineering construction of high-yield strains. IMPORTANCE Acylation is an important tailoring reaction during natural product biosynthesis. Acylation could increase the structural diversity and affect the chemical stability, volatility, biological activity, and even the cellular localization of specialized compounds. Many acetyltransferases have been reported in natural product biosynthesis. The typical example of the LbH-MAT-GAT sugar O-acetyltransferase subfamily was reported to catalyze the coenzyme A (CoA)-dependent acetylation of the 6-hydroxyl group of sugars. However, no protein of this family has been characterized to acetylate a nonsugar secondary metabolic product. Here, AniI was found to catalyze the acylation of the hydroxyl group of the pyrrolidine ring and be tolerant of diverse acyl donors and acceptors, which made the biosynthesis more efficient and exclusive for biosynthesis of compound 1 and its derivatives. Moreover, the overexpression of aniI serves as a successful example of genetic manipulation of a modification gene for the high production of final products and might set the stage for future metabolic engineering.

Increased lateral femoral condyle ratio is associated with greater risk of ALC injury in non-contact anterior cruciate ligament injury.

PURPOSE: To examine whether increased lateral femoral condyle ratio (LFCR) correlates with increased risk of Anterior cruciate ligament (ACL) injury (1) and to evaluate the relationship between the LFCR and anterolateral complex (ALC) injury in non-contact ACL torn knees (2). METHODS: Six hundred and seventy-two patients who underwent ACL reconstruction surgery between 2013 and 2019 were retrospectively reviewed, and 120 patients were finally included in the study. Forty patients (ACL + ALC injury) were included in the study group, while forty patients with isolated ACL injury (isolated ACL injury group) and 40 patients who suffered from meniscal tear without ACL or ALC injury were matched in a 1:1 fashion by age, sex, and BMI to the study group (ACL + ALC injury). The LFCR was measured on standard lateral radiographs in a blinded fashion. The differences between the three groups were analyzed by ANOVA. A ROC (Receiver Operating Characteristic) curve was produced to determine risk of ACL injury and risk of concomitant ALC injury in non-contact ACL injury. RESULTS: The mean LFCR was 71.9% ± 3.1% in the ACL + ALC injury group, 68.4% ± 3.2% in the isolated ACL injury group, and 66.8% ± 2.6% in the control group (patients who suffered from meniscal tear without ACL or ALC injury). Significantly greater LFCR was found in the ACL + ALC injury group than that in the isolated ACL injury group (p < 0.017). Greater LFCR was additionally confirmed in the ACL injury group as compared to the control group (p < 0.05). ROC curve analysis demonstrated that LFCR > 68.3% was predictive for an increased risk of ACL injury in the entire cohort. LFCR > 69.4% was predictive for an increased risk of ALC injury in non-contact ACL ruptured patients. CONCLUSION: Increased LFCR was found to be associated with greater risk of ALC injury in non-contact ACL ruptured patients. Additionally, increased LFCR was further confirmed to be correlated with increased risk of ACL injury in an Asian population. The data from this study may help recognize patients undergoing ACL reconstruction that could benefit from additional extra-articular tenodesis. LEVEL OF EVIDENCE: III.

Healing pattern classification for thoracolumbar burst fractures after posterior short-segment fixation.

BACKGROUND: Thoracolumbar burst fractures can be treated with posterior short-segment fixation. However, no classification can help to estimate whether the healed vertebral body will have sufficient stability after implant removal. We aimed to develop a Healing Pattern Classification (HPC) to evaluate the stability of the healed vertebra based on cavity size and location. METHODS: Fifty-two thoracolumbar burst fracture patients treated with posterior short-segmental fixation without fusion and followed up for an average of 3.2 years were retrospectively studied. The HPC was divided into 4 types: type I - no cavity; type II - a small cavity with or without the violation of one endplate; type III - a large cavity with or without the violation of one endplate; and type IV - a burst cavity with the violation of both endplates or the lateral cortical shell. The intraobserver and interobserver intraclass correlation coefficients (ICCs) of the HPC were assessed. The demographic characteristics and clinical outcomes of the cohort were compared between the stable group (types I and II) and the unstable group (types III and IV). Logistic regression was conducted to evaluate risk factors for unstable healing. RESULTS: The intraobserver and interobserver ICCs of the HPC were 0.86 (95% CI = 0.74-0.90) and 0.77 (95% CI = 0.59-0.86), respectively. While the unstable healing group (types III and IV) accounted for 59.6% of the patients, most of these patients were asymptomatic. The preoperative Load Sharing Classification (LSC) comminution score may predict the occurrence of unstable healing (OR = 8.4, 95% CI = 2.4-29.7). CONCLUSIONS: A reliable classification for assessing the stability of a healed vertebra was developed. With type I and II healing, the vertebra is considered stable, and the implant can be removed. With type III healing, the vertebra may have healing potential, but the implant should not be removed unless type II healing is achieved. With type IV healing, the vertebra is considered extremely unstable, and instrumentation should be maintained. Assessing the LSC comminution score preoperatively may help to predict unstable healing after surgery.

Biosynthesis of the pyrrolidine protein synthesis inhibitor anisomycin involves novel gene ensemble and cryptic biosynthetic steps.

The protein synthesis inhibitor anisomycin features a unique benzylpyrrolidine system and exhibits diverse biological and pharmacologic activities. Its biosynthetic origin has remained obscure for more than 60 y, however. Here we report the identification of the biosynthetic gene cluster (BGC) of anisomycin in Streptomyces hygrospinosus var. beijingensis by a bioactivity-guided high-throughput screening method. Using a combination of bioinformatic analysis, reverse genetics, chemical analysis, and in vitro biochemical assays, we have identified a core four-gene ensemble responsible for the synthesis of the pyrrolidine system in anisomycin: aniQ, encoding a aminotransferase that catalyzes an initial deamination and a later reamination steps; aniP, encoding a transketolase implicated to bring together an glycolysis intermediate with 4-hydroxyphenylpyruvic acid to form the anisomycin molecular backbone; aniO, encoding a glycosyltransferase that catalyzes a cryptic glycosylation crucial for downstream enzyme processing; and aniN, encoding a bifunctional dehydrogenase that mediates multistep pyrrolidine formation. The results reveal a BGC for pyrrolidine alkaloid biosynthesis that is distinct from known bacterial alkaloid pathways, and provide the signature sequences that will facilitate the discovery of BGCs encoding novel pyrrolidine alkaloids in bacterial genomes. The biosynthetic insights from this study further set the foundation for biosynthetic engineering of pyrrolidine antibiotics.

Increased lateral meniscal slope is associated with greater incidence of lateral bone contusions in noncontact ACL injury.

PURPOSE: (1) To investigate whether an increased lateral meniscal slope measured on magnetic resonance image (MRI) would be associated with greater risk of bone contusions in noncontact anterior cruciate ligament injury, and (2) to measure the relationship between the occurrence of bone contusions and associated findings observed in ACL deficient knees such as cartilage damage, anterolateral complex injury and concomitant meniscal tears. METHOD: Patients who underwent ACL reconstruction surgery between 2013 and 2018 were retrospectively reviewed. Sixty-three patients were included in the study group (ACL + bone contusions group), 56 participants were in the control group (isolated ACL group). The presence and severity of bone contusions were determined from preoperative MRIs. The lateral meniscal slope and lateral posterior tibial slope were measured on the MRIs in a blinded fashion. The predictors of lateral bone contusions including age, sex, body mass index, lateral meniscal slope and lateral posterior tibial slope were examined by multivariable logistic regression. Associated findings including concomitant meniscal lesions, intra-articular cartilage damage and anterolateral complex injury, which were also calculated by multivariable logistic regression. RESULTS: The mean lateral meniscal slope in the study group was 6.5° ± 3.5°, which was significantly larger than that in the control group (3.8° ± 2.7°; P < 0.01). In addition, increased lateral meniscal slope was significantly associated with lateral bone contusions in noncontact ACL injury (Lateral femoral condyle (LFC): AOR 16.5; 95% CI 5.40-50.20; P < 0.01; Lateral tibial plateau (LTP): AOR 31.8; 95% CI 8.68-116.7; P < 0.01). However, lateral posterior tibial slope was not significantly associated with bone contusions. Moreover, the presence of lateral bone contusions was associated with concomitant lateral meniscal tears (OR 12.4; 95% CI 3.30-46.30) and cartilage damage (OR 2.9; 95% CI 1.04-8.18). CONCLUSION: An increased lateral meniscal slope was associated with increased risk of lateral bone contusions in noncontact ACL injury. In addition, the presence of lateral bone contusions was associated with intra-articular cartilage damage, anterolateral complex injury and concomitant meniscal tears. Hence, additional information was provided for counseling patients who have increased LMS on the greater risk of knee rotational instability and identify patients undergoing ACL reconstruction who may benefit from extra-articular tenodesis. LEVEL OF EVIDENCE: IV.

CtcS, a MarR family regulator, regulates chlortetracycline biosynthesis.

BACKGROUND: Chlortetracycline (CTC) is one of the commercially important tetracyclines (TCs) family product and is mainly produced by Streptomyces. CTC is still in a great demand due to its broad-spectrum activity against pathogens. Engineering transcriptional control allows the cell to allocate its valuable resources towards protein production and provides an important method for the build-up of desired metabolites. Despite extensive efforts concerning transcriptional regulation for increasing the productivities of TCs, the regulatory mechanisms of the CTC biosynthesis remain poorly understood. RESULTS: In this study, the possible regulatory function of CtcS, a potential member of MarR (multiple antibiotic resistance regulator) family of transcriptional regulators in S. aureofaciens F3, was demonstrated. Knockdown of ctcS altered the transcription of several biosynthesis-related genes and reduced the production of tetracycline (TC) and CTC, without obvious effect on morphological differentiation and cell growth. Especially, CtcS directly repressed the transcription of the adjacent divergent gene ctcR (which encodes a putative TC resistance efflux protein). A CtcS-binding site was identified within the promoter region of ctcR by DNase I footprinting and an inverted repeat (5'-CTTGTC-3') composed of two 6-nt half sites in the protected region was found. Moreover, both CTC and TC could attenuate the binding activity of CtcS with target DNA. CONCLUSION: ctcS regulated the production of TC and CTC in S. aureofaciens F3 and the overexpression of it could be used as a simple approach for the construction of engineering strain with higher productivity. Meanwhile, CtcS was characterized as a TC- and CTC-responsive MarR family regulator. This study provides a previously unrecognized function of CtcS and will benefit the research on the regulatory machinery of the MarR family regulators.

Acute sporadic hepatitis E in the Zhejiang coastal area of China: a 14-year hospital-based surveillance study.

BACKGROUND: To examine the epidemiological trends and changes of hepatitis E virus (HEV) infection and the potential risk factors for severe infection in the Zhejiang eastern coastal area of China. METHODS: We analyzed statutory hepatitis E cases notifications and inpatient data held by the national surveillance and hospital information systems in Wenzhou, Taizhou, Ningbo, and Zhoushan cities of the Zhejiang eastern coastal area of China. RESULTS: Nine thousand four hundred sixteen hepatitis E cases were reported from 2004 to 2017, with an average incidence of 2.94 per 100,000. The overall death rate was 0.06% (6/9416). A gradual decline of hepatitis E cases was found in the coastal areas since 2007, while a rise was identified in the non-coastal areas. Annual incidence in non-coastal cities was much higher than that in coastal cities (4.345 vs. 2.945 per 100,000, relative risk = 1.5, P value < 0.001). The mean age was 52 years old and 50.55 years with a male-to-female ratio of 2.32:1 and 2.21:1 in coastal and noncoastal areas respectively (all P > 0.05). Hepatitis E cases prevalence increased with age, highest among men in their 70s (9.02 vs. 11.33 per 100,000) and women in their 60s (3.94 vs. 4.66 per 100,000) groups for both coastal and noncoastal areas respectively. A clear seasonal pattern was observed, with a peak in March (0.4429 per 100,000) in coastal areas. 202 inpatients were documented, of which 50.50% (102/202) were severe cases. Male individuals with alcohol consumption, alcohol hepatic diseases, and superinfection were the three independent highest risks for severe infections (all with P value < 0.05). CONCLUSIONS: This is to our knowledge the largest epidemiological study of hepatitis E cases in the eastern coastal area of Zhejiang province of China. The patterns of infection across the coastal areas were similar to those of the non-coastal areas, but the incidence was substantially lower and decreased gradually since 2007.

Prognostic utility of novel biomarkers in acute-on-chronic liver failure (ACLF) associated with hepatitis B: A multicenter prospective study.

AIM: Flare-ups of chronic hepatitis B can sometimes be severe and even progress to acute-on-chronic liver failure (ACLF), with high short-term mortality. A timely estimation of the risk of death should be initiated early. The aim of the present study was to determine whether novel biomarkers add prognostic information beyond current clinical scoring systems. METHODS: Patients with hepatitis B-associated ACLF were prospectively enrolled from five hospitals in China between August 2017 and March 2018. Their plasma was screened for soluble CD163 (sCD163), neutrophil gelatinase-associated lipocalin (NGAL), and copeptin. The association between these biomarkers and mortality was analyzed. The performance of the Model for End-stage Liver Disease, Asian-Pacific Association for the Study of the Liver-ACLF Research Consortium score, and the Chronic Liver Failure Consortium ACLF score, with or without biomarkers, were compared. RESULTS: One hundred fifty one patients were enrolled. Advanced ACLF patients had significantly higher levels than early ACLF individuals of plasma biomarkers sCD163 (P = 0.001), NGAL (P = 0.006), and copeptin (P = 0.049). Thirty-four deaths occurred during the 28-day follow-up period (22.5%). Both sCD163 and NGAL showed a strong independent association with 28-day mortality, whereas copeptin did not. Scoring systems incorporating sCD163 and NGAL had better discrimination and calibration, as measured by area under the receiver operating characteristic curves, the Akaike information criteria, integrated discrimination improvement, and net reclassification improvement. CONCLUSIONS: Soluble CD163 and NGAL are independently associated with short-term mortality in hepatitis B-associated ACLF. Use of a combination of sCD163 and NGAL improves prognostication.

Downregulation of long noncoding RNA Sox2ot protects PC-12 cells from hydrogen peroxide-induced injury in spinal cord injury via regulating the miR-211-myeloid cell leukemia-1 isoform2 axis.

This study aimed to investigate the effects and possible mechanisms of long noncoding RNA (lncRNA) Sox2 overlapping transcript (Sox2ot) on hydrogen peroxide (H2 O2 )-induced injury in pheochromocytoma (PC-12) cells. PC-12 cells were treated with H2 O2 to cell injury. The cells were transfected with short-hairpin RNA directed against Sox2ot (sh-Sox2ot), small interfering RNA directed against myeloid cell leukemia-1 (MCL-1) isoform2 (si-MCL-1), a miR-211 mimic, a miR-211 inhibitor, and their negative controls. Under different transfected treatments, cell viability, migration, invasion, and apoptosis as well as the expressions of apoptosis- and autophagy-related proteins were investigated. Besides, the regulatory relationships between Sox2ot and miR-211, miR-211 and MCL-1, as well as between MCL-1 and the protein kinase B (Akt)/mammalian target of the rapamycin (mTOR)/p70 ribosomal S6 protein kinase (p70S6K) signaling pathway were explored. Suppression of Sox2ot inhibited H2 O2 -induced PC-12 cell injury by increasing cell viability, migration, invasion, and decreasing apoptosis and autophagy. Moreover, suppression of Sox2ot increased miR-211 expression and alleviated H2 O2 -induced injury in PC-12 cells possibly via upregulation of miR-211. Furthermore, MCL-1 isoform2 was identified as a direct target of miR-211 and could be negatively regulated by miR-211. Suppression of miR-211 aggravated H2 O2 -induced cell injury by regulation of MCL-1 isoform2. Besides, inhibition of miR-211 suppressed the activation of the Akt/mTOR/p70S6K signaling pathway in H2 O2 -treated PC-12 cells, which was reversed after knockdown of MCL-1 isoform2 at the same time. Our findings indicate that downregulation of Sox2ot may protect PC-12 cells from H2 O2 -induced injury in SCI via targeting the miR-211/MCL-1 isoform2 axis. MCL-1 isoform2 may further regulate the activation of the Akt/mTOR/p70S6K pathway to mediate H2 O2 -induced injury. The Sox2ot-miR-211-MCL-1 isoform2 axis may be a promising therapeutic strategy for SCI.

Physiological functions of ferroportin in the regulation of renal iron recycling and ischemic acute kidney injury.

Renal iron recycling preserves filtered iron from urinary excretion. However, it remains debated whether ferroportin (FPN), the only known iron exporter, is functionally involved in renal iron recycling and whether renal iron recycling is required for systemic iron homeostasis. We deleted FPN in whole nephrons by use of a Nestin-Cre and in the distal nephrons and collecting ducts, using a Ksp-Cre, and investigated its impacts on renal iron recycling and systemic iron homeostasis. FPN deletion by Nestin-Cre, but not by Ksp-Cre, caused excess iron retention and increased ferritin heavy chain (FTH1) specifically in the proximal tubules and resulted in the reduction of serum and hepatic iron. The systemic iron redistribution was aggravated, resulting in anemia and the marked downregulation of hepatic hepcidin in elderly FPN knockout (KO)/Nestin-Cre mice. Similarly, in iron-deficient FPN KO/Nestin-Cre mice, the renal iron retention worsened anemia with the activation of the erythropoietin-erythroferrone-hepcidin pathway and the downregulation of hepatic hepcidin. Hence, FPN likely located at the basolateral membrane of the proximal tubules to export iron into the circulation and was required for renal iron recycling and systemic iron homeostasis particularly in elderly and iron-deficient mice. Moreover, FPN deletion in the proximal tubules alleviated ischemic acute kidney injury, possibly by upregulating FTH1 to limit catalytic iron and by priming antioxidant mechanisms, indicating that FPN could be deleterious in the pathophysiology of ischemic acute kidney injury (AKI) and thus may be a potential target for the prevention and mitigation of ischemic AKI.

Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury.

Histone deacetylase 6 (HDAC6) has been shown to be involved in various pathological conditions, including cancer, neurodegenerative disorders and inflammatory diseases. Nonetheless, its specific role in drug-induced nephrotoxicity is poorly understood. Cisplatin (dichlorodiamino platinum) belongs to an inorganic platinum - fundamental chemotherapeutic drug utilized in the therapy of various solid malignant tumors. However, the use of cisplatin is extremely limited by obvious side effects, for instance bone marrow suppression and nephrotoxicity. In the present study, we utilized a murine model of cisplatin-induced acute kidney injury (AKI) and a highly selective inhibitor of HDAC6, tubastatin A (TA), to assess the role of HDAC6 in nephrotoxicity and its associated mechanisms. Cisplatin-induced AKI was accompanied by increased expression and activation of HDAC6; blocking HDAC6 with TA lessened renal dysfunction, attenuated renal pathological changes, reduced expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule 1, and decreased tubular cell apoptosis. In cultured human epithelial cells, TA or HDAC6 siRNA treatment also inhibited cisplatin-induced apoptosis. Mechanistic studies demonstrated that cisplatin treatment induced phosphorylation of AKT and loss of E-cadherin in the nephrotoxic kidney, and administration of TA enhanced AKT phosphorylation and preserved E-cadherin expression. HDAC6 inhibition also potentiated autophagy as evidenced by increased expression of autophagy-related gene (Atg) 7 (Atg7), Beclin-1, and decreased renal oxidative stress as demonstrated by up-regulation of superoxide dismutase (SOD) activity and down-regulation of malondialdehyde levels. Moreover, TA was effective in inhibiting nuclear factor-κ B (NF-κB) phosphorylation and suppressing the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Collectively, these data provide strong evidence that HDAC6 inhibition is protective against cisplatin-induced AKI and suggest that HDAC6 may be a potential therapeutic target for AKI treatment.