[Therapeutic effect of intravenous thrombolysis with tenecteplase on patients with post awakening branch atheromatous disease].

Objective: To investigate the efficacy and safety of intravenous thrombolysis with Tenecteplase (TNK) in patients with post-awakening branch atheromatous disease (BAD). Methods: A retrospective collection was conducted on 178 patients with post-awakening BAD admitted to the Stroke Centre of Zhengzhou People's Hospital from January 2017 to June 2023, who had a mismatch in DWI/FLAIR on magnetic resonance imaging. The patients were divided into thrombolysis group (60 patients) and control group (118 patients) according to whether or not they were applied to intravenous thrombolysis by TNK. Propensity score matching (PSM) was used to pair and balance the confounding factors at 1∶1 between the two groups, and the 90-d long-term prognosis of the patients was assessed using the modified Rankin Scale (mRS) and the Barthel Index (BI). The National Institutes of Health Stroke Scale (NIHSS) score was used to compare the early neurological changes between the two groups.The differences in clinical outcomes were compared between the two groups. Results: Fifty-two pairs of patients, 65 males and 39 females, aged (60±9) years, were successfully matched by PSM. The thrombolysis group had lower NIHSS score than that of the control group at 24 h, 7 d, 14 d after treatment or at discharge [3(2, 5) vs 4(3, 7), 3(2, 5) vs 4(3, 5), and 2(1, 4) vs 3(2, 4)], and shorter hospital stay than that of the control group [9(7, 12) d vs 11(9, 13) d], and at the same time, the thrombolysis group was less likely to experience early neurological deterioration (END) [9.6% (5/52) vs 28.9% (15/52)], and the proportion of 90 d mRS≤1, mRS≤2, and BI scores were higher than those in the control group [63.5% (33/52) vs 30.8% (16/52), 82.7% (43/52) vs 59.6% (31/52), and (91±8) points vs (82±8) points ], all differences were statistically significant (P<0.05). The percentage of mRS≥4 points was higher in the control group than that in the thrombolysis group [23.1% (12/52) vs 7.7% (4/52)]. One case of intracranial haemorrhage occurred in the thrombolysis group, and 1 case in the control group died of pulmonary infection within 90 d of follow-up, with a case-fatality rate of 1.9% (1/52). Conclusion: In the patients with post-awakening BAD screened by MRI, TNK intravenous thrombolysis can significantly reduce the risk of END, improving long-term prognosis and has a high safety.

YAP activation inhibits inflammatory signalling and cartilage breakdown associated with reduced primary cilia expression.

OBJECTIVE: To clarify the role of YAP in modulating cartilage inflammation and degradation and the involvement of primary cilia and associated intraflagellar transport (IFT). METHODS: Isolated primary chondrocytes were cultured on substrates of different stiffness (6-1000 kPa) or treated with YAP agonist lysophosphatidic acid (LPA) or YAP antagonist verteporfin (VP), or genetically modified by YAP siRNA, all ± IL1ß. Nitric oxide (NO) and prostaglandin E2 (PGE2) release were measured to monitor IL1ß response. YAP activity was quantified by YAP nuclear/cytoplasmic ratio and percentage of YAP-positive cells. Mechanical properties of cartilage explants were tested to confirm cartilage degradation. The involvement of primary cilia and IFT was analysed using IFT88 siRNA and ORPK cells with hypomorphic mutation of IFT88. RESULTS: Treatment with LPA, or increasing polydimethylsiloxane (PDMS) substrate stiffness, activated YAP nuclear expression and inhibited IL1ß-induced release of NO and PGE2, in isolated chondrocytes. Treatment with LPA also inhibited IL1ß-mediated inflammatory signalling in cartilage explants and prevented matrix degradation and the loss of cartilage biomechanics. YAP activation reduced expression of primary cilia, knockdown of YAP in the absence of functional cilia/IFT failed to induce an inflammatory response. CONCLUSIONS: We demonstrate that both pharmaceutical and mechanical activation of YAP blocks pro-inflammatory signalling induced by IL1ß and prevents cartilage breakdown and the loss of biomechanical functionality. This is associated with reduced expression of primary cilia revealing a potential anti-inflammatory mechanism with novel therapeutic targets for treatment of osteoarthritis (OA).

Prediction of knee pain improvement over two years for knee osteoarthritis using a dynamic nomogram based on MRI-derived radiomics: a proof-of-concept study.

OBJECTIVES: To develop and validate a nomogram to detect improved knee pain in osteoarthritis (OA) by integrating magnetic resonance imaging (MRI) radiomics signature of subchondral bone and clinical characteristics. METHODS: Participants were selected from the Vitamin D Effects on Osteoarthritis (VIDEO) study. The primary outcome was 20% improvement of knee pain score over 2 years in participants administrated either vitamin D or placebo. Radiomics features of subchondral bone and clinical characteristics from 216 participants were extracted and analyzed. The participants were randomly split into the training and validation cohorts at a ratio of 8:2. Least absolute shrinkage and selection operator (LASSO) regression was used to select features and generate radiomics signatures. The optimal radiomics signature and clinical indicators were fitted into a nomogram using multivariable logistic regression model. RESULTS: The nomogram showed favorable discrimination performance [AUCtraining, 0.79 (95% CI: 0.72-0.79), AUCvalidation, 0.83 (95% CI: 0.70-0.96)] as well as a good calibration. Additional contributing value of fusion radiomics signature to the nomogram was statistically significant (NRI, 0.23; IDI, 0.14, P < 0.001 in training cohort and NRI, 0.29; IDI, 0.18, P < 0.05 in validating cohort). Decision curve analysis confirmed the clinical usefulness of nomogram. CONCLUSION: The radiomics-based nomogram comprising the MR radiomics signature and clinical variables achieves a favorable predictive efficacy and accuracy in differentiating improvement in knee pain among OA patients. This proof-of-concept study provides a promising way to predict clinically meaningful outcomes.

Erratum: Measurement of the 2νßß Decay Half-Life of

This corrects the article DOI: 10.1103/PhysRevLett.126.171801.

[Efficacy of intravenous thrombolysis with tenecteplase in treating the branch atheromatous disease].

Objective: To explore the efficacy of intravenous thrombolysis with tenecteplase (TNK) in the treatment of branch atheromatous disease (BAD). Methods: A total of 148 BAD patients hospitalized in the stroke center of Zhengzhou People's Hospital from January 2020 to March 2023 were retrospectively included. According to whether TNK was used for treatment, the patients were divided into the TNK group (52 cases) and the control group (96 cases). The propensity score matching (PSM) method was used to eliminate baseline differences between the two groups, and 46 pairs were successfully matched. Early neurological deterioration (END) was defined as an increase in the national Institutes of Health Stroke Scale (NIHSS) scores within 7 days of stroke≥2. The 90-day modified Rankin Scale (mRS) was used to compare the long-term efficacy between the two groups. A binary logistic regression model was used to analyze the influencing factors of clinical outcomes in patients with BAD. Results: Among the 92 patients, 62 were males and 30 were females, with an average age of (61.0±9.5) years. After PSM, there were statistically significant differences in NIHSS score at discharge [2 (0, 4) vs 4 (3, 8)] and length of hospital stay [9 (6, 13) d vs 11 (9, 14) d] (both P<0.05) between the two groups. The proportion of mRS 0-2 in TNK group was higher than that in the control group [82.6%(38/46) vs 60.8%(28/46)], while the proportion of END and mRS≥4 was lower than that in the control group [10.8%(5/46) vs 30.4%(14/46); 8.7%(4/46) vs 26.0%(12/46)], with statistically significant differences (P<0.05). The 90-day mortality in the control group was 2.2% (1/46), while no death was detected in the TNK group. Conclusion: Intravenous thrombolysis therapy with TNK can not only increase the proportion of 90-day mRS 0-2 in BAD patients, but also reduce the incidence of END.

[Effect of PCSK9 inhibitors on early neurological deterioration in patients with branch atheromatous disease].

Objective: To investigate the effect of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors on the incidence of early neurological deterioration during the treatment of branch atheromatous disease (BAD). Methods: A retrospective analysis of 297 BAD patients admitted to the Department of Neurology in Zhengzhou People's Hospital from January 2020 to April 2023 was made. According to whether to use PCSK9 inhibitor treatment, they were divided into PCSK9 inhibitor group (81 cases) and control group (216 cases). Propensity score matching (PSM) method was used to eliminate the general situation difference between PCSK9 inhibitor group and control group. Seventy-two cases were successfully matched in each group. The early neurological deterioration (END) and low-density lipoprotein cholesterol (LDL-C) were compared. END was defined as the National Institutes of Health Stroke Scale (NIHSS) score increase≥2 points within 72 hours after stroke. Suspicious influencing factors leading to END were screened for multivariate logistic regression model analysis. Results: After PSM matching, among the 144 patients, 90 were male and 54 were female, aged (61.2±9.6) years. After matching, The hospital stay[M(Q1, Q3)] [9(7, 11)d vs 10(8, 13)d] in PCSK9 and NIHSS score at discharge [2(1, 3) vs 3(1, 4) points] were significantly different from those in the control group (all P<0.05). In addition, the incidence of END was reduced in the PCSK9 inhibitor group [12.5%(9/72) vs 31.9%(23/72),P<0.05]. Multivariate logistic regression analysis found that C-reactive protein (CRP)(OR=1.119,95%CI: 1.010-1.240, P<0.05) and PCSK9 inhibitor (OR=0.298, 95%CI: 0.117-0.755, P<0.05) were factors associated with the development of END. Conclusion: The use of PCSK9 inhibitors in the treatment of patients with BAD can reduce the incidence of END.

[A medium- and long-term comparative observation on volumetric changes of cervical disc herniation after symmetrically or asymmetrically decompression and conservative treatment for cervical spondylotic myelopathy].

Objective: To compare the volumetric changes of cervical disc herniation (CDH) after cervical microendoscopic laminoplasty(CMEL),expansive open-door laminoplasty (EOLP) and conservative treatment. Methods: A retrospective study was conducted involving 101 patients with cervical spondylotic myelopathy(CSM),at the Department of Orthopaedic Surgery,the First Affiliated Hospital of Zhengzhou University from April 2012 to April 2021. The patients included 52 males and 49 females with an age of (54.7±11.8) years(range:25 to 86 years). Among them, 35 patients accepted CMEL treatment,33 patients accepted EOLP treatment,while 33 patients accepted conservative treatment. Volume data of CDH were measured by three-dimensional analysis of the initial and follow-up MRI images. The absorption rate and reprotrusion rate of CDH were calculated. The happening of resorption or reprotrusion was defined when the ratio was greater than 5%. The clinical outcomes and quality of life were evaluated by the Japanese Orthopaedic Association (JOA) score and the neck disability index (NDI).Quantitative data was analyzed by one-way ANOVA with post LSD-t test (multiple comparison) or Kruskal-Wallis test. Categorical data was analyzed by χ2 test. Results: The follow-up time of the CMEL group,EOLP group and the conservative treatment group were (27.6±18.8)months,(21.6±6.9)months and(24.9±16.3)months respectively with no significant difference(P>0.05). Changes of CDH volume in patients:(1) There were 96 CDH of 35 patients in the CMEL group,among which 78 showed absorption. The absorption frequency was 81.3%(78/96) and the absorption rate was ranged 5.9% to 90.9%;9 CDH showed reprotrusion,the reprotrusion frequency was 9.4% (9/96) and the reprotrusion rate was 5.9% to 13.3%;(2) There were 94 CDH of 33 patients in the EOLP group,of which 45 showed absorption. The absorption prevalence was 47.9% (45/94) and the absorption rate was 5.0% to 26.7%;20 CDH showed reprotruded,with the reprotrusion frequency of 21.3% (20/94) and the reprotrusion rate was 5.8% to 28.3%;(3) There were 102 CDH in 33 patients of the conservative group. Among them, 5 showed absorption. The absorption frequency was 4.9% (5/102),and the absorption rate was 7.2% to 14.3%;58 CDH showed reprotruded with the re-protrusion ratio of 56.9% (58/102) and the re-protrusion rate was 5.4% to 174.1%. The absorption ratio and reprotrusion ratio of the CMEL group were statistically different from EOLP group or the conservative group (P<0.01).The absorption ratio and reprotrusion ratio of the EOLP group was different from conservative group (all P<0.01). In terms of clinical outcomes, the excellent/good rate of the JOA score and NDI scores in the CMEL group were different from that of conservative group (all P<0.01) but not from that of the EOLP group(P>0.05). Conclusions: CMEL is an effective method for the treatment of CSM,making CDH easier to resorption compared to the EOLP or conservative treatment,thus making a better decompression effect on the nerves. This study enlightened on a new strategy for the clinical treatment of CSM.

[Research on the protective effect of hearing protective device for workers exposed to noise in a motor manufacturing enterprise].

Objective: To understand the current situation of noise hazard in a motor manufacturing enterprise, and to explore the protective effect of workers wearing hearing protective device and its possible influencing factors. Methods: In November 2021, a total of 179 noise workers wearing hearing protective devices in a motor manufacturing company in a city were selected as research objects. Personal attenuation rating (PAR) of workers wearing hearing protective devices was measured. Baseline PAR was analyzed for different subgroups of basic demographic information, noise exposure, and the use of hearing protective devices to evaluate the effect of the intervention. Baseline PAR was compared using nonparametric tests. Results: There were 179 workers from 35 positions in 4 types of work, and the over-standard noise rate was 51.2% (42/82), among which the noise exposure intensity of motor equipment debugging workers was the highest [94.4 dB (A) ]. Compared the baseline PAR of different characteristics, it was found that the baseline PAR of male workers, workers whose daily noise exposure time were <8 h, workers who had used the hearing protective devices for 10 to 14 years, and workers who thought the hearing protective devices were comfortable were all higher, and the differences were statistically significant (P<0.05). Baseline PAR passing rate was 43.0% (77/179), and PAR of 102 workers who did not pass baseline test increased from 0 (0, 3) dB before intervention to 14 (12, 16) dB after intervention, with statistical significance (P<0.05) . Conclusion: The noise hazard in this motor manufacturing enterprise is serious, and the protective effect of workers wearing hearing protective devices is not good. Gender, daily noise exposure time, years and comfort of wearing hearing protective device are the possible influencing factors of poor protective effect.

Coherent Picture on the Pure Spin Transport between Ag/Bi and Ferromagnets.

In a joint effort of both experiments and first-principles calculations, we resolve a hotly debated controversy and provide a coherent picture on the pure spin transport between Ag/Bi and ferromagnets. We demonstrate a strong inverse Rashba-Edelstein effect (IREE) at the interface in between Ag/Bi with a ferromagnetic metal (FM) but not with a ferromagnetic insulator. This is in sharp contrast to the previously claimed IREE at Ag/Bi interface or inverse spin Hall effect dominated spin transport. A more than one order of magnitude modulation of IREE signal is realized for different Ag/Bi-FM interfaces, casting strong tunability and a new direction for searching efficient spintronics materials.

New Direct Limit on Neutrinoless Double Beta Decay Half-Life of

The Cryogenic Underground Observatory for Rare Events (CUORE) at Laboratori Nazionali del Gran Sasso of INFN in Italy is an experiment searching for neutrinoless double beta (0νßß) decay. Its main goal is to investigate this decay in ^{130}Te, but its ton-scale mass and low background make CUORE sensitive to other rare processes as well. In this Letter, we present our first results on the search for 0νßß decay of ^{128}Te, the Te isotope with the second highest natural isotopic abundance. We find no evidence for this decay, and using a Bayesian analysis we set a lower limit on the ^{128}Te 0νßß decay half-life of T_{1/2}>3.6×10^{24} yr (90% CI). This represents the most stringent limit on the half-life of this isotope, improving by over a factor of 30 the previous direct search results, and exceeding those from geochemical experiments for the first time.

Trends in maternal mortality in India over two decades in nationally representative surveys.

OBJECTIVE: To assess national and regional trends and causes-specific distribution of maternal mortality in India. DESIGN: Nationally representative cross-sectional surveys. SETTING: All of India from 1997 to 2020. SAMPLE: About 10 000 maternal deaths among 4.3 million live births over two decades. METHODS: We analysed trends in the maternal mortality ratio (MMR) from 1997 through 2020, estimated absolute maternal deaths and examined the causes of maternal death using nationally representative data sources. We partitioned female deaths (aged 15-49 years) and live birth totals, based on the 2001-2014 Million Death Study to United Nations (UN) demographic totals for the country. MAIN OUTCOME MEASURES: Maternal mortality burden and distribution of causes. RESULTS: The MMR declined in India by about 70% from 398/100 000 live births (95% CI 378-417) in 1997-98 to 99/100 000 (90-108) in 2020. About 1.30 million (95% CI 1.26-1.35 million) maternal deaths occurred between 1997 and 2020, with about 23 800 (95% CI 21 700-26 000) in 2020, with most occurring in poorer states (63%) and among women aged 20-29 years (58%). The MMRs for Assam (215), Uttar Pradesh/Uttarakhand (192) and Madhya Pradesh/Chhattisgarh (170) were highest, surpassing India's 2016-2018 estimate of 113 (95% CI 103-123). After adjustment for education and other variables, the risks of maternal death were highest in rural and tribal areas of north-eastern and northern states. The leading causes of maternal death were obstetric haemorrhage (47%; higher in poorer states), pregnancy-related infection (12%) and hypertensive disorders of pregnancy (7%). CONCLUSIONS: India could achieve the UN 2030 MMR goals if the average rate of reduction is maintained. However, without further intervention, the poorer states will not. TWEETABLE ABSTRACT: We estimated that 1.3 million Indian women died from maternal causes over the last two decades. Although maternal mortality rates have fallen by 70% overall, the poorer states lag behind.

Clinical practice of traditional Chinese medicine for the treatment of postmenopausal osteoporosis: a literature review.

OBJECTIVE: This study aimed to evaluate the effectiveness and safety of traditional Chinese medicine (TCM) for postmenopausal osteoporosis (PMOP). METHODS: We conducted a computer literature search in five databases and comprehensively extracted all kinds of information from each article. Traditional Chinese medicine inheritance support system (TCMISS) V2.5 was adopted to perform association analysis. The effectiveness, safety and methodological quality were analyzed using randomized controlled clinical trials (RCTs). RESULTS: A total of 2880 related articles were collected. Finally, 423 articles which included 312 RCTs were included for in-depth analysis. We collected 369 Chinese medicine prescriptions and found that the top three frequently used herbs in the treatment of PMOP were Epimedii Folium (Yinyanghuo), Rehmanniae Radix Praeparata (Shudihuang) and Angelicae Sinensis Radix (Danggui). The top Chinese patent medicine was Gushukang capsule. No serious adverse reaction (AR) had been reported in the Chinese medical treatment group. CONCLUSION: The effectiveness of TCM in treating PMOP needs to be further explored, and the safety is good. Therefore, high-quality evidence is urgently needed to supplement.

Infection control measures for public transportation derived from the flow dynamics of obstructed cough jet.

During the COVID-19 pandemic, WHO and CDC suggest people stay 1 m and 1.8 m away from others, respectively. Keeping social distance can avoid close contact and mitigate infection spread. Many researchers suspect that suggested distances are not enough because aerosols can spread up to 7-8 m away. Despite the debate on social distance, these social distances rely on unobstructed respiratory activities such as coughing and sneezing. Differently, in this work, we focused on the most common but less studied aerosol spread from an obstructed cough. The flow dynamics of a cough jet blocked by the backrest and gasper jet in a cabin environment was characterized by the particle image velocimetry (PIV) technique. It was proved that the backrest and the gasper jet can prevent the front passenger from droplet spray in public transportation where maintaining social distance was difficult. A model was developed to describe the cough jet trajectory due to the gasper jet, which matched well with PIV results. It was found that buoyancy and inside droplets almost do not affect the short-range cough jet trajectory. Infection control measures were suggested for public transportation, including using backrest/gasper jet, installing localized exhaust, and surface cleaning of the backrest.

[Outcome comparison between LSA complete reconstruction and partial coverage with endovascular technique for patients with Stanford type B aortic dissection].

Objectives: To compare the short-term outcomes of branched stentgrafts for left subclavian artery (LSA) revascularization or partial LSA coverage without reconstruction in the treatment of type B aortic dissection with proximal tear close to LSA. Methods: A total of 125 type B aortic dissection patients were treated with thoracic endovascular aortic repair (TEVAR) in Xinqiao Hospital of the Army Medical University from January 2019 to March 2021. Their medical records were reviewed and the outcomes were followed up. According to the different treatment methodologies, the patients were divided into complete LSA coverage with reconstruction group (n=25) and partial LSA coverage without reconstruction group (n=100). The data of baseline characteristics, clinical outcomes, and incidence of postoperative in-hospital adverse events were collected and compared between the two groups. The adverse events during one-year follow-up were also compared between the two groups. Kaplan-Meier analysis and log-rank test were used to compare the cumulative survival rates between groups. Results: Compared with partial LSA coverage group, distance of proximal tear to LSA((8.69±2.32)mm vs. (13.77±1.71) mm) was shorter, in-hospital expenses[175 400(166 000-189 900) yuan vs. 143 700 (138 100-151 800) yuan] was higher, average length of stent [200.00 mm vs. 150.00 (150.00-150.00) mm] and operation time [155.00 (140.00-170.00) min vs. 95.00 (80.00-100.00) min] were longer, and volumes of contrast agent [300.00 (200.00-300.00) ml vs. 200.00 (200.00-300.00) ml] (P<0.05) were higher for patients in the complete LSA coverage with reconstruction group. The incidence of post-operative fever was significantly higher in complete LSA coverage with revascularization group than that in partial LSA partial coverage with reconstruction group (56% vs. 25%, P=0.003). There was no significant difference in the incidences of all-cause death, stroke, endoleak, paraplegia, and LSA branch vessel occlusion between the two groups during follow-up. Kaplan-Meier analysis showed that there was no significant difference in the cumulative survival rates between the two groups (log-rank test: P=0.572 5). Conclusion: The TEVAR with complete LSA revascularization or partial LSA coverage without reconstruction for type B aortic dissection close to LSA are safe and effective with high success rates. There is no significant difference between these two techniques in short-term outcomes.

Cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase II trial.

BACKGROUND: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting. PATIENTS AND METHODS: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks). RESULTS: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001). CONCLUSIONS: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.

Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1ß mediated articular cartilage matrix destruction.

OBJECTIVE: Cartilage health is maintained in response to a range of mechanical stimuli including compressive, shear and tensile strains and associated alterations in osmolality. The osmotic-sensitive ion channel Transient Receptor Potential Vanilloid 4 (TRPV4) is required for mechanotransduction. Mechanical stimuli inhibit interleukin-1ß (IL-1ß) mediated inflammatory signalling, however the mechanism is unclear. This study aims to clarify the role of TRPV4 in this response. DESIGN: TRPV4 activity was modulated glycogen synthase kinase (GSK205 antagonist or GSK1016790 A (GSK101) agonist) in articular chondrocytes and cartilage explants in the presence or absence of IL-1ß, mechanical (10% cyclic tensile strain (CTS), 0.33 Hz, 24hrs) or osmotic loading (200mOsm, 24hrs). Nitric oxide (NO), prostaglandin E2 (PGE2) and sulphated glycosaminoglycan (sGAG) release and cartilage biomechanics were analysed. Alterations in post-translational tubulin modifications and primary cilia length regulation were examined. RESULTS: In isolated chondrocytes, mechanical loading inhibited IL-1ß mediated NO and PGE2 release. This response was inhibited by GSK205. Similarly, osmotic loading was anti-inflammatory in cells and explants, this response was abrogated by TRPV4 inhibition. In explants, GSK101 inhibited IL-1ß mediated NO release and prevented cartilage degradation and loss of mechanical properties. Upon activation, TRPV4 cilia localisation was increased resulting in histone deacetylase 6 (HDAC6)-dependent modulation of soluble tubulin and altered cilia length regulation. CONCLUSION: Mechanical, osmotic or pharmaceutical activation of TRPV4 regulates HDAC6-dependent modulation of ciliary tubulin and is anti-inflammatory. This study reveals for the first time, the potential of TRPV4 manipulation as a novel therapeutic mechanism to supress pro-inflammatory signalling and cartilage degradation.

Association between outdoor particulate air pollution and the risk of osteoporosis: a systematic review and meta-analysis.

Air pollution is a major threat to global health, which is associated with several adverse health outcomes and increased mortality. Few studies have investigated the association between air pollution and osteoporosis, and their findings were inconclusive. Our objective is to determine whether exposure to outdoor air pollution is causally associated with risk of osteoporosis. A systematic literature search of PubMed, Web of Science, Embase, and Cochrane Library for publications up to December 2020 was conducted for studies reporting the association between air pollution and osteoporosis. Meta-analysis was performed to estimate the pooled effect size of air pollution on osteoporosis using the relative risk (RR) and 95% confidence intervals (95% CI). Quality assessment was conducted, and all statistical analyses were performed by RevMan 5.3 software. Our search identified 9 eligible studies involving 9,371,212 patients. Meta-analysis revealed that there was an increased risk of osteoporosis (total body BMD and hip fracture) as a result of exposure to air pollution including PM2.5 and NO2. However, no significant excess risk of osteoporosis was found regardless of PM10, NO, and O3. In spite of a few number of epidemiological studies selected in the present literature review, this study indicated that the increased exposure to air pollutants was positively associated with high risk of osteoporosis. Further cohort studies with large sample sizes are needed to investigate different constituents and the duration of exposure of air pollutants.

Measurement of the 2νßß Decay Half-Life of

We measured two-neutrino double beta decay of ^{130}Te using an exposure of 300.7 kg yr accumulated with the CUORE detector. Using a Bayesian analysis to fit simulated spectra to experimental data, it was possible to disentangle all the major background sources and precisely measure the two-neutrino contribution. The half-life is in agreement with past measurements with a strongly reduced uncertainty: T_{1/2}^{2ν}=7.71_{-0.06}^{+0.08}(stat)_{-0.15}^{+0.12}(syst)×10^{20} yr. This measurement is the most precise determination of the ^{130}Te 2νßß decay half-life to date.

Coordination of primary metabolism and virulence factors expression mediates the virulence of Vibrio parahaemolyticus towards cultured shrimp (Penaeus vannamei).

AIMS: Acute hepatopancreatic necrosis disease (AHPND) caused by Vibrio parahaemolyticus has emerged as a severe bacterial disease of cultured shrimp. To identify the key virulence factors, two AHPND-causing V. parahaemolyticus (VpAHPND ) strains (123 and 137) and two non-VpAHPND strains (HZ56 and ATCC 17082) were selected. METHODS AND RESULTS: Challenge tests showed that the four strains exhibited different virulence towards shrimp with cumulative mortalities at 48 h postinfection (hpi) ranging from 10 to 92%. The expression of pirABVP in strain 123 and 137 was not significantly different. Genomic analysis revealed that the two VpAHPND strains contain a plasmid with the PirABVP toxins (pirABVP ) flanked by the insertion sequence (ISVal1) that has been identified in various locations of chromosomes in VpAHPND strains. The two VpAHPND strains possessed almost identical virulence factors, while ISVal1 disrupted three genes related to flagellar motility in strain 137. Phenotype assay showed that strain 123 possessed the highest growth rate and swimming motility, followed by strain 137, suggesting that the disruption of essential genes mediated by ISVal1 significantly affected the virulence level. Transcriptome analysis of two VpAHPND strains (123 and 137) further suggested that virulence genes related to the capsule, flagella and primary metabolism were highly expressed in strain 123. CONCLUSIONS: Here for the first time, it is demonstrated that the virulence of VpAHPND is not only determined by the expression of pirABVP , but also is mediated by ISVal1 which affects the genes involved in flagellar motility and primary metabolism. SIGNIFICANCE AND IMPACT OF THE STUDY: The genomic and transcriptomic analysis of VpAHPND strains provides valuable information on the virulence factors affecting the pathogenicity of VpAHPND.

Isolation of a Bacillus cereus strain HBL-AI and its application for production of Trans-4-hydroxy-l-proline.

A new trans-4-hydroxy-l-proline (trans-Hyp) producing Bacillus cereus HBL-AI, was isolated from the air, which was screened just using l-proline as carbon and energy sources. This strain exhibited 73·4% bioconversion rate from initial l-proline (3 g l-1 ) to trans-Hyp. By sequencing the genome of this bacterium, 6244 coding sequences were obtained. Genome annotation analysis and functional expression were used to identify the proline-4-hydroxylase (BP4H) in HBL-AI. This enzyme belonged to a family of 2-oxoglutarate-related dioxygenases, which required 2-oxoglutarate and O2 as co-substrates for the reaction. Homologous modelling indicated that the enzyme had two monomers and contained conserved motifs, which included a distorted 'jelly roll' ß strand core and the residues (HXDXnH and RXS). The engineering Escherichia coli 3 Δ W3110/pTrc99a-proba-bp4h was constructed using BP4H, which transformed glucose to trans-Hyp in one step with high concentration of 46·2 g l-1 . This strategy provides a green and efficient method for synthesis of trans-Hyp and thus has a great potential in industrial application.