High Airway Occlusion Pressure Is Associated with Dyspnea and Increased Mortality in Critically Ill Mechanically Ventilated Patients.

Rationale: Airway occlusion pressure at 100 ms (P0.1) reflects central respiratory drive. Objectives: We aimed to assess factors associated with P0.1 and whether an abnormally low or high P0.1 value is associated with higher mortality and longer duration of mechanical ventilation (MV). Methods: We performed a secondary analysis of a prospective cohort study conducted in 10 ICUs in France to evaluate dyspnea in communicative MV patients. In patients intubated for more than 24 hours, P0.1 was measured with dyspnea as soon as patients could communicate and the next day. Measurements and Main Results: Among 260 patients assessed after a median time of ventilation of 4 days, P0.1 was 1.9 (1-3.5) cm H2O at enrollment, 24% had P0.1 values >3.5 cm H2O, 37% had P0.1 values between 1.5 and 3.5 cm H2O, and 39% had P0.1 values <1.5 cm H2O. In multivariable linear regression, independent factors associated with P0.1 were the presence of dyspnea (P = 0.037), respiratory rate (P < 0.001), and PaO2 (P = 0.008). Ninety-day mortality was 33% in patients with P0.1 > 3.5 cm H2O versus 19% in those with P0.1 between 1.5 and 3.5 cm H2O and 17% in those with P0.1 < 1.5 cm H2O (P = 0.046). After adjustment for the main risk factors, P0.1 was associated with 90-day mortality (hazard ratio per 1 cm H2O, 1.19 [95% confidence interval, 1.04-1.37]; P = 0.011). P0.1 was also independently associated with a longer duration of MV (hazard ratio per 1 cm H2O, 1.10 [95% confidence interval, 1.02-1.19]; P = 0.016). Conclusions: In patients receiving invasive MV, abnormally high P0.1 values may suggest dyspnea and are associated with higher mortality and prolonged duration of MV.

Neuropilin-1 regulates renin synthesis in juxtaglomerular cells.

Renin is the key enzyme of the systemic renin-angiotensin-aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and extracellular volume homeostasis. Renin is mainly produced and secreted by specialized juxtaglomerular (JG) cells in the kidney. In the present study, we report for the first time that the conserved transmembrane receptor neuropilin-1 (NRP1) participates in the development of JG cells and plays a key role in renin production. We used the myelin protein zero-Cre (P0-Cre) to abrogate Nrp1 constitutively in P0-Cre lineage-labelled cells of the kidney. We found that the P0-Cre precursor cells differentiate into renin-producing JG cells. We employed a lineage-tracing strategy combined with RNAscope quantification and metabolic studies to reveal a cell-autonomous role for NRP1 in JG cell function. Nrp1-deficient animals displayed abnormal levels of tissue renin expression and failed to adapt properly to a homeostatic challenge to sodium balance. These findings provide new insights into cell fate decisions and cellular plasticity operating in P0-Cre-expressing precursors and identify NRP1 as a novel key regulator of JG cell maturation. KEY POINTS: Renin is a centrepiece of the renin-angiotensin-aldosterone system and is produced by specialized juxtaglomerular cells (JG) of the kidney. Neuropilin-1 (NRP1) is a conserved membrane-bound receptor that regulates vascular and neuronal development, cancer aggressiveness and fibrosis progression. We used conditional mutagenesis and lineage tracing to show that NRP1 is expressed in JG cells where it regulates their function. Cell-specific Nrp1 knockout mice present with renin paucity in JG cells and struggle to adapt to a homeostatic challenge to sodium balance. The results support the versatility of renin-producing cells in the kidney and may open new avenues for therapeutic approaches.

Ribosomal Protein Dynamics and Its Association with Actin Filaments and Local Translation in Axonal Growth Cones of Dorsal Root Ganglia Neurons.

Local translation in growth cones plays a critical role in responses to extracellular stimuli, such as axon guidance cues. We previously showed that brain-derived neurotrophic factor activates translation and enhances novel protein synthesis through the activation of mammalian target of rapamycin complex 1 signaling in growth cones of dorsal root ganglion neurons. In this study, we focused on 40S ribosomal protein S6 (RPS6), 60S ribosomal protein P0/1/2 (RPP0/1/2), and actin filaments to determine how localization of ribosomal proteins changes with overall protein synthesis induced by neurotrophins. Our quantitative analysis using immunocytochemistry and super-resolution microscopy indicated that RPS6, RPP0/1/2, and actin tend to colocalize in the absence of stimulation, and that these ribosomal proteins tend to dissociate from actin and associate with each other when local protein synthesis is enhanced. We propose that this is because stimulation causes ribosomal subunits to associate with each other to form actively translating ribosomes (polysomes). This study further clarifies the role of cytoskeletal components in local translation in growth cones.

Pepper vein yellow virus P0 protein triggers NbHERC3, NbBax, and NbCRR mediated hypersensitive response.

P0 proteins encoded by the pepper vein yellow virus (PeVYV) are pathogenic factors that cause hypersensitive response (HR). However, the host gene expression related to PeVYV P0-induced HR has not been thoroughly studied. Transcriptomic technology was used to investigate the host pathways mediated by the PeVYV P0 protein to explore the molecular mechanisms underlying its function. We found 12,638 differentially expressed genes (DEGs); 6784 and 5854 genes were significantly upregulated and downregulated, respectively. Transcriptomic and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) analyses revealed that salicylic acid (SA) and jasmonic acid (JA) synthesis-related gene expression was upregulated, and ethylene synthesis-related gene expression was downregulated. Ultrahigh performance liquid chromatography-tandem mass spectrometry was used to quantify SA and JA concentrations in Nicotiana benthamiana, and the P0 protein induced SA and JA biosynthesis. We then hypothesized that the pathogenic activity of the P0 protein might be owing to proteins related to host hormones in the SA and JA pathways, modulating host resistance at different times. Viral gene silencing suppression technology was used in N. benthamiana to characterize candidate proteins, and downregulating NbHERC3 (Homologous to E6-AP carboxy-terminus domain and regulator of choromosome condensation-1 dmain protein 3) accelerated cell necrosis in the host. The downregulation of NbCRR reduced cell death, while that of NbBax induced necrosis and curled heart leaves. Our findings indicate that NbHERC3, NbBax, and NbCRR are involved in P0 protein-driven cell necrosis.

Highly Sensitive Broadband Polarized Photodetector Based on the As0.6P0.4/WSe2 Heterostructure toward Imaging and Optical Communication Application.

Polarization-sensitive photodetectors based on two-dimensional anisotropic materials still encounter the issues of narrow spectral coverage and low polarization sensitivity. To address these obstacles, anisotropic As0.6P0.4 with a narrow band gap has been integrated with WSe2 to construct a type-II heterostructure, realizing a high-performance polarization-sensitive photodetector with broad spectral range from 405 to 2200 nm. By operating in photovoltaic mode at zero bias, the device shows a very low dark current of ∼0.02 picoampere, high responsivity of 492 m A/W, and high photoswitching ratio of 6 × 104, yielding a high specific detectivity of 1.4 × 1012 Jones. The strong in-plane anisotropy of As0.6P0.4 endows the device with a capability of polarization-sensitive detection with a high polarization ratio of 6.85 under a bias voltage. As an image sensor and signal receiver, the device shows great potential in imaging and optical communication applications. This work develops an anisotropic vdW heterojunction to realize polarization-sensitive photodetectors with wide spectral coverage, fast response, and high sensitivity, providing a new candidate for potential applications of polarization-resolved electronics and photonics.

Serum tRF-33-RZYQHQ9M739P0J as a novel biomarker for auxiliary diagnosis and disease course monitoring of hepatocellular carcinoma.

Objective: In most cases, patients with hepatocellular carcinoma (HCC) develop advanced disease when diagnosed. Finding new molecules to combine with traditional biomarkers is crucial for HCC early diagnosis. In cancer development, tRNA-derived small RNAs (tsRNA) play a crucial role. Here, we aimed to identify a novel biomarker among tsRNAs that can facilitate HCC diagnosis and monitor its prognosis. Methods: We screened candidate tsRNAs in 3 pairs of HCC and adjacent tissues through high-throughput sequencing. tRF-33-RZYQQ9M739P0J was screened in tissues, sera, and cells through quantitative real-time polymerase chain reaction (qRT-PCR) for further analysis. tRF-33-RZYQHQ9M739P0J was characterized using agarose gel electrophoresis, Sanger sequencing, and nuclear and cytoplasmic RNA isolation. Experiments at room temperature and repeated freeze-thaw cycles were conducted to evaluate the detection performance of tRF-33-RZYQHQ9M739P0J. We measured the levels of differential expression of tRF-33-RZYQHQ9M739P0J in sera using qRT-PCR. We applied the chi-square test to evaluate the correlation between tRF-33-RZYQHQ9M739P0J expression levels and clinicopathological features, and assessed its prognostic value by plotting Kaplan-Meier curves. The diagnostic efficacy of tRF-33-RZYQHQ9M739P0J was evaluated using the receiver operating characteristic (ROC) curve. Finally, the downstream genes related to tRF-33-RZYQHQ9M739P0J were explored through bioinformatics prediction. Results: tRF-33-RZYQHQ9M739P0J was highly expressed in HCC tissues and sera, and its expression was correlated with metastasis, TNM stage, BCLC stage, and vein invasion. Expression of tRF-33-RZYQHQ9M739P0J were decreased after surgery in patients with HCC. High serum tRF-33-RZYQHQ9M739P0J levels are associated with low survival rates, and they can predict survival times in patients with HCC according to the Kaplan-Meier analysis. Combining tRF-33-RZYQHQ9M739P0J with serum alpha-fetoprotein and prothrombin induced by vitamin K absence II can improve the diagnostic efficiency of HCC, suggesting its potential as a biomarker for HCC. Conclusion: tRF-33-RZYQHQ9M739P0J may not only be a promising non-invasive marker for early diagnosis, but also a predictor of liver cancer progression.

Tumor microenvironment (Part I): Tissue integrity in a rat model of peripheral neural cancer.

ICAM-1 (intercellular adhesion molecule 1) and MPZ (myelin protein zero) are thought to be a factor in the integrity of nerve tissues. In this report, we attempted to trace the expression of ICAM-1, responsible for cell-to-cell adhesion, and of MPZ, the main constituent of myelin sheath, in malignant tissues of the sciatic nerve (SN) in inbred male Copenhagen rats. AT-1 Cells (anaplastic tumor 1) were injected in the perineurial sheath, and tissues of the SNs were collected after 7, 14 and 21 days and compared to a sham-operated group of rats (n = 6 each). Tissues were sectioned and histologically examined, under light microscope, and stained for measuring the immunoreactivity of ICAM-1 and MPZ under laser scanning microscope. The cancer model was established, and the tumor growth was confirmed. ICAM-1 showed severe decreases, proportional to the growing anaplastic cells, as compared to the sham group. MPZ revealed, however, a distinct defensive pattern before substantially decreasing in a comparison with sham. These results support the notion that malignancies damage peripheral nerves and cause severe axonal injury and loss of neuronal integrity, and clearly define the role of ICAM-1 and MPZ in safeguarding the nerve tissues.

Protein Production at the 100L Scale.

The Baculovirus Expression Vector System (BEVS) has revolutionized the field of recombinant protein expression by enabling efficient and high yield production. The platform offers many advantages including manufacturing speed, flexible design, and scalability. In this chapter, we describe the methods including strategies and considerations to successfully optimize and scale-up using BEVS as a tool for production (Fig. 1). As an illustrative case study, we present an example focused on the production of a viral glycoprotein.

Effects of an intratympanic injection of dexamethasone combined with gentamicin on the expression level of serum p0 protein antibodies in patients with meniere's disease

OBJECTIVES: To investigate the effects of an intratympanic injection of dexamethasone combined with gentamicin on the expression level of serum P0 protein antibodies in patients with Meniere's disease (MD). METHODS: A total of 136 patients with MD treated in our hospital were enrolled in this study. Among them, 68 patients were treated with an intratympanic injection of dexamethasone combined with gentamicin (observation group). Another 68 patients were treated with gentamicin alone (control group). RESULTS: After treatment, the expression levels of IgG and IgM in the two groups significantly decreased (p<0.05); the levels in the observation group were significantly lower than those in the control group (p<0.05). The incidences of vertigo, tinnitus, and gait instability in the observation group were significantly lower than those in the control group (p<0.05). Vestibular symptom index (VSI) scores in the observation group were significantly lower than those in the control group (p<0.05). We observed no significant difference between the two groups in the number of vertigo attacks 6 months after treatment (p>0.05). CONCLUSION: For patients with MD, dexamethasone combined with gentamicin can reduce the incidence of vertigo, tinnitus, and gait instability, but it has no effect on the efficacy or number of vertigo attacks 6 months after treatment. Therefore, the levels of myelin P0 protein antibodies after treatment can be used as predictors of vertigo at 6 months after treatment.

Association of Interleukin-10 -1082A>G (rs1800896) Polymorphism with Predisposition to Breast Cancer: a Meta-Analysis based on 17 Case-Control Studies

SUMMARY INTRODUCTION The association between the between IL-10 -1082A>G (rs1800896) polymorphism and breast cancer has been evaluated by several number case-control studies. However, these studies might be underpowered to reveal the true association. OBJECTIVE We have performed a comprehensive meta-analysis to investigate the association IL-10 -1082A>G polymorphism and breast cancer. MATERIALS AND METHODS A systematic literature search was conducted using PubMed, Google Scholar, and Web of Science up to September 20, 2017. Data was analysed with CMA software to identify the strength of the association by pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). RESULTS A total of 17 case-control studies involving 3275 cases and 3416 controls obtained from database searches were examined. Overall, there was no significant association between IL-10 -1082A>G polymorphism and breast cancer risk under all genetic models. No significant publication bias was found for the five genetic models (G vs. A OR = 1.184, 95% CI = 0.895-1.180, p= 0.230; GG vs. AA: OR = 1.430, 95% CI = 0.927-2.204, p= 0.106; GA vs. AA: OR = 0.966, 95% CI = 0.765-1.221, p= 0.774; GG+GA vs. AA: OR = 0.957, 95% CI = 0.697-1.314, p= 0.786; and GG vs. GA+AA: OR = 1.221, 95% CI = 0.981-1.518, p= 0.073). Moreover, there was no significant association between the IL-10 -1082A>G polymorphism and breast cancer risk by ethnicity. CONCLUSION Our findings indicated that IL-10 -1082A>G (rs1800896) polymorphism might not be a risk factor for the development of breast cancer.

RESUMO

Development of cell models for high-throughput screening system of Charcot-Marie-Tooth disease type 1

PURPOSE: Charcot-Marie-Tooth disease (CMT) is a peripheral neuropathy mainly divided into CMT type 1 (CMT1) and CMT2 according to the phenotype and genotype. Although molecular pathologies for each genetic causative have not been revealed in CMT2, the correlation between cell death and accumulation of misfolded proteins in the endoplasmic reticulum (ER) of Schwann cells is well documented in CMT1. Establishment of in vitro models of ER stress-mediated Schwann cell death might be useful in developing drug-screening systems for the treatment of CMT1. MATERIALS AND METHODS: To develop high-throughput screening (HTS) systems for CMT1, we generated cell models using transient expression of mutant proteins and chemical induction. RESULTS: Overexpression of wild type and mutant peripheral myelin protein 22 (PMP22) induced ER stress. Similar results were obtained from mutant myelin protein zero (MPZ) proteins. Protein localization revealed that expressed mutant PMP22 and MPZ proteins accumulated in the ER of Schwann cells. Overexpression of wild type and L16P mutant PMP22 also reduced cell viability, implying protein accumulation-mediated ER stress causes cell death. To develop more stable screening systems, we mimicked the ER stress-mediated cell death in Schwann cells using ER stress inducing chemicals. Thapsigargin treatment caused cell death via ER stress in a dose dependent manner, which was measured by expression of ER stress markers. CONCLUSION: We have developed genetically and chemically induced ER stress models using Schwann cells. Application of these models to HTS systems might facilitate the elucidation of molecular pathology and development of therapeutic options for CMT1.

Impact of a Meditation Program on Pulse-Wave Velocity, C-reactive Protein and Quality of life / Impacto de un programa de meditación sobre la velocidad de onda de pulso, la proteína C-reactiva y la calidad de vida

background: Although various studies refer to the effect of meditation on blood pressure (BP), its impact on other cardiovascular clinical variables is unknown. Objective: The aim of this study was to evaluate the effects of a meditation program on pulse wave velocity (PWV), quality of life and ultrasensitive C-reactive protein (us-CRP) in patients with ischemic heart disease or chronic heart failure. Methods: This was a randomized study with two groups of patients: a meditation group (M) and an active control group (AC) with cardiovascular health education, evaluating the difference between initial and final values at 12 weeks of B P, PWV, quality of life (assessed by the SF-36 questionnaire) and us-CRP. results: Thirty-five patients were included in the M group and 35 in the AC group; mean age was 61 years and 80% were men. Both groups had similar baseline characteristics, except for higher number of smokers and triglyceride levels in the M group. At 12 weeks, no significant differences were found for ∆PWV: +0.51 (±1.40) in AC and +0.19 (±1.53) in M (p=0.37). Conversely, ∆SF-36 was +0.79 (±7.58) in AC vs. +5.40 (±9.69) (p=0.03) in M, and ∆us-PCR was +1.17 (±2.9) in AC vs. -0.69 (±0.89) in M (p=0.02). Conclusions: A meditation program did not significantly modify PWV at 12 weeks. However, patients allocated to this intervention improved their quality of life and us-PCR was significantly reduced. Larger studies are required to confirm these findings and explore the mechanisms involved in this improvement.

Clinical and Functional Outcome of Percutaneous alcohol septal ablation in Obstructive Hypertrophic Cardiomyopathy / Resultados clínicos y funcionales de la ablación septal percutánea con alcohol en la miocardiopatía hipertrófica obstructiva

background: Percutaneous septal ablation is a therapeutic option for patients with obstructive hypertrophic cardiomyopathy refrac-tory to optimal medical therapy. However, results of initial persistence and long-term safety are still controversial. Objectives: The aim of this study was to report percutaneous alcohol septal ablation technique, clinical and functional outcome, cardiovascular events and its impact on long-term follow-up. Methods: A total of 23 patients were included in the study. Functional class (FC), left ventricular outflow tract gradient before and after the procedure and long-term cardiovascular events were evaluated. results: Median follow-up was 52 months (IR 33-72). All patients were in FC III or IV prior to the procedure, under maximum tolerated medical therapy. The procedure was successful in 91% of cases, with 85% of patients currently in FC I and 15% in FC II. Baseline left ventricular outflow tract gradient decreased from 75 mmHg (95% CI 51-89) to 25 mmHg (95% CI 10-37) (p <0.003) and with Valsalva maneuver from 118 mmHg (95% CI 88-152) to 38 mmHg (95% CI 16-69) (p <0.0002), persisting in the long-term follow-up. During hospitalization, two patients presented with complete atrioventricular block requiring permanent pacemaker implantation. No cardiovascular deaths occurred during follow up. Conclusions: Alcohol septal ablation is a promising option for the treatment of a selected population with hypertrophic obstructive cardiomyopathy, generating sustained clinical and functional improvement with low incidence of events in the long-term follow up.

Telemedicine network Program for reperfusion of Myocardial infarction / Programa en red para la reperfusión del infarto con telemedicina

background: Early management of myocardial infarction in the area of public health requires the integration of specific programs for the coordination of healthcare services. Objective: The aim of this study was to evaluate the impact on delay times and reperfusion rate of a comprehensive program for the reperfusion of myocardial infarction in a hospital network of the Southern Greater Buenos Aires. Methods: The network consists of six low-mid-complexity hospitals and a third-level referral center with 24-hour cath-lab. Stage 1 of the program (2009-2010) evaluated the existing barriers to reperfusion; Stage 2 (2011-2013) implemented the progressive incorpora-tion of improvements and Stage 3 assessed the program (2013-2014) complemented with fellows in each hospital. Program impact was evaluated by the proportion of patients reperfused and time to its implementation. results: A total of 432 patients referred from the network were hospitalized with diagnosis of ST-segment elevation myocardial infarction. Mean age was 56±9 years and 83.3% were men. The proportion of reperfused patients progressively increased: S1 60.7%, S2 69% and S3 78%, p for trend=0.01. Time to reperfusion decreased significantly between S1 and S3, from 120 minutes (IQR 55-240) to 90 minutes (IQR 35-150), p=0.04, with a median reduction of 30 minutes in the door-to-balloon and door-to-needle times. Conclusions: The application of a program for myocardial reperfusion based on the diagnosis of barriers was associated with 28.5% increase in reperfusion, and a significant reduction in the implementation times. This public network model built on algorithms adapted to local barriers may contribute to improve the care of myocardial infarction in our country.

The study on serum level and clinical significance of anti-ribosomal protein P0 antibody in DLE and SLE patients / 实用医学杂志

Objectives To study the serum level and the clinical significance of anti-ribosomal protein P0 antibody in discoid lupus erythematosus(DLE) and systemic lupus erythematosus(SLE) patients. Methods Serum anti-RPLP0 IgG antibody of 18 DLE patients and 23 SLE patients were tested by Enzyme-Linked Immunosorbent Assay (ELISA). Direct immunofluoreseence (DIF) was used to examined the immunoreaetants from skin lesion. Serum antibody and complement C3 were detected by conventional methods. Results Anti-ribosomal P0 antibody was higher in SLE patients (1.23 ± 0.62. mean ± SD) than in patients with DLE (0.53 ± 0.18, P<0.001) and healthy controls (0.72 ± 0.16, P<0.001), but was no difference in the later two groups (P=0.5). Among SLE patients , anti-ribosomal P0 protein antibody were much higher in patients with arthritis , nephritis and specific skin lesion than in those without these disorders (P<0.05). Anti-ribosomal P0 antibody was not associated with SLEDAI and CLASI(P=0.012). Conclusions There is no difference of serum anti-ribosomal P0 antibodies between healthy controls and DLE patients. SLE patients have higher level of serum anti-ribosomal P0 antibody , specially in those with specific skin lesion.

Clinical significance of anti-ribosomal P0 protein antibodies / 中华风湿病学杂志

Objective To study the clinical value of anti-ribosomal P0 protein antibodies (anti-P0). Methods Line immuno-assay and immunoblotting methods were used to detect anti-P0 and rRNP antibodies of 49 SEE patients and 61 patients with other rheumatic diseases.The expressions of anti-P0 were compared with those of rRNP antibodies.Possible relations between anti-P0 and clinical features and other antibodies in SLE were explored.Results 36.7%and 6.1% of SEE patients showed positive anti-P0 and rRNP antibodies respectively.Anti-P0 was always negative in patients with other rheumatic diseases (P＜0.01).Among SLE pa tients,incidence of skin rash was 77.8%(35.5%) ff anti-P0 was found to be positive (negative) (P＜0.05). Besides,for patients with positive and negative anti-P0,the chance of positive anti-SmD1 was 61.1% and 19.4% respectively (P＜0.01).Sensitiviy of anti-P0 for SLE diagnosis was 36.73% with specificity and positive predictive value as high as 100%,and 66.30% as the negative predictive value.Conclusion Sera anti-P0 is highly specific for SLE and it is associated with the occurence of rash and the expression of anti-StuD 1 anti bodies in SEE.