Gene-based association tests in family samples using GWAS summary statistics.

Genome-wide association studies (GWAS) have led to rapid growth in detecting genetic variants associated with various phenotypes. Owing to a great number of publicly accessible GWAS summary statistics, and the difficulty in obtaining individual-level genotype data, many existing gene-based association tests have been adapted to require only GWAS summary statistics rather than individual-level data. However, these association tests are restricted to unrelated individuals and thus do not apply to family samples directly. Moreover, due to its flexibility and effectiveness, the linear mixed model has been increasingly utilized in GWAS to handle correlated data, such as family samples. However, it remains unknown how to perform gene-based association tests in family samples using the GWAS summary statistics estimated from the linear mixed model. In this study, we show that, when family size is negligible compared to the total sample size, the diagonal block structure of the kinship matrix makes it possible to approximate the correlation matrix of marginal Z scores by linkage disequilibrium matrix. Based on this result, current methods utilizing summary statistics for unrelated individuals can be directly applied to family data without any modifications. Our simulation results demonstrate that this proposed strategy controls the type 1 error rate well in various situations. Finally, we exemplify the usefulness of the proposed approach with a dental caries GWAS data set.

Long Noncoding RNA HAFML Promotes Migration and Invasion of Rheumatoid Fibroblast-like Synoviocytes.

The aggressive phenotype exhibited by fibroblast-like synoviocytes (FLSs) is critical for the progression of joint destruction in rheumatoid arthritis (RA). Long noncoding RNAs (lncRNAs) have crucial roles in the pathogenesis of diverse disorders; however, few have been identified that might be able to control the joint damage in RA. In this study, we identified an lncRNA, ENST00000509194, which was expressed at abnormally high levels in FLSs and synovial tissues from patients with RA. ENST00000509194 positively modulates the migration and invasion of FLSs by interacting with human Ag R (HuR, also called ELAVL1), an RNA-binding protein that mainly stabilizes mRNAs. ENST00000509194 binds directly to HuR in the cytoplasm to form a complex that promotes the expression of the endocytic adaptor protein APPL2 by stabilizing APPL2 mRNA. Knockdown of HuR or APPL2 impaired the migration and invasion of RA FLSs. Given its close association with HuR and FLS migration, we named ENST00000509194 as HAFML (HuR-associated fibroblast migratory lncRNA). Our findings suggest that an increase in synovial HAFML might contribute to FLS-mediated rheumatoid synovial aggression and joint destruction, and that the lncRNA HAFML might be a potential therapeutic target for dysregulated fibroblasts in a wide range of diseases.

Comorbidity profiling identifies potential subtype of elderly patients with nasopharyngeal carcinoma.

BACKGROUND: Few studies have assessed the comprehensive associations among comorbid diseases in elderly patients with nasopharyngeal carcinoma (NPC). This study sought to identify potential comorbidity patterns and explore the relationship of comorbidity patterns with the mortality risk in elderly patients with NPC. METHODS: A total of 452 elderly patients with NPC were enrolled in the study. The network analysis and latent class analysis were applied to mine comorbidity patterns. Propensity score matching was used for adjusting confounders. A restricted cubic spline model was used to analyze the nonlinear association between age and the risk of all-cause mortality. RESULTS: We identified 2 comorbidity patterns, metabolic disease-related comorbidity (MDRC) and organ disease-related comorbidity (ODRC) in elderly patients with NPC. Patients in MDRC showed a significantly higher risk of all-cause mortality (71.41% vs 87.97%, HR 1.819 [95% CI, 1.106-2.994], P = .031) and locoregional relapse (68.73% vs 80.88%, HR 1.689 [95% CI, 1.055-2.704], P = .042). Moreover, in patients with MDRC pattern, we observed an intriguing inverted S-shaped relationship between age and all-cause mortality among patients aged 68 years and older. The risk of mortality up perpetually with age increasing in ODRC group, specifically within the age range of 68-77 years (HR 4.371, 1.958-9.757). CONCLUSION: Our study shed light on the potential comorbidity patterns in elderly patients with NPC, thereby providing valuable insights into the development of comprehensive health management strategies for this specific population.

Influence of chlorine on co-processing of hazardous wastes in brick kilns.

Brick kiln co-treatment is a novel industrial hazardous wastes (IHWs) utilization process. However, the effects of chlorine (Cl) in wastes on heavy metals (HMs) during this process are overlooked. This study investigated the stabilization/solidification (S/S) and volatilization, as well as long and short-term leaching, of HMs in Cl-containing bricks. The results indicated enhanced formations of stable mineral phases (NiFe2O4, Ni2SiO4, Cd3Al2Si3O12, CdSiO3, FeCr2O4, Cr2O3, CuFe2O4, and CuAl2O4) in bricks at a low sintering temperature (800 °C) due to the affinity between Cl and HMs. By comparing HM concentrations before and after sintering in bricks, the study observed that Cl's presence significantly elevated the volatilization rates for Cd and Cu by 30.8% and 14.2%, respectively. In contrast, the effect on volatilization for Ni and Cr was not significant. Additionally, utilizing the NEN 7375 method, the cumulative leaching rates of Ni, Cd, Cr, and Cu over a 64-day experiment under extremely acidic conditions were 0.22%, 7.18%, 0.01%, and 1.46%, respectively. Similarly, higher short-term leaching rates of Cd (4.03%) and Cu (5.73%) than those of Ni (0.94%) and Cr (0.08%) were observed. This finding might be attributed to the lower stability of the Cd and Cu solid phases under acidic environments compared to those of Ni and Cr. Surface wash-off, dissolution, and diffusion were the processes governing HM leaching from bricks. The 10-year projections revealed a minimal release of HMs during future extended leaching, implying the successful S/S of HMs. This study provides a reference for assessing the environmental impacts of brick kiln co-processing of Cl-containing IHWs.

MRCIP: a robust Mendelian randomization method accounting for correlated and idiosyncratic pleiotropy.

Mendelian randomization (MR) is a powerful instrumental variable (IV) method for estimating the causal effect of an exposure on an outcome of interest even in the presence of unmeasured confounding by using genetic variants as IVs. However, the correlated and idiosyncratic pleiotropy phenomena in the human genome will lead to biased estimation of causal effects if they are not properly accounted for. In this article, we develop a novel MR approach named MRCIP to account for correlated and idiosyncratic pleiotropy simultaneously. We first propose a random-effect model to explicitly model the correlated pleiotropy and then propose a novel weighting scheme to handle the presence of idiosyncratic pleiotropy. The model parameters are estimated by maximizing a weighted likelihood function with our proposed PRW-EM algorithm. Moreover, we can also estimate the degree of the correlated pleiotropy and perform a likelihood ratio test for its presence. Extensive simulation studies show that the proposed MRCIP has improved performance over competing methods. We also illustrate the usefulness of MRCIP on two real datasets. The R package for MRCIP is publicly available at https://github.com/siqixu/MRCIP.

A novel penalized inverse-variance weighted estimator for Mendelian randomization with applications to COVID-19 outcomes.

Mendelian randomization utilizes genetic variants as instrumental variables (IVs) to estimate the causal effect of an exposure variable on an outcome of interest even in the presence of unmeasured confounders. However, the popular inverse-variance weighted (IVW) estimator could be biased in the presence of weak IVs, a common challenge in MR studies. In this article, we develop a novel penalized inverse-variance weighted (pIVW) estimator, which adjusts the original IVW estimator to account for the weak IV issue by using a penalization approach to prevent the denominator of the pIVW estimator from being close to zero. Moreover, we adjust the variance estimation of the pIVW estimator to account for the presence of balanced horizontal pleiotropy. We show that the recently proposed debiased IVW (dIVW) estimator is a special case of our proposed pIVW estimator. We further prove that the pIVW estimator has smaller bias and variance than the dIVW estimator under some regularity conditions. We also conduct extensive simulation studies to demonstrate the performance of the proposed pIVW estimator. Furthermore, we apply the pIVW estimator to estimate the causal effects of five obesity-related exposures on three coronavirus disease 2019 (COVID-19) outcomes. Notably, we find that hypertensive disease is associated with an increased risk of hospitalized COVID-19; and peripheral vascular disease and higher body mass index are associated with increased risks of COVID-19 infection, hospitalized COVID-19, and critically ill COVID-19.

A/B-Site Management Strategy to Boost Electrocatalytic Overall Water Splitting on Perovskite Oxides in an Alkaline Medium.

In this paper, Pr0.7Sr0.3Co1-xRuxO3 perovskite oxides were synthesized by the sol-gel method as bifunctional catalysts for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). The overpotentials of PSCR0.05 against HER and OER at 10 mA cm-2 were 319 and 321 mV in alkaline medium, respectively. The Tafel slopes of HER and OER were 87.32 and 118.1 mV/dec, respectively. PSCR0.05 showed the largest electrochemical active area, the smallest charge transfer resistance, and excellent long-term durability. Meanwhile, the PSCR0.05 electrocatalyst was applied for overall water splitting and its cell voltage was maintained at 1.77 V at 10 mA cm-2. The super-exchange interaction between adjacent RuO6-CoO6 octahedra in perovskite made of PSCR0.05 contains sufficient active sites (such as Co2+/Co3+, Ru3+/Ru4+, and O22-/O-). The increase of surface oxygen vacancy and active site is the main reason for the improvement of difunctional catalyst performance. In this work, the electrocatalytic performance of perovskite-type oxides was further optimized by the method of A- and B-site cationic doping regulation, which provides a new idea for perovskite-type bifunctional electrocatalysts.

Maximizing Electrostatic Polarity of Non-Sacrificial Electrolyte Additives Enables Stable Zinc-Metal Anodes for Aqueous Batteries.

Although additives are widely used in aqueous electrolytes to inhibit the formation of dendrites and hydrogen evolution reactions on Zn anodes, there is a lack of rational design principles and systematic mechanistic studies on how to select a suitable additive to regulate reversible Zn plating/stripping chemistry. Here, using saccharides as the representatives, we reveal that the electrostatic polarity of non-sacrificial additives is a critical descriptor for their ability to stabilize Zn anodes. Non-sacrificial additives are found to continuously modulate the solvation structure of Zn ions and form a molecular adsorption layer (MAL) for uniform Zn deposition, avoiding the thick solid electrolyte interphase layer due to the decomposition of sacrificial additives. A high electrostatic polarity renders sucrose the best hydrated Zn2+ desolvation ability and facilitates the MAL formation, resulting in the best cycling stability with a long-term reversible plating/stripping cycle life of thousands of hours. This study provides theoretical guidance for the screening of optimal additives for high-performance ZIBs.

Acetylation of fructose-bisphosphate aldolase-mediated glycolysis is essential for Bombyx mori nucleopolyhedrovirus infection.

Bombyx mori nucleopolyhedrovirus (BmNPV) is a baculovirus that infects silkworms, and its interaction with silkworm has been considered an important model in the field of insect virology. Accumulating evidence indicates that most viruses promote glycolytic metabolism in host cells to favor infection. However, similar reports are lacking in insects, especially in the area of post-translational modifications of proteins. In this study, we found that BmNPV infection induced the acetylation of fructose-bisphosphate aldolase (ALDO) on lysine 42 (K42) to promote its enzyme activity. To explore the underlying mechanisms, site-directed mutagenesis of deacetylated mimic (K/R) was performed. The results demonstrated that K42 acetylation promoted viral proliferation by exacerbating the glycolytic flux induced by BmNPV infection, which resulted in increased ATP, glucose uptake and lactate accumulation. Inhibiting glycolysis with 2-deoxygucose (2DG) revealed that glycolysis was essential for optimal BmNPV infection. Finally, we showed that BmNPV-infected cells enhanced the transcription of glycolysis-related genes, including Glut1, Hk2 and Ldh. In parallel, K42 acetylation of ALDO also promoted the expression of these genes. Therefore, acetylation of ALDO could be considered a regulator of BmNPV-induced glycolysis. These finding provide insights into the interaction between silkworm and BmNPV.

Heavy metal and metalloid emissions during co-processing of waste in a sintering kiln: Migration characteristics in the kiln and long-term leaching from bricks.

Heavy metals (HMs) in mixed hazardous waste can be volatilized in the kiln for preparing sintered bricks, which greatly increases the environmental risk. In this study, the volatilization, transformation, and leaching of HMs from bricks were evaluated. Field tests and laboratory leaching experiments were carried out. HM-contaminated soil was used to prepare sintered bricks at high-temperature in a tunnel kiln. Release of HMs from brick under rainfall conditions was investigated in laboratory simulation experiments. The field tests showed that the total amount of Pb, Zn, Cd distributed to the gas phase were all less than 2%, but the amount of Hg entering the gas phase 40.1%-60.5% in the particulate forms. The As leaching rate increased after sintering of bricks in the kiln, which was attributed to the increased formation of soluble arsenate and the reduced availability of sorption sites. The tank leaching test indicated that the release mechanism of trance elements (Cr, As, Zn, Cd, Pb and Ni) was mainly controlled by diffusion. This study provides useful knowledge for decreasing the volatilization and leaching of HMs from sintered bricks prepared using hazardous waste.

Penalized Fieller's confidence interval for the ratio of bivariate normal means.

Constructing a confidence interval for the ratio of bivariate normal means is a classical problem in statistics. Several methods have been proposed in the literature. The Fieller method is known as an exact method, but can produce an unbounded confidence interval if the denominator of the ratio is not significantly deviated from 0; while the delta and some numeric methods are all bounded, they are only first-order correct. Motivated by a real-world problem, we propose the penalized Fieller method, which employs the same principle as the Fieller method, but adopts a penalized likelihood approach to estimate the denominator. The proposed method has a simple closed form, and can always produce a bounded confidence interval by selecting a suitable penalty parameter. Moreover, the new method is shown to be second-order correct under the bivariate normality assumption, that is, its coverage probability will converge to the nominal level faster than other bounded methods. Simulation results show that our proposed method generally outperforms the existing methods in terms of controlling the coverage probability and the confidence width and is particularly useful when the denominator does not have adequate power to reject being 0. Finally, we apply the proposed approach to the interval estimation of the median response dose in pharmacology studies to show its practical usefulness.

Effects of intravenous lidocaine, dexmedetomidine, and their combination on IL-1, IL-6 and TNF-α in patients undergoing laparoscopic hysterectomy: a prospective, randomized controlled trial.

BACKGROUND: Surgical-related inflammatory responses have negative effects on postoperative recovery. Intravenous (IV) lidocaine and dexmedetomidine inhibits the inflammatory response. We investigated whether the co-administration of lidocaine and dexmedetomidine could further alleviate inflammatory responses compared with lidocaine or dexmedetomidine alone during laparoscopic hysterectomy. METHODS: A total of 160 patients were randomly allocated into four groups following laparoscopic hysterectomy: the control group (group C) received normal saline, the lidocaine group (group L) received lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion), the dexmedetomidine group (group D) received dexmedetomidine (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion), and the lidocaine plus dexmedetomidine group (group LD) received a combination of lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion) and dexmedetomidine (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion). The levels of plasma interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) at different time points were the primary outcomes. Secondary outcomes included hemodynamic variables, postoperative visual analogue scale (VAS) scores, time to first flatus, and incidence of nausea and vomiting after surgery. RESULTS: The levels of plasma IL-1, IL-6, and TNF-α were lower in groups D and LD than in group C and were lowest in group LD at the end of the procedure and 2 h after the operation (P < 0.05). The VAS scores were decreased in groups D and LD compared with group C (P < 0.05). The heart rate (HR) was decreased at the end of the procedure and 2 h after the operation in groups D and LD compared to groups C and L (P < 0.001). The mean blood pressure (MBP) was lower at 2 h after the operation in groups L, D, and LD than in group C (P < 0.001). There was a lower incidence of postoperative nausea and vomiting (PONV) in group LD than in group C (P < 0.05). CONCLUSIONS: The combination of lidocaine and dexmedetomidine significantly alleviated the inflammatory responses, decreased postoperative pain, and led to fewer PONV in patients undergoing laparoscopic hysterectomy. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03276533 ), registered on August 23, 2017.

Ultrasound-guided bilateral superficial cervical plexus block enhances the quality of recovery of uremia patients with secondary hyperparathyroidism following parathyroidectomy: a randomized controlled trial.

BACKGROUND: Parathyroidectomy has been proposed as a method for reducing parathyroid hormone levels. We evaluated the effects of ultrasound-guided bilateral superficial cervical plexus block (BSCPB) on the quality of recovery of uremia patients with secondary hyperparathyroidism (SHPT) following parathyroidectomy. METHODS: Eighty-two uremia patients who underwent parathyroidectomy and exhibited SHPT were randomly allocated to the BSCPB group or the control group (CON group). The patients received ultrasound-guided BSCPB with 7.5 ml of ropivacaine 0.5% on each side (BSCPB group) or equal amount of 0.9% normal saline (CON group). The primary outcome of the Quality of Recovery-40(QoR-40) score was recorded on the day before surgery and postoperative day 1(POD1). Secondary outcomes including total consumption of remifentanil, time to first required rescue analgesia, number of patients requiring rescue analgesia, and total consumption of tramadol during the first 24 h after surgery were recorded. The occurrence of postoperative nausea or vomiting (PONV) and the visual analogue scale (VAS) scores were assessed and recorded. RESULTS: The scores on the pain and emotional state dimensions of the QoR-40 and the total QoR-40 score were higher in the BSCPB group than in the CON group on POD1 (P = 0.000). Compared with the CON group, the total consumption of remifentanil was significantly decreased in the BSCPB group (P = 0.000). The BSCPB group exhibited longer time to first required rescue analgesia (P = 0.018), fewer patients requiring rescue analgesia (P = 0.000), and lower postoperative total consumption of tramadol during the first 24 h after surgery (P = 0.000) than the CON group. The incidence of PONV was significantly lower in the BSCPB group than in the CON group (P = 0.013). The VAS scores in the BSCPB group were lower than those in the CON group at all time-points after surgery (P = 0.000). CONCLUSION: Ultrasound-guided BSCPB with ropivacaine 0.5% can enhance the quality of recovery, postoperative analgesia, and reduce the incidence of PONV in uremia patients with SHPT following parathyroidectomy. TRIAL REGISTRATION: ChiCTR1900027185 . (Prospective registered). Initial registration date was 04/11/2019.

Effects of lidocaine, dexmedetomidine, and their combination infusion on postoperative nausea and vomiting following laparoscopic hysterectomy: a randomized controlled trial.

BACKGROUND: A few studies have reported that administration of lidocaine and dexmedetomidine relieves the incidence of postoperative nausea and vomiting (PONV). We explored whether combined infusion of lidocaine plus dexmedetomidine had lower occurrence of PONV undergoing laparoscopic hysterectomy with general anesthesia. METHODS: A total of 248 women undergoing elective laparoscopic hysterectomy were allocated into the following four groups: the control group (group C, n = 62) received an equal volume of saline, the lidocaine group (group L, n = 62) received intravenous lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion), the dexmedetomidine group (group D, n = 62) received dexmedetomidine administration (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion), and the lidocaine plus dexmedetomidine group (group LD, n = 62) received combination of lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion) and dexmedetomidine administration (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion). The primary outcome was the incidence of nausea, vomiting, and PONV during the first 48 h after surgery. The secondary outcomes included the incidence of total 24 h PONV after surgery, intraoperative remifentanil requirement, postoperative pain visual analogue scale (VAS) scores and fentanyl consumption, the incidence of bradycardia, agitation, shivering, and mouth dry during post-anesthesia care unit (PACU) stay period. RESULTS: The occurrence of nausea and PONV in group LD (5.0 and 8.3%) at 0-2 h after operation was lower than group C (21.7 and 28.3%) (P < 0.05). There was no statistically significant difference with respect to occurrence of nausea and PONV in groups L (13.3 and 20.0%) and D (8.3 and 13.3%) at 0-2 h after operation compared to group C (21.7 and 28.3%). The incidence of nausea, vomiting, and PONV at 2-24 and 24-48 h after surgery in all four groups was not statistically significant. The incidence of total 24 h PONV in group LD (33.3%) was significantly decreased compared to group C (60.0%) (P < 0.05). The cumulative consumption of fentanyl at 6 and 12 h after surgery was significantly reduced in group LD compared to other three groups (P < 0.05). The pain VAS scores were significantly decreased at 2, 6, and 12 h after operation in group LD compared to other three groups (P < 0.05). Remifentanil dose in the intraoperative period was significantly lower in groups LD and D compared with groups C and L (P < 0.05). The number of mouth dry, bradycardia, and over sedation during the PACU stay period was markedly increased in group LD (28.3, 30.0, and 35.0%, respectively) compared with groups C (1.7, 1.7, and 3.3%, respectively) and L (3.3, 5.0, and 6.7%, respectively) (P < 0.05). CONCLUSIONS: Lidocaine combined with dexmedetomidine infusion markedly decreased the occurrence of nausea and PONV at 0-2 h as well as the total 24 h PONV. However, it significantly increased the incidence of mouth dry, bradycardia, and over sedation during the PACU stay period after laparoscopic hysterectomy with general anesthesia. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03809923 ), registered on January 18, 2019.

A robust test for X-chromosome genetic association accounting for X-chromosome inactivation and imprinting.

The X chromosome is known to play an important role in many sex-specific diseases. However, only a few single-nucleotide polymorphisms on the X chromosome have been found to be associated with diseases. Compared to the autosomes, conducting association tests on the X chromosome is more intractable due to the difference in the number of X chromosomes between females and males. On the other hand, X-chromosome inactivation takes place in female mammals, which is a phenomenon in which the expression of one copy of two X chromosomes in females is silenced in order to achieve the same gene expression level as that in males. In addition, imprinting effects may be related to certain diseases. Currently, there are some existing approaches taking X-chromosome inactivation into account when testing for associations on the X chromosome. However, none of them allows for imprinting effects. Therefore, in this paper, we propose a robust test, ZXCII, which accounts for both X-chromosome inactivation and imprinting effects without requiring specifying the genetic models in advance. Simulation studies are conducted in order to investigate the validity and performance of ZXCII under various scenarios of different parameter values. The simulation results show that ZXCII controls the type I error rate well when there is no association. Furthermore, with regards to power, ZXCII is robust in all of the situations considered and generally outperforms most of the existing methods in the presence of imprinting effects, especially under complete imprinting effects.

The Glaesserella parasuis phosphoglucomutase is partially required for lipooligosaccharide synthesis.

Lipooligosaccharides (LOSs) are virulence determinants of Glaesserella parasuis, a pathogen of the respiratory tract of pigs. We previously reported that disruption of the galU or galE gene in G. parasuis results in increased sensitivity to porcine serum, indicating that the galactose catabolism pathway is required for polysaccharide formation in G. parasuis. Here, we evaluated the role of the HAPS_0849 gene in LOS synthesis. The G. parasuis SC096 HAPS_0849 mutant produced a highly truncated LOS molecule, although a small fraction of intact LOS was still observed, and this mutant was found to be more sensitive to serum than the parental strain. HAPS_0849 was overexpressed and purified for biochemical assays, and this protein exhibited phosphoglucomutase (PGM) activity. Heterologous expression of a pgm gene from Escherichia coli in the HAPS_0849 mutant led to restoration of the wild-type LOS glycoform, further demonstrating the PGM function of HAPS_0849 in G. parasuis. The autoagglutination and biofilm formation ability of this strain were also investigated. Disruption of HAPS_0849 led to an increased tendency to autoagglutinate and form more biofilms, and these enhanced phenotypes were observed in the absence of glucose. In addition, LOSs from HAPS_0849, galU and lgtB mutants had similar truncated glycoforms, while LOSs from the galE and lex-1 mutants exhibited another type of defective LOS pattern. These findings imply that HAPS_0849 may function upstream of GalU in the generation of glucose 1-phosphate. In conclusion, our results preliminarily described the functions of HAPS_0849 in G. parasuis, and this gene was partially required for LOS synthesis.

Role of small ubiquitin-like modifier proteins-1 (SUMO-1) in regulating migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is featured by erosive cartilage and bone destruction. The enhancing aggressive property of fibroblast-like synoviocytes (FLSs) plays a critical role in this process. Small ubiquitin-like modifier (SUMO) proteins, including SUMO-1, SUMO-2, SUMO-3 and SUMO-4, participate in regulating many cellular events such as survival, migration and signal transduction in some cell lines. However, their roles in the pathogenesis of RA are not well established. Therefore, we evaluated the role of SUMO proteins in RA FLSs migration and invasion. We found that expression of both SUMO-1 and SUMO-2 was elevated in FLSs and synovial tissues (STs) from patients with RA. SUMO-1 suppression by small interference RNA (siRNA) reduced migration and invasion as well as MMP-1 and MMP-3 expression in RA FLSs. We also demonstrated that SUMO-1 regulated lamellipodium formation during cell migration. To explore further into molecular mechanisms, we evaluated the effect of SUMO-1 knockdown on the activation of Rac1/PAK1, a critical signaling pathway that controls cell motility. Our results indicated that SUMO-1-mediated SUMOylation controlled Rac1 activation and modulated downstream PAK1 activity. Inhibition of Rac1 or PAK1 also decreased migration and invasion of RA FLSs. Our findings suggest that SUMO-1 suppression could be protective against joint destruction in RA by inhibiting aggressive behavior of RA FLSs.

Effects of intravenous infusion of lidocaine and dexmedetomidine on inhibiting cough during the tracheal extubation period after thyroid surgery.

BACKGROUND: Intravenous lidocaine and dexmedetomidine treatments have been proposed as methods for inhibiting cough. We compared the efficacy of intravenous lidocaine and dexmedetomidine treatments on inhibiting cough during the tracheal extubation period after thyroid surgery. METHODS: One hundred eighty patients undergoing thyroid surgeries were randomly allocated to the LIDO group (received lidocaine 1.5 mg/kg loading, 1.5 mg/kg/h infusion), the DEX group (received dexmedetomidine 0.5 µg/kg loading, 0.4 µg/kg/h infusion) and the CON group (received saline), with 60 cases in each group. The primary outcomes of cough were recorded. Secondary outcomes included hemodynamic variables, awareness time, volume of drainage, the postoperative visual analogue scale and adverse effects were recorded. RESULTS: The incidence of cough were significantly lower in the LIDO group (28.3%) and the DEX group (31.7%) than that in the CON group (66.7%) (P = 0.000). Additionally, both moderate and severe cough were significantly lower in the LIDO group (13.3%) and the DEX group (13.4%) than these in the CON group (43.4%) (P < 0.05). Compared with the two treatment groups, both mean arterial blood pressure and heart rate were significantly increased in the CON group during tracheal extubation (P < 0.05). Compared with the CON group, the volume of drainage was significantly reduced in the two treatment groups within 48 h after surgery (P < 0.05). compared with the CON group, the postoperative visual analogue scale was significantly lower in groups LIDO and DEX after surgery(P < 0.05). Compared with the LIDO group and the CON group, the time to awareness was longer in the DEX group (P < 0.05). In the DEX group, bradycardia was noted in 35 patients, while no bradycardia was noted in LIDO group and CON group. CONCLUSION: Compared with intravenous infusions of normal saline, both lidocaine and dexmedetomidine had equal effectiveness in attenuating cough and hemodynamic changes during the tracheal extubation period after thyroid surgery, and both of these treatments were able to reduce the volume of postoperative bleeding and provide better analgesic effect after surgery. But intravenous infusions of dexmedetomidine resulted in bradycardia and delayed the time to awareness when compared with lidocaine and normal saline. TRIAL REGISTRATION: ChiCTR1800017482 . (Prospective registered). Initial registration date was 01/08/2018.

A statistical measure for the skewness of X chromosome inactivation based on family trios.

BACKGROUND: X chromosome inactivation (XCI) is an important gene regulation mechanism in females to equalize the expression levels of X chromosome between two sexes. Generally, one of two X chromosomes in females is randomly chosen to be inactivated. Nonrandom XCI (XCI skewing) is also observed in females, which has been reported to play an important role in many X-linked diseases. However, there is no statistical measure available for the degree of the XCI skewing based on family data in population genetics. RESULTS: In this article, we propose a statistical approach to measure the degree of the XCI skewing based on family trios, which is represented by a ratio of two genotypic relative risks in females. The point estimate of the ratio is obtained from the maximum likelihood estimates of two genotypic relative risks. When parental genotypes are missing in some family trios, the expectation-conditional-maximization algorithm is adopted to obtain the corresponding maximum likelihood estimates. Further, the confidence interval of the ratio is derived based on the likelihood ratio test. Simulation results show that the likelihood-based confidence interval has an accurate coverage probability under the situations considered. Also, we apply our proposed method to the rheumatoid arthritis data from USA for its practical use, and find out that a locus, rs2238907, may undergo the XCI skewing against the at-risk allele. But this needs to be further confirmed by molecular genetics. CONCLUSIONS: The proposed statistical measure for the skewness of XCI is applicable to complete family trio data or family trio data with some paternal genotypes missing. The likelihood-based confidence interval has an accurate coverage probability under the situations considered. Therefore, our proposed statistical measure is generally recommended in practice for discovering the potential loci which undergo the XCI skewing.

Piperlongumine inhibits the proliferation, migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis.

OBJECTIVES: Recent studies have indicated that piperlongumine (PLM) may exert anti-inflammatory effects. In the present study, we determined the effect of PLM on the proliferation, apoptosis, migration and invasion of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) (referred to herein as RA FLS). We further explored the mechanisms by which the studied compound inhibits the functions of RA FLS. METHODS: RA FLS viability and apoptosis were tested using MTT and Annexin V/PI assays, respectively. We performed an EDU assay to examine the proliferation of RA FLS. The migration and invasion of these cells were measured using a transwell chamber method and wound closure assay. The MMP-1, MMP-3, and MMP-13 levels in the culture supernatants of RA FLS were detected using a Luminex Assay kit. The intracellular ROS levels were detected using DCFH-DA. The expression levels of signal transduction proteins were measured using western blot. RESULTS: We found that PLM induced apoptosis in RA FLS at concentrations of 15 and 20 µM. The proliferation of RA FLS was downregulated by PLM at concentrations of 1, 5 and 10 µM. Migration and invasion of RA FLS were reduced by PLM at concentrations of 1, 5 and 10 µM. PLM also inhibited cytoskeletal reorganization in migrating RA FLS and decreased TNF-α-induced intracellular ROS production. Moreover, we demonstrated the inhibitory effect of PLM on activation of the p38, JNK, NF-κB and STAT3 pathways. CONCLUSIONS: Our findings suggest that PLM can inhibit proliferation, migration and invasion of RA FLS. Moreover, these data suggests that PLM might have therapeutic potential for the treatment of RA.