Genome-scale targeted mutagenesis in Brassica napus using a pooled CRISPR library.

The recently constructed mutant libraries of diploid crops by the CRISPR-Cas9 system have provided abundant resources for functional genomics and crop breeding. However, because of the genome complexity, it is a big challenge to accomplish large-scale targeted mutagenesis in polyploid plants. Here, we demonstrate the feasibility of using a pooled CRISPR library to achieve genome-scale targeted editing in an allotetraploid crop of Brassica napus A total of 18,414 sgRNAs were designed to target 10,480 genes of interest, and afterward, 1104 regenerated transgenic plants harboring 1088 sgRNAs were obtained. Editing interrogation results revealed that 93 of the 178 genes were identified as mutated, thus representing an editing efficiency of 52.2%. Furthermore, we have discovered that Cas9-mediated DNA cleavages tend to occur at all the target sites guided by the same individual sgRNA, a novel finding in polyploid plants. Finally, we show the strong capability of reverse genetic screening for various traits with the postgenotyped plants. Several genes, which might dominate the fatty acid profile and seed oil content and have yet to be reported, were unveiled from the forward genetic studies. Our research provides valuable resources for functional genomics, elite crop breeding, and a good reference for high-throughput targeted mutagenesis in other polyploid plants.

An Ultrathin Composite Polymer Electrolyte Dual-Reinforced by a Polymer of Intrinsic Microporosity (PIM-1) and Poly(tetrafluoroethylene) (PTFE) Porous Membrane.

The performances of solid-state polymer electrolytes are urgently required to be further improved for high energy density lithium metal batteries. Herein, a highly reinforced ultrathin composite polymer electrolyte (PLPP) is successfully fabricated in a large scale by densely filling the well-dispersed mixture of polyethylene oxide (PEO), Li-salt (LiTFSI) and a polymer of intrinsic microporosity (PIM-1) into porous poly(tetrafluoroethylene) (PTFE) matrix. Based on the macro-plus-micro synergistic enhancement of the PTFE with excellent mechanical properties and the soluble PIM-1 with suitable functional groups, the PLPP electrolyte exhibits excellent properties including mechanical stress, thermal stability, lithium-ion transference number, voltage window and ionic conductivity, which are all superior to the typical PEO/LiTFSI electrolytes. As a result, the Li/PLPP/Li symmetric cell can stably cycle for > 2000 h, and the LiFePO4/PLPP/Li full cell exhibits excellent rate performance (>10 C) and high cycling stability with an initial capacity of 158.8 mAh g-1 and a capacity retention of 78.8% after 300 cycles. In addition, the excellent mechanical properties as well as the wide voltage window reasonably result in the stable operation of full cells with either high-loading cathode up to 28.1 mg cm-2 or high voltage cathode with high energy density.

GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.

ALKBH5-mediated m6A demethylation of pri-miR-199a-5p exacerbates myocardial ischemia/reperfusion injury by regulating TRAF3-mediated pyroptosis.

Myocardial ischemia‒reperfusion injury (MI/RI) is closely related to pyroptosis. alkB homolog 5 (ALKBH5) is abnormally expressed in the MI/RI models. However, the detailed molecular mechanism of ALKBH5 in MI/RI has not been elucidated. In this study, rats and H9C2 cells served as experimental subjects and received MI/R induction and H/R induction, respectively. The abundance of the targeted molecules was evaluated using RT-qPCR, Western blotting, immunohistochemistry, immunofluorescence, and enzyme-linked immunosorbent assay. The heart functions of the rats were evaluated using echocardiography, and heart injury was evaluated. Cell viability and pyroptosis were determined using cell counting Kit-8 and flow cytometry, respectively. Total m6A modification was measured using a commercial kit, and pri-miR-199a-5p m6A modification was detected by Me-RNA immunoprecipitation (RIP) assay. The interactions among the molecules were validated using RIP and luciferase experiments. ALKBH5 was abnormally highly expressed in H/R-induced H9C2 cells and MI/RI rats. ALKBH5 silencing improved injury and inhibited pyroptosis. ALKBH5 reduced pri-miR-199a-5p m6A methylation to block miR-199a-5p maturation and inhibit its expression. TNF receptor-associated Factor 3 (TRAF3) is a downstream gene of miR-199a-5p. Furthermore, in H/R-induced H9C2 cells, the miR-199a-5p inhibitor-mediated promotion of pyroptosis was reversed by ALKBH5 silencing, and the TRAF3 overexpression-mediated promotion of pyroptosis was offset by miR-199a-5p upregulation. ALKBH5 silencing inhibited pri-miR-199a-5p expression and enhanced pri-miR-199a-5p m6A modification to promote miR-199a-5p maturation and enhance its expression, thereby suppressing pyroptosis to alleviate MI/RI through decreasing TRAF3 expression.

PsrA is a novel regulator contributes to antibiotic synthesis, bacterial virulence, cell motility and extracellular polysaccharides production in Serratia marcescens.

Serratia marcescens is a Gram-negative bacterium of the Enterobacteriaceae family that can produce numbers of biologically active secondary metabolites. However, our understanding of the regulatory mechanisms behind secondary metabolites biosynthesis in S. marcescens remains limited. In this study, we identified an uncharacterized LysR family transcriptional regulator, encoding gene BVG90_12635, here we named psrA, that positively controlled prodigiosin synthesis in S. marcescens. This phenotype corresponded to PsrA positive control of transcriptional of the prodigiosin-associated pig operon by directly binding to a regulatory binding site (RBS) and an activating binding site (ABS) in the promoter region of the pig operon. We demonstrated that L-proline is an effector for the PsrA, which enhances the binding affinity of PsrA to its target promoters. Using transcriptomics and further experiments, we show that PsrA indirectly regulates pleiotropic phenotypes, including serrawettin W1 biosynthesis, extracellular polysaccharide production, biofilm formation, swarming motility and T6SS-mediated antibacterial activity in S. marcescens. Collectively, this study proposes that PsrA is a novel regulator that contributes to antibiotic synthesis, bacterial virulence, cell motility and extracellular polysaccharides production in S. marcescens and provides important clues for future studies exploring the function of the PsrA and PsrA-like proteins which are widely present in many other bacteria.

Clinical efficacy of acupoint catgut embedding in the treatment of allergic rhinitis: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of acupoint catgut embedding in the treatment of allergic rhinitis by Meta-analysis. METHODS: Pubmed, Web of Science, Embase, Elsevier, CNKI, and VIP databases were searched for clinical randomized controlled trials (RCTS) on acupoint catgut embedding for allergic rhinitis from the establishment of the database to December 30, 2022. RevMan5.4 and Stata12 software were used for Meta-analysis. RESULTS: A total of 17 articles were included, involving 1231 patients. Meta-analysis showed that the total effective rate of acupoint catgut embedding for allergic rhinitis was higher than that of the control group [Pooled Odds Ratio = 5.19, 95%CI (3.14, 8.58), P < 0.00001]. Sensitivity analysis indicated that the total effective rate of acupoint catgut embedding in the treatment of allergic rhinitis was stable. The efficacy of the acupoint embedding group was better than that of the western medicine group [OR = 5.78, 95%CI (3.25, 10.27), P < 0.00001]. Acupoint embedding decreased serum IL-33 levels [MD = -70.79, 95%CI (-102.60, -38.98), P < 0.0001] and improved TNNSS score [MD = -0.25, 95%CI (-0.40, -0.11), P = 0.0005] was statistically different from the control group. CONCLUSION: Acupoint catgut embedding in the treatment of allergic rhinitis has a certain effect, but the accuracy of this conclusion still needs to be verified by higher-quality RCT in the later stage.

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes.

BACKGROUND: Patients with Parkinson's disease (PD) have consistently demonstrated brain structure abnormalities, indicating the presence of shared etiological and pathological processes between PD and brain structures; however, the genetic relationship remains poorly understood. OBJECTIVE: The aim of this study was to investigate the extent of shared genetic architecture between PD and brain structural phenotypes (BSPs) and to identify shared genomic loci. METHODS: We used the summary statistics from genome-wide association studies to conduct MiXeR and conditional/conjunctional false discovery rate analyses to investigate the shared genetic signatures between PD and BSPs. Subsequent expression quantitative trait loci mapping in the human brain and enrichment analyses were also performed. RESULTS: MiXeR analysis identified genetic overlap between PD and various BSPs, including total cortical surface area, average cortical thickness, and specific brain volumetric structures. Further analysis using conditional false discovery rate (FDR) identified 21 novel PD risk loci on associations with BSPs at conditional FDR < 0.01, and the conjunctional FDR analysis demonstrated that PD shared several genomic loci with certain BSPs at conjunctional FDR < 0.05. Among the shared loci, 16 credible mapped genes showed high expression in the brain tissues and were primarily associated with immune function-related biological processes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between PD and BSPs and identified multiple shared genomic loci and risk genes, which are likely related to immune-related biological processes. These findings provide insight into the complex genetic architecture associated with PD. © 2023 International Parkinson and Movement Disorder Society.

Chao Nang Qing prescription promotes granulosa cell apoptosis and autophagy by targeting GATA3.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrine disease in women of reproductive age, with complex pathological symptoms and mechanisms. This study explored the mechanism of action of Chao Nang Qing prescription (CNQP) in PCOS. METHODS: CNQP-medicated serum was prepared for culturing KGN granulosa cells. GATA3 knockdown, MYCT1 overexpression, and MYCT1 knockdown vectors were constructed to transfect KGN cells. Cell proliferation and apoptosis, as well as the expression of autophagy-related LC3-II/I, Beclin-1, and p62, were analyzed. ChIP was used to detect the binding of GATA3 and the MYCT1 promoter, and dual-luciferase reporter assay was used to analyze the influence of GATA3 on MYCT1 promoter activity. RESULTS: CNQP treatment reduced proliferation, increased apoptosis, elevated LC3-II/I, Beclin-1, GATA3, and MYCT1 expression, and decreased p62 expression in KGN cells. GATA3 bound to the MYCT1 promoter to promote MYCT1 expression. MYCT1 overexpression impeded proliferation and stimulated apoptosis and autophagy in KGN cells. Compared to CNQP treatment alone, GATA3 or MYCT1 knockdown before CNQP treatment promoted proliferation and reduced apoptosis and autophagy in KGN cells. CONCLUSION: CNQP may modulate KGN cell activity by upregulating GATA3 and MYCT1 expression, thereby slowing down the progression of PCOS.

Dissecting the Meiotic Recombination Patterns in a Brassica napus Double Haploid Population Using 60K SNP Array.

Meiotic recombination not only maintains the stability of the chromosome structure but also creates genetic variations for adapting to changeable environments. A better understanding of the mechanism of crossover (CO) patterns at the population level is useful for crop improvement. However, there are limited cost-effective and universal methods to detect the recombination frequency at the population level in Brassica napus. Here, the Brassica 60K Illumina Infinium SNP array (Brassica 60K array) was used to systematically study the recombination landscape in a double haploid (DH) population of B. napus. It was found that COs were unevenly distributed across the whole genome, and a higher frequency of COs existed at the distal ends of each chromosome. A considerable number of genes (more than 30%) in the CO hot regions were associated with plant defense and regulation. In most tissues, the average gene expression level in the hot regions (CO frequency of greater than 2 cM/Mb) was significantly higher than that in the regions with a CO frequency of less than 1 cM/Mb. In addition, a bin map was constructed with 1995 recombination bins. For seed oil content, Bin 1131 to 1134, Bin 1308 to 1311, Bin 1864 to 1869, and Bin 2184 to 2230 were identified on chromosomes A08, A09, C03, and C06, respectively, which could explain 8.5%, 17.3%, 8.6%, and 3.9% of the phenotypic variation. These results could not only deepen our understanding of meiotic recombination in B. napus at the population level, and provide useful information for rapeseed breeding in the future, but also provided a reference for studying CO frequency in other species.

Reversible Regulation of Polar Gas Molecules by Azobenzene-Based Photoswitchable Metal-Organic Framework Thin Films.

The development of tunable molecule separation membranes requires materials with remote controllability and ultra-high separation capability. In this paper, a novel photoswitchable metal organic framework (MOF) thin film (Cu2(AzoBPDC)2) was prepared by liquid phase epitaxial layer-by-layer assembly to realize the reversible remote-controlled switching. The azobenzene side groups in the Cu2(AzoBPDC)2 thin film showed excellent reversible photoswitching performance under UV (365 nm) and Vis (450 nm) irradiation, achieving the remote-controlled mode of the diffusion flux of polar gas molecules in the MOF thin film.

A Recyclable and Scalable High-Capacity Organic Battery.

Redox organic electrode materials (OEMs) have attracted extensive attention for batteries due to the possibility to be designed with high performance. However, the practical application of OEMs requires rigor criteria such as low cost, recyclability, scalability and high performance etc. and hence seems still far away. Here, we demonstrate an OEM for high performance aqueous organic batteries. Quantification of the charge storage confirmed the storage of protons with fast reaction kinetics, thereby enabling the high performance at high mass loading. As a result, the laminated pouch cells delivered Ampere-hour-scale capacity with excellent cycling performance. Benefited from the small molecular nature and the stable both charged and discharged states, the electrodes can be recycled at any states of charge with high yields (more than 90 %). This work provides a substantial step in the practical applications of OEMs for the future sustainable batteries.

Individualized right ventricular outflow tract reconstruction using autologous pulmonary tissue in situ for the treatment of pulmonary atresia with ventricular septum defect.

OBJECTIVE: The study aims to evaluate the feasibility and effectiveness of an individualized procedure for right ventricular outflow tract (RVOT) reconstruction in pulmonary atresia with ventricular septal defect (PA-VSD). METHODS: RVOT was reconstructed using autologous pulmonary artery tissue preserved in situ as the posterior wall and a bovine jugular vein patch (BJVP) as the anterior wall in patients with PA-VSD (observation group). The size of the BJVP made from a bovine jugular vein conduit (BJVC) was individually calculated using a formula based on the child's weight and the size of the autologous pulmonary artery (the diameter of BJVC DB⁢J⁢V⁢C = Dt⁢h⁢e⁢o⁢r⁢e⁢t⁢i⁢c⁢a⁢l-W⁢z^-4π). Its effect was then compared with the conventional modified Rastelli procedure based on the BJVC (control group). RESULTS: A total of 22 patients that underwent the new procedure were simultaneously compared with the 25 patients in the control group. No deaths occurred in both groups. Notably, there were no significant differences in mechanical ventilation, ICU and postoperative residence, cardiopulmonary bypass, and aortic cross-clamp time. In the follow-up, which spanned for 8-12 years (mean 9.2 years), only four cases with moderate regurgitation were noted in the observation group without obstruction. In the control group, two patients had a conduit replacement. Three patients suffered from anastomotic stenosis, which was corrected by balloon dilatation. CONCLUSION: Individualized RVOT reconstruction with autologous pulmonary tissue preserved in situ as the posterior wall is adequate for treating PA-VSD.

Development of a novel predictive model for lymph node metastasis in patients with endometrial endometrioid carcinoma.

BACKGROUND: Globally, the burden of endometrial endometrioid carcinoma (EEC) increases annually. However, the histological grade of EEC remains unelucidated. We developed a novel model for predicting lymph node metastasis (LNM) in patients with endometrioid carcinoma (EC), which has not been well established. METHODS: A total of 344 patients with EEC were classified into training (n = 226) and validation (n = 118) cohorts. To develop a nomogram to predict LNM, independent predictors were defined using univariate and multivariate regression analyses. The calibration curve, area under the decision curve analysis (DCA), and receiver operating characteristic curve were used to evaluate the performance of the nomogram. RESULTS: Independent predictors of LNM in EC were identified in the univariate analysis, including mitosis; microcystic, elongated, and fragmented patterns; lymphovascular invasion (LVI); necrosis; and high-grade pattern. Mitosis, LVI, and high-grade pattern remained independent predictors of LNM in multivariate analysis. An LNM nomogram that was constructed by incorporating the five predictors showed reliable discrimination and calibration. DCA showed that the LNM nomogram scoring system had significant clinical application value. In addition, a high nomogram score (score > 150) was a significant prognosticator for survival in both LNM-positive and LNM-negative ECs. CONCLUSIONS: Our novel predictive model for LNM in patients with EC has the potential to assist surgeons in making optimal treatment decisions.

Landscape and progress of global peptide drugs in obstetrics and gynaecology.

Peptides have gained popularity in the global market during recent years and have been placed between small molecule drugs and biologics. However, little is known about the comprehensive landscape of peptide drugs in obstetrics and gynaecology. Herein, we analysed new peptide drug-related clinical trials in obstetrics and gynaecology registered on ClinicalTrials.gov. The number and percentage were used for statistical analysis, and a time trend analysis was conducted by calculating the annual growth rate. We aimed to provide the first overview of the changing landscape and status of global peptide drugs in this prospective field, including exploring drug targets, the cutting-edge oncotherapy of peptide vaccines and peptide-drug conjugates, and unsolved challenges with oral administration.

Horner syndrome after thyroid-related surgery: a review.

BACKGROUND: Horner syndrome (HS) is caused by damage to the cervical sympathetic nerve. HS is a rare complication after thyroidectomy. The main manifestations of HS include miosis and ptosis of the eyelids, which seriously affect esthetics and quality of life. At present, there is a lack of research on HS after thyroidectomy, and its etiology is not completely clear. This review aimed to evaluate how to reduce the incidence of HS and promote the recovery from HS as well as to provide a reference for the protection of cervical sympathetic nerves during surgery. RESULTS: HS caused by thyroid surgery is not particularly common, but it is still worthy of our attention. After searching with "Horner Syndrome," "Thyroid" as keywords, a total of 22 related cases were screened in PubMed. The results showed that open surgery, endoscopy, microwave ablation, and other surgical methods may have HS after operation. In addition, the statistics of 1213 thyroid surgeries in our hospital showed that the incidence of HS after endoscopic surgery (0.39%) was slightly higher than that after open surgery (0.29%). Further, this review analyzed potential causes of HS after thyroidectomy, so as to provide a theoretical basis for reducing its incidence. CONCLUSION: Preventing HS during thyroidectomy is a difficult problem. The close and highly variable anatomical relationship between the thyroid and cervical sympathetic nerves increases the risk of sympathetic nerve damage during thyroidectomy. Surgery and the use of energy equipment are also closely related to the occurrence of HS.

Mid-term outcomes of right subaxillary approach versus median sternotomy incision for ventricular septal defect with patent ductus arteriosus.

BACKGROUND: This study aimed to evaluate and compare two surgical approaches to repair ventricular septal defect (VSD) with patent ductus arteriosus (PDA) and to explore the patients' health-related quality of life (HRQoL). METHODS: We conducted a retrospective study of all patients who had surgical repair of VSD and PDA between 2013 and 2015 using the right subaxillary approach (group A) or the median sternotomy incision (group B). The outcomes of both techniques were compared. Paediatric QoL Inventory 4.0 scale was applied to assess patients' HRQoL in the 6th postoperative year. Multiple linear regression analysis was performed to explore factors associated with higher HRQoL scores. RESULTS: A total of 128 patients were included (group A, n = 70 and group B, n = 58). Patients in group A were older and heavier than patients in group B. In group B, the diameters of VSD and PDA were larger and the pulmonary artery pressures were higher than those in group A (p < 0.001). No mortality occurred on a mean follow-up of 8.3 ± 1.2 years. Patients in group A had higher HRQoL scores than those in group B in terms of emotional and social functioning dimensions. The right subaxillary approach (OR: 3.56; 95% CI 1.65-5.46), higher parents' education level (OR: 1.62; 95% CI 0.65-2.31), and better family economic status (OR: 1.48; 95% CI 0.79-2.45) were associated with higher HRQoL scores. CONCLUSIONS: Younger and smaller patients receiving median sternotomy incisions due to large defects and pulmonary hypertension had lower HRQoL scores. The right subaxillary approach, higher parents' education level, and better family economic status were associated with higher HRQoL scores.

Regulator RcsB Controls Prodigiosin Synthesis and Various Cellular Processes in Serratia marcescens JNB5-1.

Prodigiosin (PG), a red linear tripyrrole pigment normally secreted by Serratia marcescens, has received attention for its reported immunosuppressive, antimicrobial, and anticancer properties. Although several genes have been shown to be important for prodigiosin synthesis, information on the regulatory mechanisms behind this cellular process remains limited. In this work, we identified that the transcriptional regulator RcsB encoding gene BVG90_13250 (rcsB) negatively controlled prodigiosin biosynthesis in S. marcescens Disruption of rcsB conferred a remarkably increased production of prodigiosin. This phenotype corresponded to negative control of transcription of the prodigiosin-associated pig operon by RcsB, probably by binding to the promoter region of the prodigiosin synthesis positive regulator FlhDC. Moreover, using transcriptomics and further experiments, we revealed that RcsB also controlled some other important cellular processes, including swimming and swarming motilities, capsular polysaccharide production, biofilm formation, and acid resistance (AR), in S. marcescens Collectively, this work proposes that RcsB is a prodigiosin synthesis repressor in S. marcescens and provides insight into the regulatory mechanism of RcsB in cell motility, capsular polysaccharide production, and acid resistance in S. marcescensIMPORTANCE RcsB is a two-component response regulator in the Rcs phosphorelay system, and it plays versatile regulatory functions in Enterobacteriaceae However, information on the function of the RcsB protein in bacteria, especially in S. marcescens, remains limited. In this work, we illustrated experimentally that the RcsB protein was involved in diverse cellular processes in S. marcescens, including prodigiosin synthesis, cell motility, capsular polysaccharide production, biofilm formation, and acid resistance. Additionally, the regulatory mechanism of the RcsB protein in these cellular processes was investigated. In conclusion, this work indicated that RcsB could be a regulator for prodigiosin synthesis and provides insight into the function of the RcsB protein in S. marcescens.

Remimazolam tosilate in upper gastrointestinal endoscopy: A multicenter, randomized, non-inferiority, phase III trial.

BACKGROUND AND AIM: Remimazolam tosilate (RT) is a new short-acting GABA(A) receptor agonist, having potential to be an effective option for procedural sedation. Here, we aimed to compare the efficacy and safety of RT with propofol in patients undergoing upper gastrointestinal endoscopy. METHODS: This positive-controlled, non-inferiority, phase III trial recruited patients at 17 centers, between September 2017 and November 2017. A total of 384 patients scheduled to undergo upper gastrointestinal endoscopy were randomly assigned to receive RT or propofol. Primary endpoint was the success rate of sedation. Adverse events (AEs) were recorded to evaluate safety. RESULTS: The success rate of sedation in the RT group was non-inferior to that in the propofol group (97.34% vs 100.00%; difference in rate -2.66%, 95% CI -4.96 to -0.36, meeting criteria for non-inferiority). Patients in the RT group had longer time to adequate sedation (P < 0.0001) but shorter time to fully alert (P < 0.0001) than that in the propofol group. The incidences of hypotension (13.04% vs 42.86%, P < 0.0001), treatment-related hypotension (0.54% vs 5.82%, P < 0.0001), and respiratory depression (1.09% vs 6.88%, P = 0.0064) were significantly lower in the RT group. AEs were reported in 74 (39.15%) patients in the RT group and 114 (60.32%) patients in the propofol group, with significant difference (P < 0.0001). CONCLUSION: This trial established non-inferior sedation success rate of RT compared with propofol. RT allows faster recovery from sedation compared with propofol. The safety profile is favorable and appears to be superior to propofol, indicating that it was feasible and well tolerated for patients.

Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.

CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.

A Modified Approach with Caval Transection for Supracardiac Total Anomalous Pulmonary Venous Connection: Comparison Between Conventional and Sutureless Surgery in 173 Patients.

The efficacy of primary sutureless repair for supracardiac total anomalous pulmonary venous connection (TAPVC) needs to be confirmed. This study aimed to compare the long-term outcomes between the conventional surgery and the sutureless technique with a modified approach in superior TAPVC. Between January 2008 and December 2018, 173 patients with supracardiac TAPVC underwent surgery either with the conventional procedure (n = 130) or the sutureless repair (n = 43). Multivariate analysis and competing-risk analysis were used to identify risk factors for early death and postoperative pulmonary venous obstruction (PVO), respectively. Among 173 patients who underwent repair of supracardiac TAPVC, 46 (28%) had preoperative PVO, and 22 (12.7%) had postoperative PVO. The sutureless group had a lower postoperative PVO rate compared with the conventional group (p = 0.027). The risk factors for death were age ≤ 28 days [odds ratio (OR), 11.56; 95% confidence interval (CI) 1.33-100.47, p = 0.015], weight ≤ 3 kg (OR 9.57; 95% CI 1.58-58.09, p = 0.009), emergency operation (OR 19.24; 95% CI 3.18-116.35, p = 0.002), cardiopulmonary bypass time (OR 2.16; 95% CI 1.36-3.43, p = 0.003), cross-clamp time (OR 1.73; 95% CI 1.20-2.50, p = 0.022), and duration of ventilation (OR 1.11; 95% CI 1.02-1.21, p = 0.027). Age ≤ 28 days [Hazard Ratio (HR) 1.92; 95% CI 1.92-11.02, p < 0.001] and preoperative PVO (HR 41.70; 95% CI 8.15-213.5, p < 0.001) were associated with postoperative PVO. The sutureless repair is a reliable technique for supracardiac TAPVC. Age ≤ 28 days is associated with 30-day mortality and postoperative PVO.