Injectable Nanocomposite Hydrogels with Strong Antibacterial, Osteoinductive, and ROS-Scavenging Capabilities for Periodontitis Treatment.

Injectable antibacterial and osteoinductive hydrogels have received considerable attention for promoting bone regeneration owing to their versatile functionalities. However, a current hydrogel with antibacterial, osteoinductive, and antioxidant properties by a facile method for periodontitis treatment is still missing. To overcome this issue, we designed an injectable hydrogel system (GPM) composed of gelatin, Ti3C2Tx MXene nanosheets, and poly-l-lysine using a simple enzymatic cross-linking technique. Physicochemical characterization demonstrated that the GPM hydrogel matrix exhibited excellent stability, moderate tissue adhesion ability, and good mechanical behavior. The GPM hydrogels significantly inhibited the growth of Porphyromonas gingivalis, scavenged reactive oxygen species, attenuated inflammatory responses, and enhanced bone tissue regeneration. Intriguingly, the arrangement of the junctional epithelium, alveolar bone volume, and alveolar bone height in the GPM-treated periodontal disease group recovered to that of the healthy group. Therefore, our injectable hydrogel system with versatile functions may serve as an excellent tissue scaffold for the treatment of periodontitis.

Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated Mesenchymal Stem Cell Recruitment and Histone Acetylation-Mediated Osteogenesis.

Cranial bone defects remain a major clinical challenge, increasing patients' life burdens. Tricarboxylic acid (TCA) cycle metabolites play crucial roles in facilitating bone tissue regeneration. However, the development of TCA cycle metabolite-modified biomimetic grafts for skull bone regeneration still needs to be improved. The mechanism underlying the release of TCA cycle metabolites from biomaterials in regulating immune responses and mesenchymal stem cell (MSC) fate (migration and differentiation) remains unknown. Herein, this work constructs biomimetic hydrogels composed of gelatin and chitosan networks covalently cross-linked by genipin (CGG hydrogels). A series of TCA cycle metabolite-coordinated CGG hydrogels with strong mechanical and antiswelling performances are subsequently developed. Remarkably, the citrate (Na3Cit, Cit)-coordinated CGG hydrogels (CGG-Cit hydrogels) with the highest mechanical modulus and strength significantly promote skull bone regeneration in rat and murine cranial defects. Mechanistically, using a transgenic mouse model, bulk RNA sequencing, and single-cell RNA sequencing, this work demonstrates that CGG-Cit hydrogels promote Gli1+ MSC migration via neutrophil-secreted oncostatin M. Results also indicate that citrate improves osteogenesis via enhanced histone H3K9 acetylation on osteogenic master genes. Taken together, the immune microenvironment- and MSC fate-regulated CGG-Cit hydrogels represent a highly efficient and facile approach toward skull bone tissue regeneration with great potential for bench-to-bedside translation.

Optimal treatment strategy for recurrent hepatocellular carcinoma based on recurrence time and tumor size: A propensity score matching study.

BACKGROUND: Recurrent hepatocellular carcinoma (RHCC) is commonly treated with transcatheter arterial chemoembolization (TACE) combined with microwave ablation (MWA) or repeated hepatectomy(RH), but the optimal treatment strategy is still controversial. This study aimed to compare the efficacy and safety of TACE-MWA and RH in RHCC patients after initial radical hepatectomy. METHODS: A total of 210 RHCC patients were included between June 2014 and January 2021, with 126 patients in the TACE-MWA group and 84 patients in the RH group. The primary endpoints were median repeat recurrence-free survival (rRFS) and overall survival (OS), and the secondary endpoint was complications. Propensity-score matching (PSM) was conducted to minimize bias. Subgroup analysis based on recurrence patterns (recurrence time and tumor size) was performed, and prognostic factors were studied. RESULTS: Before PSM, the RH group had better median OS (37.0 vs 26.0 months, P<0.001) and rRFS (15.0 vs 14.0 months, P = 0.003). After PSM, the RH group also had a better median OS (33.5 vs 29.0 months, P = 0.038), but there was no significant difference in median rRFS between the two groups (14.0 vs 13.0 months, P = 0.099). Subgroup analysis showed that when RHCC diameter>5 cm, RH had a better median OS (33.5 vs 25.0 months, P = 0.013) and rRFS (14.0 vs 10.9 months, P = 0.030). When the RHCC diameter was≤5 cm, there was no significant difference in the median OS (37.0 vs 31.0 months, P = 0.338) and rRFS (15.0 vs 17.0 months, P = 0.758) between the two groups. When RHCC relapses in the early stage (≤2 years), there is no significant difference in the median OS (26.0 vs 26.0 months, P = 0.310) and rRFS (12.0 vs 10.5 months, P = 0.089) between the two groups. When RHCC relapses in the late stage (>2 years), the RH group has better median OS (41.0 vs 33.0 months, P<0.001) and rRFS (30.0 vs 20.0 months, P = 0.010). CONCLUSION: Individualized therapy is necessary for RHCC. TACE -MWA may be a good choice for RHCC with early recurrence or tumor diameter ≤5 cm. However, RH should be the first choice for RHCC with late recurrence or tumor diameter>5 cm.

Divalent Anion-Induced Biohydrogels with High Strength, Anti-swelling, and Bioactive Capability for Enhanced Skull Bone Regeneration.

Increased intracranial pressure after traumatic brain injury (TBI) is an urgent problem in clinical practice. A pliable hydrogel is preferred for cranioplasty applications after TBI since it can protect brain tissue and promote bone healing. Nevertheless, biohydrogels for cranial bone regeneration still face challenges of poor mechanical properties, large swelling ratios, and low osteogenesis activity. Herein, inspired by Hofmeister effects, biopolymer hydrogels composed of protein and polysaccharides were treated with a Hofmeister series including a series of monovalent and divalent anions. Our results reveal that the divalent anion-cross-linked biohydrogels exhibit stronger mechanical properties and lower swelling ratios compared with monovalent-anion treated gels. Intriguingly, the divalent HPO42- anion induced biohybrid hydrogels with excellent mechanical behaviors (3.7 ± 0.58 MPa, 484 ± 76.7 kPa, and 148.3 ± 6.85 kJ/m3), anti-swelling capability (16.7%), and gradual degradation ability, significantly stimulating osteogenic differentiation and in vivo cranial bone regeneration. Overall, this study may provide new insights into the design of biomimetic hydrogels for treating cranial bone defects after TBI.

Mitochondrial Dynamics: Working with the Cytoskeleton and Intracellular Organelles to Mediate Mechanotransduction.

Cells are constantly exposed to various mechanical environments; therefore, it is important that they are able to sense and adapt to changes. It is known that the cytoskeleton plays a critical role in mediating and generating extra- and intracellular forces and that mitochondrial dynamics are crucial for maintaining energy homeostasis. Nevertheless, the mechanisms by which cells integrate mechanosensing, mechanotransduction, and metabolic reprogramming remain poorly understood. In this review, we first discuss the interaction between mitochondrial dynamics and cytoskeletal components, followed by the annotation of membranous organelles intimately related to mitochondrial dynamic events. Finally, we discuss the evidence supporting the participation of mitochondria in mechanotransduction and corresponding alterations in cellular energy conditions. Notable advances in bioenergetics and biomechanics suggest that the mechanotransduction system composed of mitochondria, the cytoskeletal system, and membranous organelles is regulated through mitochondrial dynamics, which may be a promising target for further investigation and precision therapies.

Prognostic factors of nivolumab in advanced hepatocellular carcinoma: a systematic review and meta-analysis.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, and a major unresolved medical issue. According to the guideline recommendations of the European Association for the Study of the Liver in 2018 and the American Society for Clinical Oncology (ASCO) Guideline, nivolumab is a reasonable option for appropriate advanced stage HCC. EVIDENCE ACQUISITION: We searched the PubMed, Embase and CNKI (China National Knowledge Infrastructure) databases for all articles within a range of published years from 2010 to 2020 of nivolumab in advanced hepatocellular carcinoma and carried out this meta-analysis on all published studies to estimate prognostic factors of nivolumab in advanced hepatocellular carcinoma. EVIDENCE SYNTHESIS: Finally, 6 studies with 627 advanced hepatocellular carcinoma patients treated with nivolumab met the inclusion criteria for this study. Our results indicated that α-fetoprotein (AFP), eastern Cooperative Oncology Group (ECOG) performance status, Child­Pugh Class, portal vein invasion, protein induced by vitamin K absence­II (PIVKA­II), and albumin­bilirubin (ALBI) score were prognostic factor of nivolumab in advanced hepatocellular carcinoma; however, hepatitis C virus (HBV) infection, Barcelona Clinic Liver Cancer (BCLC) stage, and extrahepatic metastasis were not significant prognostic factors. CONCLUSIONS: Our meta-analysis indicated the potential prognostic factor of nivolumab in advanced hepatocellular carcinoma. However, ongoing clinical and translational research may provide us a better understanding of the prognostic factor and mechanisms.

Current status of surgery for portal hypertension in China: a national multi-center survey analysis / 中华器官移植杂志

Objective:To explore the current status of surgery for portal hypertension to grasp current status and future development of surgery in China.Methods:This study is jointly sponsored by China Hepatobiliary & Pancreatic Specialist Alliance & Portal Hypertension Alliance in China (CHESS).Comprehensive surveying is conducted for basic domestic situations of surgery for portal hypertension, including case load, surgical approaches, management of postoperative complications, primary effects, existing confusion and obstacles, liver transplantation(LT), laparoscopic procedures and transjugular intrahepatic portosystemic shunt(TIPS), etc.Results:A total of 8 512 cases of portal hypertension surgery are performed at 378 hospitals nationwide in 2021.Splenectomy plus devascularization predominated(53.0%)and laparoscopy accounted for 76.1%.Primary goal is preventing rebleeding(67.0%) and 72.8% of hospitals used preventive anticoagulants after conventional surgery.And 80.7% of teams believe that the formation of postoperative portal vein thrombosis is a surgical dilemma and 65.3% of hospitals practiced both laparoscopy and TIPS.The major reasons for patients with portal hypertension not receiving LT are due to a lack of qualifications for LT(69.3%)and economic factors(69.0%).Conclusions:Surgery is an integral part of management of portal hypertension in China.However, it is imperative to further standardize the grasp of surgical indications, the handling of surgical operation and the management of postoperative complications.Moreover, prospective, multi-center randomized controlled clinical studies should be performed.

Influence of the connotation of the prevention and treatment recommendations of the physical examination report on the intention of the medical examiner / 中华健康管理学杂志

Objective:To explore the influence on the willingness to seek medical treatment by revising the recommendations for prevention and treatment in the medical examination report.Methods:Revising the prevention and treatment recommendations for four diseases, including proteinuria, hyperuricemia, hydronephrosis and renal insufficiency to clearly inform the etiology and prognosis of them. Using a cross-sectional study method, pre-revision prevention and treatment recommendations (version A) and post-revision prevention and treatment recommendations (version B) questionnaires were randomly distributed to medical examiners and at the health management center of our hospital in Wuhan. An ordinal logistic regression model and a binary logistic regression model were used to analyze the correlation of the understanding of diseases and the willingness to seek medical treatment with different connotation of the prevention and treatment recommendations, respectively.Results:A total of 530 valid questionnaires were collected, of which 267 were from version A and 263 from version B. There was no significant difference in the socio-demographic profile of respondents between version A and version B. For the four high risk factors of kidney diseases mentioned above, version B was better than version A in terms of understanding and willingness to seek medical treatment ( P<0.001). The level of understanding OR(95% CI) were 3.691(2.570, 5.301), 2.238(1.511, 3.320), 4.293(6.353, 2.903) and 5.275(7.877, 3.529) respectively. The willingness to seek medical treatment OR(95% CI) were 3.554(2.441, 5.175), 2.850(1.975, 4.114), 5.144(3.457, 7.654) and 4.225(2.868, 6.224) respectively. All the P values were lower than 0.001. Conclusions:Improving the connotation of prevention and treatment recommendations in the medical examination report can help increase the willingness for early medical consultation.

Collective dynamics of actin and microtubule and its crosstalk mediated by FHDC1.

The coordination between actin and microtubule network is crucial, yet this remains a challenging problem to dissect and our understanding of the underlying mechanisms remains limited. In this study, we used travelling waves in the cell cortex to characterize the collective dynamics of cytoskeletal networks. Our findings show that Cdc42 and F-BAR-dependent actin waves in mast cells are mainly driven by formin-mediated actin polymerization, with the microtubule-binding formin FH2 domain-containing protein 1 (FHDC1) as an early regulator. Knocking down FHDC1 inhibits actin wave formation, and this inhibition require FHDC1's interaction with both microtubule and actin. The phase of microtubule depolymerization coincides with the nucleation of actin waves and microtubule stabilization inhibit actin waves, leading us to propose that microtubule shrinking and the concurrent release of FHDC1 locally regulate actin nucleation. Lastly, we show that FHDC1 is crucial for multiple cellular processes such as cell division and migration. Our data provided molecular insights into the nucleation mechanisms of actin waves and uncover an antagonistic interplay between microtubule and actin polymerization in their collective dynamics.

Sensitive quantitative detection of SARS-CoV-2 in clinical samples using digital warm-start CRISPR assay

Quantifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in clinical samples is crucial for assessing the infectivity of coronavirus disease 2019 and the efficacy of antiviral drugs. Here, we describe a digital warm-start CRISPR (WS-CRISPR) assay for sensitive quantitative detection of SARS-CoV-2 in clinical samples. The WS-CRISPR assay combines low-temperature reverse transcription dual-priming mediated isothermal amplification (RT-DAMP) and CRISPR-Cas12a-based detection in one-pot, attributed to the mediation role by pyrophosphatase and phosphorothioated primers. The WS-CRISPR assay is initiated at above 50 {degrees}C and overcomes undesired premature target amplification at room temperature, enabling accurate digital nucleic acid quantification. By targeting SARS-CoV-2s nucleoprotein gene, digital WS-CRISPR assay is able to detect down to 5 copies/l SARS-CoV-2 RNA in the chip within 90 minutes. It is clinically validated by quantitatively determining 32 clinical swab samples and three clinical saliva samples, showing 100% agreement with RT-PCR results. Moreover, the digital WS-CRISPR assay has been demonstrated to directly detect SARS-CoV-2 in heat-treated saliva samples without RNA extraction, showing high tolerance to inhibitors. Thus, the digital WS-CRISPR method, as a sensitive and reliable CRISPR assay, facilitates accurate SARS-CoV-2 detection toward digitized quantification.

Fish c-Jun N-Terminal Kinase (JNK) Pathway Is Involved in Bacterial MDP-Induced Intestinal Inflammation.

The c-Jun NH2-terminal kinases (JNKs) are an evolutionarily conserved family of serine/threonine protein kinases that play critical roles in the pathological process in species ranging from insects to mammals. However, the function of JNKs in bacteria-induced intestinal inflammation is still poorly understood. In this study, a fish JNK (CiJNK) pathway was identified, and its potential roles in bacterial muramyl dipeptide (MDP)-induced intestinal inflammation were investigated in Ctenopharyngodon idella. The present CiJNK was found to possess a conserved dual phosphorylation motif (TPY) in a serine/threonine protein kinase (S_TKc) domain and to contain several potential immune-related transcription factor binding sites, including nuclear factor kappa B (NF-κB), activating protein 1 (AP-1), and signal transducer and activator of downstream transcription 3 (STAT3), in its 5' flanking regions. Quantitative real-time PCR results revealed that the mRNA levels of the JNK pathway genes in the intestine were significantly upregulated after challenge with a bacterial pathogen (Aeromonas hydrophila) and MDP in a time-dependent manner. Additionally, the JNK pathway was found to be involved in regulating the MDP-induced expression levels of inflammatory cytokines (IL-6, IL-8, and TNF-α) in the intestine of grass carp. Moreover, the nutritional dipeptide carnosine and Ala-Gln could effectively alleviate MDP-induced intestinal inflammation by regulating the intestinal expression of JNK pathway genes and inflammatory cytokines in grass carp. Finally, fluorescence microscopy and dual-reporter assays indicated that CiJNK could associate with CiMKK4 and CiMKK7 involved in the regulation of the AP-1 signaling pathway. Overall, these results provide the first experimental demonstration that the JNK signaling pathway is involved in the intestinal immune response to MDP challenge in C. idella, which may provide new insight into the pathogenesis of inflammatory bowel disease.

JAK2 Mediates the Regulation of Pept1 Expression by Leptin in the Grass Carp (Ctenopharyngodon idella) Intestine.

Oligopeptide transporter 1 (Pept1) is located on the brush border membrane of the intestinal epithelium and plays an important role in dipeptide and tripeptide absorption from protein digestion. In this study, we cloned and characterized the cDNA sequence of Janus kinase 2 (JAK2) from Ctenopharyngodon idella. The expression patterns of JAK2 in various tissues and developmental stages were characterized by quantitative real-time PCR (qRT-PCR). The mRNA expression levels of JAK2 and Pept1 regulated by leptin in the intestine were also analyzed in vitro and in vivo. The cDNA sequence of JAK2 is 3378 bp in length, and the mRNA of JAK2 was broadly expressed in all tissues and embryonic stages of C. idella analyzed. In addition, we found that leptin regulated expression of JAK2 and Pept1 in the intestine; Pept1 expression was down-regulated by the JAK2 inhibitor AG490 in vivo and in vitro. Furthermore, luciferase experiments showed that overexpression of the JAK2 gene significantly upregulated the activity of the Pept1 5' regulatory sequence in C. idella. In conclusion, these results may help in elucidating the regulatory effect of the leptin-mediated JAK2 pathway on intestinal Pept1 expression in C. idella and the molecular mechanism of peptide transport by the intestinal transporter Pept1 in fishes.

All-in-One Dual CRISPR-Cas12a (AIOD-CRISPR) Assay: A Case for Rapid, Ultrasensitive and Visual Detection of Novel Coronavirus SARS-CoV-2 and HIV virus

A recent outbreak of novel coronavirus (SARS-CoV-2), the causative agent of COVID-19, has spread rapidly all over the world. Human immunodeficiency virus (HIV) is another deadly virus and causes acquired immunodeficiency syndrome (AIDS). Rapid and early detection of these viruses will facilitate early intervention and reduce disease transmission risk. Here, we present an All-In-One Dual CRISPR-Cas12a (termed "AIOD-CRISPR") assay method for simple, rapid, ultrasensitive, one-pot, and visual detection of coronavirus SARS-CoV-2 and HIV virus. In our AIOD CRISPR assay, a pair of crRNAs was introduced to initiate dual CRISPR-Cas12a detection and improve detection sensitivity. The AIOD-CRISPR assay system was successfully utilized to detect nucleic acids (DNA and RNA) of SARS-CoV-2 and HIV with a sensitivity of few copies. Also, it was evaluated by detecting HIV-1 RNA extracted from human plasma samples, achieving a comparable sensitivity with real-time RT-PCR method. Thus, our method has a great potential for developing next-generation point-of-care molecular diagnostics.

Myelin sheath structure and regeneration in peripheral nerve injury repair.

Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of the myelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath.

Molecular characterization and taurine regulation of two novel CDOs (CDO1 and CDO2) from Carassius auratus.

Cysteine oxygenase (CDO) is a mononuclear nonhemoglobin enzyme that catalyzes the production of taurine through the cysteine (Cys) pathway and plays a key role in the biosynthesis of taurine in mammals. However, the function of CDOs in bony fish remains poorly understood. In this study, we cloned CDO genes (CaCDO1 and CaCDO2) from Carassius auratus. The cDNA sequences of both CaCDO1 and CaCDO2 encoded putative proteins with 201 amino acids, which included structural features typical of the CDO protein family. Multiple sequence alignment and phylogenetic analysis showed that CaCDO1 and CaCDO2 shared high sequence identities and similarities with C. carpio homologs. Quantitative real-time polymerase chain reaction (qRT-PCR) results revealed that CaCDO1 and CaCDO2 were both broadly expressed in all selected tissues and developmental stages in C. auratus but had differing mRNA levels. In addition, compared to those of the taurine-free group, the in vivo mRNA expression levels of both CaCDO1 and CaCDO2 significantly decreased with increasing dietary taurine levels from 1.0 to 9.0 g/kg. Furthermore, in vitro taurine treatments showed similar inhibitory effects on the expression of CaCDO1 and CaCDO2 in the intestines of C. auratus. Our results also showed that the mRNA expression of CaCDO2 in the intestines was higher than that of CaCDO1 in response to in vivo and in vitro taurine supplementation. Overall, these data may provide new insights into the regulation of fish CDO expression and provide valuable knowledge for improving dietary formulas in aquaculture.

Mitogen-activated protein kinase kinase 6 is involved in the immune response to bacterial di-/tripeptide challenge in grass carp Ctenopharyngodon idella.

Mitogen-activated protein kinase kinase 6 (MKK6) is an essential component of the p38MAPK signaling pathway, which is involved in the modulation of inflammation, cell apoptosis and survival responses in mammals. However, the function of MKK6s in teleosts is still unclear. In this study, a fish MKK6 homolog (CiMKK6) was first identified from the grass carp (Ctenopharyngodon idella), a freshwater fish. CiMKK6 cDNA encodes a putative protein of 357 amino acids that contains conserved structural characteristics of the MKK6 family, including the S_TKc domain, SVAKT motif and DVD site. The deduced CiMKK6 protein exhibits high sequence homology with other reported fish MKK6s and shares the closest relationship with MKK6 from Danio rerio. Quantitative real-time PCR (qRT-PCR) analysis revealed that CiMKK6 mRNA was widely expressed in all tested tissues and stages of embryonic development. Additionally, the transcript levels of CiMKK6 in the intestine were significantly upregulated in response to bacterial muramyl dipeptide (MDP) and L-Ala-γ-D-Glu-meso-diaminopimelic acid (Tri-DAP) stimulation. Moreover, subcellular localization analysis indicated that CiMKK6 was distributed in both the cytoplasm and the nucleus of HEK293T cells. Finally, overexpression of CiMKK6 significantly enhanced the transcriptional activity of the AP-1 reporter gene in HEK293T cells. Overall, these findings may help better clarify the immune function of teleost MKK6s and provide new insight into the immune defense mechanisms of grass carp.

Efficacy comparison of two minimally invasive operations on cholecystolithiasis combined with choledocholithiasis / 国际外科学杂志

Objective To compare the clinical efficacy of laparoscopic cholecystectomy(LC) + endoscopic sphincterotomy combined with balloon dilation(ESBD) with laparoscopic cholecystectomy(LC) + common bile duct exploration(LCBDE) on cholecystolithiasis combined with choledocholithiasis.Methods The clinical data of 102 patients with gallbladder stones with common bile duct stones from October 2015 to October 2017 were reviewed from the Second Affiliated Hospital of Chongqing Medical University.Forty eight patients received LC + ESBD and 54 patients subjected to LC ± LCBDE.The operation time,intraoperative blood loss,abdominal drainage time,antibiotic utilization rate,stone residue rate were compared between the two groups.Measurement data with normal distribution were represented as (Mean ± SD),and t test was used to compare between groups.Measurement data with skewed distribution were represented as M(P25,P75),Mann-whitney U test was used to compare between groups.Categorical variables were describedas counts and percentages and were compared using chi-square test.Results The operation time,intraoperative blood loss,postoperative abdominal drainage time,and antibiotic utilization rate in the LC + ESBD group were (108.0 ± 23.4) min,(18.0 ± 7.1) ml,(1.83 ± 1.57) d,and 47.9％(23/48).The LC +LCBDE groupa were (169.6±37.8) min,(86.4±37.0) ml,(4.80±2.02) d,and 87.0％ (47/54),respectively,there were statistically significant differences between the two groups(P ＜0.05).The stone residual rate of the LC + ESBD group was 0,and the LC + LCBDE group was 5.6％ (3/54),respectively.There was no significant difference between the two groups(P ＞ 0.05).Conclusions LC + ESBD and LC + LCBDE both are safe and effective methods to treat cholecystolithiasis combined with choledocholithiasis.However,some data of LC + ESBD group are better than the LC + LCBDE group,such as general anesthesia time,surgical trauma and recovery time.Therefore,compared with LC + LCBDE,LC + ESBD may be the more suitable operation type for patients who have cardiovascular diseases and poor tolerance.

Regain Strain-Hardening in High-Strength Metals by Nanofiller Incorporation at Grain Boundaries.

Grain refinement to the nano/ultrafine-grained regime can make metals several times stronger, but this process is usually accompanied by a dramatic loss of ductility. Such strength-ductility trade-off originates from a lack of strain-hardening capacity in tiny grains. Here, we present a strategy to regain the strain-hardening ability of high-strength metals by incorporation of extrinsic nanofillers at grain boundaries. We demonstrate that the dislocation storage ability in Cu grains can be considerably improved through this novel grain-boundary engineering approach, leading to a remarkably enhanced strain-hardening capacity and tensile ductility (uniform elongation). Experiments and large-scale atomistic simulations reveal that a key benefit of incorporated nanofillers is a reduction in the grain-boundary energy, enabling concurrent dislocation storage near the boundaries and in the Cu grain interior during straining. The strategy of grain-boundary engineering through nanofillers is easily controllable, generally applicable, and may open new avenues for producing nanostructured metals with extraordinary mechanical properties.

FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing.

Free fatty acid receptors 2 and 3 (FFAR2/FFA2/GPR43 and FFAR3/FFA3/GPR41) are mammalian receptors for gut microbiota-derived short-chain fatty acids (SCFAs). These receptors are promising drug targets for obesity, colitis, colon cancer, asthma, and arthritis. Here, we demonstrate that FFAR2 and FFAR3 interact to form a heteromer in primary human monocytes and macrophages via proximity ligation assay, and during heterologous expression in HEK293 cells via bimolecular fluorescence complementation and fluorescence resonance energy transfer. The FFAR2-FFAR3 heteromer displayed enhanced cytosolic Ca2+ signaling (1.5-fold increase relative to homomeric FFAR2) and ß-arrestin-2 recruitment (30-fold increase relative to homomeric FFAR3). The enhanced heteromer signaling was attenuated by FFAR2 antagonism (CATPB), Gαq inhibition (YM254890), or Gαi inhibition (pertussis toxin). Unlike homomeric FFAR2/3, the heteromer lacked the ability to inhibit cAMP production but gained the ability to induce p38 phosphorylation in HEK293 and inflammatory monocytes via a CATPB- and YM254890-sensitive mechanism. Our data, taken together, reveal that FFAR2 and FFAR3 may interact to form a receptor heteromer with signaling that is distinct from the parent homomers-a novel pathway for drug targeting.-Ang, Z., Xiong, D., Wu, M., Ding, J. L. FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing.

Clathrin Assembly Defines the Onset and Geometry of Cortical Patterning.

Assembly of the endocytic machinery is a constitutively active process that is important for the organization of the plasma membrane, signal transduction, and membrane trafficking. Existing research has focused on the stochastic nature of endocytosis. Here, we report the emergence of the collective dynamics of endocytic proteins as periodic traveling waves on the cell surface. Coordinated clathrin assembly provides the earliest spatial cue for cortical waves and sets the direction of propagation. Surprisingly, the onset of clathrin waves, but not individual endocytic events, requires feedback from downstream factors, including FBP17, Cdc42, and N-WASP. In addition to the localized endocytic assembly at the plasma membrane, intracellular clathrin and phosphatidylinositol-3,4-bisphosphate predict the excitability of the plasma membrane and modulate the geometry of traveling waves. Collectively, our data demonstrate the multiplicity of clathrin functions in cortical pattern formation and provide important insights regarding the nucleation and propagation of single-cell patterns.