Hyper-Interferon Sensitive influenza induces adaptive immune responses and overcomes resistance to anti-PD-1 in murine non-small cell lung cancer.

Despite recent advances in immunotherapy with immune checkpoint inhibitors (ICI), many patients with non-small cell lung cancer (NSCLC) fail to respond or develop resistance after an initial response. In situ vaccination (ISV) with engineered viruses has emerged as a promising antigen-agnostic strategy that can both condition the tumor microenvironment (TME) and augment anti-tumor T cell responses to overcome immune resistance. We engineered a live attenuated viral vaccine, Hyper-Interferon Sensitive virus (HIS), by conducting a genome-wide functional screening and introducing eight interferon (IFN)-sensitive mutations in the influenza genome. Compared to wild-type (WT) influenza, HIS replication was attenuated in immunocompetent hosts, enhancing its potential as a safe option for cancer therapy. HIS ISV elicited robust yet transient type I IFN responses in murine NSCLCs, leading to an enrichment of polyfunctional effector Th1 CD4 and cytotoxic CD8 T cells into the tumor. HIS ISV demonstrated enhanced anti-tumor efficacy compared to WT in multiple syngeneic murine models of NSCLC with distinct driver mutations and varying mutational burden. This efficacy was dependent on host type 1 IFN responses and T lymphocytes. HIS ISV overcame resistance to anti-PD-1 in LKB-1 deficient murine NSCLC, resulting in improved overall survival and enduring systemic tumor-specific immunity. These studies provide compelling evidence to support further clinical evaluation of HIS as a novel 'off-the-shelf' ISV strategy for patients with NSCLC refractory to ICI.

The Emerging Role of Three-dimensional Technologies in Orthoplastic Surgery.

Three-dimensional (3D) planning and manufacturing technologies have become integral to head and neck reconstruction following tumor resection. These technologies facilitate the prototyping of patient-specific solutions in both digital and physical form. Three-dimensional tumor models and cutting guides help conceptualize and verify the surgical approach, as well as serve as a blueprint for reconstruction. Computer-aided renderings have been shown to add precision to bony contouring to achieve functional and aesthetic goals following tumor resection, such as in mastication, oral competence, speech, and symmetric facial aesthetics. Three-dimensional technologies have also been introduced in orthopedic oncology, making limb-salvage surgery the mainstay of treatment in cases where amputation was historically required. The advent of customized 3D cutting guides and plates allows surgeons to spare surrounding healthy tissue, markedly enhancing postoperative quality of life and significantly reducing associated morbidities. Borrowing from these applications of 3D planning and modeling, our institution has recently implemented these technologies for the reconstructive planning of soft tissue defects following sarcoma resection. Here we present a series of cases that demonstrate the workflow and clinical outcomes associated with the utilization of 3D planning techniques in orthoplastic surgery.

Monolithic integrated optoelectronic chip for vector force detection.

Sensors with a small footprint and real-time detection capabilities are crucial in robotic surgery and smart wearable equipment. Reducing device footprint while maintaining its high performance is a major challenge and a significant limitation to their development. Here, we proposed a monolithic integrated micro-scale sensor, which can be used for vector force detection. This sensor combines an optical source, four photodetectors, and a hemispherical silicone elastomer component on the same sapphire-based AlGaInP wafer. The chip-scale optical coupling is achieved by employing the laser lift-off techniques and the flip-chip bonding to a processed sapphire substrate. This hemispherical structure device can detect normal and shear forces as low as 1 mN within a measurement range of 0-220 mN for normal force and 0-15 mN for shear force. After packaging, the sensor is capable of detecting forces over a broader range, with measurement capabilities extending up to 10 N for normal forces and 0.2 N for shear forces. It has an accuracy of detecting a minimum normal force of 25 mN and a minimum shear force of 20 mN. Furthermore, this sensor has been validated to have a compact footprint of approximately 1.5 mm2, while maintaining high real-time response. We also demonstrate its promising potential by combining this sensor with fine surface texture perception in the fields of compact medical robot interaction and wearable devices.

Efficacy and Safety of High-Viscosity Bone Cement in Percutaneous Vertebroplasty for Kummell's Disease.

Background: To analyze and evaluate the clinical outcomes of using high-viscosity bone cement compared to low-viscosity bone cement in percutaneous vertebroplasty (PVP) for treatment of Kummell's disease. Methods: From July 2017 to July 2019, 68 Kummell's disease patients who underwent PVP were chosen and separated into 2 groups: H group (n = 34), were treated with high-viscosity bone cement and L group (n = 34), treated with low-viscosity bone cement during treatment. The operation time, number of fluoroscopy tests done, and amount of bone cement perfusion were recorded for both groups. Clinical outcomes were compared, by measuring their Visual Analog Scale (VAS), Oswestry Disability Index (ODI), Kyphosis Cobb's angle, vertebral height compression rate, and other complications. Results: High-viscosity group showed less operation time and reduced number of fluoroscopy tests than the low-viscosity group (P < 0.05). When compared to preoperative period, both groups' VAS and ODI scores were significantly reduced at 1 day and 1 year postoperatively (P < 0.05). The vertebral height compression rate and Cobb's angle were significantly lower (P < 0.05) in both groups after surgery compared with those before surgery (P < 0.05). The cement leakage rate in group H was 26.5%, which was significantly lower than that in group L, which was 61.8% (P < 0.05). Conclusions: High-viscosity and low-viscosity bone cement in PVP have similar clinical efficacy in reducing pain in patients during the treatment, but in contrast, high-viscosity bone cement shortens the operative time, reduces number of fluoroscopy views and vertebral cement leakage and improves surgical safety.

Germline RECQL gene mutations in Chinese patients with breast cancer.

Introduction: Breast cancer is the most common malignant tumor in women, seriously threatening health and survival. TP-dependent DNA helicase Q1 (RECQL) is a breast cancer susceptibility gene with possible familial links. However, RECQL gene mutations among Chinese women with breast cancer have not been evaluated. Therefore, this study assessed RECQL mutations and their relationships with clinicopathological and epidemiological characteristics in Chinese women with breast cancer. Method: Clinical information was also obtained via the hospital information system and a follow-up questionnaire. Peripheral venous blood (2 mL) was extracted from all patients and stored at -80°C for future use; the early venous blood samples were from our hospital's sample bank. RECQL gene sequencing were performed by the Shanghai Aishe Gene Company (China). Results: We found that a RECQL mutation is a susceptibility factor for breast cancer. Moreover, patients with RECQL mutations were more likely to have a family history of breast cancer than those without. Also, patients with RECQL variants of uncertain significance (VUS) were less likely to develop invasive ductal carcinoma than those without. In addition, unexplained RECQL mutations occurred more often in patients with human epidermal growth factor receptor 2+ breast cancer than in those with other subtypes. Discussion: These results provide a basis for creating screening criteria specific to Chinese women. However, the frequency of RECQL mutations was low, and the number of pathogenic mutations was too small and could not be analyzed. Thus, more extensive, long-term studies that include other functional experiments are needed to verify these results.

Arthroscopic wafer procedure versus ulnar shortening osteotomy for ulnar impaction syndrome: a systematic review and meta-analysis.

PURPOSE: This study aimed to systematically compare the efficacy and safety of arthroscopic wafer procedure (AWP) versus ulnar shortening osteotomy (USO) for ulnar impaction syndrome (UIS) treatment. METHODS: All the studies included in this meta-analysis compared the efficacy of AWP to USO for UIS and were acquired through a comprehensive search across multiple databases. The meta-analysis was performed by calculating the effect sizes with the Cochrane Collaboration's RevMan 5.4 software. RESULTS: A total of 8 articles were included in this analysis, comprising 148 cases in the AWP group and 163 cases in the USO group. The pooled estimates indicated no significant differences in combined Darrow's Criteria or Modified Mayo Wrist Score, Modified Mayo Wrist Score, DASH scores, grip strength, VAS score, and postoperative ulnar variation. On the other hand, the patients in the AWP group exhibited fewer complications (OR = 0.17, 95%CI 0.05-0.54, P = 0.003) and a lower reoperation rate (OR = 0.12, 95%CI 0.05-0.28, P < 0.00001) than those in the USO group. CONCLUSIONS: The two surgical techniques were both effective in treating UIS but the AWP group showed fewer complications and a lower reoperation rate. Therefore, AWP may present a superior alternative for UIS treatment.

The first dorsal metacarpal artery flaps versus reverse homodigital dorsal flaps for thumb reconstruction: a systematic review and meta-analysis.

PURPOSE: This review was performed to systematically compare the effectiveness and safety of the first dorsal metacarpal artery flaps (FDMAF) and reverse homodigital dorsal flaps (RHDF) for thumb reconstruction. METHODS: All literatures, which compared FDMAF versus RHDF for thumb reconstruction, were acquired through a comprehensive search in multiple databases from inception until 31st August 2022. A meta-analysis was performed using the Cochrane Collaboration's RevMan 5.4 software. RESULTS: A total of 19 articles were retrieved, comprising 396 patients in the FDMAF group and 423 patients in the RHDF group. The pooled estimates suggested that there were no significant differences in venous congestion, complications about flap necrosis and reduced range of motion (ROM) of thumb, static 2-point discrimination (S-2PD) between the two groups. On the other hand, patients in the RHDF group had less vascular crisis (odds ratio [OR] = 3.15, 95%CI, 1.31-7.56), complications about poor cortical reorientation (OR = 440.02, 95%CI, 91.97-2105.27) and higher satisfaction rate (OR = 0.56, 95% CI, 0.33-0.96) than those in the FDMAF group. CONCLUSIONS: The two surgical procedures were both safe and reliable since no significant differences were found in flap necrosis between the two groups. However, the patients in the RHDF group had less complications about vascular crisis, poor cortical reorientation and higher satisfaction rate. Accordingly, we thought RHDF may be more superior for thumb reconstruction than FDMAF.

Cation-π Interactions Greatly Influence Ion Transportability of the Light-Driven Sodium Pump KR2: A Molecular Dynamics Study.

Krokinobacter eikastus rhodopsin 2 (KR2) is a typical light-driven sodium pump. Although wild-type KR2 exhibits high Na+ selectivity, mutagenesis performed on the residues constituting the entrance enables permeation of K+ and Cs+, while the underlying mechanism remains elusive. This study presents a comprehensive molecular dynamics investigation, including force field optimization, metadynamics, and alchemical free energy methods, to explore the N61L/G263F mutant of KR2, which exhibits transportability for K+ and Cs+. The introduced Phe263 residue can directly promote ion binding at the entrance through cation-π interactions, while the N61L mutation can enhance ion binding at Phe46 by relieving steric hindrance. These results suggest that cation-π interactions may significantly influence the ion transportability and selectivity of KR2, which can provide important insights for protein engineering and the design of artificial ion transporters.

Practical Methods of Assessing Coronal Alignment and Outcomes in Adult Spinal Deformity Surgery: A Comparative Analysis.

STUDY DESIGN: Asymptomatic cohort: prospective, cross-sectional, multicenter. Symptomatic: retrospective, multisurgeon, single-center. OBJECTIVE: To assess the association between cranial coronal alignment and adult spinal deformity (ASD) surgical risk and outcomes. SUMMARY OF BACKGROUND DATA: ASD leads to decreased quality of life. Studies have shown that coronal malignment (CM) is associated with worse surgical outcomes. MATERIALS AND METHODS: A total of 468 adult participants were prospectively enrolled in the asymptomatic cohort. Totally, 172 symptomatic ASD patients with 2-year follow-ups were retrospectively enrolled in the symptomatic cohort. Three cranial plumb line parameters: the positions of the plumb lines from the midpoint between the medial orbital rims (ORB-L5), the odontoid (OD-L5), and the C7 centroid (C7-L5) relative to the L5 pedicle, were measured. Each subject had plumb line medial (M), touching (T), or lateral (L) to either pedicle. The association between each group of patients and radiographic parameters, intraoperative variables, patient-reported outcomes, and clinical outcomes were analyzed. RESULTS: In the asymptomatic cohort, OD-L5 was medial to or touching the L5 pedicle in 98.3% of volunteers. In the symptomatic patients, preoperative OD-L5-L exhibited higher mean age (56.2±14.0), odontoid-coronal vertical axis (OD-CVA) (5.5±3.3 cm), Oswestry disability index (ODI) score (40.6±18.4), pelvic fixation rate (56/62, 90.3%), OR time (528.4±144.6 min), median estimated blood loss (1300 ml), and durotomy rate (24/62, 38.7%). A similar pattern of higher CVA, preoperative ODI, intraoperative pelvic fixation rate, OR time, estimated blood loss, and durotomy rate was observed in ORB-L5-L and C7-L5-L patients. Final follow-up postoperative OD-L5-L was associated with higher rates of proximal junctional kyphosis (13.0%) and pseudarthrosis (17.4%). CONCLUSION: Preoperative OD-L5, ORB-L5, and C7-L5 lateral to pedicles were associated with worse preoperative ODI and higher intraoperative complexity. Postoperative OD-L5-L was associated with higher rates of proximal junctional kyphosis and pseudarthrosis. Postoperative CM, approximated by the cranial plumb line lateral to the L5 pedicles, was associated with sagittal plane complications.

Sensory re-education after free neurovascular toe pulp flap for digital pulp reconstruction.

PURPOSE: To evaluate the effectiveness of a sensory re-education (SR) program after free neurovascular toe pulp flap for finger or thumb pulp defect reconstruction. METHODS: From January 2015 to January 2020, 49 patients with finger or thumb pulp defects treated with free fibular side flaps of the great toe or tibial side flaps of the second toe were recruited. The patients were randomly divided into two groups one month after surgery. The training group received the SR program, and the control group underwent the traditional rehabilitation program. Clinical evaluation included Semmes-Weinstein Monofilament (SWM) tests, static two-point discrimination (2-PD), and sensibility grading, measured at 1, 3, 6, 9, and 12 months postoperatively. RESULTS: A total of 42 patients completed the follow-up, including 22 (16 males) patients in the training group and 20 patients (12 males) in the control group. Compared with 1 month after the operation, significant improvements in sensory recovery were observed at 3, 6, 9, and 12 months postoperatively in both groups. In addition, earlier sensory recovery was seen in the SR group compared to the control group, showing significant differences at 3 and 6 months but not at 9 and 12 months postoperatively. CONCLUSION: Although SR seemed to accelerate preliminary sensory recovery after free neurovascular toe pulp flaps for digital defect reconstruction, the program should be reconsidered as it offers no significant improvement over the control group at later follow-up stages.

Comparison of the Odontoid and Orbital-Coronal Vertical Axis Lines in Evaluating Coronal Alignment and Outcomes in Adult Spinal Deformity Surgery.

STUDY DESIGN: Asymptomatic Multi-Ethnic Alignment Normative Study (MEANS) cohort: cross-sectional, multi-center. Symptomatic cohort: retrospective, multi-surgeon, single-center. OBJECTIVE: To assess the association of odontoid-coronal vertical axis (OD-CVA) and orbital-coronal vertical axis (ORB-CVA) with radiographic parameters, patient-reported outcomes (PROs), and clinical outcomes. SUMMARY OF BACKGROUND DATA: Previous literature studied the OD-CVA in an asymptomatic cohort and ORB-CVA in a symptomatic cohort, demonstrating their correlations with radiographic parameters and ORB-CVA with outcomes. METHODS: 468 asymptomatic adult participants were prospectively enrolled in the MEANS cohort. 174 symptomatic ASD patients with 6 fused levels and 2-year follow-ups were retrospectively enrolled in the symptomatic cohort. The association between OD-CVA and ORB-CVA, and radiographic parameters, perioperative variables, PROs, and outcomes were analyzed. Pearson's correlation was used to assess correlation and logistic regression odds of outcomes. RESULTS: In the MEANS cohort, the ORB-CVA correlated with C7-CVA (r=0.58) and OD-CVA (r=0.74). In the symptomatic cohort, preoperative ORB-CVA correlated better with leg length discrepancy (LLD) (r=0.17, P=0.029) while preoperative OD-CVA correlated better with C7-CVA (r=0.90, P<0.001). Postoperative ORB-CVA correlated with postoperative C7-CVA (r=0.66, P<0.001) and postoperative OD-CVA correlated stronger with postoperative C7-CVA (r=0.81, P<0.001). Both preoperative OD-CVA (r=0.199) and ORB-CVA (r=0.208) correlated with preoperative Oswestry Disability Index (ODI). ORB-CVA correlated better than OD-CVA in the preoperative SRS-22r pain category but worse in total and other subcategories. Preoperative ORB-CVA was associated with increased odds of intraoperative complication (OR=1.28, 1.01-1.22), like OD-CVA (OR=1.30, 1.12-1.53). Neither preoperative ORB-CVA nor OD-CVA was associated with reoperations and readmissions after multivariate analysis. Preoperative OD-ORB mismatch >1.5 cm was not associated with increased odds of intraoperative and postoperative complications, reoperations, or readmissions. CONCLUSION: ORB-CVA and OD-CVA correlated with radiographic parameters, PROs, and intraoperative complications. ORB-CVA and OD-CVA can be used interchangeably as cranial coronal parameters in ASD surgery.

ASPSCR-1 and Sirt-5 alleviate Clonorchis liver fluke rCsNOSIP-induced oxidative stress, proliferation, and migration in cholangiocarcinoma cells.

BACKGROUND: Clonorchiasis, caused by the infection of Clonorchis sinensis (C. sinensis), is a kind of neglected tropical disease, but it is highly related to cholangiocarcinoma. It has been well known that NO from chronic inflammation responses are thought to be a major component of the damage and ultimate carcinogenesis ESPs such as nitric oxide synthase interacting protein (NOSIP) are thought to enhance the damage. The objective of this study was to identify the protein candidates interact with recombinant CsNOSIP (rCsNOSIP) and explore their role involved in CCA development or progression. METHODS: We applied HuProt microarray containing 21,000 probe sets for a systematic identification of rCsNOSIP-binding proteins and grouped binding hits by gene function. Pull-down assays were used to confirm the interaction of rCsNOSIP with alveolar soft part sarcoma (ASPSCR-1) and sirtuins 5 (Sirt-5). ASPSCR-1/Sirt-5 over-expression and siRNA knockdown experiments were employed for obtain of ASPSCR-1/Sirt-5 high or low expression (ASP-oe/Sirt5-oe or ASP-si/Sirt5-si) cholangiocarcinoma cell line (CCLP-1) cells. Nitric oxide (NO) and reactive oxygen species assay (ROS) as well as cell proliferation and wound-healing assays were performed to observe the effect of rCsNOSIP on ASP-oe/Sirt5-oe or ASP-si/Sirt5-si CCLP-1 cells. RESULTS: Seventy candidate proteins protein "hits" were detected as rCsNOSIP-binding proteins by HuProt microarray and bioinformatics analysis. Pull down assay showed that ASPSCR-1 and Sirt-5 could interact with rCsNOSIP. In addition, endotoxin-free-rCsNOSIP could increase the production of NO and ROS and promote the migration of CCLP-1 cells, while its effect on enhancing cell proliferation was not significant. Furthermore, ROS/NO production, proliferation, or migration were increased in ASP-si or Sirt5-si CCLP-1 cells but decreased in Asp-oe or Sirt5-oe CCLP-1 cells when stimulated with rCsNOSIP. CONCLUSIONS: Our findings suggest that CsNOSIP as a component of CsESPs might promote the development and invasion of CCA and Sirt5/ ASPSCR1 as host molecules might play a novel protective role against adverse stimulus during C. sinensis infection. This work supports the idea that CsESPs induce the occurrence and progression of CCA through ROS/RNS-induced oxidative and nitrative DNA damage.

Construction and immune evaluation of the recombinant duck adenovirus type 3 delivering capsid protein VP1 of the type 1 duck hepatitis virus.

Adenovirus serves as an excellent viral vector and is employed in vector vaccine research. Duck hepatitis A virus type 1 (DHAV1) and duck adenovirus type 3 (DAdV3) cause significant economic losses in the Chinese duck industry. In this study, we found an excellent exogenous gene insertion site in DAdV3 genome of CH-GD-12-2014 strain, within 3 intergenic regions (IGR). Subsequently, we generated a recombinant duck adenovirus named rDAdV3-VP1-188, which exhibits excellent replication characteristics and immunogenicity of DAdV3 and DHAV1. Animal experiments showed that rDAdV3-VP1-188 can provide 100% protection against the DAdV3 and 80% protection against DHAV1. These results showed that rDAdV3-VP1-188 could induce protection against DAdV3 and DHAV1 in ducks, thus indicating the feasibility of DAdV3 as a vector for the development of avian vector vaccines. These insights contribute to the further development of DAdV3 vectors and other adenovirus vectors.

Mechanisms underlying large-leaf yellow tea mediated inhibition of cognitive impairment in the 5xFAD model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia and is characterized by amyloid-ß (Aß) peptides and hyperphosphorylated Tau proteins. Evidence indicates that AD and type 2 diabetes mellitus (T2DM) share pathophysiological characteristics, including impaired insulin sensitivity. Large-leaf yellow tea (LYT) has been widely recognized for its health benefits, and we previously found that LYT can improve peripheral insulin resistance. PURPOSE: This study aimed to investigate the protective effects and underlying mechanisms of LYT in the 5xFAD mouse model of AD. METHODS: HPLC and spectrophotometric methods determined the chemical composition of the LYT extract. 5xFAD mice were treated with LYT supplementation (2 and 4 mg/ml) in drinking water for six months. Barnes and Y mazes were used to evaluate cognitive function, and the open field test assessed anxiety-like behavior. Immunofluorescence, silver, and Nissl staining were used to evaluate the pathological effects of LYT extract. A FRET-based assay assessed ß-site APP cleavage enzyme 1 (BACE1) activity, ELISA measured Aß levels in the brain, and Western blot analyses explored protein expression levels. RESULTS: Our results revealed that LYT significantly attenuated memory impairment and anxiety levels and alleviated cerebral neural damage. A reduction of senile plaques was also observed in both the cortex and hippocampus. LYT significantly inhibited the activity of BACE1, which resulted in a lower Aß protein level. In addition, LYT enhanced insulin receptor substrate 1 (IRS-1)-mediated phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), further suppressed glycogen synthase kinase-3ß (GSK3ß), and ultimately inhibited hyperphosphorylation of the protein Tau. The inhibitory effect of the LYT extract on the phosphorylation of Tau and BACE1 activity was dose-dependent. CONCLUSION: LYT improves cognitive ability and reduces Aß production by inhibiting BACE1 activity. Decreases of Tau protein hyperphosphorylation upon LYT treatment appear to be associated with the regulation of the IRS-1/PI3K/AKT/GSK3ß axis. Thus, the findings of this study also provide new evidence that LYT regulates insulin signaling pathways within the central nervous system.

Efficacy of peritoneal drainage in very-low-birth-weight neonates with Bell's stage II necrotizing enterocolitis: A single-center retrospective study.

BACKGROUND: Currently, pediatric surgeons are challenged by a lack of consensus on the optimal management strategy (conservative or surgical) for children with Bell's stage II necrotizing enterocolitis (NEC). AIM: To evaluate the clinical efficacy of peritoneal drainage in very-low-birth-weight (VLBW) neonates with modified Bell's stage II NEC. METHODS: This was a retrospective analysis of 102 NEC (modified Bell's stage II) neonates born with VLBW who were treated at the Fujian Children's Hospital (Fujian Branch of Shanghai Children's Medical Center) between January 2017 and January 2020; these included 24 cases in the peritoneal drainage group, 36 cases in the exploratory laparotomy group, and 42 cases in the conservative treatment group. RESULTS: The general characteristics were comparable in the three groups (P > 0.05). Compared with conservative treatment, peritoneal drainage was associated with significantly shorter fasting time, abdominal distension relief time, fecal occult blood (OB) negative conversion time, and reduced hospital length of stay (HLOS) (P < 0.05 for all). Despite some advantages of peritoneal drainage over conservative treatment in terms of cure, conversion to laparotomy, intestinal perforation, intestinal stenosis, and abdominal abscess rates, the differences were not statistically significant (P > 0.05). Compared to exploratory laparotomy, the fecal OB negative conversion time was significantly shorter in the peritoneal drainage group (P < 0.05); similarly, the exploratory laparotomy group showed longer fasting time, abdominal distension relief time, HLOS, and higher complication rate compared to peritoneal drainage group, but the between-group differences were not statistically significant (P > 0.05). CONCLUSION: Peritoneal drainage, an easy-to-operate procedure, can improve the clinical symptoms of VLBW neonates with Bell's stage II NEC and help reduce the HLOS.

Martynoside rescues 5-fluorouracil-impaired ribosome biogenesis by stabilizing RPL27A.

Martynoside (MAR), a bioactive component in several well-known tonic traditional Chinese herbs, exhibits pro-hematopoietic activity during 5-fluorouracil (5-FU) treatment. However, the molecular target and the mechanism of MAR are poorly understood. Here, by adopting the mRNA display with a library of even-distribution (md-LED) method, we systematically examined MAR-protein interactions in vitro and identified the ribosomal protein L27a (RPL27A) as a key cellular target of MAR. Structural and mutational analysis confirmed the specific interaction between MAR and the exon 4,5-encoded region of RPL27A. MAR attenuated 5-FU-induced cytotoxicity in bone marrow nucleated cells, increased RPL27A protein stability, and reduced the ubiquitination of RPL27A at lys92 (K92) and lys94 (K94). Disruption of MAR binding at key residues of RPL27A completely abolished the MAR-induced stabilization. Furthermore, by integrating label-free quantitative ubiquitination proteomics, transcriptomics, and ribosome function assays, we revealed that MAR restored RPL27A protein levels and thus rescued ribosome biogenesis impaired by 5-FU. Specifically, MAR increased mature ribosomal RNA (rRNA) abundance, prevented ribosomal protein degradation, facilitated ribosome assembly, and maintained nucleolar integrity. Collectively, our findings characterize the target of a component of Chinese medicine, reveal the importance of ribosome biogenesis in hematopoiesis, and open up a new direction for improving hematopoiesis by targeting RPL27A.

Identification of Two Novel Carbapenemase-Encoding Hybrid Plasmids Harboring blaNDM-5 and blaKPC-2 in a Clinical ST11-KL47 Klebsiella pneumoniae.

Background: Emergence of blaKPC and blaNDM co-harboring Klebsiella pneumoniae has escalated the threat of Carbapenem-resistant Klebsiella pneumoniae (CRKP) to healthcare. It remains unknown the prevalence and molecular characteristics of CRKP co-producing KPC and NDMs carbapenemases in Henan. Methods and Results: Twenty-seven CRKP strains isolated from different times were selected randomly in affiliated cancer hospital of Zhengzhou University from January 2019 to January 2021, among which one KPC-2 and NDM-5 positive CRKP named K9 was isolated from an abdominal pus sample of a 63-year-old male patient with leukemia. Sequencing of K9 determined that K9 belonged to ST11-KL47, which is resistant to antibiotics such as meropenem, ceftazidime-avibactam and tetracycline. K9 carried two different plasmids that contained blaNDM-5 and blaKPC-2. Both plasmids were shown to be novel hybrid plasmids and IS26 played an important role in generation of two plasmids. Gene blaKPC-2 was flanked by the NTEKPC-Ib-like genetic structure (IS26-ΔTn3-ISKpn8-blaKPC-2-ISKpn6-IS26) and was located on a conjugative IncFII/R/N type hybrid plasmid. Conclusion: The resistance gene blaNDM-5 located on a region organized as IS26-blaNDM-5-ble-trpF-dsbD-ISCR1-sul1-aadA2-dfrA12-IntI1-IS26 was carried by a phage-plasmid. We described a clinical CRKP co-producing KPC-2 and NDM-5 and emphasized an urgent need to control their further spread.

Ring-opening Polymerization of Enantiopure Bicyclic Ether-ester Monomers toward Closed-loop Recyclable and Crystalline Stereoregular Polyesters via Chemical Upcycling of Bioplastic.

Although great successes have been achieved, the preparation of closed-loop recyclable polyesters with high working temperatures still remains as a big challenge. Herein, we present the syntheses of a series of enantiopure bicyclic ether-ester monomers by upcycling of poly(3-hydroxybutyrate) bioplastic. The "living"/controlled ring-opening polymerizations of these enantiopure monomers to produce stereoregular polyesters with controlled molecular weights and well-defined chain ends were achieved. The effects of stereoconfiguration and substituent on polymerization kinetics and thermodynamics as well as the thermal properties of resultant polyesters were investigated. Of note, the stereoregular polyesters are semi-crystalline materials with melting temperatures up to 176 °C, even higher than the commodity polyolefin plastics. These polyesters can be depolymerized back to recover pristine monomers, thus successfully establishing a closed-loop life cycle.

The Lumbosacral Fractional Curve vs Maximum Coronal Cobb Angle in Adult Spinal Deformity Patients with Coronal Malalignment: Which Matters More?

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: In patients undergoing adult spinal deformity (ASD) surgery we sought to: 1) report preoperative and postoperative lumbosacral fractional (LSF) curve and maximum coronal Cobb angles and 2) determine their impact on radiographic, clinical, and patient-reported outcomes (PROs). METHODS: A single-institution cohort study was undertaken. The LSF curve was the cobb angle between the sacrum and most tilted lower lumbar vertebra. Coronal/sagittal vertical axis (CVA/SVA) were collected. Patients were compared between 4 groups: 1) Neutral Alignment (NA); 2) coronal malalignment only (CM); 3) Sagittal malalignment only (SM); and 4) Combined-Coronal-Sagittal-Malalignment (CCSM). Outcomes including postoperative CM, postoperative coronal vertical axis, complications, readmissions, reoperation, and PROs. RESULTS: A total of 243 patients underwent ASD surgery with mean total instrumented levels of 13.5. Mean LSF curve was 12.1±9.9°(0.2-62.3) and mean max Cobb angle was 43.0±26.5° (0.0-134.3). The largest mean LSF curves were seen in patients with CM (14.6°) and CCSM (13.1°) compared to NA (12.1°) and SM (9.5°) (p=0.100). A higher LSF curve was seen in patients with fusion to the sacrum and instrumentation to the pelvis (p=0.009), and a higher LSF curve was associated with more TLIFs (p=0.031). Postoperatively, more TLIFs were associated with greater amount of LSF curve correction (p<0.001). Comparing the LSF and the max Cob angle among Qiu types, the highest mean max Cobb angle was in Qiu Type B patients (p=0.025), whereas the highest mean LSF curve was in Qiu Type C patients (p=0.037). Moreover, 82.7% of patients had a LSF curve opposite the max Cobb angle. The LSF curve was larger than the max Cobb angle in 22/243 (9.1%) patients, and most of these 22 patients were Qiu Type A (59.1%). Regarding correction, the max Cobb angle achieved more correction than the LSF curve, judged by the percent improved from preop (54.5% Cobb vs. 46.5% LSF, p=0.025) in patients with max cobb>20° and LSF curve >5°. The LSF curve underwent greater correction in Qiu Type C patients (9.2°) compared to Type A (5.7°) and Type B (5.1°) (p=0.023); however, the max Cobb angle was similarly corrected among Qiu Types: Type A 21.8°, Type B 24.6°, and Type C 25.4° (p=0.602). Minimal differences were seen comparing the preop/postop/change in LSF curve and max Cobb angle regarding postop CM, postop CVA, complications, readmissions, reoperation, and PROs. CONCLUSIONS: The LSF curve was highest in patients with CM, CCSM, and Qiu Type C curves. Most patients had a LSF curve opposite the max Cobb angle. The max Cobb angle was more often corrected than the LSF curve. The LSF curve underwent greater correction among Qiu Type C patients, whereas the max Cobb angle was similarly corrected among all Qiu Types. No clear trend was seen regarding postoperative complications and PROs between the LSF curve and max Cobb angle.