Cross-species metabolomic profiling reveals phosphocholine-mediated liver protection from cold and ischemia/reperfusion.

Cold and ischemia/reperfusion (IR)-associated injuries are seemingly inevitable during liver transplantation and hepatectomy. Because Syrian hamsters demonstrate intrinsic tolerance to transplantation-like stimuli, cross-species comparative metabolomic analyses were conducted with hamster, rat, and donor liver samples to seek hepatic cold and IR-adaptive mechanisms. Lower hepatic phosphocholine contents were found in recipients with early graft-dysfunction and with virus-caused cirrhosis or high model for end-stage liver disease scores (≥30). Choline/phosphocholine deficiency in cultured human THLE-2 hepatocytes and animal models weakened hepatocellular cold tolerance and recovery of glutathione and ATP production, which was rescued by phosphocholine supplements. Among the biological processes impacted by choline/phosphocholine deficiency, 3 lipid-related metabolic processes were downregulated, whereas phosphocholine elevated the expression of genes in methylation processes. Consistently, in THLE-2, phosphocholine enhanced the overall RNA m6A methylation, among which the transcript stability of fatty acid desaturase 6 (FADS6) was improved. FADS6 functioned as a key phosphocholine effector in the production of polyunsaturated fatty acids, which may facilitate the hepatocellular recovery of energy and redox homeostasis. Thus, our study reveals the choline-phosphocholine metabolism and its downstream FADS6 functions in hepatic adaptation to cold and IR, which may inspire new strategies to monitor donor liver quality and improve recipient recovery from the liver transplantation process.

Injectable ultrasound-powered bone-adhesive nanocomposite hydrogel for electrically accelerated irregular bone defect healing.

The treatment of critical-size bone defects with irregular shapes remains a major challenge in the field of orthopedics. Bone implants with adaptability to complex morphological bone defects, bone-adhesive properties, and potent osteogenic capacity are necessary. Here, a shape-adaptive, highly bone-adhesive, and ultrasound-powered injectable nanocomposite hydrogel is developed via dynamic covalent crosslinking of amine-modified piezoelectric nanoparticles and biopolymer hydrogel networks for electrically accelerated bone healing. Depending on the inorganic-organic interaction between the amino-modified piezoelectric nanoparticles and the bio-adhesive hydrogel network, the bone adhesive strength of the prepared hydrogel exhibited an approximately 3-fold increase. In response to ultrasound radiation, the nanocomposite hydrogel could generate a controllable electrical output (-41.16 to 61.82 mV) to enhance the osteogenic effect in vitro and in vivo significantly. Rat critical-size calvarial defect repair validates accelerated bone healing. In addition, bioinformatics analysis reveals that the ultrasound-responsive nanocomposite hydrogel enhanced the osteogenic differentiation of bone mesenchymal stem cells by increasing calcium ion influx and up-regulating the PI3K/AKT and MEK/ERK signaling pathways. Overall, the present work reveals a novel wireless ultrasound-powered bone-adhesive nanocomposite hydrogel that broadens the therapeutic horizons for irregular bone defects.

Nomogram construction and validation of axial deviation in patients with tibial defects treated with the Ilizarov bone transport technique.

INTRODUCTION: The Ilizarov bone transport technique is widely recognised as an effective method for treating large segment bone defects in clinical practice. However, axial deviation is a common complication in the treatment of tibial large segment bone defects, which can have a serious impact on the clinical efficacy of bone transport. Our study aims to construct and validate a nomogram for predicting axial deviation of tibial bone transport. METHOD: This study retrospectively collected data from 363 patients who underwent the tibial Ilizarov technique for bone transport. Univariate and multivariate logistic regression analyses were performed to determine the independent risk factors for axial deviation, which were later used to construct a nomogram. The nomogram was evaluated using the decision curve analysis (DCA), the calibration curve, and the area under the receiver operating characteristic curve (AUC). RESULTS: Of the 363 patients who underwent Ilizarov tibial bone transport, 31.7% (115/363) experienced axial deviation. Multivariate logistic regression analysis showed that gender, height, defect site, and external fixation index were important risk factors for axial deviation. The AUC value of the nomogram model was 0.705. The calibration curve and the decision curve analysis showed a good consistency between the actual axial deviation and the predicted probability. CONCLUSION: The model assigns a quantitative risk score to each variable, which can be used to predict the risk of axial deviation during tibial bone transport.

Towards a Nonperturbative Formulation of the Jet Charge.

The jet charge is an old observable that has proven uniquely useful for discrimination of jets initiated by different flavors of light quarks, for example. In this Letter, we propose an approach to understanding the jet charge by establishing simple, robust assumptions that hold to good approximation nonperturbatively, such as isospin conservation and large particle multiplicity in the jets, forgoing any attempt at a perturbative analysis. From these assumptions, the jet charge distribution with fixed particle multiplicity takes the form of a Gaussian by the central limit theorem and whose mean and variance are related to fractional-power moments of single particle energy distributions. These results make several concrete predictions for the scaling of the jet charge with the multiplicity, explaining many of the results already in the literature, and new results we validate in Monte Carlo simulation.

Combination of Photothermal Therapy with Anti-Inflammation Therapy Attenuates the Inflammation Tumor Microenvironment and Weakens Immunosuppression for Enhancement Antitumor Treatment.

Photothermal therapy has gained widespread attention in cancer treatment, although its efficacy is suppressed due to the inflammatory response and immunosuppression, resulting in a discounted therapeutic effect. In this contribution, a high-performance NIR absorption organic small chromophore is developed, which is encapsulated into Pluronic F-127 to fabricate NIR absorption organic nanoparticles (TTM NPs) with excellent photothermal conversion efficiency (51.49%) for photothermal therapy. TTM NPs based photothermal therapy are combined with Aspisol, a kind of nonsteroidal anti-inflammatory drug, to weaken the inflammation and immunosuppression tumor microenvironment and enhance the antitumor effect. The results prove that the combination therapy realizes effective thermal elimination of primary tumors, inhibition of distant tumors, and suppression of tumor metastasis. The data show that combination therapy can suppress the expression of inflammatory factors, enhance dendritic cell activation and maturation, reverse the immunosuppression, facilitate T cell infiltration, and restore antitumor cytotoxic T lymphocyte activity. This study provides a paradigm to extend the development of photothermal therapy.

pH-responsive cinnamaldehyde-TiO2 nanotube coating: fabrication and functions in a simulated diabetes condition.

Current evidence has suggested that diabetes increases the risk of implanting failure, and therefore, appropriate surface modification of dental implants in patients with diabetes is crucial. TiO2 nanotube (TNT) has an osteogenic nanotopography, and its osteogenic properties can be further improved by loading appropriate drugs. Cinnamaldehyde (CIN) has been proven to have osteogenic, anti-inflammatory, and anti-bacterial effects. We fabricated a pH-responsive cinnamaldehyde-TiO2 nanotube coating (TNT-CIN) and hypothesized that this coating will exert osteogenic, anti-inflammatory, and anti-bacterial functions in a simulated diabetes condition. TNT-CIN was constructed by anodic oxidation, hydroxylation, silylation, and Schiff base reaction to bind CIN, and its surface characteristics were determined. Conditions of diabetes and diabetes with a concurrent infection were simulated using 22-mM glucose without and with 1-µg/mL lipopolysaccharide, respectively. The viability and osteogenic differentiation of bone marrow mesenchymal stem cells, polarization and secretion of macrophages, and resistance to Porphyromonas gingivalis and Streptococcus mutans were evaluated. CIN was bound to the TNT surface successfully and released better in low pH condition. TNT-CIN showed better osteogenic and anti-inflammatory effects and superior bacterial resistance than TNT in a simulated diabetes condition. These findings indicated that TNT-CIN is a promising, multifunctional surface coating for patients with diabetes needing dental implants. Graphical abstract.

Casticin inhibits nasopharyngeal carcinoma growth by targeting phosphoinositide 3-kinase.

BACKGROUND: Casticin, an isoflavone compound extracted from the herb Fructus Viticis, has demonstrated anti-inflammatory and anticancer activities and properties. The aim of this study was to investigate the effects and mechanisms of casticin in nasopharyngeal carcinoma (NPC) cells and to determine its potential for targeted use as a medicine. METHODS: NPC cells were used to perform the experiments. The CCK­8 assay and colony formation assays were used to assess cell viability. Flow cytometry was used to measure the cell cycle and apoptosis analysis (annexin V/PI assay). A three-dimensional (3D) tumour sphere culture system was used to characterize the effect of casticin on NPC stem cells. In silico molecular docking prediction and high-throughput KINOME scan assays were used to evaluate the binding of casticin to phosphoinositide 3-kinase (PI3K), including wild-type and most of mutants variants. We also used the SelectScreen assay to detect the IC50 of ATP activity in the active site of the target kinase. Western blotting was used to evaluate the changes in key proteins involved cell cycle, apoptosis, stemness, and PI3K/protein kinase B (AKT) signalling. The effect of casticin treatment in vivo was determined by using a xenograft mouse model. RESULTS: Our results indicate that casticin is a new and novel selective PI3K inhibitor that can significantly inhibit NPC proliferation and that it induces G2/GM arrest and apoptosis by upregulating Bax/BCL2 expression. Moreover, casticin was observed to affect the self-renewal ability of the nasopharyngeal carcinoma cell lines, and a combination of casticin with BYL719 was observed to induce a decrease in the level of the phosphorylation of mTORC1 downstream targets in BYL719-insensitive NPC cell lines. CONCLUSION: Casticin is a newly emerging selective PI3K inhibitor with potential for use as a targeted therapeutic treatment for nasopharyngeal carcinoma. Accordingly, casticin might represent a novel and effective agent against NPC and likely has high potential for combined use with pharmacological agents targeting PI3K/AKT.

Fine-mapping qFS07.1 controlling fiber strength in upland cotton (Gossypium hirsutum L.).

KEY MESSAGE: qFS07.1 controlling fiber strength was fine-mapped to a 62.6-kb region containing four annotated genes. RT-qPCR and sequence of candidate genes identified an LRR RLK gene as the most likely candidate. Fiber strength is an important component of cotton fiber quality and is associated with other properties, such as fiber maturity, fineness, and length. Stable QTL qFS07.1, controlling fiber strength, had been identified on chromosome 7 in an upland cotton recombinant inbred line (RIL) population from a cross (CCRI35 × Yumian1) described in our previous studies. To fine-map qFS07.1, an F2 population with 2484 individual plants from a cross between recombinant line RIL014 and CCRI35 was established. A total of 1518 SSR primer pairs, including 1062, designed from chromosome 1 of the Gossypium raimondii genome and 456 from chromosome 1 of the G. arboreum genome (corresponding to the QTL region) were used to fine-map qFS07.1, and qFS07.1 was mapped into a 62.6-kb genome region which contained four annotated genes on chromosome A07 of G. hirsutum. RT-qPCR and comparative analysis of candidate genes revealed a leucine-rich repeat protein kinase (LRR RLK) family protein to be a promising candidate gene for qFS07.1. Fine mapping and identification of the candidate gene for qFS07.1 will play a vital role in marker-assisted selection (MAS) and the study of mechanism of cotton fiber development.

Fine mapping and RNA-Seq unravels candidate genes for a major QTL controlling multiple fiber quality traits at the T1 region in upland cotton.

BACKGROUND: Improving fiber quality is a major challenge in cotton breeding, since the molecular basis of fiber quality traits is poorly understood. Fine mapping and candidate gene prediction of quantitative trait loci (QTL) controlling cotton fiber quality traits can help to elucidate the molecular basis of fiber quality. In our previous studies, one major QTL controlling multiple fiber quality traits was identified near the T1 locus on chromosome 6 in Upland cotton. RESULTS: To finely map this major QTL, the F2 population with 6975 individuals was established from a cross between Yumian 1 and a recombinant inbred line (RIL118) selected from a recombinant inbred line population (T586 × Yumian 1). The QTL was mapped to a 0.28-cM interval between markers HAU2119 and SWU2302. The QTL explained 54.7 % (LOD = 222.3), 40.5 % (LOD = 145.0), 50.0 % (LOD = 194.3) and 30.1 % (LOD = 100.4) of phenotypic variation with additive effects of 2.78, -0.43, 2.92 and 1.90 units for fiber length, micronaire, strength and uniformity, respectively. The QTL region corresponded to a 2.7-Mb interval on chromosome 10 in the G. raimondii genome sequence and a 5.3-Mb interval on chromosome A06 in G. hirsutum. The fiber of Yumian 1 was much longer than that of RIL118 from 3 DPA to 7 DPA. RNA-Seq of ovules at 0 DPA and fibers at 5 DPA from Yumian 1 and RIL118 showed four genes in the QTL region of the G. raimondii genome to be extremely differentially expressed. RT-PCR analysis showed three genes in the QTL region of the G. hirsutum genome to behave similarly. CONCLUSIONS: This study mapped a major QTL influencing four fiber quality traits to a 0.28-cM interval and identified three candidate genes by RNA-Seq and RT-PCR analysis. Integration of fine mapping and RNA-Seq is a powerful strategy to uncover candidates for QTL in large genomes.

Early Cambrian ocean anoxia in South China.

The cause of the most marked changes in the evolution of life, which define the first-order stratigraphic boundary between the Precambrian and the Phanerozoic eon, remains enigmatic and a highly topical subject of debate. A global ocean anoxic event, triggered by large-scale hydrogen sulphide (H(2)S) release to surface waters, has been suggested by Wille et al., on the basis of two data sets from South China and Oman, to explain the fundamental biological changes across the Precambrian/Cambrian (PC/C) boundary. Here we report a new precise SHRIMP U-Pb zircon age of 532.3 +/- 0.7 million years (Myr) ago (Fig. 1) for a volcanic ash bed in the critical unit that reflects the ocean anoxic event, the lowermost black shale sequence of the Niutitang Formation in the Guizhou Province, South China. This age is significantly younger than the precise PC/C boundary age of 542.0 +/- 0.3 Myr ago, approximately 10 Myr younger than the extinction of the Ediacaran fauna, and thus challenging the view of a major ocean anoxic event having been responsible for the major changes in the direction of evolution at the PC/C boundary.

Medial patellar ligament reconstruction in combination with derotational distal femoral osteotomy for treating recurrent patellar dislocation in the presence of increased femoral anteversion: a systematic review.

BACKGROUND: Medial patellar ligament reconstruction (MPFL-R) in combination with derotational distal femoral osteotomy (DDFO) for treating recurrent patellar dislocation (RPD) in the presence of increased femoral anteversion is one of the most commonly used surgical techniques in the current clinical practice. However, there are limited studies on the clinical outcomes of MPFL-R in combination with DDFO to treat RPD in the presence of increased femoral anteversion. PURPOSE: To study the role of MPFL-R in combination with DDFO in the treatment of RPD in the presence of increased femoral anteversion. METHODS: A systematic review was performed according to the PRISMA guidelines by searching the Medline, Embase, Web of Science, and Cochrane Library databases through June 1, 2023. Studies of patients who received MPFL-R in combination with DDFO after presenting with RPD and increased femoral anteversion were included. Methodological quality was assessed using the MINORS (Methodological Index for Nonrandomized Studies) score. Each study's basic characteristics, including characteristic information, radiological parameters, surgical techniques, patient-reported outcomes, and complications, were recorded and analyzed. RESULTS: A total of 6 studies with 231 patients (236 knees) were included. Sample sizes ranged from 12 to 162 patients, and the majority of the patients were female (range, 67-100%). The mean age and follow-up ranges were 18 to 24 years and 16 to 49 months, respectively. The mean femoral anteversion decreased significantly from 34° preoperatively to 12° postoperatively. In studies reporting preoperative and postoperative outcomes, significant improvements were found in the Lysholm score, Kujala score, International Knee Documentation Committee score, and visual analog scale for pain. Postoperative complications were reported in all studies, with an overall reported complication rate of 4.7%, but no redislocations occurred during the follow-up period. CONCLUSION: For RPD with increased femoral anteversion, MPFL-R in combination with DDFO leads to a good clinical outcome and a low redislocation rate. However, there was no consensus among researchers on the indications for MPFL-R combined with DDFO in the treatment of RPD.

Bioinformatics and systems biology approaches to identify potential common pathogeneses for sarcopenia and osteoarthritis.

Sarcopenia, a geriatric syndrome characterized by progressive loss of muscle mass and strength, and osteoarthritis, a common degenerative joint disease, are both prevalent in elderly individuals. However, the relationship and molecular mechanisms underlying these two diseases have not been fully elucidated. In this study, we screened microarray data from the Gene Expression Omnibus to identify associations between sarcopenia and osteoarthritis. We employed multiple statistical methods and bioinformatics tools to analyze the shared DEGs (differentially expressed genes). Additionally, we identified 8 hub genes through functional enrichment analysis, protein-protein interaction analysis, transcription factor-gene interaction network analysis, and TF-miRNA coregulatory network analysis. We also discovered potential shared pathways between the two diseases, such as transcriptional misregulation in cancer, the FOXO signalling pathway, and endometrial cancer. Furthermore, based on common DEGs, we found that strophanthidin may be an optimal drug for treating sarcopenia and osteoarthritis, as indicated by the Drug Signatures database. Immune infiltration analysis was also performed on the sarcopenia and osteoarthritis datasets. Finally, receiver operating characteristic (ROC) curves were plotted to verify the reliability of our results. Our findings provide a theoretical foundation for future research on the potential common pathogenesis and molecular mechanisms of sarcopenia and osteoarthritis.

Bioinformatics and system biology approach to identify potential common pathogenesis for COVID-19 infection and sarcopenia.

Sarcopenia is a condition characterized by age-related loss of muscle mass and strength. Increasing evidence suggests that patients with sarcopenia have higher rates of coronavirus 2019 (COVID-19) infection and poorer post-infection outcomes. However, the exact mechanism and connections between the two is unknown. In this study, we used high-throughput data from the GEO database for sarcopenia (GSE111016) and COVID-19 (GSE171110) to identify common differentially expressed genes (DEGs). We conducted GO and KEGG pathway analyses, as well as PPI network analysis on these DEGs. Using seven algorithms from the Cytoscape plug-in cytoHubba, we identified 15 common hub genes. Further analyses included enrichment, PPI interaction, TF-gene and miRNA-gene regulatory networks, gene-disease associations, and drug prediction. Additionally, we evaluated immune cell infiltration with CIBERSORT and assessed the diagnostic accuracy of hub genes for sarcopenia and COVID-19 using ROC curves. In total, we identified 66 DEGs (34 up-regulated and 32 down-regulated) and 15 hub genes associated with sarcopenia and COVID-19. GO and KEGG analyses revealed functions and pathways between the two diseases. TF-genes and TF-miRNA regulatory network suggest that FOXOC1 and hsa-mir-155-5p may be identified as key regulators, while gene-disease analysis showed strong correlations with hub genes in schizophrenia and bipolar disorder. Immune infiltration showed a correlation between the degree of immune infiltration and the level of infiltration of different immune cell subpopulations of hub genes in different datasets. The ROC curves for ALDH1L2 and KLF5 genes demonstrated their potential as diagnostic markers for both sarcopenia and COVID-19. This study suggests that sarcopenia and COVID-19 may share pathogenic pathways, and these pathways and hub genes offer new targets and strategies for early diagnosis, effective treatment, and tailored therapies for sarcopenia patients with COVID-19.

Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity.

The multibasic furin cleavage site at the S1/S2 boundary of the spike protein is a hallmark of SARS-CoV-2 and plays a crucial role in viral infection. However, the mechanism underlying furin activation and its regulation remain poorly understood. Here, we show that GalNAc-T3 and T7 jointly initiate clustered O-glycosylations in the furin cleavage site of the SARS-CoV-2 spike protein, which inhibit furin processing, suppress the incorporation of the spike protein into virus-like-particles and affect viral infection. Mechanistic analysis reveals that the assembly of the spike protein into virus-like particles relies on interactions between the furin-cleaved spike protein and the membrane protein of SARS-CoV-2, suggesting a possible mechanism for furin activation. Interestingly, mutations in the spike protein of the alpha and delta variants of the virus confer resistance against glycosylation by GalNAc-T3 and T7. In the omicron variant, additional mutations reverse this resistance, making the spike protein susceptible to glycosylation in vitro and sensitive to GalNAc-T3 and T7 expression in human lung cells. Our findings highlight the role of glycosylation as a defense mechanism employed by host cells against SARS-CoV-2 and shed light on the evolutionary interplay between the host and the virus.

Cold-induced FOXO1 nuclear transport aids cold survival and tissue storage.

Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.

Accelerated Bone Reconstruction by the Yoda1 Bilayer Membrane via Promotion of Osteointegration and Angiogenesis.

Guided bone regeneration membranes are widely used to prevent fibroblast penetration and facilitate bone defect repair by osteoblasts. However, the current clinically available collagen membranes lack bone induction and angiogenic capacities, exhibiting limited bone regeneration. The mechanically sensitive channel, Piezo1, which is activated by Yoda1, has been reported to play crucial roles in osteogenesis and angiogenesis. Nevertheless, the application of Yoda1 alone is unsustainable to maintain this activity. Therefore, this study fabricates a Yoda1-loading bilayer membrane using electrospinning technology. Its inner layer in contact with the bone defect is composed of vertically aligned fibers, which regulate the proliferation and differentiation of cells, release Yoda1, and promote bone regeneration. Its outer layer in contact with the soft tissue is dense with oriented fibers by UV cross-linking, mainly preventing fibroblast infiltration and inhibiting the immune response. Furthermore, the loaded Yoda1 affects osteogenesis and angiogenesis via the Piezo1/RhoA/Rho-associated coiled-coil-containing protein kinase 1/Yes1-associated transcriptional regulator signaling pathway. The results reveal that the Yoda1 bilayer membrane is efficient and versatile in accelerating bone regeneration, suggesting its potential as a novel therapeutic agent for various clinical issues.

Evaluation of the clinical performance of p16/Ki-67 dual-staining cytology for cervical lesion detection in premenopausal and postmenopausal Chinese women.

BACKGROUND: Studies on the clinical performance of p16/Ki-67 dual-staining in detecting cervical lesions by menopausal status were limited. METHODS: 4364 eligible women were enrolled with valid p16/Ki-67, HR-HPV, and LBC test results, including 542 cancer and 217 CIN2/3 cases. The positivity rates of p16 and Ki-67 single staining and p16/ Ki-67 dual-staining were analyzed by different pathological grades and age groups. The sensitivity (SEN), specificity (SPE), positive predictive value (PPV), and negative predictive value (NPV) of each test in different subgroups were calculated and compared. RESULTS: P16/Ki-67 dual-staining positivity increased with histopathological severity in premenopausal and postmenopausal women (P < 0.05), while no increasing trends of individual expression of p16 single staining and Ki-67 single staining were observed in postmenopausal women. P16/Ki-67 showed higher SPE (88.09% vs. 81.91%, P < 0.001) and PPV (33.8% vs. 13.18%, P < 0.001) in detecting CIN2/3, and higher SEN (89.97% vs. 82.61%, P = 0.012) and SPE (83.22% vs. 79.89%, P = 0.011) in detecting cancer in premenopausal women than postmenopausal women. For triaging the HR-HPV+ population to identify CIN2/3, p16/Ki-67 performed comparably to LBC in the premenopausal women, and showed higher PPV (51.14% vs. 23.08%, P < 0.001) in premenopausal than postmenopausal women. For triaging ASC-US/LSIL population, p16/Ki-67 demonstrated higher SPE and lower colposcopy referral rate than HR-HPV in both premenopausal and postmenopausal women. CONCLUSIONS: Expressions of p16/Ki-67 dual-staining between premenopausal and postmenopausal women are varied. P16/Ki-67 performs better in detecting cervical lesions in premenopausal women. For triaging, p16/Ki-67 is suitable for HR-HPV+ women, especially premenopausal women, to identify CIN2/3 and women with ASC-US/LSIL.

Synergy of 5-aminolevulinate supplement and CX3CR1 suppression promotes liver regeneration via elevated IGF-1 signaling.

Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy (PHx), while few clinical treatments focus on safely accelerating regeneration. Recently, we discovered that supplementing 5-aminolevulinate (5-ALA) improves liver cold adaptation and functional recovery, leading us to uncover a correlation between 5-ALA metabolic activities and post-PLT recovery. In a mouse 2/3 PHx model, 5-ALA supplements enhanced liver regeneration, promoting infiltration and polarization of anti-inflammatory macrophages via P53 signaling. Intriguingly, chemokine receptor CX3CR1 functions to counterbalance these effects. Genetic ablation or pharmacological inhibition of CX3CR1 (AZD8797; phase II trial candidate) augmented the macrophagic production of insulin-like growth factor 1 (IGF-1) and subsequent hepatocyte growth factor (HGF) production by hepatic stellate cells. Thus, short-term treatments with both 5-ALA and AZD8797 demonstrated pro-regeneration outcomes superior to 5-ALA-only treatments in mice after PHx. Overall, our findings may inspire safe and effective strategies to better treat PLT and PHx patients.

Molecular characterization of the bla(KPC-2) gene in clinical isolates of carbapenem-resistant Klebsiella pneumoniae from the pediatric wards of a Chinese hospital.

The present study was conducted to confirm the presence of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae associated with a nosocomial outbreak in a Chinese pediatric hospital. From July 2009 to January 2011, 124 nonduplicated K. pneumoniae isolates were collected from specimens from patients of pediatric units in the hospital. Twelve of the 124 isolates possessed the bla(KPC-2) gene and showed 7 different pulsed-field gel electrophoresis (PFGE) patterns. Meanwhile, 16S rRNA methylase, acc(6')-Ib-cr, and several types of ß-lactamases were also produced by the majority of the KPC-producing isolates. Class 1 integron-encoded intI1 integrase gene was subsequently found in all strains, and amplification, sequencing, and comparison of DNA between 5' conserved segment and 3' conserved segment region showed the presence of several known antibiotic resistance gene cassettes of various sizes. The conjugation and plasmid-curing experiments indicated some KPC-2-encoding genes were transmissible. In addition, conjugal cotransfer of multidrug-resistant phenotypes with KPC-positive phenotypes was observed in KPC-producing strains. Restriction endonuclease analysis and DNA hybridization with a KPC-specific probe showed that the bla(KPC-2) gene was carried by plasmid DNA from K. pneumoniae of PFGE pattern B. The overall results indicate that the emergence and outbreak of KPC-producing K. pneumoniae in our pediatric wards occurred in conjunction with plasmids coharboring 16S rRNA methylase and extended-spectrum ß-lactamases.