Limited protection of pneumococcal vaccines against emergent Streptococcus pneumoniae serotype 14/ST876 strains.

PURPOSE: Streptococcus pneumoniae (Spn) is a major cause of child death. We investigated the epidemiology of S. pneumoniae in a pediatric fever clinic and explored the genomics basis of the limited vaccine response of serotype 14 strains worldwide. METHODS: Febrile disease and pneumonia were diagnosed following criteria from the WHO at the end of 2019 at a tertiary children's hospital. Spn was isolated by culture from nasopharyngeal (NP) swabs. The density was determined by lytA-base qPCR. Isolates were serotyped by Quellung and underwent antimicrobial susceptibility testing. Whole-genome sequencing was employed for molecular serotyping, MLST, antibiotic gene determination, SNP calling, recombination prediction, and phylogenetic analysis. RESULTS: The presence of pneumococcus in the nasopharynx (87.5%, 7/8, p = 0.0227) and a high carriage (100%, 7/7, p = 0.0123) were significantly associated with pneumonia development. Living with siblings (73.7%, 14/19, p = 0.0125) and non-vaccination (56.0%, 28/50, p = 0.0377) contributed significantly to the Spn carriage. Serotype 14 was the most prevalent strain (16.67%, 5/30). The genome analysis of 1497 serotype 14 strains indicated S14/ST876 strains were only prevalent in China, presented limited vaccine responses with higher recombination activities within its cps locus, and unique variation patterns in the genes wzg and lrp. CONCLUSION: With the lifting of the one-child policy, it will be crucial for families with multiple children to get PCV vaccinations in China. Due to the highly variant cps locus and distinctive variation patterns in capsule shedding and binding proteins genes, the prevalent S14/ST876 strains have shown poor response to current vaccines. It is necessary to continue monitoring the molecular epidemiology of this vaccine escape clone.

Pathologic outcomes of transanal versus laparoscopic total mesorectal excision for rectal cancer: a meta-analysis of 26 studies.

PURPOSE: Transanal total mesorectal excision (TaTME) has the potential advantages for patients with low rectal cancer. The objective of this meta-analysis was to identify the pathologic outcomes between the TaTME and laparoscopic total mesorectal excision (LaTME) in rectal cancer. METHODS: The literature searches were conducted in PubMed, Cochrane Library, and EMBASE with English language restriction. The primary endpoint was circumferential margin (CRM), and the secondary endpoints were distal resection margin (DRM), mesorectal excision quality, and harvested lymph nodes. RESULTS: Our research identified 1090 articles, and 26 studies met the inclusion criteria for the meta-analysis. The positive CRM was lower in the TaTME than the LaTME (OR = 0.72; 95% CI = 0.53, 0.98; P = 0.04). There was no significant difference in the positive CRM between the TaTME and LaTME published after 2016 (OR = 0.80; 95% CI = 0.57, 1.12; P = 0.19), prospective study (OR = 2.70; 95% CI = 0.51, 14.24; P = 0.24), respective study (OR = 0.76; 95% CI = 0.55, 1.04; P = 0.09), BMI > 26 (OR = 1.00; 95% CI = 0.63, 1.58; P = 0.98), or sample size > 100 (OR = 0.84; 95% CI = 0.57, 1.23; P = 0.38). In addition, there was no significant difference observed between the TaTME and LaTME in terms of DRM, mesorectum incompleteness, and harvested lymph nodes. CONCLUSIONS: The TaTME is associated with lower positive CRM compared to the LaTME and similar pathologic outcomes including DRM, harvested lymph node, and mesorectal excision quality.

Redox chemistry changes in the Panthalassic Ocean linked to the end-Permian mass extinction and delayed Early Triassic biotic recovery.

The end-Permian mass extinction represents the most severe biotic crisis for the last 540 million years, and the marine ecosystem recovery from this extinction was protracted, spanning the entirety of the Early Triassic and possibly longer. Numerous studies from the low-latitude Paleotethys and high-latitude Boreal oceans have examined the possible link between ocean chemistry changes and the end-Permian mass extinction. However, redox chemistry changes in the Panthalassic Ocean, comprising ∼85-90% of the global ocean area, remain under debate. Here, we report multiple S-isotopic data of pyrite from Upper Permian-Lower Triassic deep-sea sediments of the Panthalassic Ocean, now present in outcrops of western Canada and Japan. We find a sulfur isotope signal of negative Δ33S with either positive δ34S or negative δ34S that implies mixing of sulfide sulfur with different δ34S before, during, and after the end-Permian mass extinction. The precise coincidence of the negative Δ33S anomaly with the extinction horizon in western Canada suggests that shoaling of H2S-rich waters may have driven the end-Permian mass extinction. Our data also imply episodic euxinia and oscillations between sulfidic and oxic conditions during the earliest Triassic, providing evidence of a causal link between incursion of sulfidic waters and the delayed recovery of the marine ecosystem.

Sensitive and selective detection of uracil-DNA glycosylase activity with a new pyridinium luminescent switch-on molecular probe.

Uracil-deoxyribonucleic acid glycosylase (UDG) is known to function as an important base-excision repair enzyme and eliminate uracil from DNA molecules to maintain genomic integrity. A new small organic molecule (DID-VP) with interesting structural properties was synthesized as a G-quadruplex selective ligand and was demonstrated to be a sensitive luminescent switch-on probe in a convenient luminescent assay specifically for UDG detection in fetal bovine serum samples under rapid and simple conditions. This newly developed analytical method is based on the UDG enzymatic activity to unwind a duplex DNA substrate, and comprises a G-quadruplex-forming sequence (ON1) and uracil-containing DNA strand (ON2) to generate a remarkable fluorescence signal through the specific interaction of DID-VP with ON1. This luminescent switch-on assay is able to achieve high sensitivity and specificity for UDG over other enzymes. The application range of the present analytical system is found to be 0.05 to 1.00 U mL(-1) UDG with a very low detection limit of 0.005 U mL(-1). The recovery study of UDG in real samples gave a very good performance with 75.05%-102.7% recovery. In addition, an extended application of the assay in screening of UDG inhibitors is demonstrated. A good dose-dependence of the luminescence response with respect to the concentration of UDG inhibitors in samples was observed.

Risk of Esophageal Adenocarcinoma After Bariatric Surgery: A Meta-Analysis of Retrospective Studies.

PURPOSE: This study aims to systematically review and meta-analyze the evidence on the risk of esophageal adenocarcinoma (EAC) following metabolic and bariatric surgery (MBS). MATERIALS AND METHODS: A systematic literature search was conducted on the China National Knowledge Infrastructure (CNKI), Wanfang, EMBASE, MEDLINE, Web of Science, The Cochrane Library, and PubMed databases. Meta-analysis utilized odds ratios (ORs) and 95% confidence intervals (CIs) to analyze the correlation between MBS and the risk of EAC. Meta-analysis was performed using STATA software (version 12.0). RESULTS: Fourteen studies involving patients with obesity undergoing bariatric surgery and control groups receiving conventional treatment were included. The meta-analysis indicated a reduction in the overall incidence of esophageal cancer after bariatric surgery (OR = 0.69, 95% CI: 0.51-0.95, P = 0.022). Subgroup analysis results demonstrated a decreased risk of EAC in European patients with obesity undergoing MBS treatment (OR: 0.60, 95% CI: 0.38-0.95, P = 0.028). In studies with a sample size greater than or equal to 100,000 patients, the risk of EAC in patients with obesity undergoing MBS was significantly lower than the non-surgery group (OR: 0.59, 95% CI: 0.42-0.83, P = 0.003). Articles published before 2020 and those published in 2020 or earlier showed a significant difference in the incidence of EAC between the surgery and non-surgery groups (OR: 0.57, 95% CI: 0.43-0.75, P < 0.001). The risk of EAC in patients with obesity with a follow-up time of less than 5 years was statistically significant (OR: 0.46, 95% CI: 0.25-0.82, P = 0.009). CONCLUSION: Our meta-analysis results suggest a reduced risk of esophageal cancer in patients with obesity after bariatric surgery. PROSPERO REGISTRATION: CRD 42024505177.

Liver-Derived Ketogenesis via Overexpressing HMGCS2 Promotes the Recovery of Spinal Cord Injury.

The liver is the major ketogenic organ of the body, and ketones are reported to possess favorable neuroprotective effects. This study aims to elucidate whether ketone bodies generated from the liver play a critical role in bridging the liver and spinal cord. Mice model with a contusive spinal cord injury (SCI) surgery is established, and SCI induces significant histological changes in mice liver. mRNA-seq of liver tissue shows the temporal changes of ketone bodies-related genes, ß-hydroxybutyrate dehydrogenase (BDH1) and solute carrier family 16 (monocarboxylic acid transporters), member 6 (SLC16A6). Then, an activated ketogenesis model is created with adult C57BL/6 mice receiving the tail intravenous injection of GPAAV8-TBG-Mouse-Hmgcs2-CMV- mCherry -WPRE (HMGCS2liver ) and mice receiving equal AAV8-Null being the control group (Vectorliver ). Then, the mice undergo either a contusive SCI or sham surgery. The results show that overexpression of HMG-CoA synthase (Hmgcs2) in mice liver dramatically alleviates SCI-mediated pathological changes and promotes ketogenesis in the liver. Amazingly, liver-derived ketogenesis evidently alleviates neuron apoptosis and inflammatory microglia activation and improves the recovery of motor function of SCI mice. In conclusion, a liver-spinal cord axis can be bridged via ketone bodies, and enhancing the production of the ketone body within the liver has neuroprotective effects on traumatic SCI.

Role of tcaA, a potential target as a ceftobiprole resistance breaker in MRSA ß-lactam resistance.

OBJECTIVES: Using a random forest algorithm, we previously found that teicoplanin-associated gene A (tcaA) might play a role in resistance of methicillin-resistant Staphylococcus aureus (MRSA) to ß-lactams, which we have investigated further here. METHODS: Representative MRSA strains of prevalent clones were selected to identify the role of tcaA in the MRSA response to ß-lactams. tcaA genes were deleted by homologous recombination in the selected MRSA strains, and antibiotic susceptibility tests were applied to evaluate the effect of tcaA on the minimum inhibitory concentrations (MICs) of glycopeptides and ß-lactams. Scanning electron microscopy, RNA sequencing, and quantitative reverse transcription-polymerase chain reaction were performed to explore the mechanism of tcaA in MRSA resistance to ß-lactams. RESULTS: The MIC of penicillin plus clavulanate decreased from 3 mg/L to 0.064 mg/L and that of oxacillin decreased from 16 to 0.5 mg/L when tcaA was knocked out in the LAC strain. Compared with wild-type MRSA isolates, when tcaA was deleted, all selected strains were more susceptible to ß-lactams. Susceptibility to ceftobiprole was restored in the ceftobiprole-resistant strain when tcaA was deleted. tcaA knockout caused "log-like" abnormal division of MRSA, and tcaA deficiency mediated low expression of mecA, ponA, and murA2. CONCLUSIONS: Machine learning is a reliable tool for identifying drug resistance-related genes. tcaA may be involved in S. aureus cell division and may affect mecA, ponA, and murA2 expression. Furthermore, tcaA is a potential resistance breaker target for ß-lactams, including ceftobiprole, in MRSA.

Integrated genomic analysis of antibiotic resistance and virulence determinants in invasive strains of Streptococcus pneumoniae.

Introduction: Streptococcus pneumoniae is an important human pathogen that may cause severe invasive pneumococcal diseases (IPDs) in young children and the elderly. A comprehensive comparative whole-genome analysis of invasive and non-invasive serotype strains offers great insights that are applicable to vaccine development and disease control. Methods: In this study, 58 invasive (strains isolated from sterile sites) and 71 non-invasive (serotypes that have not been identified as invasive in our study) pneumococcal isolates were identified among the 756 pneumococcal isolates obtained from seven hospitals in Zhejiang, China (2010-2022). Serotyping, antimicrobial resistance tests, and genomic analyses were conducted to characterize these strains. Results and discussion: The three most invasive serotypes were 23F, 14, and 6B. The invasive pneumococcal isolates' respective resistance rates against penicillin, ceftriaxone, tetracycline, and erythromycin were 34.5%, 15.5%, 98.3%, and 94.7%. Whole-genome sequencing indicated that the predominant invasive clonal complexes were CC271, CC876, and CC81. The high rate of penicillin non-susceptible Streptococcus pneumoniae (PNSP) is related to the clonal distribution of resistance-conferring penicillin-binding proteins (PBP). Interestingly, we found a negative correlation between invasiveness and resistance in the invasive pneumococcal serotype strains, which might be due to the proclivity of certain serotypes to retain their ß-lactam resistance. Moreover, the mutually exclusive nature of zmpC and rrgC+srtBCD suggests their intricate and potentially redundant roles in promoting the development of IPD. These findings reveal significant implications for pneumococcal vaccine development in China, potentially informing treatment strategies and measures to mitigate disease transmission.

Mog1 deficiency promotes cardiac contractile dysfunction and isoproterenol-induced arrhythmias associated with cardiac fibrosis and Cx43 remodeling.

Our earlier studies identified MOG1 as a Nav1.5-binding protein that promotes Nav1.5 intracellular trafficking to plasma membranes. Genetic studies have identified MOG1 variants responsible for cardiac arrhythmias. However, the physiological functions of MOG1 in vivo remain incompletely characterized. In this study, we generated Mog1 knockout (Mog1-/-) mice. Mog1-/- mice did not develop spontaneous arrhythmias at the baseline, but exhibited a prolongation of QRS duration. Mog1-/- mice treated with isoproterenol (ISO), but not with flecainide, exhibited an increased risk of arrhythmias and even sudden death. Mog1-/- mice had normal cardiac morphology, however, LV systolic dysfunction was identified and associated with an increase in ventricular fibrosis. Whole-cell patch-clamping and Western blotting analysis clearly demonstrated the normal cardiac expression and function of Nav1.5 in Mog1-/- mice. Further RNA-seq and iTRAQ analysis identified critical pathways and genes, including extracellular matrix (Mmp2), gap junction (Gja1), and mitochondrial components that were dysregulated in Mog1-/- mice. RT-qPCR, Western blotting, and immunofluorescence assays revealed reduced cardiac expression of Gja1 in Mog1-/- mice. Dye transfer assays confirmed impairment of gap-junction function; Cx43 gap-junction enhancer ZP123 decreased arrhythmia inducibility in ISO-treated Mog1-/- mice. Transmission electron microscopy analysis revealed abnormal sarcomere ultrastructure and altered mitochondrial morphology in Mog1-/- mice. Mitochondrial dynamics was found to be disturbed, and associated with a trend toward increased mitochondrial fusion in Mog1-/- mice. Meanwhile, the level of ATP supply was increased in the hearts of Mog1-/- mice. These results indicate that MOG1 plays an important role in cardiac electrophysiology and cardiac contractile function.

Induction of the macrolide-resistance efflux pump Mega inhibits intoxication of Staphylococcus aureus strains by Streptococcus pneumoniae.

Streptococcus pneumoniae (Spn) kills Staphylococcus aureus (Sau) through a contact-dependent mechanism that is catalyzed by cations, including iron, to convert hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals (•OH). There are two well-characterized ABC transporters that contribute to the pool of iron in Spn, named Pia and Piu. Some Spn strains have acquired genes mef(E)/mel encoding another ABC trasporter (Mega) that produces an inducible efflux pump for resistance to macrolides. In macrolide-resistant Spn clinical isolates the insertion of Mega class 1. IV and 2. IVc deleted the locus piaABCD and these strains were attenuated for intoxicating Sau. The goal of this study was to investigate if the disruption of iron acquisition, or the antimicrobial-resistance activity of Mega, contributed to inhibiting the killing mechanism. Neither depletion of iron with 2,2'-dipyridyl-d8 (DP) nor incubating with a double knockout mutant SpnΔpiaAΔpiuA, inhibited killing of Sau. Clinical Spn strains carrying Mega1. IV or Mega2. IVc showed a significant delay for killing Sau. An ex vivo recombination system was used to transfer Mega1. IV or Mega2. IVc to reference Spn strains, which was confirmed by whole genome sequencing, and recombinants TIGR4Mega2. IVc, D39Mega2. IVc, and D39Mega1. IV were delayed for killing Sau. We then compared Sau killing of selected Mega-carrying Spn strains when incubated with sub-inhibitory erythromycin (Mega-induced) or sub-inhibitory cefuroxime. Remarkably, killing of Sau was completely inhibited under the Mega-induced condition whereas incubation with cefuroxime did not interfere with killing. Both mef(E) and mel were upregulated > 400-fold, and spxB (encoding an enzyme responsible for production of most H2O2) was upregulated 14.2-fold, whereas transcription of the autolysin (lytA) gene was downregulated when incubated with erythromycin. We demonstrated that erythromycin induction of Mega inhibits the •OH-mediated intoxication of Sau and that the inhibition occurred at the post-translational level suggesting that an imbalance of ions in the membrane inhibits these reactions.

Nickel isotopes link Siberian Traps aerosol particles to the end-Permian mass extinction.

The end-Permian mass extinction (EPME) was the most severe extinction event in the past 540 million years, and the Siberian Traps large igneous province (STLIP) is widely hypothesized to have been the primary trigger for the environmental catastrophe. The killing mechanisms depend critically on the nature of volatiles ejected during STLIP eruptions, initiating about 300 kyr before the extinction event, because the atmosphere is the primary interface between magmatism and extinction. Here we report Ni isotopes for Permian-Triassic sedimentary rocks from Arctic Canada. The δ60Ni data range from -1.09‰ to 0.35‰, and exhibit the lightest δ60Ni compositions ever reported for sedimentary rocks. Our results provide strong evidence for global dispersion and loading of Ni-rich aerosol particles into the Panthalassic Ocean. Our data demonstrate that environmental degradation had begun well before the extinction event and provide a link between global dispersion of Ni-rich aerosols, ocean chemistry changes, and the EPME.

Robotic-assisted versus conventional laparoscopic surgery for colorectal cancer: Short-term outcomes at a single center.

BACKGROUND: The robotic technique has been established as an alternative approach to laparoscopy for colorectal surgery. The aim of this study was to compare the short-term outcomes of robot-assisted and laparoscopic surgery in colorectal cancer. METHODS: The cases of robot-assisted or laparoscopic colorectal resection were collected retrospectively between July 2015 and September 2018. We evaluated patient demographics, perioperative characteristics, and pathologic examinations. Short-term outcomes included time to passage of flatus and length of postoperative hospital stay. RESULTS: A total of 580 patients were included in the study. There were 271 patients in the robotic colorectal surgery (RCS) group and 309 in the laparoscopic colorectal surgery (LCS) group. The time to passage of flatus in the RCS group was 3.62 days shorter than the LCS group. The total costs were increased by 2,258.8 USD in the RCS group compared to the LCS group (P < 0.001). CONCLUSION: The present study suggests that colorectal cancer robotic surgery was more beneficial to patients because of a shorter postoperative recovery time of bowel function and shorter hospital stays.

Large mass-independent sulphur isotope anomalies link stratospheric volcanism to the Late Ordovician mass extinction.

Volcanic eruptions are thought to be a key driver of rapid climate perturbations over geological time, such as global cooling, global warming, and changes in ocean chemistry. However, identification of stratospheric volcanic eruptions in the geological record and their causal link to the mass extinction events during the past 540 million years remains challenging. Here we report unexpected, large mass-independent sulphur isotopic compositions of pyrite with Δ33S of up to 0.91‰ in Late Ordovician sedimentary rocks from South China. The magnitude of the Δ33S is similar to that discovered in ice core sulphate originating from stratospheric volcanism. The coincidence between the large Δ33S and the first pulse of the Late Ordovician mass extinction about 445 million years ago suggests that stratospheric volcanic eruptions may have contributed to synergetic environmental deteriorations such as prolonged climatic perturbations and oceanic anoxia, related to the mass extinction.

Short-Term Outcomes of Robotic versus Laparoscopic Total Mesorectal Excision for Rectal Cancer: A Cohort Study.

The aim of this study was to evaluate and compare the intestinal function recovery time and other short-term outcomes between robotic-assisted total mesorectal excision (R-TME) and laparoscopic total mesorectal excision (L-TME) for rectal cancer. This is a retrospective study using a prospectively collected database. Patients' records were obtained from Gansu Provincial Hospital between July 2015 and October 2017. Eighty patients underwent R-TME, and 116 with the same histopathological stage of the tumor underwent an L-TME. Both operations were performed by the same surgeon, comparing intra- and postoperative outcomes intergroups. The time to the first passage of flatus (P < 0.001), the time to the first postoperative oral fluid intake (P < 0.001), and the length of hospital stay (P < 0.01) of the R-TME group were about three days faster than those in the L-TME group. The rate of conversion to open laparotomy (P = 0.038) and postoperative urinary retention (P = 0.016) were significantly lower in the R-TME group than in the L-TME group. Intraoperative blood loss of the R-TME group was more than that of the L-TME group (P < 0.01).The operation time, number of lymph nodes harvested, and rate of positive circumferential resection margin were similar intergroup. The total cost of the R-TME group was higher than that of the L-TME group, but with a lack of statistical significance (85,623.91 ± 13,310.50 vs 67,356.79 ± 17,107.68 CNY, P = 0.084). The R-TME is safe and effective and has better postoperative short-term outcomes and faster intestinal function recovery time, contrasting with the L-TME. The large, multicenter, prospective studies were needed to validate the advantages of robotic surgery system used in rectal cancer.

The application of transanal total mesorectal excision for patients with middle and low rectal cancer: A systematic review and meta-analysis.

BACKGROUND: Recently, in order to overcome the shortcomings of laparoscopic surgery in the treatment of low rectal cancer, a new kind of surgical procedure, transanal total mesorectal excision (TaTME), has rapidly become a research hotspot in the field of rectal cancer surgery study. Our study aimed to evaluate the efficacy and safety of transanal total mesorectal excision (TaTME) for the patients with rectal cancer. METHODS: Relevant studies were searched from the databases of the Cochrane Library, PubMed, Embase, Web of science. All relevant studies were collected to evaluate the efficacy and safety of TaTME for patients with rectal cancer. The quality of the included studies was assessed by the Newcastle-Ottawa Quality Assessment Scale (NOS) and Cochrane Library Handbook 5.1.0. Data analysis was conducted using the Review Manager 5.3 software. RESULTS: Thirteen studies including 859 patients were included in our analysis. In terms of efficacy, compared with laparoscopic total mesorectal excision (LaTME), meta-analysis showed that the rate of complete tumor resection increased and the risk of positive circumferential margins decreased in the TaTME group. For complete tumor resection and positive circumferential margins in the TaTME group, the odds ratios (ORs) and 95% confidence intervals (CIs) were 1.93 and 1.09 to 3.42 (P = .02) and 0.43 and 0.22 to 0.82 (P = .01), respectively. Concerning safety, results showed that the rates of postoperative complications were similar in the 2 groups, and differences in the risk of ileus and anastomotic leakage were not statistically significant (OR = 0.75, 95%CI = 0.51-1.09, P = .13; OR = 0.91, 95%CI = 0.46-1.78, P = .78; OR = 0.79, 95%CI = 0.45-1.38, P = .40). CONCLUSIONS: The results of this meta-analysis show that TaTME is associated with a reduced positive circumferential resection margin (CRM) rate, and could achieve complete tumor resection and improved the long-term survival in patients with mid- and low-rectal cancer.

87Sr/86Sr evidence from the epeiric Martin Ridge Basin for enhanced carbonate weathering during the Hirnantian.

A pronounced positive δ13C excursion in the Hirnantian Age has been documented globally, reflecting large perturbations of carbon cycling in the Late Ordovician oceans. Increased organic-carbon burial or enhanced carbonate weathering during glacioeustatic sea-level regression has been proposed to account for this anomalous C-isotope excursion. To test the two competing hypotheses, we measured 87Sr/86Sr and δ13C of carbonates from the Copenhagen Canyon section in Nevada, USA. Our data reveal two rapid negative 87Sr/86Sr shifts that coincide with two prominent positive δ13C excursions and glacial advances. Numerical model simulations suggest that enhanced weathering of carbonates driven by glacio-eustatically controlled sea-level fall is required to produce the observed drops of 87Sr/86Sr and the coeval large positive δ13C excursions, possibly with or without increased organic carbon burial.

Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines.

PURPOSE: To determine whether curcumin ameliorates acute and chronic radiation skin toxicity and to examine the expression of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-18, IL-1Ra, tumor necrosis factor [TNF]-alpha, and lymphotoxin-beta) or fibrogenic cytokines (transforming growth factor [TGF]-beta) during the same acute and chronic phases. METHODS AND MATERIALS: Curcumin was given intragastrically or intraperitoneally to C3H/HeN mice either: 5 days before radiation; 5 days after radiation; or both 5 days before and 5 days after radiation. The cutaneous damage was assessed at 15-21 days (acute) and 90 days (chronic) after a single 50 Gy radiation dose was given to the hind leg. Skin and muscle tissues were collected for measurement of cytokine mRNA. RESULTS: Curcumin, administered before or after radiation, markedly reduced acute and chronic skin toxicity in mice (p < 0.05). Additionally, curcumin significantly decreased mRNA expression of early responding cytokines (IL-1 IL-6, IL-18, TNF-alpha, and lymphotoxin-beta) and the fibrogenic cytokine, TGF-beta, in cutaneous tissues at 21 days postradiation. CONCLUSION: Curcumin has a protective effect on radiation-induced cutaneous damage in mice, which is characterized by a downregulation of both inflammatory and fibrogenic cytokines in irradiated skin and muscle, particularly in the early phase after radiation. These results may provide the molecular basis for the application of curcumin in clinical radiation therapy.

Interleukin 1beta (IL1B) signaling is a critical component of radiation-induced skin fibrosis.

Interleukin 1 beta (IL1B), a potent pro-inflammatory cytokine, is directly up-regulated by radiation and is known to regulate other inflammation-related molecules, such as the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs). However, the nature of the interaction of IL1B with MMPs and TIMPs in radiation-induced skin fibrosis is unknown. We examined the response of primary dermal keratinocytes, fibroblasts and endothelial cells to single-fraction radiation (10 Gy) and compared the results to a temporal sequence of histology from irradiated C57BL/6 and IL1R1 knockout mice. These studies showed that keratinocytes are the major IL1-producing cells in vitro and that radiation induces an immediate and chronic elevation in the expression of IL1B mRNA in the skin of C57BL/6 mice. This elevation was principally early and was less pronounced in the IL1R1 knockout strain, which also demonstrated reduced late radiation fibrosis. Radiation also increased expression of MMP mRNA in C57BL/6 mice. Finally, exogenous IL1B protein induced robust endogenous IL1B mRNA expression, along with a brisk increase in MMPs and collagen III, but only in the C57BL/6 mice. In conclusion, these data suggest that IL1B plays a critical role in radiation-induced fibrosis and that the increased MMPs fail to block the IL1-related collagen accumulation.

Mid-Cretaceous carbon cycle perturbations and Oceanic Anoxic Events recorded in southern Tibet.

The organic carbon isotope (δ13Corg) curve for ~1.7-km-thick mid-Cretaceous strata of the Chaqiela section in Gamba area, southern Tibet is presented in this study. C-isotopic chemostratigraphic correlation combined with biostratigraphic constraints show that the Chaqiela section spans early Aptian through early Campanian period, and that almost all of the carbon cycle perturbations and Oceanic Anoxic Events during the mid-Cretaceous period are well recorded in the continental margin area of the southeastern Tethys Ocean. Significantly, two levels of methane-derived authigenic carbonates were identified at the onset of OAE1b near the Aptian-Albian boundary. We suggest that an increase in methane release from gas hydrates, potentially driven by sea-level fall and bottom water temperature increase, may have contributed to the large negative δ13Corg excursions and global warming during OAE1b.

New pyridinium-based fluorescent dyes: A comparison of symmetry and side-group effects on G-Quadruplex DNA binding selectivity and application in live cell imaging.

A series of C1-, C2-and C3-symmetric pyridinium conjugates with different styrene-like side groups were synthesized and were utilized as G-quadruplex selective fluorescent probes. The new compounds were well-characterized. Their selectivity, sensitivity, and stability towards G-quadruplex were studied by fluorescence titration, native PAGE experiments, FRET and circular dichroism (CD) analyses. These new compounds investigated in the fluorescence assays were preferentially bound with G-quadruplex DNA compared with other type of nucleic acids and it is fascinating to realize the effects of molecular symmetry and associated side groups showing unexpectedly great influence on the fluorescent signal enhancement for the discrimination of G-quadruplexes DNA from other nucleic acids. This may correlate with the pocket symmetry and shape of the G-quadruplex DNA inherently. Among the compounds, a C2-symmetric dye (2,6-bis-((E)-2-(1H-indol-3-yl)-vinyl)-1-methylpyridin-1-ium iodide) with indolyl-groups substituted was screened out from the series giving the best selectivity and sensitivity towards G-quadruplexes DNA, particularly telo21, due to its high equilibrium binding constant (K=2.17×10(5)M(-1)). In addition, the limit of detection (LOD) of the dye to determine telo21 DNA in bioassays was found as low as 33nM. The results of the study give insight and certain crucial factors, such as molecular symmetry and the associated side groups, on developing of effective fluorescent dyes for G-quadruplex DNA applications including G-quadruplex structure stabilization, biosensing and clinical applications. The compound was also demonstrated as a very selective G-quadruplex fluorescent agent for living cell staining and imaging.