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Frailty is an established risk factor for adverse outcomes following non-cardiac surgery. The Hospital Frailty Risk Score (HFRS) is a recently described frailty assessment tool that harnesses administrative data and is composed of 109 International Classification of Disease variables. We aimed to examine the incremental prognostic utility of the HFRS in a generalizable surgical population. Using linked administrative databases, a retrospective cohort of patients admitted for non-cardiac surgery between October 1st, 2008 and September 30th, 2019 in Alberta, Canada was created. Our primary outcome was a composite of death, myocardial infarction or cardiac arrest at 30-days. Multivariable logistic regression was undertaken to assess the impact of HFRS on outcomes after adjusting for age, sex, components of the Charlson Comorbidity Index (CCI), Revised Cardiac Risk Index (RCRI) and peri-operative biomarkers. The final cohort consisted of 712,808 non-cardiac surgeries, of which 55·1% were female and the average age was 53·4 +/- 22·4 years. Using the HFRS, 86.3% were considered low risk, 10·7% were considered intermediate risk and 3·1% were considered high risk for frailty. Intermediate and high HFRS scores were associated with increased risk of the primary outcome with an adjusted odds ratio of 1·61 (95% CI 1·50-1.74) and 1·55 (95% CI 1·38-1·73). Intermediate and high HFRS were also associated with increased adjusted odds of prolonged hospital stay, in-hospital mortality, and 1-year mortality. The HFRS is a minimally onerous frailty assessment tool that can complement perioperative risk stratification in identifying patients at high risk of short- and long-term adverse events.

BackgroundWith the increasing incidence of papillary thyroid carcinoma (PTC), PTC continues to garner attention worldwide; however its pathogenesis remains to be elucidated. The purpose of this study was to explore key biomarkers and potential new therapeutic targets for, PTC.MethodsGEO2R and Venn online software were used for screening of differentially expressed genes. Hub genes were screened via STRING and Cytoscape, followed by Gene Ontology and KEGG enrichment analysis. Finally, survival analysis and expression validation were performed using the UALCAN online software and immunohistochemistry.ResultsWe identified 334 consistently differentially expressed genes (DEGs) comprising 136 upregulated and 198 downregulated genes. Gene Ontology enrichment analysis results suggested that the DEGs were mainly enriched in cancer-related pathways and functions. PPI network visualization was performed and 17 upregulated and 13 downregulated DEGs were selected. Finally, the expression verification and overall survival analysis conducted using the Gene Expression Profiling Interactive Analysis Tool (GEPIA) and UALCAN showed that LPAR5, TFPI, and ENTPD1 were associated with the development of PTC and the prognosis of PTC patients, and the expression of LPAR5, TFPI and ENTPD1 was verified using a tissue chip.ConclusionsIn summary, the hub genes and pathways identified in the present study not only provide information for the development of new biomarkers for PTC but will also be useful for elucidation of the pathogenesis of PTC.

Rapidly increasing pyrethroid insecticide resistance and changes in vector biting and resting behavior pose serious challenges in malaria control. Mosquito repellents, especially spatial repellents, have received much attention from industry. We attempted to simulate interactions between mosquitoes and repellents using a machine learning method, the Self-Propelled Particle (SPP) model, which we modified to include attractiveness/repellency effects. We simulated a random walk scenario and scenarios with insecticide susceptible/resistant mosquitoes against repellent alone and against repellent plus attractant (to mimic a human host). Simulation results indicated that without attractant/repellent, mosquitoes would fly anywhere in the cage at random. With attractant, all mosquitoes were attracted to the source of the odor by the end. With repellent, all insecticide-susceptible mosquitoes eventually moved to the corner of the cage farthest from the repellent release point, whereas, a high proportion of highly resistant mosquitoes might reach the attractant release point (the human) earlier in the simulation. At fixed concentration, a high proportion of mosquitoes could be able to reach the host when the relative repellency efficacy (compare to attractant efficacy) was 1. This result implies that repellent may not be sufficient against highly physiologically insecticide resistant mosquitoes, since very high concentrations of repellent are neither practically feasible nor cost-effective.

To establish 24-h urinary creatinine excretion reference ranges based on anthropometry in healthy Chinese children, a cross-sectional survey was conducted using twice-sampled 24-h urine and anthropometric variables. Age- and sex-specific 24-h creatinine excretion reference ranges (crude and related to individual anthropometric variables) were derived. During October 2013 and May 2014, urine samples were collected. Anthropometric variables were measured in the first survey. Data of 710 children (377 boys and 333 girls) aged 8-13 years who completed the study were analyzed. No significant difference was observed in 24-h urine volumes between the two samples (median [interquartile range): 855.0 [600.0-1272.0) mL vs. 900.0 [660.0-1220.0) mL, P = 0.277). The mean 24-h urine creatinine excretion was regarded as representative of absolute daily creatinine excretion in children. Sex-specific, body-weight-adjusted creatinine excretion reference values were 15.3 mg/kg/day (0.1353 mmol/kg/day) for boys and 14.3 mg/kg/day (0.1264 mmol/kg/day) for girls. Differences were significant between boys and girls within the same age group but not across different age groups within the same sex. Ideal 24-h creatinine excretion values for height were derived for potential determination of the creatinine height index. These data can serve as reference ranges to calculate ratios of analyte to creatinine. The creatinine height index can be used to assess somatic protein status.

BACKGROUND:Strained intensive care unit (ICU) capacity represents a supply-demand mismatch in ICU care. Limited data have explored health care worker (HCW) perceptions of strain. METHODS:Cross-sectional survey of HCW across 16 Alberta ICUs. A web-based questionnaire captured data on demographics, strain definition, and sources, impact and strategies for management. RESULTS:658 HCW responded (33%; 95%CI, 32-36%), of which 452 were nurses (69%), 128 allied health (19%), 45 physicians (7%) and 33 administrators (5%). Participants (agreed/strongly agreed: 94%) reported that strain was best defined as "a time-varying imbalance between the supply of available beds, staff and/or resources and the demand to provide high-quality care for patients who may become or who are critically ill"; while some recommended defining "high-quality care", integrating "safety", and families in the definition. Participants reported significant contributors to strain were: "inability to discharge ICU patients due to lack of available ward beds" (97%); "increases in the volume" (89%); and "acuity and complexity of patients requiring ICU support" (88%). Strain was perceived to "increase stress levels in health care providers" (98%); and "burnout in health care providers" (96%). The highest ranked strategies were: "have more consistent and better goals-of-care conversations with patients/families outside of ICU" (95%); and "increase non-acute care beds" (92%). INTERPRETATION:Strain is perceived as common. HCW believe precipitants represent a mix of patient-related and operational factors. Strain is thought to have negative implications for quality of care, HCW well-being and workplace environment. Most indicated strategies "outside" of ICU settings were priorities for managing strain.

Access to facilities, services and socio-economic opportunities plays a critical role in the growth and decline of cities and human settlements. Previous attempts to explain changes in socio-economic indicators by differences in accessibility have not been convincing as countries with highly developed transport infrastructure have only seen marginal benefits of infrastructure improvements. Australia offers an ideal case for investigating the effects of accessibility on development since it is seen as home to some of the most liveable cities in the world while, at the same time, it also has some of the most isolated settlements. We investigate herein the connectivity and accessibility of all 1814 human settlements (population centers exceeding 200 persons) in Australia, and how they relate to the socio-economic characteristics of, and opportunities in, each population center. Assuming population as a proxy indicator of available opportunities, we present a simple ranking metric for a settlement using the number of population and the distance required to access all other settlements (and the corresponding opportunities therein). We find a strikingly unequal distribution of access to opportunities in Australia, with a marked prominence of opportunities in capital cities in four of the eight states. The two largest cities of Sydney and Melbourne have a dominant position across all socio-economic indicators, compared to all the other cities. In general, we observe across all the settlements that a decrease in access to opportunities is associated with relatively greater socio-economic disadvantage including increased median age and unemployment rate and decreased median household income. Our methodology can be used to better understand the potential benefits of improved accessibility based on infrastructure development, especially for remote areas and for cities and towns with many socio-economically disadvantaged population.

Resistant hypertension is defined as high blood pressure that remains above treatment goals in spite of the concurrent use of three antihypertensive agents from different classes. Despite the important health consequences of resistant hypertension, few studies of resistant hypertension have been conducted. To perform a genome-wide association study for resistant hypertension, we defined and identified cases of resistant hypertension and hypertensives with treated, controlled hypertension among >47,500 adults residing in the US linked to electronic health records (EHRs) and genotyped as part of the electronic MEdical Records & GEnomics (eMERGE) Network. Electronic selection logic using billing codes, laboratory values, text queries, and medication records was used to identify resistant hypertension cases and controls at each site, and a total of 3,006 cases of resistant hypertension and 876 controlled hypertensives were identified among eMERGE Phase I and II sites. After imputation and quality control, a total of 2,530,150 SNPs were tested for an association among 2,830 multi-ethnic cases of resistant hypertension and 876 controlled hypertensives. No test of association was genome-wide significant in the full dataset or in the dataset limited to European American cases (n = 1,719) and controls (n = 708). The most significant finding was CLNK rs13144136 at p = 1.00x10-6 (odds ratio = 0.68; 95% CI = 0.58-0.80) in the full dataset with similar results in the European American only dataset. We also examined whether SNPs known to influence blood pressure or hypertension also influenced resistant hypertension. None was significant after correction for multiple testing. These data highlight both the difficulties and the potential utility of EHR-linked genomic data to study clinically-relevant traits such as resistant hypertension.

In an effort to accommodate MOCA to better fit for the Chinese context, this study was designed to employ the MOCA criteria to screen mild cognitive impairment (MCI) and analyze associated risk factors in military retirees.Three hundred and four retired military cadres were recruited using a random cluster sampling technique with information collected including personal, prevalence, MOCA scale, and related neuropsychiatry scale. Thirty retirees were randomly chosen to be further analyzed one month later using the revised MOCA scale.①Our data indicated an incidence rate of 64.8% for mild cognitive impairment in retired military cadres. The incidence rate for MCI was significantly higher in those aged 80 or above compared with those 80 years of age or younger (P

In the past decade, developing countries have been experiencing rapid land use and land cover changes, including deforestation and cultivation of previously forested land. However, little is known about the impact of deforestation and land-use changes on the life history of malaria vectors and their effects on malaria transmission. This study examined the effects of deforestation and crop cultivation on the adult survivorship of major malaria mosquitoes, Anopheles sinensis and An. minimus in the China-Myanmar border region. We examined three conditions: indoor, forested, and banana plantation. Mean survival time of An. sinensis in banana plantation environment was significantly longer than those in forested environment, and mosquitoes exhibited the longest longevity in the indoor environment. This pattern held for both males and females, and also for An. minimus. To further test the effect of temperature on mosquito survival, we used two study sites with different elevation and ambient temperatures. Significantly higher survivorship of both species was found in sites with lower elevation and higher ambient temperature. Increased vector survival in the deforested area could have an important impact on malaria transmission in Southeast Asia. Understanding how deforestation impacts vector survivorship can help combat malaria transmission.

Despite recent increases in the cure rate of acute lymphoblastic leukemia (ALL), adult ALL remains a high-risk disease that exhibits a high relapse rate. In this study, we found that the histone demethylase retinoblastoma binding protein-2 (RBP2) was overexpressed in both on-going and relapse cases of adult ALL, which revealed that RBP2 overexpression was not only involved in the pathogenesis of ALL but that its overexpression might also be related to relapse of the disease. RBP2 knockdown induced apoptosis and attenuated leukemic cell viability. Our results demonstrated that BCL2 is a novel target of RBP2 and supported the notion of RBP2 being a regulator of BCL2 expression via directly binding to its promoter. As the role of RBP2 in regulating apoptosis was confirmed, RBP2 overexpression and activation of BCL2 might play important roles in ALL development and progression.

A good physical map is essential to guide sequence assembly in de novo whole genome sequencing, especially when sequences are produced by high-throughput sequencing such as next-generation-sequencing (NGS) technology. We here present a novel method, Feature sets-based Genome Mapping (FGM). With FGM, physical map and draft whole genome sequences can be generated, anchored and integrated using the same data set of NGS sequences, independent of restriction digestion. Method model was created and parameters were inspected by simulations using the Arabidopsis genome sequence. In the simulations, when ~4.8X genome BAC library including 4,096 clones was used to sequence the whole genome, ~90% of clones were successfully connected to physical contigs, and 91.58% of genome sequences were mapped and connected to chromosomes. This method was experimentally verified using the existing physical map and genome sequence of rice. Of 4,064 clones covering 115 Mb sequence selected from ~3 tiles of 3 chromosomes of a rice draft physical map, 3,364 clones were reconstructed into physical contigs and 98 Mb sequences were integrated into the 3 chromosomes. The physical map-integrated draft genome sequences can provide permanent frameworks for eventually obtaining high-quality reference sequences by targeted sequencing, gap filling and combining other sequences.

Adverse associations between air pollution and myocardial infarction (MI) are widely reported in medical literature. However, inconsistency and sensitivity of the findings are still big concerns. An exploratory investigation was undertaken to examine associations between air pollutants and risk of acute MI (AMI) hospitalization in Alberta, Canada. A time stratified case-crossover design was used to assess the transient effect of five air pollutants (carbon monoxide (CO), nitrogen dioxide (NO2), nitric oxide (NO), ozone (O3) and particulate matter with an aerodynamic diameter ≤2.5 (PM2.5)) on the risk of AMI hospitalization over the period 1999-2009. Subgroups were predefined to see if any susceptible group of individuals existed. A three-step procedure, including univariate analysis, multivariate analysis, and bootstrap model averaging, was used. The multivariate analysis was used in an effort to address adjustment uncertainty; whereas the bootstrap technique was used as a way to account for regression model uncertainty. There were 25,894 AMI hospital admissions during the 11-year period. Estimating health effects that are properly adjusted for all possible confounding factors and accounting for model uncertainty are important for making interpretations of air pollution-health effect associations. The most robust findings included: (1) only 1-day lag NO2 concentrations (6-, 12- or 24-hour average), but not those of CO, NO, O3 or PM2.5, were associated with an elevated risk of AMI hospitalization; (2) evidence was suggested for an effect of elevated risk of hospitalization for NSTEMI (Non-ST Segment Elevation Myocardial Infarction), but not for STEMI (ST segment elevation myocardial infarction); and (3) susceptible subgroups included elders (age ≥65) and elders with hypertension. As this was only an exploratory study there is a need to replicate these findings with other methodologies and datasets.

Maize rough dwarf disease (MRDD) is a destructive viral disease in China, which results in 20-30% of the maize yield losses in affected areas and even as high as 100% in severely infected fields. Understanding the genetic basis of resistance will provide important insights for maize breeding program. In this study, a diverse maize population comprising of 527 inbred lines was evaluated in four environments and a genome-wide association study (GWAS) was undertaken with over 556000 SNP markers. Fifteen candidate genes associated with MRDD resistance were identified, including ten genes with annotated protein encoding functions. The homologous of nine candidate genes were predicted to relate to plant defense in different species based on published results. Significant correlation (R2 = 0.79) between the MRDD severity and the number of resistance alleles was observed. Consequently, we have broadened the resistant germplasm to MRDD and identified a number of resistance alleles by GWAS. The results in present study also imply the candidate genes in defense pathway play an important role in resistance to MRDD in maize.

Different locations and study periods were used in the assessment of the relationships between heatwaves and mortality. However, little is known about the comparability and consistency of the previous effect estimates in the literature. This study assessed the heatwave-mortality relationship using different study periods in the three largest Australian cities (Brisbane, Melbourne and Sydney).Daily data on climatic variables and mortality for the three cities were obtained from relevant government agencies between 1988 and 2011. A consistent definition of heatwaves was used for these cities. Poisson generalised additive model was fitted to assess the impact of heatwaves on mortality.Non-accidental and circulatory mortality significantly increased during heatwaves across the three cities even with different heatwave definitions and study periods. Using the summer data resulted in the largest increase in effect estimates compared to those using the warm season or the whole year data.The findings may have implications for developing standard approaches to evaluating the heatwave-mortality relationship and advancing heat health warning systems. It also provides an impetus to methodological advance for assessing climate change-related health consequences.

This paper reports the fossil zokors (Myospalacinae) collected from the lower Pliocene (~4.4 Ma) of Zanda Basin, southwestern Tibet, which is the first record in the hinterland of Tibetan Plateau within the Himalayan Range. Materials include 29 isolated molars belonging to Prosiphneus eriksoni (Schlosser, 1924) by having characters including large size, highly fused roots, upper molars of orthomegodont type, m1 anterior cap small and centrally located, and first pair of m1 reentrants on opposing sides, high crowns, and high value of dentine tract parameters. Based on the cladistics analysis, all seven species of Prosiphneus and P. eriksoni of Zanda form a monophyletic clade. P. eriksoni from Zanda, on the other hand, is nearly the terminal taxon of this clade. The appearance of P. eriksoni in Zanda represents a significant dispersal in the early Pliocene from its center of origin in north China and Mongolian Plateau, possibly via the Hol Xil-Qiangtang hinterland in northern Tibet. The fast evolving zokors are highly adapted to open terrains at a time when regional climates had become increasingly drier in the desert zones north of Tibetan Plateau during the late Miocene to Pliocene. The occurrence of this zokor in Tibet thus suggests a rather open steppe environment. Based on fossils of large mammals, we have formulated an "out of Tibet" hypothesis that suggests earlier and more primitive large mammals from the Pliocene of Tibet giving rise to the Ice Age megafauna. However, fossil records for large mammals are still too poor to evaluate whether they have evolved from lineages endemic to the Tibetan Plateau or were immigrants from outside. The superior record of small mammals is in a better position to address this question. With relatively dense age intervals and numerous localities in much of northern Asia, fossil zokors provide the first example of an "into Tibet" scenario--earlier and more primitive taxa originated from outside of the Tibetan Plateau and the later the lineage became extinct in southwestern Tibet.

Fusarium wilt of common bean (Phaseolus vulgaris L.), caused by Fusarium oxysporum Schlechtend.:Fr. f.sp. phaseoli (Fop), is one of the most important diseases of common beans worldwide. Few natural sources of resistance to Fop exist and provide only moderate or partial levels of protection. Despite the economic importance of the disease across multiple crops, only a few of Fop induced genes have been analyzed in legumes. Therefore, our goal was to identify transcriptionally regulated genes during an incompatible interaction between common bean and the Fop pathogen using the cDNA amplified fragment length polymorphism (cDNA-AFLP) technique. We generated a total of 8,730 transcript-derived fragments (TDFs) with 768 primer pairs based on the comparison of a moderately resistant and a susceptible genotype. In total, 423 TDFs (4.9%) displayed altered expression patterns after inoculation with Fop inoculum. We obtained full amplicon sequences for 122 selected TDFs, of which 98 were identified as annotated known genes in different functional categories based on their putative functions, 10 were predicted but non-annotated genes and 14 were not homologous to any known genes. The 98 TDFs encoding genes of known putative function were classified as related to metabolism (22), signal transduction (21), protein synthesis and processing (20), development and cytoskeletal organization (12), transport of proteins (7), gene expression and RNA metabolism (4), redox reactions (4), defense and stress responses (3), energy metabolism (3), and hormone responses (2). Based on the analyses of homology, 19 TDFs from different functional categories were chosen for expression analysis using quantitative RT-PCR. The genes found to be important here were implicated at various steps of pathogen infection and will allow a better understanding of the mechanisms of defense and resistance to Fop and similar pathogens. The differential response genes discovered here could also be used as molecular markers in association mapping or QTL analysis.

Baicalin, the main active ingredient of the Scutellaria root, exerts anti-oxidant and anti-apoptotic effects in cardiovascular diseases. However, the therapeutic mechanism of baicalin remains unknown. Cultured neonatal rat cardiomyocytes were pre-treated with baicalin (0-50 µM) for 24 h, and subsequently treated with tunicamycin (100 ng/ml). Cell viability was detected by MTT assay, and cell damage was determined by LDH release and TUNEL assay. The expression of CHOP, JNK, caspase-3, eNOS was analyzed by western blot. NO was measured by DAF-FM staining. As a result, treatment with baicalin significantly reduced apoptosis induced by ER stress inducer tunicamycin in cardiomyocytes. Molecularly, baicalin ameliorated tunicamycin-induced ER stress by downregulation of CHOP. In addition, baicalin inverted tunicamycin-induced decreases of eNOS mRNA and protein levels, phospho eNOS and NO production through CHOP pathway. However, the protective effects of baicalin were significantly decreased in cardiomyocytes treated with L-NAME, which suppressed activation of nitric oxide synthase. In conclusion, our results implicate that baicalin could protect cardiomyocytes from ER stress-induced apoptosis via CHOP/eNOS/NO pathway, and suggest the therapeutic values of baicalin against ER stress-associated cardiomyocyte apoptosis.

Tigecycline is a broad-spectrum, first-in-class glycylcycline antibiotic currently used to treat complicated skin and intra-abdominal infections, as well as community-acquired pneumonia. In addition, we have demonstrated that tigecycline also has in vitro and in vivo activity against acute myeloid leukemia (AML) due to its ability to inhibit mitochondrial translation. Tigecycline is relatively unstable after reconstitution, and this instability may limit the use of the drug in ambulatory infusions for the treatment of infection and may prevent the development of optimal dosing schedules for the treatment of AML. This study sought to identify a formulation that improved the stability of the drug after reconstitution and maintained its antimicrobial and antileukemic activity. A panel of chemical additives was tested to identify excipients that enhanced the stability of tigecycline in solution at room temperature for up to one week. We identified a novel formulation containing the oxygen-reducing agents ascorbic acid (3 mg/mL) and pyruvate (60 mg/mL), in saline solution, pH 7.0, in which tigecycline (1 mg/mL) remained intact when protected from light for at least 7 days. This formulation also preserved the drug's antibacterial and antileukemic activity in vitro. Moreover, the novel formulation retained tigecycline's antileukemic activity in vivo. Thus, we identified and characterized a novel formulation for tigecycline that preserves its stability and efficacy after reconstitution.

Resistance to Phytophthora sojae isolate PsMC1 was evaluated in 102 F2∶3 families derived from a cross between the resistant soybean cultivar Wandou 15 and the susceptible cultivar Williams and genotyped using simple sequence repeat (SSR) markers. The segregation ratio of resistant, segregating, and susceptible phenotypes in the population suggested that the resistance in Wandou 15 was dominant and monogenic. Twenty-six polymorphic SSR markers were identified on soybean chromosome 17 (Molecular linkage group D2; MLG D2), which were linked to the resistance gene based on bulked segregation analysis (BSA). Markers Sattwd15-24/25 and Sattwd15-47 flanked the resistance gene at a distance of 0.5 cM and 0.8 cM, respectively. Two cosegregating markers, Sattwd15-28 and Sattwd15-32, were also screened in this region. This is the first Rps resistance gene mapped on chromosome 17, which is designated as Rps10. Eight putative genes were found in the mapped region between markers Sattwd15-24/25 and Sattwd15-47. Among them, two candidate genes encoding serine/threonine (Ser/Thr) protein kinases in Wandou 15 and Williams were identified and sequenced. And the differences in genomic sequence and the putative amino acid sequence, respectively, were identified within each candidate gene between Wandou 15 and Williams. This novel gene Rps10 and the linked markers should be useful in developing soybean cultivars with durable resistance to P. sojae.

We have successfully delivered a reactive alkylating agent, chlorambucil (Cbl), to the mitochondria of mammalian cells. Here, we characterize the mechanism of cell death for mitochondria-targeted chlorambucil (mt-Cbl) in vitro and assess its efficacy in a xenograft mouse model of leukemia. Using a ρ° cell model, we show that mt-Cbl toxicity is not dependent on mitochondrial DNA damage. We also illustrate that re-targeting Cbl to mitochondria results in a shift in the cell death mechanism from apoptosis to necrosis, and that this behavior is a general feature of mitochondria-targeted Cbl. Despite the change in cell death mechanisms, we show that mt-Cbl is still effective in vivo and has an improved pharmacokinetic profile compared to the parent drug. These findings illustrate that mitochondrial rerouting changes the site of action of Cbl and also alters the cell death mechanism drastically without compromising in vivo efficacy. Thus, mitochondrial delivery allows the exploitation of Cbl as a promiscuous mitochondrial protein inhibitor with promising therapeutic potential.

A shortage of Cenozoic vertebrate fossils in the Tibetan Plateau has been an obstacle in our understanding of biological evolution in response to changes in tectonism, topography, and environment. This is especially true for Paleogene records, so far known by only two sites along the northern rim of the Plateau. We report a Hongyazi Basin in northern Tibetan Plateau that produces at least three mammalian faunas that span Oligocene through late Miocene. Located at the foothills of the Danghe Nanshan and presently connected to the northern margin of the Suganhu Basin through the Greater Haltang River, the intermountain basin is controlled by the tectonics of the Danghe Nanshan to the north and Chahan'ebotu Mountain to the south, making the basin sediments well suited for inferring the evolutionary history of these two mountain ranges. At the bottom of the local section, the Oligocene Haltang Fauna is best compared to the early Oligocene Desmatolagus-Karakoromys decessus assemblage in the Dingdanggou Fauna in Tabenbuluk Basin. The Middle Miocene Ebotu Fauna from the middle Hongyazi section shares many taxa with the late Middle Miocene Tunggur mammal assemblage in Inner Mongolia, such as Heterosminthus orientalis, Megacricetodon sinensis, Democricetodon lindsayi, and Alloptox gobiensis. Toward the top of the section, the Hongyazi Fauna includes late Miocene elements typical of Hipparion faunas of North China. All three faunas are of typical North China-Central Asian characteristics, suggesting a lack of geographic barriers for faunal differentiation through the late Miocene. Sedimentary packages producing these faunas are arrayed from north to south in progressively younger strata, consistent with a compressive regime to accommodate shortening between Danghe Nanshan and Chahan'ebotu Mountain by thrust faults and folds. With additional constraints from vertebrate fossils along the northern flanks of the Danghe Nanshan, an eastward propagation of the Danghe Nanshan is postulated.

Oncogenic signaling promotes tumor invasion and metastasis, in part, by increasing the expression of tri- and tetra- branched N-glycans. The branched N-glycans bind to galectins forming a multivalent lattice that enhances cell surface residency of growth factor receptors, and focal adhesion turnover. N-acetylglucosaminyltransferase I (MGAT1), the first branching enzyme in the pathway, is required for the addition of all subsequent branches. Here we have introduced MGAT1 shRNA into human HeLa cervical and PC-3-Yellow prostate tumor cells lines, generating cell lines with reduced transcript, enzyme activity and branched N-glycans at the cell surface. MGAT1 knockdown inhibited HeLa cell migration and invasion, but did not alter cell proliferation rates. Swainsonine, an inhibitor of α-mannosidase II immediately downstream of MGAT1, also inhibited cell invasion and was not additive with MGAT1 shRNA, consistent with a common mechanism of action. Focal adhesion and microfilament organization in MGAT1 knockdown cells also indicate a less motile phenotype. In vivo, MGAT1 knockdown in the PC-3-Yellow orthotopic prostate cancer xenograft model significantly decreased primary tumor growth and the incidence of lung metastases. Our results demonstrate that blocking MGAT1 is a potential target for anti-cancer therapy.

The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK) signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP) analysis showed that activated c-Jun binds to the activator protein-1 (AP-1) binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA) against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with JNK activators in the treatment of MM.

Calcyclin-binding protein (CacyBP/SIP), identified on the basis of its ability to interact with S100 proteins in a calcium-dependent manner, was previously found to inhibit the proliferation and tumorigenesis of gastric cancer cells in our laboratory. Importantly, the effects of S100 proteins on the biological behavior of CacyBP/SIP in gastric cancer remain unclear. Herein, we report the construction of eukaryotic expression vectors for wild-type CacyBP/SIP and a truncated mutant lacking the S100 protein binding domain (CacyBP/SIPΔS100). The expressions of the wild-type and truncated recombinant proteins were demonstrated by transfection of MKN45 gastric cancer cells. Co-immunoprecipitation assays demonstrated interaction between S100A6 and wild-type CacyBP/SIP in MKN45 cells. Removal of the S100 protein binding domain dramatically reduced the affinity of CacyBP/SIP for S100 proteins as indicated by reduced co-immunoprecipitation of S100A6 by CacyBP/SIPΔS100. The MTT assay, FACS assay, clonogenic assay and tumor xenograft experiment were performed to assess the effect of CacyBP/SIP on cell growth and tumorigenesis in vitro and in vivo. Overexpression of CacyBP/SIP inhibited the proliferation and tumorigenesis of MKN45 gastric cancer cells; the proliferation and tumorigenesis rates were even further reduced by the expression of CacyBP/SIPΔS100. We also showed that S100 proteins negatively regulate CacyBP/SIP-mediated inhibition of gastric cancer cell proliferation, through an effect on β-catenin protein expression and transcriptional activation of Tcf/LEF. Although the underlying mechanism of action requires further investigation, this study provides new insight into the interaction between S100 proteins and CacyBP/SIP, which might enrich our knowledge of S100 proteins and be helpful for our understanding of the development of gastric cancer.

Finite Element Analysis (FEA) is a powerful tool gaining use in studies of biological form and function. This method is particularly conducive to studies of extinct and fossilized organisms, as models can be assigned properties that approximate living tissues. In disciplines where model validation is difficult or impossible, the choice of model parameters and their effects on the results become increasingly important, especially in comparing outputs to infer function. To evaluate the extent to which performance measures are affected by initial model input, we tested the sensitivity of bite force, strain energy, and stress to changes in seven parameters that are required in testing craniodental function with FEA. Simulations were performed on FE models of a Gray Wolf (Canis lupus) mandible. Results showed that unilateral bite force outputs are least affected by the relative ratios of the balancing and working muscles, but only ratios above 0.5 provided balancing-working side joint reaction force relationships that are consistent with experimental data. The constraints modeled at the bite point had the greatest effect on bite force output, but the most appropriate constraint may depend on the study question. Strain energy is least affected by variation in bite point constraint, but larger variations in strain energy values are observed in models with different number of tetrahedral elements, masticatory muscle ratios and muscle subgroups present, and number of material properties. These findings indicate that performance measures are differentially affected by variation in initial model parameters. In the absence of validated input values, FE models can nevertheless provide robust comparisons if these parameters are standardized within a given study to minimize variation that arise during the model-building process. Sensitivity tests incorporated into the study design not only aid in the interpretation of simulation results, but can also provide additional insights on form and function.

Creatine kinase catalyzes the reversible transfer of the N-phosphoryl group from phosphocreatine to ADP to generate ATP and plays a key role in highly energy-demanding processes such as muscle contraction and flagellar motility; however, its role in signal transduction (which frequently involves ATP-consuming phosphorylation) and consequent cell-fate decisions remains largely unknown. Here we report that creatine kinase B was significantly up-regulated during the differentiation of double-positive thymocytes into single-positive thymocytes. Ectopic expression of creatine kinase B led to increased ATP level and enhanced phosphorylation of the TCR signaling proteins. Consequentially, transgenic expression of creatine kinase B promoted the expression of Nur77 and Bim proteins and the cell death of TCR signaled thymocyte. In addition, the activation, proliferation and cytokine secretion of T cells were also enhanced by the expression of creatine kinase B transgene. In contrast, treatment of T cells with specific creatine kinase inhibitor or creatine kinase B shRNA resulted in severely impaired T cell activation. Taken together, our results indicate that creatine kinase B plays an unexpected role in modulating TCR-mediated signaling and critically regulates thymocyte selection and T cell activation.

Oncogenic signaling promotes tumor invasion and metastasis, in part, by increasing the expression of tri- and tetrabranched N-glycans. The branched N-glycans bind to galectins forming a multivalent lattice that enhances cell surface residency of growth factor receptors, and focal adhesion turnover. N-acetylglucosaminyltransferase I (MGAT1), the first branching enzyme in the pathway, is required for the addition of all subsequent branches. Here we have introduced MGAT1 shRNA into human HeLa cervical and PC-3-Yellow prostate tumor cells lines, generating cell lines with reduced transcript, enzyme activity and branched N-glycans at the cell surface. MGAT1 knockdown inhibited HeLa cell migration and invasion, but did not alter cell proliferation rates. Swainsonine, an inhibitor of a-mannosidase II immediately downstream of MGAT1, also inhibited cell invasion and was not additive with MGAT1 shRNA, consistent with a common mechanism of action. Focal adhesion and microfilament organization in MGAT1 knockdown cells also indicate a less motile phenotype. In vivo, MGAT1 knockdown in the PC-3-Yellow orthotopic prostate cancer xenograft model significantly decreased primary tumor growth and the incidence of lung metastases. Our results demonstrate that blocking MGAT1 is a potential target for anti-cancer therapy. [ABSTRACT FROM AUTHOR]

Calcyclin-binding protein (CacyBP/SIP), identified on the basis of its ability to interact with S100 proteins in a calciumdependent manner, was previously found to inhibit the proliferation and tumorigenesis of gastric cancer cells in our laboratory. Importantly, the effects of S100 proteins on the biological behavior of CacyBP/SIP in gastric cancer remain unclear. Herein, we report the construction of eukaryotic expression vectors for wild-type CacyBP/SIP and a truncated mutant lacking the S100 protein binding domain (CacyBP/SIPDS100). The expressions of the wild-type and truncated recombinant proteins were demonstrated by transfection of MKN45 gastric cancer cells. Co-immunoprecipitation assays demonstrated interaction between S100A6 and wild-type CacyBP/SIP in MKN45 cells. Removal of the S100 protein binding domain dramatically reduced the affinity of CacyBP/SIP for S100 proteins as indicated by reduced co-immunoprecipitation of S100A6 by CacyBP/SIPDS100. The MTT assay, FACS assay, clonogenic assay and tumor xenograft experiment were performed to assess the effect of CacyBP/SIP on cell growth and tumorigenesis in vitro and in vivo. Overexpression of CacyBP/SIP inhibited the proliferation and tumorigenesis of MKN45 gastric cancer cells; the proliferation and tumorigenesis rates were even further reduced by the expression of CacyBP/SIPDS100. We also showed that S100 proteins negatively regulate CacyBP/SIP-mediated inhibition of gastric cancer cell proliferation, through an effect on b-catenin protein expression and transcriptional activation of Tcf/LEF. Although the underlying mechanism of action requires further investigation, this study provides new insight into the interaction between S100 proteins and CacyBP/SIP, which might enrich our knowledge of S100 proteins and be helpful for our understanding of the development of gastric cancer. [ABSTRACT FROM AUTHOR]