Survival of CD4+CD8+ double positive (DP) thymocytes plays a critical role in shaping the peripheral T cell repertoire. However, the mechanisms responsible for the regulation of DP thymocyte lifespan remain poorly understood. In this work, we demonstrate that TCF-1 regulates DP thymocyte survival by up-regulating RORγt. Microarray analysis revealed that RORγt was significantly down-regulated in TCF-1−/− thymocytes that underwent accelerated apoptosis, whereas RORγt was greatly up-regulated in thymocytes that had enhanced survival due to transgenic expression of a stabilized β-catenin (β-catTg), a TCF-1 activator. Both TCF-1−/− and RORγt−/− DP thymocytes underwent similar accelerated apoptosis. Forced expression of RORγt successfully rescued TCF-1−/− DP thymocytes from apoptosis, whereas ectopically expressed TCF-1 was not able to rescue the defective T cell development due to lack of RORγt-supported survival. Furthermore, activation of TCF-1 by stabilized β-catenin was able to enhance DP thymocyte survival only in the presence of RORγt, indicating that RORγt acts downstream of TCF-1 in the regulation of DP thymocyte survival. Moreover, β-catenin/TCF-1 directly interacted with the RORγt promoter region and stimulated its activity. Therefore, our data demonstrate that TCF-1 enhances DP thymocyte survival through transcriptional up-regulation of RORγt, which we have previously shown to be an essential survival molecule for DP thymocytes.

Abstract

Aim: A growing body of evidence has shown that increased formation of oxidized molecules and reactive oxygen species within the vasculature (i.e., the extracellular space) plays a crucial role in the initiation and progression of atherosclerosis and in the formation of unstable plaques. Peroxiredoxin 4 (PRDX4) is the only known secretory member of the antioxidant PRDX family. However, the relationship between PRDX4 and susceptibility to atherosclerosis has remained unclear. Results: To define the role of PRDX4 in hyperlipidemia-induced atherosclerosis, we generated hPRDX4 transgenic (Tg) and apolipoprotein E (apoE) knockout mice (hPRDX4+/+/apoE−/−). After feeding the mice a high-cholesterol diet, they showed fewer atheromatous plaques, less T-lymphocyte infiltration, lower levels of oxidative stress markers, less necrosis, a larger number of smooth muscle cells, and a larger amount of collagen, resulting in thickened fibrous cap formation and possible stable plaque phenotype as compared with apoE−/− mice. We also detected greater suppression of apoptosis and decreased Bax expression in hPRDX4+/+/apoE−/− mice than in apoE−/− mice. Bone marrow transplantation from hPRDX4+/+ donors to apoE−/− mice confirmed the antiatherogenic aspects of PRDX4, revealing significantly suppressed atherosclerotic progression. Innovation: In this study, we demonstrated for the first time that PRDX4 suppressed the development of atherosclerosis in apoE−/− mice fed a high-cholesterol diet. Conclusion: These data indicate that PRDX4 is an antiatherogenic factor and, by suppressing oxidative damage and apoptosis, that it may protect against the formation of vulnerable (unstable) plaques. Antioxid. Redox Signal. 17, 1362–1375.

Cranial radiation therapy can induce cognitive decline. Impairments of hippocampal neurogenesis are thought to be a paramountly important mechanism underlying radiation-induced cognitive dysfunction. In the mature nervous system, DNA double-strand breaks (DSBs) are mainly repaired by non-homologous end-joining (NHEJ) pathways. It has been demonstrated that NHEJ deficiencies are associated with impaired neurogenesis. In our study, rats were randomly divided into five groups to be irradiated by single doses of 0 (control), 0 (anesthesia control), 2, 10, and 20 Gy, respectively. The cognitive function of the irradiated rats was measured by open field, Morris water maze and passive avoidance tests. Real-time PCR was also used to detect the expression level of DNA DSB repair-related genes involved in the NHEJ pathway, such as XRCC4, XRCC5and XRCC6, in the hippocampus. The influence of different radiation doses on cognitive function in rats was investigated. From the results of the behavior tests, we found that rats receiving 20 Gy irradiation revealed poorer learning and memory, while no significant loss of learning and memory existed in rats receiving irradiation from 0–10 Gy. The real-time PCR and Western blot results showed no significant difference in the expression level of DNA repair-related genes between the 10 and 20 Gy groups, which may help to explain the behavioral results, i.e. DNA damage caused by 0–10 Gy exposure was appropriately repaired, however, damage induced by 20 Gy exceeded the body's maximum DSB repair ability. Ionizing radiation-induced cognitive impairments depend on the radiation dose, and more directly on the body's own ability to repair DNA DSBs via the NHEJ pathway.

N-linked glycosylation of protein is a posttranslational modification found in all three domains of life. The flagellin proteins of the archaeon Methanococcus maripaludis are known to be modified with an N-linked tetrasaccharide consisting of N-acetylgalactosamine (GalNAc), a diacetylated glucuronic acid (GlcNAc3NAc), an acetylated and acetamidino-modified mannuronic acid with a substituted threonine group (ManNAc3NAmA6Thr), and a novel terminal sugar residue [(5S)-2-acetamido-2,4-dideoxy-5-O-methyl-α-l-erythro-hexos-5-ulo-1,5-pyranose]. To identify genes involved in biosynthesis of the component sugars of this glycan, three genes, mmp1081, mmp1082, and mmp1083, were targeted for in-frame deletion, based on their annotation and proximity to glycosyltransferase genes known to be involved in assembly of the glycan. Mutants carrying a deletion in any of these three genes remained flagellated and motile. A strain with a deletion of mmp1081 had lower-molecular-mass flagellins in Western blots. Mass spectrometry of purified flagella revealed a truncated glycan with the terminal sugar absent and the threonine residue and the acetamidino group missing from the third sugar. No glycan modification was seen in either the Δmmp1082 or Δmmp1083 mutant grown in complex Balch III medium. However, a glycan identical to the Δmmp1081 glycan was observed when the Δmmp1082 or Δmmp1083 mutant was grown under ammonia-limited conditions. We hypothesize that MMP1082 generates ammonia and tunnels it through MMP1083 to MMP1081, which acts as the amidotransferase, modifying the third sugar residue of the M. maripaludis glycan with the acetamidino group.

Background

The Functional Assessment of Cancer Therapy (FACT) is one of the most commonly used self-report instruments for evaluation of health-related quality of life in oncology patients. However, cultural considerations necessitate testing of the subscales in different populations. We sought to qualitatively and quantitatively investigate the applicability and psychometric properties of the Chinese version of the FACT-Cervix (FACT-Cx) in Chinese women with cervical cancer.

Methods

Ten personal interviews were conducted in order to explore patients’ opinions about the scale and its items in depth. In addition the questionnaire was administered to 400 women with cervical cancer to test its psychometric properties. Reliability was assessed using Cronbach’s alpha coefficient and item-subscale correlation while validity was evaluated using factor analysis and known-group validity.

Results

Some items related to sex and the ability to give birth were questioned in the personal interviews, mostly regarding their significance and acceptance in the Chinese cultural context. The Cronbach’s alphas of FACT-Cx and the subscales were greater than 0.7, except for the cervical-cancer-specific subscale which was 0.57. Factor analysis demonstrated that the FACT-G construct generally paralleled the original. There were significant differences in the FACT-Cx and some subscales between those receiving and not receiving treatment and among the patients with different performance status.

Conclusions

In general, psychometric properties of the Chinese version supported its use with cervical cancer patients in Mainland China. Further work is needed to improve the psychometric adequacy of the cervical-cancer-specific subscale and adjust it to cultural considerations.

Background

Although many studies have documented health effects of ambient temperature, little evidence is available in subtropical or tropical regions, and effect modifiers remain uncertain. We examined the effects of daily mean temperature on mortality and effect modification in the subtropical city of Guangzhou, China.

Methods

A Poisson regression model combined with distributed lag non-linear model was applied to assess the non-linear and lag patterns of the association between daily mean temperature and mortality from 2003 to 2007 in Guangzhou. The case-only approach was used to determine whether the effect of temperature was modified by individual characteristics, including sex, age, educational attainment and occupation class.

Results

Hot effect was immediate and limited to the first 5 days, with an overall increase of 15.46% (95% confidence interval: 10.05% to 20.87%) in mortality risk comparing the 99th and the 90th percentile temperature. Cold effect persisted for approximately 12 days, with a 20.39% (11.78% to 29.01%) increase in risk comparing the first and the 10th percentile temperature. The effects were especially remarkable for cardiovascular and respiratory mortality. The effects of both hot and cold temperatures were greater among the elderly. Females suffered more from hot-associated mortality than males. We also found significant effect modification by educational attainment and occupation class.

Conclusions

There are significant mortality effects of hot and cold temperatures in Guangzhou. The elderly, females and subjects with low socioeconomic status have been identified as especially vulnerable to the effect of ambient temperatures.

The human X and Y chromosomes evolved from an ordinary pair of autosomes during the past 200–300 million years1–3. Due to genetic decay, the human MSY (male-specific region of Y chromosome) retains only three percent of the ancestral autosomes’ genes4,5. This evolutionary decay was driven by a series of five “stratification” events. Each event suppressed X-Y crossing over within a chromosome segment or “stratum”, incorporated that segment into the MSY, and subjected its genes to the erosive forces that attend the absence of crossing over2,6. The last of these events occurred 30 million years ago (mya), or 5 million years before the human and Old World monkey (OWM) lineages diverged. Although speculation abounds regarding ongoing decay and looming extinction of the human Y chromosome7–10, remarkably little is known about how many MSY genes were lost in the human lineage in the 25 million years that have followed its separation from the OWM lineage. To explore this question, we sequenced the MSY of the rhesus macaque, an OWM, and compared it to the human MSY. We discovered that, during the last 25 million years, MSY gene loss in the human lineage was limited to the youngest stratum (stratum 5), which comprises three percent of the human MSY. Within the older strata, which collectively comprise the bulk of the human MSY, gene loss evidently ceased more than 25 mya. Likewise, the rhesus MSY has not lost any older genes (from strata 1–4) during the past 25 million years, despite major structural differences from the human MSY. The rhesus MSY is simpler, with few amplified gene families or palindromes that might enable intrachromosomal recombination and repair. We present an empirical reconstruction of human MSY evolution in which each stratum transitioned from rapid, exponential loss of ancestral genes to strict conservation through purifying selection.

Background

Enterococci are among the leading causes of hospital-acquired infections in the United States and Europe, with Enterococcus faecalis and Enterococcus faecium being the two most common species isolated from enterococcal infections. In the last decade, the proportion of enterococcal infections caused by E. faecium has steadily increased compared to other Enterococcus species. Although the underlying mechanism for the gradual replacement of E. faecalis by E. faecium in the hospital environment is not yet understood, many studies using genotyping and phylogenetic analysis have shown the emergence of a globally dispersed polyclonal subcluster of E. faecium strains in clinical environments. Systematic study of the molecular epidemiology and pathogenesis of E. faecium has been hindered by the lack of closed, complete E. faecium genomes that can be used as references.

Results

In this study, we report the complete genome sequence of the E. faecium strain TX16, also known as DO, which belongs to multilocus sequence type (ST) 18, and was the first E. faecium strain ever sequenced. Whole genome comparison of the TX16 genome with 21 E. faecium draft genomes confirmed that most clinical, outbreak, and hospital-associated (HA) strains (including STs 16, 17, 18, and 78), in addition to strains of non-hospital origin, group in the same clade (referred to as the HA clade) and are evolutionally considerably more closely related to each other by phylogenetic and gene content similarity analyses than to isolates in the community-associated (CA) clade with approximately a 3–4% average nucleotide sequence difference between the two clades at the core genome level. Our study also revealed that many genomic loci in the TX16 genome are unique to the HA clade. 380 ORFs in TX16 are HA-clade specific and antibiotic resistance genes are enriched in HA-clade strains. Mobile elements such as IS16 and transposons were also found almost exclusively in HA strains, as previously reported.

Conclusions

Our findings along with other studies show that HA clonal lineages harbor specific genetic elements as well as sequence differences in the core genome which may confer selection advantages over the more heterogeneous CA E. faecium isolates. Which of these differences are important for the success of specific E. faecium lineages in the hospital environment remain(s) to be determined.

Trastuzumab shows remarkable efficacy in treatment of ErbB2-positive breast cancers when used alone or in combination with other chemotherapeutics. However, acquired resistance develops in most treated patients, necessitating alternate treatment strategies. Increased aerobic glycolysis is a hallmark of cancer and inhibition of glycolysis may offer a promising strategy to preferentially kill cancer cells. In this study, we investigated the antitumor effects of trastuzumab in combination with glycolysis inhibitors in ErbB2-positive breast cancer. We found that trastuzumab inhibits glycolysis via downregulation of heat shock factor 1 (HSF1) and lactate dehydrogenase A (LDH-A) in ErbB2-positive cancer cells, resulting in tumor growth inhibition. Moreover, increased glycolysis via HSF1 and LDH-A contributes to trastuzumab resistance. Importantly, we found that combining trastuzumab with glycolysis inhibition synergistically inhibited trastuzumab-sensitive and -resistant breast cancers in vitro and in vivo, due to more efficient inhibition of glycolysis. Taken together, our findings show how glycolysis inhibition can dramatically enhance the therapeutic efficacy of trastuzumab in ErbB2-positive breast cancers, potentially useful as a strategy to overcome trastuzumab resistance.

In many types of cancer, the expression of the immunoregulatory protein B7-H3 has been associated with poor prognosis. Previously, we observed a link between B7-H3 and tumor cell migration and invasion, and in present work we have investigated the role of B7-H3 in chemoresistance in breast cancer. We observed that silencing of B7-H3, via stable shRNA or transient siRNA transfection, increased the sensitivity of multiple human breast cancer cell lines to paclitaxel as a result of enhanced drug-induced apoptosis. Overexpression of B7-H3 made the cancer cells more resistant to the drug. Next, we investigated the mechanisms behind B7-H3 mediated paclitaxel resistance, and found that the level of Stat3 Tyr705 phosphorylation was decreased in B7-H3 knockdown cells, along with the expression of its direct downstream targets Mcl-1 and Survivin. The phosphorylation of Jak2, an upstream molecule of Stat3, was also significantly decreased. In contrast, reexpression of B7-H3 in B7-H3 knockdown and low B7-H3- expressing cells increased the phosphorylation of Jak2 and Stat3. In vivo animal experiments showed that B7-H3 knock down tumors displayed a slower growth rate than the control xenografts. Importantly, paclitaxel treatment showed a strong anti-tumor activity in the mice with B7-H3 knockdown tumors, but only a marginal effect in the control group. Taken together, our data demonstrate that in breast cancer cells B7-H3 induces paclitaxel resistance, at least partially by interfering with Jak2/Stat3 pathway. These results provide novel insight into the function of B7-H3 and encourage the design and testing of approaches targeting this protein and its partners.

Background. Acute coronary syndromes (ACSs) are clinically cardiovascular events associated with dyslipidemia in common. Single nucleotide polymorphisms (SNPs) and haplotypes in the APOA1/C3/A5 gene cluster are associated with diabetes and familial combined hyperlipidaemia (FCH). Little is known about whether the polymorphisms in these genes affect lipid homeostasis in patients with ACSs. The present paper aimed to examine these associations with 4 SNPs in the APOA1 −75G > A, the APOC3 −455T > C, and APOA5 −1131T > C, c.553G > T variant to ACSs in Chinese Han. Methods. Chinese Han of 229 patients with ACSs and 254 unrelated controls were analyzed. Four SNPs in APOA1/C3/A5 cluster were genotyped and lipid was determined. Results. Our data show that minor allelic frequencies of APOC3 −455T > C, APOA5 −1131T > C, and c.553G > T polymorphisms in patients with ACSs were significantly higher than control group (P < 0.05). Furthermore, the 3 polymorphic sites were strongly of linkage disequilibrium, and minor alleles of 3 SNP sites had higher TG level than wild alleles (P < 0.05), APOC3 −455C and APOA5 c.553T allele carriers also had lower level of HDL-C. Conclusions. The minor alleles of APOC3 −455T > C, APOA5 −1131T > C, and c.553G > T polymorphisms are closely associated with ACSs.

The Slit family of guidance cues binds to Roundabout (Robo) receptors and modulates cell migration. We report here that ectopic expression of Slit2 and Robo1 or recombinant Slit2 treatment of Robo1-expressing colorectal epithelial carcinoma cells recruited an ubiquitin ligase Hakai for E-cadherin (E-cad) ubiquitination and lysosomal degradation, epithelial-mesenchymal transition (EMT), and tumor growth and liver metastasis, which were rescued by knockdown of Hakai. In contrast, knockdown of endogenous Robo1 or specific blockade of Slit2 binding to Robo1 prevented E-cad degradation and reversed EMT, resulting in diminished tumor growth and liver metastasis. Ectopic expression of Robo1 also triggered a malignant transformation in Slit2-positive human embryonic kidney 293 cells. Importantly, the expression of Slit2 and Robo1 was significantly associated with an increased metastatic risk and poorer overall survival in colorectal carcinoma patients. We conclude that engagement of Robo1 by Slit2 induces malignant transformation through Hakai-mediated E-cad ubiquitination and lysosomal degradation during colorectal epithelial cell carcinogenesis.

Background

Toll-like receptors (TLRs) signalling is reported to be primed by the infection of human malaria parasite, Plasmodium falciparum. However, little is known about the regulation of macrophages TLR signalling by the infection of lethal or non-lethal strain of rodent malaria parasites.

Methods

BALB/c mice were infected with non-lethal strain Plasmodium yoelii 17XNL or lethal strain P. yoelii 17XL. Peritoneal macrophages were isolated to study its immune response to pRBC lysate, and TLRs (TLR2, TLR4, and TLR9) agonists, and the expression of TLRs and intracellular signalling molecules were also investigated by flow cytometry and semi-quantitive RT-PCR.

Results

The reactivity of peritoneal macrophages from the mice infected with lethal strain P. y 17XL or non-lethal strain P. y 17XNL were enhanced to pRBC lysate, and TLR2, TLR4, and TLR9 agonists at one, three and five days post-infection. Of all the tested TLRs, only TLR2 was up-regulated on peritoneal macrophages of mice infected with either strain. However, transcription of intracellular signalling molecules MyD88, IRAK-1, and TRAF-6 was significantly up-regulated in peritoneal macrophages from mice infected either with P. yoelii 17XL or P. yoelii 17XNL at one, three and five days post-infection. However, the enhanced TLRs response of macrophage from P. yoelii 17XNL-infected mice persisted for a much longer time than that from P. yoelii 17XL-infected mice.

Conclusion

Both P. yoelii 17XL and 17XNL strains could enhance the response of peritoneal macrophages to pRBC lysate and TLR agonists, through up-regulating the expression of TLR2 and intracellular signalling molecules MyD88, IRAK-1, and TRAF-6. In addition, prolonged high response of macrophage from P. yoelii 17XNL-infected mice might be associated with the more efficiently controlling of P. yoelii 17XNL growth in mice at early stage.

More than 80% of thymocytes are CD4+CD8+ double positive (DP) cells which subject to positive/negative selection. The lifespan of DP thymocytes is critical in shaping the peripheral T cell repertoire essential for mounting immune responses against foreign, but not self, antigens. During T cell maturation, if the first round of T cell receptor (TCR) α chain rearrangement fails to generate a productive T cell receptor, DP cells start another round of α chain rearrangement until positive selection or cell death intervenes. Thus, the lifespan of DP cells determines how many rounds of α chain rearrangement can be carried out, and influences the likelihood of completing positive selection. The anti-apoptotic protein Bcl-xL is the ultimate effector regulating DP cell survival, and several transcription factors critical for T cell development, such as TCF-1, E proteins, c-Myb, and RORγt, regulate DP survival via a Bcl-xL-dependent pathway. However, the relationship between these transcription factors in this process is largely unclear. Recent results are revealing an interactive network among these critical factors during regulation of DP thymocyte survival. This review will discuss how these transcription factors potentially work together to control DP thymocyte survival that is critical for successful completion of T cell development.

Severe liver injury that occurs when immune cells mistakenly attack an individual's own liver cells leads to autoimmune hepatitis. In mice, acute hepatitis can be induced by concanavalin A (ConA) treatment, which causes rapid activation of CD1d-positive natural killer (NK) T cells. These activated NKT cells produce large amounts of cytokines, which induce strong inflammation that damages liver tissues. Here we show that PKC-θ−/− mice were resistant to ConA-induced hepatitis due to essential function of PKC-θ in NKT cell development and activation. A dosage of ConA (25 mg/kg) that was lethal to wild-type (WT) mice failed to induce death resulting from liver injury in PKC-θ−/− mice. Correspondingly, ConA-induced production of cytokines such as IFNγ, IL-6, and TNFα, which mediate the inflammation responsible for liver injury, were significantly lower in PKC-θ−/− mice. Peripheral NKT cells had developmental defects at early stages in the thymus in PKC-θ−/− mice, and as a result their frequency and number were greatly reduced. Furthermore, PKC-θ−/− bone marrow adoptively transferred to WT mice displayed similar defects in NKT cell development, suggesting an intrinsic requirement for PKC-θ in NKT cell development. In addition, upon stimulation with NKT cell-specific lipid ligand, peripheral PKC-θ−/− NKT cells produced lower levels of inflammatory cytokines than that of WT NKT cells, suggesting that activation of NKT cells also requires PKC-θ. Our results suggest PKC-θ is an essential molecule required for activation of NKT cell to induce hepatitis, and thus, is a potential drug target for prevention of autoimmune hepatitis.

Overwhelming activation of IL-17, a gene involved in inflammation, leads to exaggerated Th17 responses associated with numerous autoimmune conditions, such as experimental autoimmune encephalomyelitis (EAE). Here we show that TCF-1 is a critical factor to repress IL-17 gene locus by chromatin modifications during T cell development. Deletion of TCF-1 resulted in increased IL-17 gene expression both in thymus and peripheral T cells, which led to enhanced Th17 differentiation. As a result, TCF-1-/- mice were susceptible to Th17-dependent EAE induction. Rag1-/- mice reconstituted with TCF-1-/- T cells were also susceptible to EAE, indicating TCF-1 is intrinsically required to repress IL-17. However, expression of wild-type TCF-1 or dominant negative TCF-1 did not interfere with Th17 differentiation in mature T cells. Furthermore, expression of TCF-1 in TCF-1-/- T cells could not restore Th17 differentiation to wild-type levels, indicating that TCF-1 cannot affect IL-17 production at the mature T cell stage. This is also supported by the normal up-regulation or activation in mature TCF-1-/- T cells of factors known to regulate Th17 differentiation, including RORγt and Stat3. We observed hyperacetylation together with trimethylation of Lys-4 at the IL-17 locus in TCF-1-/- thymocytes, two epigenetic modifications indicating an open active state of the gene. Such epigenetic modifications were preserved even when TCF-1-/- T cells migrated out of thymus. Therefore, TCF-1 mediates an active process to repress IL-17 gene expression via epigenetic modifications during T cell development. This TCF-1-mediated repression of IL-17 is critical for peripheral T cells to generate balanced immune responses.

Background

Patients with chronic heart failure (HF) have cognitive deficits in memory, psychomotor speed, and executive function and poor health-related quality of life (HRQL), but the association between cognitive deficits and HRQL is unknown.

Objectives

The objectives of this study were to 1) evaluate the relationship between heart failure (HF) severity, age, comorbidities, and cognitive deficits and health-related quality of life (HRQL) among patients with chronic HF; and 2) examine whether cognitive deficits mediated the relationship between HF severity and HRQL.

Design and Sample

This study was part of a larger explanatory study; 249 patients with HF completed face-to-face interviews.

Methods

Measures of HF severity, comorbidity (multiple comorbid conditions, hypertension, and depressive symptoms), cognitive function (domains of language, working memory, memory, psychomotor speed, and executive function), and HRQL were obtained. Clinical variables were abstracted from patients’ records. Statistical analyses were conducted using descriptive statistics, Pearson’s correlation coefficients, and multiple linear regression analyses.

Results

Overall, the HRQL of patients was moderately poor. Heart failure severity, age, depressive symptoms, and total recall memory explained 55% of the variance in HRQL, but the contribution of memory was minimal (1%). Patients with more severe HF, younger age, and more depressive symptoms had poorer HRQL. Other cognitive function variables, multiple comorbidity, and hypertension were not significant explanatory variables for HRQL. Cognitive deficits did not mediate the relationship between HF severity and HRQL.

Conclusions

Novel interventions targeted at improving HRQL continue to be urgently needed, particularly among younger patients and patients with depressive symptoms. Measures of HRQL are not sufficient as outcomes when investigating cognitive deficits in HF. Investigators need to include outcome measures of patients’ actual abilities to perform daily activities and HF self-care.

Background:

Patients with heart failure (HF) have been found to have cognitive deficits, but it remains unclear whether these deficits are associated with HF or with aging or comorbid conditions common in HF.

Objectives:

To 1) determine the types, frequency, and severity of cognitive deficits among patients with chronic HF compared to age- and education-matched healthy participants and participants with major medical conditions other than HF; and 2) evaluate the relationships between HF severity, age, and comorbidities and cognitive deficits.

Methods:

A sample of 414 participants completed the study (249 HF patients, 63 healthy and 102 medical participants). The HF patients completed measures of HF severity, comorbidity (multiple comorbidity, hypertension, depressive symptoms), and neuropsychological functioning. Blood pressure and oxygen saturation were assessed at interview; clinical variables were abstracted from records. Participants in the comparison groups completed the same measures as the HF patients except those specific to HF.

Results:

Compared to the healthy and medical participants, HF patients had poorer memory, psychomotor speed, and executive function. Significantly more HF patients (24%) had deficits in three or more domains. Higher (worse) HF severity was associated with more cognitive deficits; HF severity interacted with age to explain deficits in executive function. Surprisingly, men with HF had poorer memory, psychomotor speed, and visuospatial recall ability than women. Multiple comorbidity, hypertension, depressive symptoms, and medications were not associated with cognitive deficits in this sample.

Discussion:

Heart failure results in losses in memory, psychomotor speed, and executive function in almost one fourth of patients. Patients with more severe HF are at risk for cognitive deficits. Older patients with more severe HF may have more problems in executive function and men with HF may be at increased risk for cognitive deficits. Studies are urgently needed to identify the mechanisms for the cognitive deficits in HF and test innovative interventions to prevent cognitive loss and decline.

In the title complex, [ZnBr2(C13H19N3O)], the ZnII atom is five-coordinated by the three N-donor atoms of the Schiff base ligand and by two Br atoms in a distorted square-pyramidal geometry. The morpholine ring adopts a chair conformation.

Polysaccharides constitute a major component of bacterial cell surfaces and play critical roles in bacteria/host interactions. The biosynthesis of such molecules, however, has mainly been characterized through in vivo genetic studies, thus precluding discernment of the details of this pathway. Accordingly, we present a chemical approach which enabled reconstitution of the E. coli O-polysaccharide biosynthetic pathway in vitro. Starting with chemically prepared N-Acetyl-D-galactosamine-diphospho-undecaprenyl, the E. coli O86 oligosaccharide repeating unit was assembled via sequential enzymatic glycosylation. Successful expression of the putative polymerase Wzy via a chaperone co-expression system then allowed demonstration of polymerization in vitro using this substrate. Analysis of additional substrates revealed a defined mode of recognition for Wzy towards the lipid moiety. Specific polysaccharide chain length modality was furthermore demonstrated to result from the action of Wzz. Collectively, polysaccharide biosynthesis was chemically reconstituted in vitro, providing a well-defined system for further underpinning molecular details of this biosynthetic pathway.

Background

MicroRNAs (miRNAs) are a class of short regulatory RNAs encoded in the genome of DNA viruses, some single cell organisms, plants and animals. With the rapid development of technology, more and more miRNAs are being discovered. However, the origin and evolution of most miRNAs remain obscure. Here we report the origin and evolution dynamics of a human miRNA family.

Results

We have shown that all members of the miR-1302 family are derived from MER53 elements. Although the conservation scores of the MER53-derived pre-miRNA sequences are low, we have identified 36 potential paralogs of MER53-derived miR-1302 genes in the human genome and 58 potential orthologs of the human miR-1302 family in placental mammals. We suggest that in placental species, this miRNA family has evolved following the birth-and-death model of evolution. Three possible mechanisms that can mediate miRNA duplication in evolutionary history have been proposed: the transposition of the MER53 element, segmental duplications and Alu-mediated recombination. Finally, we have found that the target genes of miR-1302 are over-represented in transportation, localization, and system development processes and in the positive regulation of cellular processes. Many of them are predicted to function in binding and transcription regulation.

Conclusions

The members of miR-1302 family that are derived from MER53 elements are placental-specific miRNAs. They emerged at the early stage of the recent 180 million years since eutherian mammals diverged from marsupials. Under the birth-and-death model, the miR-1302 genes have experienced a complex expansion with some members evolving by segmental duplications and some by Alu-mediated recombination events.

The title compound, C15H16N4O, was prepared by the reaction of pyridine-3-carbaldehyde with 4-dimethyl­amino­benzo­hydrazide in methanol. The dihedral angle between the pyridine and the benzene rings is 5.1 (3)°. In the crystal structure, the hydrazone mol­ecules are linked through inter­molecular N—H⋯O hydrogen bonds, forming chains along the b axis.

Background

Gardnerella vaginalis is described as a common vaginal bacterial species whose presence correlates strongly with bacterial vaginosis (BV). Here we report the genome sequencing and comparative analyses of three strains of G. vaginalis. Strains 317 (ATCC 14019) and 594 (ATCC 14018) were isolated from the vaginal tracts of women with symptomatic BV, while Strain 409-05 was isolated from a healthy, asymptomatic individual with a Nugent score of 9.

Principal Findings

Substantial genomic rearrangement and heterogeneity were observed that appeared to have resulted from both mobile elements and substantial lateral gene transfer. These genomic differences translated to differences in metabolic potential. All strains are equipped with significant virulence potential, including genes encoding the previously described vaginolysin, pili for cytoadhesion, EPS biosynthetic genes for biofilm formation, and antimicrobial resistance systems, We also observed systems promoting multi-drug and lantibiotic extrusion. All G. vaginalis strains possess a large number of genes that may enhance their ability to compete with and exclude other vaginal colonists. These include up to six toxin-antitoxin systems and up to nine additional antitoxins lacking cognate toxins, several of which are clustered within each genome. All strains encode bacteriocidal toxins, including two lysozyme-like toxins produced uniquely by strain 409-05. Interestingly, the BV isolates encode numerous proteins not found in strain 409-05 that likely increase their pathogenic potential. These include enzymes enabling mucin degradation, a trait previously described to strongly correlate with BV, although commonly attributed to non-G. vaginalis species.

Conclusions

Collectively, our results indicate that all three strains are able to thrive in vaginal environments, and therein the BV isolates are capable of occupying a niche that is unique from 409-05. Each strain has significant virulence potential, although genomic and metabolic differences, such as the ability to degrade mucin, indicate that the detection of G. vaginalis in the vaginal tract provides only partial information on the physiological potential of the organism.

Aurora kinases are key regulators of cell mitosis and have been implicated in the process of tumorigenesis. In recent years, the Aurora kinases have attracted much interest as promising targets for cancer treatment. Here we report on the roles of Aurora A and Aurora B kinases in clear cell renal cell carcinoma (ccRCC). Using genomewide expression array analysis of 174 patient samples of ccRCC, we found that expression levels of Aurora A and B were significantly elevated in ccRCC compared to normal kidney samples. High expression levels of Aurora A and Aurora B were significantly associated with advanced tumor stage and poor patient survival. Inhibition of Aurora kinase activity with the drug VX680 (also referred to as MK-0457) inhibited ccRCC cell growth in vitro and led to ccRCC cell accumulation in the G2/M phase and apoptosis. Growth of ccRCC xenograft tumors was also inhibited by VX680 treatment, accompanied by a reduction of tumor microvessel density. Analysis of endothelial cell lines demonstrated that VX680 inhibits endothelial cell growth with effects similar to that seen in ccRCC cells. Our findings suggest that VX680 inhibits the growth of ccRCC tumors by targeting the proliferation of both ccRCC tumor cells and tumor-associated endothelial cells. Aurora kinases and their downstream cell cycle proteins have an important role in ccRCC and may be potent prognostic markers and therapy targets for this disease.