Objective. By specific knockout of carnitine palmitoyl transferase 1b (CPT1b) in skeletal muscles, we explored the effect of CPT1b deficiency on lipids and insulin sensitivity. Methods. Mice with specific knockout of CPT1b in skeletal muscles (CPT1b M−/−) were used for the experiment group, with littermate C57BL/6 as controls (CPT1b). General and metabolic profiles were measured and compared between groups. mRNA expression and CPT1 activity were measured in skeletal muscle tissues and compared between groups. Mitochondrial fatty acid oxidation (FAO), triglycerides (TAGs), diglycerides (DAGs), and ceramides were examined in skeletal muscles in two groups. Phosphorylated AKT (pAkt) and glucose transporter 4 (Glut4) were determined with real-time polymerase chain reaction (RT-PCR). Insulin tolerance test, glucose tolerance test, and pyruvate oxidation were performed in both groups. Results. CPT1b M−/− model was successfully established, with impaired muscle CPT1 activity. Compared with CPT1b mice, CPT1b M−/− mice had similar food intake but lower body weight or fat mass and higher lipids but similar glucose or insulin levels. Their mitochondrial FAO of skeletal muscles was impaired. There were lipids accumulations (TAGs, DAGs, and ceramides) in skeletal muscle. However, pAkt and Glut4, insulin sensitivity, glucose tolerance, and pyruvate oxidation were preserved. Conclusion. Skeletal muscle-specific CPT1 deficiency elevates lipotoxic intermediates but preserves insulin sensitivity.
Small vessel (SV) and large vessel (LV) brain infarcts are distinct pathologies. Using a homebound elderly sample, the numbers of either infarct subtypes were similar between those apolipoprotein E4 allele (ApoE4) carriers (n = 80) and noncarriers (n = 243). We found that the higher the number of SV infarcts, but not LV infarcts, a participant had, the higher the activity of substrate V degradation in serum especially among ApoE4 carriers (β=+0.154, SE = 0.031, P < .0001) after adjusting for the confounders. Since substrate V degradation could be mediated by insulin-degrading enzyme (IDE) or/and angiotensin-converting enzyme (ACE), but no relationship was found between SV infarcts and specific ACE activities, blood IDE may be a useful biomarker to distinguish the brain infarct subtypes. Insulin-degrading enzyme in blood may also imply an important biomarker and a pathological event in Alzheimer disease through SV infarcts in the presence of ApoE4.
small vessel brain infarct; apolipoprotein E4 allele; substrate V degradation
Kaempferol (Kae), a natural flavonoid, is widely distributed in fruits and vegetables. Previous studies have identified Kae as a possible cancer preventive and therapeutic agent. We found Kae to exhibit potent antiproliferation and anti-migration effects in human bladder cancer EJ cells. Kaempferol robustly induced apoptosis in EJ cells in a dose-dependent manner, as evidenced by increased cleavage of caspase-3. Furthermore, we found Kae-induced apoptosis in EJ cells to be associated with phosphatase and the tensin homolog deleted on the chromosome 10 (PTEN)/PI3K/Akt pathway. Kae significantly increased PTEN and decreased Akt phosphorylation. Kae-induced apoptosis was partially attenuated in PTEN-knockdown cells. Our findings indicate that Kae could be an alternative medicine for bladder cancer, based on a PTEN activation mechanism.
kaempferol; bladder cancer; apoptosis; PTEN; Akt
Mitochondria are one of the major sources of reactive oxygen species (ROS) in the cell. When exceeding the capacity of antioxidant mechanisms, ROS production may lead to different pathologies, such as ischemia-reperfusion injury, neurodegeneration, anemia and ageing. As a consequence of the endosymbiotic origin of mitochondria, eukaryotic cells have developed different transport mechanisms that coordinate mitochondrial function with other cellular compartments. Four mitochondrial ATP-binding cassette (ABC) transporters have been described to date in mammals: ABCB6, ABCB8, ABCB7 and ABCB10. ABCB10 is located in the inner mitochondrial membrane forming homodimers, with the ATP binding domain facing the mitochondrial matrix. ABCB10 expression is highly induced during erythroid differentiation and its overexpression increases hemoglobin synthesis in erythroid cells. However, ABCB10 is also expressed in nonerythroid tissues, suggesting a role not directly related to hemoglobin synthesis. Recent evidence points toward ABCB10 as an important player in the protection from oxidative stress in mammals. In this regard, ABCB10 is required for normal erythropoiesis and cardiac recovery after ischemia-reperfusion, processes intimately related to mitochondrial ROS generation. Here, we review the current knowledge on mitochondrial ABC transporters and ABCB10 and discuss the potential mechanisms by which ABCB10 and its transport activity may regulate oxidative stress. We discuss ABCB10 as a potential therapeutic target for diseases in which increased mitochondrial ROS production and oxidative stress play a major role.
mitochondria; oxidative stress; ABCB10; ABC-me; erythropoiesis; ischemia-reperfusion
Lyme disease is caused by spirochete bacteria from the Borrelia burgdorferi sensu lato (B. burgdorferi s.l.) species complex. To reconstruct the evolution of B. burgdorferi s.l. and identify the genomic basis of its human virulence, we compared the genomes of 23 B. burgdorferi s.l. isolates from Europe and the United States, including B. burgdorferi sensu stricto (B. burgdorferi s.s., 14 isolates), B. afzelii (2), B. garinii (2), B. “bavariensis” (1), B. spielmanii (1), B. valaisiana (1), B. bissettii (1), and B. “finlandensis” (1).
Robust B. burgdorferi s.s. and B. burgdorferi s.l. phylogenies were obtained using genome-wide single-nucleotide polymorphisms, despite recombination. Phylogeny-based pan-genome analysis showed that the rate of gene acquisition was higher between species than within species, suggesting adaptive speciation. Strong positive natural selection drives the sequence evolution of lipoproteins, including chromosomally-encoded genes 0102 and 0404, cp26-encoded ospC and b08, and lp54-encoded dbpA, a07, a22, a33, a53, a65. Computer simulations predicted rapid adaptive radiation of genomic groups as population size increases.
Intra- and inter-specific pan-genome sizes of B. burgdorferi s.l. expand linearly with phylogenetic diversity. Yet gene-acquisition rates in B. burgdorferi s.l. are among the lowest in bacterial pathogens, resulting in high genome stability and few lineage-specific genes. Genome adaptation of B. burgdorferi s.l. is driven predominantly by copy-number and sequence variations of lipoprotein genes. New genomic groups are likely to emerge if the current trend of B. burgdorferi s.l. population expansion continues.
Borrelia burgdorferi; Lyme borreliosis; Pan-genome; Single-nucleotide polymorphisms; Phylogenetic tree; Genome evolution simulation
Acupuncture modulates brain activity at the limbic–paralimbic–neocortical network (LPNN) and the default mode network (DMN). Since these brain networks show gender differences when mediating emotional and cognitive tasks, we thus hypothesize that women and men may also respond differently to acupuncture procedure at these brain regions. In order to test this hypothesis, we retrieved the data of 38 subjects, 19 females and 19 males, who had brain fMRI during acupuncture from previous studies and reanalyzed them based on sex status. Deactivation at the LPNN/DMN during needle manipulation of acupuncture was more extensive in females than in males, particularly in the posterior cingulate (BA31), precuneus (BA7m) and angular gyrus (BA39). The functional correlations between the right BA31 and pregenual cingulate (BA32), hippocampus or contralateral BA31 were significantly stronger in females than in males. The angular gyrus (BA39) was functionally correlated with BA31 in females; in contrast, it was anticorrelated with BA31 in males. Soreness, a major component of the psychophysical responses to needle manipulation, deqi, was correlated in intensity with deactivation of the angular gyrus in females; no such relationships were observed in males. In contrast to lesser deactivation at the LPNN/DMN networks, needle manipulation during acupuncture induced greater activation at the secondary somatosensory cortex and stronger functional connectivity with the anterior-middle cingulate (BA32/24) in males than in females. Our study suggests that brains with sex dimorphism may process the acupuncture stimulation differently between women and men.
Acupuncture; Brain activity; Sex; Gender
Sporadic Alzheimer’s disease (AD) patients have low amyloid-β peptide (Aβ) clearance in the central nervous system (CNS). The peripheral Aβ clearance may also be important but its role in AD remains unclear. We aimed to study the Aβ degrading proteases including insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE) and others in blood. Using the fluorogenic substrate V—a substrate of IDE and other metalloproteases, we showed that human serum degraded the substrate V, and the activity was inhibited by adding increasing dose of Aβ. The existence of IDE activity was demonstrated by the inhibition of insulin, amylin or EDTA, and further confirmed by immunocapture of IDE using monoclonal antibodies. The involvement of ACE was indicated by the ability of the ACE inhibitor, lisinopril, to inhibit the substrate V degradation. To test the variations of substrate V degradation in humans, we used serum samples from a homebound elderly population with cognitive diagnoses. Compared with the elderly who had normal cognition, those with probable AD and amnestic mild cognitive impairment (amnestic MCI) had lower peptidase activities. Probable AD or amnestic MCI as an outcome remained negatively associated with serum substrate V degradation activity after adjusting for the confounders. The elderly with probable AD had lower serum substrate V degradation activity compared with those who had vascular dementia. The blood proteases mediating Aβ degradation may be important for the AD pathogenesis. More studies are needed to specify each Aβ degrading protease in blood as a useful biomarker and a possible treatment target for AD.
Aβ; degradation; protease; insulin degrading enzyme; angiotensin convertingenzyme; serum; alzheimer’s disease
Previous work from our team and others has shown that manual acupuncture at LI4 (hegu), ST36 (zusanli), and LV3 (taichong) deactivates a limbic-paralimbic-neocortical brain network, and at the same time activates somatosensory regions of the brain. The objective of the present study was to explore the specificity and commonality of the brain response to manual acupuncture at LI4, ST36, and LV3, acupoints that are located on different meridians and are used to treat pain disorders. We used functional magnetic resonance imaging (fMRI) to monitor the brain responses to acupuncture at 3 different acupoints; we examined 46 healthy subjects who, according to their psychophysical responses, experienced deqi sensation during acupuncture. Brain responses to stimulation at each of the acupoints were displayed in conjunction with one another to show the spatial distribution. We found clusters of deactivation in the medial prefrontal, medial parietal and medial temporal lobes showing significant convergence of two or all three of the acupoints. The largest regions showing common responses to all three acupoints were the right subgenual BA25, right subgenual cingulate, right isthmus of the cingulum bundle, and right BA31. We also noted differences in major sections of the medial prefrontal and medial temporal lobes, with LI4 predominating in the pregenual cingulate and hippocampal formation, ST36 predominating in the subgenual cingulate, and LV3 predominating in the posterior hippocampus and posterior cingulate. The results suggest that although these acupoints commonly used for anti-pain and modulatory effects may mobilize the same intrinsic global networks, with substantial overlap of common brain regions to mediate its actions, our findings showing preferential response of certain limbic-paralimbic structures suggests acupoints may also exhibit relative specificity.
acupuncture; fMRI; limbic-paralimbic-neocortical network; default mode; acupoint specificity; deqi
Inhibitors of apoptosis (IAPs) play important roles in apoptosis and NF-κB activation. In this study, we cloned and characterized three IAPs (LvIAP1-3) from the Pacific white shrimp, Litopenaeusvannamei. LvIAP1-3 proteins shared signature domains and exhibited significant similarities with other IAP family proteins. The tissue distributions of LvIAP1-3 were studied. The expression of LvIAP1-3 was induced in the muscle after white spot syndrome virus (WSSV) infection. LvIAP1 expression in the gill, hemocytes, hepatopancreas, and intestine was responsive to WSSV and Vibrioalginolyticus infections. LvIAP2 expression in the gill, hemocytes, and hepatopancreas was also responsive to WSSV infection. The expression of LvIAP3 in the gill, hemocytes, and intestine was reduced after V. alginolyticus infection. When overexpressed in Drosophila S2 cells, GFP labeled-LvIAP2 was distributed in the cytoplasm and appeared as speck-like aggregates in the nucleus. Both LvIAP1 and LvIAP3 were widely distributed throughout the cytoplasm and nucleus. The expression of LvIAP1, LvIAP2, and LvIAP3 was significantly knocked down by dsRNA-mediated gene silencing. In the gill of LvIAP1- or LvIAP3-silenced shrimp, the expression of WSSV VP28 was significantly higher than that of the dsGFP control group, suggesting that LvIAP1 and LvIAP3 may play protective roles in host defense against WSSV infection. Intriguingly, the LvIAP2-silenced shrimp all died within 48 hours after dsLvIAP2 injection. In the hemocytes of LvIAP2-silenced shrimps, the expression of antimicrobial peptide genes (AMPs), including Penaeidins, lysozyme, crustins, Vibriopenaeicidae-induced cysteine and proline-rich peptides (VICPs), was significantly downregulated, while the expression of anti-lipopolysaccharide factors (ALFs) was upregulated. Moreover, LvIAP2 activated the promoters of the NF-κB pathway-controlled AMPs, such as shrimp Penaeidins and Drosophila drosomycin and attacin A, in Drosophila S2 cells. Taken together, these results reveal that LvIAP1 and LvIAP3 might participate in the host defense against WSSV infection, and LvIAP2 might be involved in the regulation of shrimp AMPs.
BACKGROUND & AIMS
Inflammatory bowel disease (IBD) is associated with increased apoptosis of intestinal epithelial cells (IECs). Mutations in the tumor suppressor p53 appear during early stages of progression from colitis to cancer. We investigated the role of p53 and its target, p53-upregulated modulator of apoptosis (PUMA), in inflammation-induced apoptosis of IECs.
Apoptosis was induced in mouse models of mucosal inflammation. Responses of IECs to acute, T-cell activation were assessed in wild-type, p53−/−, Bid−/−, Bim−/−, Bax3−/−, Bak−/−, PUMA−/−, and Noxa−/− mice. Responses of IECs to acute and chronic colitis were measured in mice following 1 or 3 cycles of dextran sulfate sodium (DSS), respectively. Apoptosis was assessed by TUNEL staining and measuring activity of caspases 3 and 9; levels of p53 and PUMA were assessed in colon tissue from patients with and without ulcerative colitis.
Apoptosis of IECs occurred in the lower crypts of colitic tissue from humans and mice. Colitis induction with anti-CD3 or 3 cycles of DSS increased apoptosis and protein levels of p53 and PUMA in colonic crypt IECs. In p53−/− and PUMA−/− mice, apoptosis of IECs was significantly reduced but inflammation was not. Levels of p53 and PUMA were increased in inflamed mucosal tissues of mice with colitis and in patients with UC, compared with controls. Induction of PUMA in IECs of p53−/− mice indicated that PUMA-mediated apoptosis was independent of p53.
In mice and humans, colon inflammation induces apoptosis of IECs via p53-dependent and -independent mechanisms; PUMA also activates an intrinsic apoptosis pathway associated with colitis.
IBD; UC; Crohn’s Disease; Cell Death; Signaling
Both plasma amyloid-β peptide 40 (Aβ40) and homocysteine (tHcy) are linked to vascular disease, which is related to depression in the elderly. We sought to study whether the relationship between tHcy and plasma Aβ40 differs in those with and without depression.
Study Design and Methods
In a cross-sectional study of 1058 homebound elders, vascular depression was defined as a score ≥ 16 on the Center for Epidemiological Studies Depression scale (CES-D) along with self-reported cardiovascular disease (CVD). Plasma Aβ40 and Aβ42, and serum tHcy and creatinine were measured.
Elders with high tHcy had higher concentrations of plasma Aβ40 (median: 147.5 vs. 123.1 pg/ml, P < 0.0001) and Aβ42 (median: 20.2 vs. 16.6 pg/ml, P < 0.0001) than those with low tHcy. In elders with depression, the relationship between logarithm of plasma Aβ40 (LogAβ40), but not LogAβ42, and tHcy was significant (β = +0.010, SE = 0.004, P = 0.007); in contrast, this relationship was not observed in those without depression. Subjects with vascular depression had the highest concentration of tHcy (mean ± SD: 12.8 ± 4.6 vs. 11.7 ± 4.5 vs. 11.9 + 5.5, P = 0.008) compared to those without CVD and those without depression. Depressed subjects without CVD had the lowest concentration of plasma Aβ42 (median: 15.5 vs. 19.1 vs. 18.7, P = 0.01) compared to those with CVD and those without depression.
Vascular depression, which is associated with tHcy and Aβ40 in blood, appears to be different from depression that is associated with low plasma Aβ42. This suggests that reducing tHcy and Aβ40 may be an adjunct treatment for vascular depression.
Aβ; Homocysteine; Depression
During an analysis of the virome of bats from Myanmar, a large number of reads were annotated to orthohepadnaviruses. We present the full genome sequence and a morphological analysis of an orthohepadnavirus circulating in bats. This virus is substantially different from currently known members of the genus Orthohepadnavirus and represents a new species.
hepatitis; bats; bat hepatitis virus; full genome; viral morphology; prevalence; viruses; Myanmar
The Toll-like receptor (TLR)-mediated NF-κB pathway is tightly controlled because overactivation may result in severe damage to the host, such as in the case of chronic inflammatory diseases and cancer. In mammals, sterile-alpha and armadillo motif-containing protein (SARM) plays an important role in negatively regulating this pathway. While Caenorhabditis elegans SARM is crucial for an efficient immune response against bacterial and fungal infections, it is still unknown whether Drosophila SARM participates in immune responses. Here, Litopenaeus vannamei SARM (LvSARM) was cloned and functionally characterized. LvSARM shared signature domains with and exhibited significant similarities to mammalian SARM. Real-time quantitative PCR analysis indicated that the expression of LvSARM was responsive to Vibrio alginolyticus and white spot syndrome virus (WSSV) infections in the hemocyte, gill, hepatopancreas and intestine. In Drosophila S2 cells, LvSARM was widely distributed in the cytoplasm and could significantly inhibit the promoters of the NF-κB pathway-controlled antimicrobial peptide genes (AMPs). Silencing of LvSARM using dsRNA-mediated RNA interference increased the expression levels of Penaeidins and antilipopolysaccharide factors, which are L.vannamei AMPs, and increased the mortality rate after V. alginolyticus infection. Taken together, our results reveal that LvSARM may be a novel component of the shrimp Toll pathway that negatively regulates shrimp AMPs, particularly Penaeidins and antilipopolysaccharide factors.
Mdm2 inhibits p53 transactivation by forming a p53-Mdm2 complex on chromatin. Upon DNA damage-induced complex disruption, such latent p53 can be activated, but in cells overexpressing Mdm2 because of a homozygous single nucleotide polymorphism at position 309 (T→G) of mdm2, the complex is highly stable and cannot be disrupted by DNA damage, rendering p53 inactive.
To determine whether the p53 response phenotype is influenced differentially in cells with variable mdm2 genotypes, we compared responses to DNA damage and targeted p53-Mdm2 complex disruption by Nutlin-3 in the following wild-type p53 human cancer cell lines: A875 and CCF-STTG-1 (G/G for mdm2 SNP309), SJSA-1 (mdm2 genomic amplification and T/T for mdm2 SNP309), MCF-7 (estrogen-induced Mdm2 overexpression and T/G for mdm2 SNP309), ML-1 and H460 (T/T for mdm2 SNP309), and K562 (p53-null and T/G for mdm2 SNP309). We also examined mdm2 gene-splicing patterns in these lines by cloning and sequencing analyses.
While Mdm2-overexpressing G/G cells were resistant to p53 activation by DNA damage, they were sensitive to Nutlin-3. Strikingly, the p53 G1 checkpoint in G/G cells was activated by Nutlin-3 but not by etoposide, whereas in other Mdm2-overexpressing cells, both drugs activated p53 and subsequent G1 arrest or apoptosis. cDNA clones lacking exons 5–9 were generated at a high frequency in cells overexpressing Mdm2.
Nutlin-3 and DNA damage distinguish a differential phenotype in human cancer cells with G/G mdm2 SNP309 from other Mdm2 overexpressers. Categorization of the Mdm2 isoforms produced and their influence on p53 activity will help in characterization and treatment development for different cancers.
p53; Mdm2; SNP309; Phenotype; Nutlin-3
Brain-derived neurotrophic factor (BDNF) has been associated with regulation of body weight and appetite. The goal of this study was to examine the interactions of a functional variant (rs6265) in the BDNF gene with dietary intake for obesity traits in the Boston Puerto Rican Health Study. BDNF rs6265 was genotyped in 1147 Puerto Rican adults and examined for association with obesity-related traits. Men (n = 242) with the GG genotype had higher BMI (P = 0.009), waist circumference (P = 0.002), hip (P = 0.002), and weight (P = 0.03) than GA or AA carriers (n = 94). They had twice the risk of being overweight (BMI ≥ 25) relative to GA or AA carriers (OR = 2.08, CI = 1.02–4.23, and P = 0.043). Interactions between rs6265 and polyunsaturated fatty acids (PUFA) intake were associated with BMI, hip, and weight, and n-3 : n-6 PUFA ratio with waist circumference in men. In contrast, women (n = 595) with the GG genotype had significantly lower BMI (P = 0.009), hip (P = 0.029), and weight (P = 0.027) than GA or AA carriers (n = 216). Women with the GG genotype were 50% less likely to be overweight compared to GA or AA carriers (OR = 0.05, CI = 0.27–0.91, and P = 0.024). In summary, BDNF rs6265 is differentially associated with obesity risk by sex and interacts with PUFA intake influencing obesity traits in Boston Puerto Rican men.
The identification of new virus strains is important for the study of infectious disease, but current (or existing) molecular biology methods are limited since the target sequence must be known to design genome-specific PCR primers. Thus, we developed a new method for the discovery of unknown viruses based on the cDNA - random amplified polymorphic DNA (cDNA-RAPD) technique. Getah virus, belonging to the family Togaviridae in the genus Alphavirus, is a mosquito-borne enveloped RNA virus that was identified using the Virus-Discovery-cDNA RAPD (VIDISCR) method.
A novel Getah virus was identified by VIDISCR from suckling mice exposed to mosquitoes (Aedes albopictus) collected in Yunnan Province, China. The non-structural protein gene, nsP3, the structural protein gene, the capsid protein gene, and the 3'-untranslated region (UTR) of the novel Getah virus isolate were cloned and sequenced. Nucleotide sequence identities of each gene were determined to be 97.1–99.3%, 94.9–99.4%, and 93.6–99.9%, respectively, when compared with the genomes of 10 other representative strains of Getah virus.
The VIDISCR method was able to identify known virus isolates and a novel isolate of Getah virus from infected mice. Phylogenetic analysis indicated that the YN08 isolate was more closely related to the Hebei HB0234 strain than the YN0540 strain, and more genetically distinct from the MM2021 Malaysia primitive strain.
Getah virus; Identification; Virus-Discovery; cDNA RAPD
There is a recent emergence of interest in the genes involved in gametic recognition as drivers of reproductive isolation. The recent population genomic sequencing of two species of sexually primitive yeasts (Liti G, Carter DM, Moses AM, Warringer J, Parts L, James SA, Davey RP, Roberts IN, Burt A, Koufopanou V et al. [23 co-authors]. 2009. Population genomics of domestic and wild yeasts. Nature 458:337–341.) has provided data for systematic study of the roles these genes play in the early evolution of sex and speciation. Here, we discovered that among genes encoding cell surface proteins, the sexual adhesin genes have evolved significantly more rapidly than others, both within and between Saccharomyces cerevisiae and its closest relative S. paradoxus. This result was supported by analyses using the PAML pairwise model, a modified McDonald–Kreitman test, and the PAML branch model. Moreover, using a combination of a new statistic of neutrality, an information theory–based measure of evolutionary variability, and functional characterization of amino acid changes, we found that a higher proportion of amino acid changes are fixed in the sexual adhesins than in other proteins and a greater proportion of the fixed amino acid changes either between the two species or the two subgroups of S. paradoxus are functionally dissimilar or radically different. These results suggest that the accelerated evolution of sexual adhesin genes may facilitate speciation, or incipient speciation, and promote sexual selection in general.
sex genes; cell surface proteins; yeast; modified McDonald–Kreitman test; evolutionary variability; adaptive evolution
Myeloid differentiation factor 88 (MyD88) is a universal and essential signaling protein in Toll-like receptor/interleukin-1 receptor-induced activation of nuclear factor-kappa B. In this study, two MyD88 protein variants (LvMyD88 and LvMyD88-1) were identified in Litopenaeus vannamei. The LvMyD88 cDNA is 1,848 bp in length and contains an open reading frame (ORF) of 1,428 bp, whereas the LvMyD88-1 cDNA is 1,719 bp in length and has an ORF of 1,299 bp. Both variants encode proteins with death and Toll/interleukin-1 receptor domains and share 91% sequence identity. In healthy L. vannamei, the LvMyD88 genes were highly expressed in hemocytes but at a low level in the hepatopancreas. The LvMyD88s expression was induced in hemocytes after challenge with lipopolysaccharide, CpG-ODN2006, Vibrio parahaemolyticus, Staphyloccocus aureus, and white spot syndrome virus, but not by poly I∶C. Overexpression of LvMyD88 and LvMyD88-1 in Drosophila Schneider 2 cells led to activation of antimicrobial peptide genes and wsv069 (ie1), wsv303, and wsv371. These results suggested that LvMyD88 may play a role in antibacterial and antiviral response in L. vannamei. To our knowledge, this is the first report on MyD88 in shrimp and a variant of MyD88 gene in invertebrates.
The histone H3K27 demethylases UTX and JMJD3 are important regulatory factors that modulate gene expression by altering the physical state of chromatin. Previous studies have indicated an abnormal H3K27 methylation status in carcinogenesis. We therefore investigated the expression patterns of UTX and JMJD3 in renal cell carcinoma (RCC) and their roles in cancer development.
The mRNA expression levels of the UTX and JMJD3 genes were determined in cancer tissues and adjacent normal tissues in 36 patients with primary RCC, using quantitative real-time-polymerase chain reaction. The UTX and JMJD3 protein contents were measured by western blotting and immunohistochemical analysis.
UTX and JMJD3 transcripts were significantly increased in cancer tissues compared to normal tissues (P < 0.05). mRNA levels of the inhibitor of cyclin-dependent kinases 4 and 6 p16INK4a were also increased in cancer tissues (P < 0.001). Western blotting indicated that levels of both demethylases were increased in cancer tissues. The level of tri-methylated H3K27 (H3K27me3) was lower in cancer tissues compared to normal tissues, but expression of the H3K27 methyltransferase EZH2 was increased (P < 0.05). These results suggest that the two H3K27 demethylases may play critical roles in the regulation of H3K27 methylation status in RCC. Immunohistochemical analysis confirmed that UTX and JMJD3 expression were upregulated in cancer tissues compared to adjacent tissues.
This study demonstrated that UTX and JMJD3 were upregulated in cancer tissues, suggesting that they may be involved in the development of primary RCC. The potential roles of H3K27 demethylases as biomarkers in the early diagnosis of RCC need to be further explored.
Renal cell carcinoma; Histone H3K27 demethylase; UTX; JMJD3; Epigenetics
Hepatocyte death and proliferation contribute to hepatocellular carcinoma development following carcinogen exposure or chronic liver inflammation. However, the role and the molecular targets of hepatocyte death in relation to compensatory proliferation remain to be fully characterized. In this study, we investigated the role of PUMA, a BH3-only protein important for both p53-dependent and -independent apoptosis, in a diethylnitrosamine (DEN)-induced liver carcinogenesis model. PUMA deficiency significantly decreased the multiplicity and size of liver tumors. DEN treatment induced p53-independent PUMA expression, PUMA-dependent hepatocyte death, and compensatory proliferation. Furthermore, inhibition or deletion of JNK1 abrogated PUMA induction, hepatocyte death, and compensatory proliferation. These results provide direct evidence that JNK1/PUMA-dependent apoptosis promotes chemical hepatocarcinogenesis via compensatory proliferation, and suggest apoptotic inducers as potential therapeutic targets in liver injury and cancer.
PUMA; JNK1; liver cancer; apoptosis; proliferation
Background and Purpose
Gait impairment is common in the elderly, especially those with stroke and white matter hyperintensities (WMH) on conventional brain MRI. Diffusion Tensor Imaging (DTI) is more sensitive to white matter damage than conventional MRI. The relationship between DTI measures and gait has not been previously evaluated. Our purpose was to investigate the relationship between the integrity of white matter in the corpus callosum as determined by DTI and quantitative measures of gait in the elderly.
One hundred seventy-three participants of a community-dwelling elderly cohort had neurological and neuropsychological examinations and brain MRI. Gait function was measured by Tinetti gait (0-12), balance (0-16) and total (0-28) scores. DTI assessed Fractional Anisotropy in the genu and splenium of the corpus callosum. Conventional MRI was used to evaluate for brain infarcts and WMH volume.
Participants with abnormal gait had low fractional anisotropy in the genu of the corpus callosum but not the splenium. Multiple regressions analyses showed an independent association between these genu abnormalities and all three Tinetti scores (p <0.001). This association remained significant after adding MRI infarcts and WMH volume to the analysis.
The independent association between quantitative measures of gait function and DTI findings shows that white matter integrity in the genu of corpus callosum is an important marker of gait in the elderly. DTI analyses of white matter tracts in brain and spinal cord may improve knowledge about the pathophysiology of gait impairment and help target clinical interventions.
Gait; Mobility; MRI; Diffusion; Diffusion-Weighted Imaging; Epidemiology; Magnetic Resonance; Neuroradiology; White Matter Disease
A number of studies have reported on the effects of iron supplementation in low birth weight infants; however, no systematic review of the available evidence has been conducted to date. Hence, we performed a systematic review of the literature to examine the effects of iron supplementation on hematologic iron status, growth, neurodevelopment, and adverse effects in low birth weight/premature infants.
We searched the Cochrane Library, Medline, and PubMed for articles reporting on the effects of iron supplementation in low weight infants. The following search terms were used: “preterm born infant(s)/children”; “preterm infants”; “prematurely born children” “weight less than 1500 g at birth”; “born prematurely”; “low birth weight infant(s)”; “infants born preterm”; “prematurity”; “small-for-gestational age”; “very small gestational age infants”; “iron supplementation”; “iron intake”; “iron supplements”; “ferric and/or ferrous compounds”; and “ferrous sulphate/fumarate/sulfate”.
A total of 15 studies were identified and included in the systematic review. Supplemental iron was given orally or as an iron-fortified formula in 14/15 studies. The duration of treatment ranged from 1 week to 18 months. Iron supplementation significantly increased hematologic measures of iron status (including hemoglobin, hematocrit, serum ferritin) relative to placebo or over time in most studies. All controlled studies that examined iron-deficiency anemia (IDA)/ID reported a decreased prevalence of IDA/ID with iron supplementation. Dose dependent decreases in the prevalence of IDA/ID were reported in several studies. Of the 5 studies reporting on growth, none found any significant effect on growth-related parameters (length, height, weight, and head circumference). Only 2 studies reported on neurodevelopment; no marked effects were reported. There were no consistently reported adverse effects, including oxidative stress, inhibited nutrient absorption, morbidity, or the requirement for blood transfusion.
The available data suggest that iron supplementation increases the levels of hematologic indicators of iron status and reduces the prevalence of IDA/ID in low birth weight/premature infants. There is insufficient evidence to make a definitive statement regarding the effects of iron supplementation on growth, neurodevelopment, or the occurrence of adverse effects in low birth weight/premature infants.
Anemia; Infant; Iron deficiency; Iron supplementation; Low birth weight
Depression is associated with an increase in the incidence of type 2 diabetes, but the mechanism is unclear. We aimed to study the relationship between depression and glycemic intake in the elderly, and examine whether antidepressant use modified this relationship.
Design, Setting and Participants
We evaluated 976 homebound elders in a cross-sectional study. Depressed was defined by having a Center for Epidemiological Studies Depression (CES-D) score ≥ 16. Antidepressant use was documented. Glycemic index (GI), Glycemic load (GL), and fasting blood insulin levels were measured.
Depressed elders had slightly higher GI (Mean ± SD: 55.8 ± 3.8 vs. 55.1 ± 3.7, P = 0.003) and higher insulin levels (Median: 84.0 vs. 74.4 pmole/ml, P = 0.05) than non-depressed elders. Depressed elders receiving antidepressants, primarily selective serotonin reuptake inhibitors (SSRI), had lower GI (Mean ± SD: 55.1 ± 4.7 vs. 56.2 ± 3.4, P = 0.002) and GL (Median: 170.3 vs. 6826.3, P = 0.03) than those not taking antidepressants. After adjusting for potential confounding variables, GI remained positively associated with depression (β = + 0.65, SE = 0.28, P = 0.02); logarithm of GL was positively associated with depression (β = + 0.33, SE = 0.17, P = 0.05) and negatively associated with antidepressant use (β = − 0.54, SE = 0.18, P = 0.003).
Prospective studies are needed to examine whether high glycemic intake is a mediating factor between late life depression and the risk of type 2 diabetes.
It has been known for decades that human Lyme disease is caused by the three spirochete species Borrelia burgdorferi, Borrelia afzelii, and Borrelia garinii. Recently, Borrelia valaisiana, Borrelia spielmanii, and Borrelia bissettii have been associated with Lyme disease. We report the complete genome sequences of B. valaisiana VS116, B. spielmanii A14S, and B. bissettii DN127.
Lipin-1 proteins are phosphatidic acid phosphatases catalyzing the conversion from phosphatidic acid to diacylglycerol. Two alternative splicing isoforms, lipin-1α and -1β, are localized at different subcellular compartments. A third splicing isoform, lipin-1γ was recently cloned and its subcellular localization is unknown. Here, we demonstrate that lipin-1γ is localized to lipid droplets, an association mediated by a hydrophobic, lipin-1γ-specific domain. Additional expression of lipin-1γ altered lipid droplet morphology without affecting the triacylglycerol level. In human tissues, lipin-1γ is the main lipin-1 isoform expressed in normal human brain, suggesting a specialized role in regulating brain lipid metabolism.
Lipin; phosphatidic acid phosphatase; lipid droplets; brain