Multicellular bacterial communities (biofilms) abound in nature, and their successful formation and survival is likely to require cell-cell communication--including quorum sensing--to co-ordinate ...appropriate gene expression. The only mode of quorum sensing that is shared by both Gram-positive and Gram-negative bacteria involves the production of the signalling molecule autoinducer 2 by LuxS. A survey of the current literature reveals that luxS contributes to biofilm development in some bacteria. However, inconsistencies prevent biofilm development being attributed to the production of AI2 in all cases.
Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate ...limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4–45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.
Graphical abstract: ACCi treatment alone (green arrow) leads to increased apoB particle production in the liver as shown by increased production of LDL-apoB. Fenofibrate combined with ACCi treatment (red inhibitory symbol) prevented the increased LDL-apoB particle production. Display omitted
To better understand sexual orientation from an evolutionary perspective, we investigated whether, compared to heterosexual men, the fewer direct descendants of homosexual men could be ...counterbalanced by a larger number of other close biological relatives. We also investigated the extent to which three patterns generally studied separately––handedness, number of biological older brothers, and hair-whorl rotation pattern––correlated with each other, and for evidence of replication of previous findings on how each pattern related to sexual orientation. We surveyed at Gay Pride and general community festivals, analyzing data for 894 heterosexual men and 694 homosexual men, both groups predominantly (~80%) white/non-Hispanic. The Kinsey distribution of sexual orientation for men recruited from the general community festivals approximated previous population-based surveys. Compared to heterosexual men, homosexual men had both more relatives, especially paternal relatives, and more homosexual male relatives. We found that the familiality for male sexual orientation decreased with relatedness, i.e., when moving from first-degree to second-degree relatives. We also replicated the fraternal birth order effect. However, we found no significant correlations among handedness, hair whorl rotation pattern, and sexual orientation, and, contrary to some previous research, no evidence that male sexual orientation is transmitted predominantly through the maternal line.
Objective
To provide a strategic framework for the prevention of bipolar disorder (BD) that incorporates a ‘Big Data’ approach to risk assessment for BD.
Methods
Computerized databases (e.g., Pubmed, ...PsychInfo, and MedlinePlus) were used to access English‐language articles published between 1966 and 2012 with the search terms bipolar disorder, prodrome, ‘Big Data’, and biomarkers cross‐referenced with genomics/genetics, transcriptomics, proteomics, metabolomics, inflammation, oxidative stress, neurotrophic factors, cytokines, cognition, neurocognition, and neuroimaging. Papers were selected from the initial search if the primary outcome(s) of interest was (were) categorized in any of the following domains: (i) ‘omics’ (e.g., genomics), (ii) molecular, (iii) neuroimaging, and (iv) neurocognitive.
Results
The current strategic approach to identifying individuals at risk for BD, with an emphasis on phenotypic information and family history, has insufficient predictive validity and is clinically inadequate. The heterogeneous clinical presentation of BD, as well as its pathoetiological complexity, suggests that it is unlikely that a single biomarker (or an exclusive biomarker approach) will sufficiently augment currently inadequate phenotypic‐centric prediction models. We propose a ‘Big Data’‐ bioinformatics approach that integrates vast and complex phenotypic, anamnestic, behavioral, family, and personal ‘omics’ profiling. Bioinformatic processing approaches, utilizing cloud‐ and grid‐enabled computing, are now capable of analyzing data on the order of tera‐, peta‐, and exabytes, providing hitherto unheard of opportunities to fundamentally revolutionize how psychiatric disorders are predicted, prevented, and treated. High‐throughput networks dedicated to research on, and the treatment of, BD, integrating both adult and younger populations, will be essential to sufficiently enroll adequate samples of individuals across the neurodevelopmental trajectory in studies to enable the characterization and prevention of this heterogeneous disorder.
Conclusions
Advances in bioinformatics using a ‘Big Data’ approach provide an opportunity for novel insights regarding the pathoetiology of BD. The coordinated integration of research centers, inclusive of mixed‐age populations, is a promising strategic direction for advancing this line of neuropsychiatric research.
Herein we review the evidence supporting Food and Drug Administration (FDA) approved and emerging treatments for bipolar depression.
A PubMed search of all English-language articles published up to ...July 2013 was conducted. The search terms were quetiapine, olanzapine-fluoxetine, olanzapine, lurasidone, ketamine, modafinil/armodafinil, and lamotrigine. The search was augmented with a manual review of relevant article reference lists, as well as posters presented at national and international meetings. Articles selected for review were based on the adequacy of sample size, the use of standardized diagnostic instruments, validated assessment measures, and overall manuscript quality.
Olanzapine-fluoxetine combination (OFC), quetiapine, and lurasidone are FDA-approved for the acute treatment of bipolar depression. Lurasidone is the most recently approved agent for bipolar depression. Olanzapine-fluoxetine combination and quetiapine are approved as single modality therapies while lurasidone is approved as a monotherapy and as an adjunct to lithium or divalproex. The overall effect size of the 3 treatments in mitigating depressive symptoms is similar. Clinically significant weight gain and metabolic disruption as well as sedation are significant limitations of OFC and quetiapine. The minimal propensity for weight gain as well as the metabolic neutrality of lurasidone in the bipolar population is a clinically significant advantage. Evidence also supports lamotrigine with compelling evidence as an adjunct to lithium and in recurrence prevention paradigm; suggested evidence also exists for ketamine and modafinil/armodafinil; notwithstanding, these treatments remain investigational.
Relatively few agents are FDA-approved for bipolar depression. The selection and sequencing of agents in bipolar depression should give primacy to those agents that are FDA-approved. Further refinement of the selection process will need to pay careful attention to the relative hazards of weight gain and metabolic disruption in this highly susceptible population. Other agents with differential mechanisms (eg, ketamine) offer a promising alternative in bipolar depression.
We measured the turnover rates of the LDLR (low-density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type 9) in mice by metabolic labeling with heavy water and mass ...spectrometry. Approach and Results: In liver of mice fed high-cholesterol diets, LDLR mRNA levels and synthesis rates were markedly lower with complete suppression of cholesterol synthesis and higher cholesterol content, consistent with the Brown-Goldstein model of tissue cholesterol homeostasis. We observed markedly lower PCSK9 mRNA levels and synthesis rates in liver and lower concentrations and synthesis rates in plasma. Hepatic LDLR half-life (t½) was prolonged, consistent with an effect of reduced PCSK9, and resulted in no reduction in hepatic LDLR content despite reduced mRNA levels and LDLR synthesis rates. These changes in PCSK9 synthesis complement and expand the well-established model of tissue cholesterol homeostasis in mouse liver, in that reduced synthesis and levels of PCSK9 counterbalance lower LDLR synthesis by promoting less LDLR catabolism, thereby maintaining uptake of LDL cholesterol into liver despite high intracellular cholesterol concentrations.
Lower hepatic synthesis and secretion of PCSK9, an SREBP2 (sterol response element binding protein) target gene, results in longer hepatic LDLR t½ in response to cholesterol feeding in mice in the face of high intracellular cholesterol content. PCSK9 modulation opposes the canonical lowering of LDLR mRNA and synthesis by cholesterol surplus and preserves LDLR levels. The physiological and therapeutic implications of these opposing control mechanisms over liver LDLR are of interest and may reflect subservience of hepatic cholesterol homeostasis to whole body cholesterol needs.
Activated CD4 T cells connect to airway smooth muscle cells (ASMCs) in vitro via lymphocyte-derived membrane conduits (LMCs) structurally similar to membrane nanotubes with unknown intercellular ...signals triggering their formation. We examined the structure and function of CD4 T cell-derived LMCs, and we established a role for ASMC-derived basic fibroblast growth factor 2 (FGF2b) and FGF receptor (FGFR)1 in LMC formation. Blocking FGF2b's synthesis and FGFR1 function reduced LMC formation. Mitochondrial flux from ASMCs to T cells was partially FGF2b and FGFR1 dependent. LMC formation by CD4 T cells and mitochondrial transfer from ASMCs was increased in the presence of asthmatic ASMCs that expressed more mRNA for FGF2b compared with normal ASMCs. These observations identify ASMC-derived FGF2b as a factor needed for LMC formation by CD4 T cells, affecting intercellular communication.
Multicellular bacterial communities (biofilms) abound in nature, and their successful formation and survival is likely to require cell-cell communication-including quorum sensing-to co-ordinate ...appropriate gene expression. The only mode of quorum sensing that is shared by both Gram-positive and Gram-negative bacteria involves the production of the signalling molecule autoinducer 2 by LuxS. A survey of the current literature reveals that luxS contributes to biofilm development in some bacteria. However, inconsistencies prevent biofilm development being attributed to the production of AI2 in all cases.
The capability of Chlorella vulgaris to remove nitrogen in the form of ammonia and/or ammonium ions from wastewater effluent in a local wastewater treatment plant （i.e., the Mill Creek Plant in ...Cincinnati, Ohio, U.S.A.） was studied. The wastewater effluent leaving the plant was found to include high concentra- tions of nitrogen （7.7±0.19 mg/L） （ammonia （NH3） and/or ammonium ion （NH4＋）） and total inorganic carbon （58.6±0.28 mg/L） at pH 7, and to be suitable for growing Chlorella vulgaris. When Chlorella vulgaris was cul- tivated in a batch mode under a closed system, half of the nitrogen concentration was dramatically removed in 48 h after a 24-h lag-phase period. Total inorganic carbon concentration also concomitantly decreased during the rapid growth-phase. The total biomass weight gained during the entire cultivation period balanced out well with the total amount of inorganic carbon and nitrogen removed from the culture medium. These results indicate that wastewater can be synergistically used to polish residual nutrients in wastewater as well as to cultivate microalgae for biofuel production.
PDF
