A new perspective of human origin and dispersals derived from the microevolution of teeth

Recent genetic studies have heightened the expectation that the origin of modern humans will be defined, but one clear vision has yet to be developed. The study of teeth has historically been an informative means to help define human dispersals. Quantitative tooth data is presented encompassing worldwide human populations. A null hypothesis phylogeny developed from the multivariate analysis of the microevolution of the dental phenotype was interpreted to be broadly in accord with the dominant interpretation of genetic, archaeological, and other dental data by showing that the first division in the dispersion of extant humanity was within sub-Sahara Africans; i.e., San, and Western Africans and Bantu. This "out-of-Africa" interpretation of the graphical results suggests that the first modern human African emigrants not to go extinct were Southeast Asian Negritos. All Eurasians then emerged and expanded through a series of extinct antecedent populations branching from the short lineage extending from Negritos to Australian aborigines. Caucasoids were the first group to fission from this stock. Under this hypothesis, the next to have emerged were antecedent Southeast Asians, from which present Southeast Asians and then antecedent east Central Asians then diverged. Independently, people from the region of Mongolia and all Native Americans arose as daughter populations from antecedent east Central Asians. The broad outline of humanity studied here cannot disprove the equally explanatory protean multiregional hypotheses, but with the inclusion of hominids and further modern human populations either parts of the multiregional hypothesis or the outlined more linear evolutionary scenario likely can be refuted.     

Effect of gonadectomy on AgRP-induced weight gain in rats

Agouti-related peptide (AgRP), the endogenous antagonist to the melanocortin 3 and 4 receptors, elicits robust hyperphagia and weight gain in rodents when administered directly into the central nervous system. The relative influence of AgRP to cause weight gain in rodents partially depends on the activity level of the melanocortin agonist-producing proopiomelanocortin neurons. Both proopiomelanocortin and AgRP neurons within the arcuate nucleus receive energy storage information from circulating peripheral signals such as leptin and insulin. Another modulator of AgRP activity includes the cell surface molecule syndecan-3. Because leptin and insulin affect food intake in a sexually dimorphic way in rodents and syndecan-3-deficient mice regulate adiposity levels through distinct physiological mechanisms, we hypothesized that AgRP-induced weight gain would also be sexually dimorphic in rats. In the present study, the behavioral and physiological effects of centrally-administered AgRP in male and female were investigated. In male rats, AgRP (1 nmol) induced 5 days (P < 0.0001) of significantly elevated feeding compared with vehicle-treated controls, while females displayed 3 days of hyperphagia (P < 0.05). However, 1 wk after the injection, both male and female rats gained the same percent body weight (6%). Interestingly, female rats exhibited a greater reduction in energy expenditure (Vo2) following AgRP compared with male rats (P < 0.05). Removal of the gonads did not alter cumulative food intake in male or female rats but did attenuate the dramatic reduction in Vo2 exhibited by females. Both intact and gonadectomized rats demonstrated significantly increased respiratory quotient supporting the anabolic action of AgRP (P < 0.01). These findings are novel in that they reveal sex-specific underlying physiology used to achieve weight gain following central AgRP in rats.     

Haplotype association analysis of AGT variants with hypertension-related traits: the HyperGEN study

OBJECTIVE: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. METHODS: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. RESULTS: In Blacks, two SNPs in exon 5 and 3'UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p=0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p=0.009) and gripSBP emerged in Whites. CONCLUSION: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.     

Oral Administration of the Pimelic Diphenylamide HDAC Inhibitor HDACi 4b Is Unsuitable for Chronic Inhibition of HDAC Activity in the CNS In Vivo

Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general.     

The insect-phase gRNA transcriptome in Trypanosoma brucei

One of the most striking examples of small RNA regulation of gene expression is the process of RNA editing in the mitochondria of trypanosomes. In these parasites, RNA editing involves extensive uridylate insertions and deletions within most of the mitochondrial messenger RNAs (mRNAs). Over 1200 small guide RNAs (gRNAs) are predicted to be responsible for directing the sequence changes that create start and stop codons, correct frameshifts and for many of the mRNAs generate most of the open reading frame. In addition, alternative editing creates the opportunity for unprecedented protein diversity. In Trypanosoma brucei, the vast majority of gRNAs are transcribed from minicircles, which are approximately one kilobase in size, and encode between three and four gRNAs. The large number (5000–10 000) and their concatenated structure make them difficult to sequence. To identify the complete set of gRNAs necessary for mRNA editing in T. brucei, we used Illumina deep sequencing of purified gRNAs from the procyclic stage. We report a near complete set of gRNAs needed to direct the editing of the mRNAs.     

Targeted next generation sequencing identifies clinically actionable mutations in patients with melanoma

Somatic sequencing of cancers has produced new insight into tumorigenesis, tumor heterogeneity, and disease progression, but the vast majority of genetic events identified are of indeterminate clinical significance. Here, we describe a NextGen sequencing approach to fully analyzing 248 genes, including all those of known clinical significance in melanoma. This strategy features solution capture of DNA followed by multiplexed, high‐throughput sequencing and was evaluated in 31 melanoma cell lines and 18 tumor tissues from patients with metastatic melanoma. Mutations in melanoma cell lines correlated with their sensitivity to corresponding small molecule inhibitors, confirming, for example, lapatinib sensitivity in ERBB4 mutant lines and identifying a novel activating mutation of BRAF. The latter event would not have been identified by clinical sequencing and was associated with responsiveness to a BRAF kinase inhibitor. This approach identified focal copy number changes of PTEN not found by standard methods, such as comparative genomic hybridization (CGH). Actionable mutations were found in 89% of the tumor tissues analyzed, 56% of which would not be identified by standard‐of‐care approaches. This work shows that targeted sequencing is an attractive approach for clinical use in melanoma.     

Acute Binge Drinking Increases Serum Endotoxin and Bacterial DNA Levels in Healthy Individuals

Binge drinking, the most common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its biological consequences are poorly defined. Previous studies demonstrated that chronic alcohol use results in increased gut permeability and increased serum endotoxin levels that contribute to many of the biological effects of chronic alcohol, including alcoholic liver disease. In this study, we evaluated the effects of acute binge drinking in healthy adults on serum endotoxin levels. We found that acute alcohol binge resulted in a rapid increase in serum endotoxin and 16S rDNA, a marker of bacterial translocation from the gut. Compared to men, women had higher blood alcohol and circulating endotoxin levels. In addition, alcohol binge caused a prolonged increase in acute phase protein levels in the systemic circulation. The biological significance of the in vivo endotoxin elevation was underscored by increased levels of inflammatory cytokines, TNFα and IL-6, and chemokine, MCP-1, measured in total blood after in vitro lipopolysaccharide stimulation. Our findings indicate that even a single alcohol binge results in increased serum endotoxin levels likely due to translocation of gut bacterial products and disturbs innate immune responses that can contribute to the deleterious effects of binge drinking.     

Ungulate Carcasses Perforate Ecological Filters and Create Biogeochemical Hotspots in Forest Herbaceous Layers Allowing Trees a Competitive Advantage

Ecological filters and nutrient heterogeneity are important in the function of ecosystems. Herbaceous layers alter forest ecosystems by filtering tree species during early stages of tree reproduction and influencing nutrient cycling. Important aspects about how tree species successfully establish below and extend above this ecological filter are unanswered in forest ecology. We experimentally tested the effects of large ungulate carcasses on the filtering function of herbaceous layers. Even well-utilized carcasses created unexpected disturbances that reduced herbaceous cover, which effectively perforated the herbaceous layer filter that can differentially influence tree reproduction. Carcasses also created lasting biogeochemical “hotspots” in forest soils that may help maintain plant biodiversity by creating resource heterogeneity and shifting competitive relationships. Because the spatial distribution of carcasses is influenced by predators, these data establish an unrecognized link between large carnivores, prey carcasses, and ecosystem processes. This link supports a novel understanding of disturbance by large herbivores in forest ecosystems by demonstrating an important interaction between predator–prey functional traits and tree seedling dynamics on either side of a major ecological filter.