The rockefeller university

Mandibular prognathism is a facial skeletal malocclusion. Until now, the genetic mechanism has been unclear. The goal of this study was to identify candidate genes or genomic regions directly associated with mandibular prognathism development, by employing whole genome sequencing. A large Chinese family was recruited, composed of 9 affected and 12 unaffected individuals, and the inheritance pattern of this family tends to be autosomal dominant. A single-nucleotide missense mutation in the ADAMTS1 gene (c. 742I>T) was found to segregate in the family, given that the affected individuals must be heterozygous for the mutation. For mutation validation, we screened this candidate mutation and 15 tag single-nucleotide polymorphisms in the coding sequence of ADAMTS1 among 230 unrelated cases and 196 unrelated controls using Sequenom Massarray and found that 3 in 230 cases carried this mutation and none of the controls did. Final results suggested that 2 single-nucleotide polymorphisms (rs2738, rs229038) of ADAMTS1 were significantly associated with mandibular prognathism.

The trillions of bacteria that make up the human microbiome are believed to encode functions that are important to human health; however, little is known about the specific effectors that commensal bacteria use to interact with the human host. Functional metagenomics provides a systematic means of surveying commensal DNA for genes that encode effector functions. Here, we examine 3,000 Mb of metagenomic DNA cloned from three phenotypically distinct patients for effectors that activate NF-kappa B, a transcription factor known to play a central role in mediating responses to environmental stimuli. This screen led to the identification of 26 unique commensal bacteria effector genes (Cbegs) that are predicted to encode proteins with diverse catabolic, anabolic, and ligand-binding functions and most frequently interact with either glycans or lipids. Detailed analysis of one effector gene family (Cbeg12) recovered from all three patient libraries found that it encodes for the production of N-acyl-3-hydroxypalmitoyl-glycine (commendamide). This metabolite was also found in culture broth from the commensal bacterium Bacteroides vulgatus, which harbors a gene highly similar to Cbeg12. Commendamide resembles long-chain N-acyl-amides that function as mammalian signaling molecules through activation of G-protein-coupled receptors (GPCRs), which led us to the observation that commendamide activates the GPCR G2A/GPR132. G2A has been implicated in disease models of autoimmunity and atherosclerosis. This study shows the utility of functional metagenomics for identifying potential mechanisms used by commensal bacteria for host interactions and outlines a functional metagenomics-based pipeline for the systematic identification of diverse commensal bacteria effectors that impact host cellular functions.

Leptin is a hormone produced by the adipose tissue that acts in the brain, stimulating white fat breakdown. We find that the lipolytic effect of leptin is mediated through the action of sympathetic nerve fibers that innervate the adipose tissue. Using intravital two-photon microscopy, we observe that sympathetic nerve fibers establish neuro-adipose junctions, directly "enveloping'' adipocytes. Local optogenetic stimulation of sympathetic inputs induces a local lipolytic response and depletion of white adipose mass. Conversely, genetic ablation of sympathetic inputs onto fat pads blocks leptin-stimulated phosphorylation of hormone-sensitive lipase and consequent lipolysis, as do knockouts of dopamine beta-hydroxylase, an enzyme required for catecholamine synthesis. Thus, neuro-adipose junctions are necessary and sufficient for the induction of lipolysis in white adipose tissue and are an efferent effector of leptin action. Direct activation of sympathetic inputs to adipose tissues may represent an alternative approach to induce fat loss, circumventing central leptin resistance.

Great advances have been made in signaling information on brain activity in individuals, or passing between an individual and a computer or robot. These include recording of natural activity using implants under the scalp or by external means or the reverse feeding of such data into the brain. In one recent example, noninvasive transcranial magnetic stimulation (TMS) allowed feeding of digitalized information into the central nervous system (CNS). Thus, noninvasive electroencephalography (EEG) recordings of motor signals at the scalp, representing specific motor intention of hand moving in individual humans, were fed as repetitive transcranial magnetic stimulation (rTMS) at a maximum intensity of 2.0T through a circular magnetic coil placed flush on each of the heads of subjects present at a different location. The TMS was said to induce an electric current influencing axons of the motor cortex causing the intended hand movement: the first example of the transfer of motor intention and its expression, between the brains of two remote humans. However, to date the mechanisms involved, not least that relating to the participation of magnetic induction, remain unclear. In general, in animal biology, magnetic fields are usually the poor relation of neuronal current: generally "unseen" and if apparent, disregarded or just given a nod. Niels Bohr searched for a biological parallel to complementary phenomena of physics. Pertinently, the two-brains hypothesis (TBH) proposed recently that advanced animals, especially man, have two brains i.e., the animal CNS evolved as two fundamentally different though interdependent, complementary organs: one electro-ionic (tangible, known and accessible), and the other, electromagnetic (intangible and difficult to access) - a stable, structured and functional 3D compendium of variously induced interacting electro-magnetic (EM) fields. Research on the CNS in health and disease progresses including that on brain-brain, brain-computer and brain-robot engineering. As they grow even closer, these disciplines involve their own unique complexities, including direction by the laws of inductive physics. So the novel TBH hypothesis has wide fundamental implications, including those related to TMS. These require rethinking and renewed research engaging the fully complementary equivalence of mutual magnetic and electric field induction in the CNS and, within this context, a new mathematics of the brain to decipher higher cognitive operations not possible with current brain-brain and brain-machine interfaces. Bohr may now rest.

H1 and ZEUS have published single-differential cross sections for inclusive D*(+/-)-meson production in deep-inelastic ep scattering at HERA from their respective final data sets. These cross sections are combined in the common visible phase-space region of photon virtuality Q(2) > 5 GeV2, electron inelasticity 0.02 < y < 0.7 and the D*(+/-) meson's transverse momentum p(T)(D*) > 1.5 GeV and pseudorapidity vertical bar eta(D*)vertical bar < 1.5. The combination procedure takes into account all correlations, yielding significantly reduced experimental uncertainties. Double-differential cross sections d(2)sigma/dQ(2)dy are combined with earlier D*(+/-) data, extending the kinematic range down to Q(2) > 1.5 GeV2. Perturbative next-to-leading-order QCD predictions are compared to the results.

The proper organization of the microtubule-based mitotic spindle is proposed to depend on nanometer-sized motor proteins generating forces that scale with a micron-sized geometric feature, such as microtubule overlap length. However, it is unclear whether such regulation can be achieved by any mitotic motor protein. Here, we employ an optical-trap- and total internal reflection fluorescence (TIRF)-based assay to show that ensembles of kinesin-5, a conserved mitotic motor protein, can push apart overlapping antiparallel microtubules to generate a force whose magnitude scales with filament overlap length. We also find that kinesin-5 can produce overlap-length-dependent "brake-like'' resistance against relative microtubule sliding in both parallel and antiparallel geometries, an activity that has been suggested by cell biological studies but had not been directly measured. Together, these findings, along with numerical simulations, reveal how a motor protein can function as an analog converter, "reading'' simple geometric and dynamic features in cytoskeletal networks to produce regulated force outputs.

A CD1d-binding glycolipid, a-Galactosylceramide (alpha GalCer), activates invariant NK T cells and acts as an adjuvant. We previously identified a fluorinated phenyl ring-modified aGalCer analog, 7DW8-5, displaying nearly 100-fold stronger CD1d binding affinity. In the current study, 7DW8-5 was found to exert a more potent adjuvant effect than aGalCer for a vaccine based on radiation-attenuated sporozoites of a rodent malaria parasite, Plasmodium yoelii, also referred to as irradiated P. yoelii sporozoites (IrPySpz). 7DW8-5 had a superb adjuvant effect only when the glycolipid and IrPySpz were conjointly administered i.m. Therefore, we evaluated the effect of distinctly different biodistribution patterns of alpha GalCer and 7DW8-5 on their respective adjuvant activities. Although both glycolipids induce a similar cytokine response in sera of mice injected i.v., after i.m. injection, alpha GalCer induces a systemic cytokine response, whereas 7DW8-5 is locally trapped by CD1d expressed by dendritic cells (DCs) in draining lymph nodes (dLNs). Moreover, the i.m. coadministration of 7DW8-5 with IrPySpz results in the recruitment of DCs to dLNs and the activation and maturation of DCs. These events cause the potent adjuvant effect of 7DW8-5, resulting in the enhancement of the CD8(+) T cell response induced by IrPySpz and, ultimately, improved protection against malaria. Our study is the first to show that the colocalization of a CD1d-binding invariant NK T cell-stimulatory glycolipid and a vaccine, like radiation-attenuated sporozoites, in dLN-resident DCs upon i.m. conjoint administration governs the potency of the adjuvant effect of the glycolipid.

Studies of linkage disequilibrium (LD) and its variation in the genome are of central importance for understanding evolutionary history, population structure, and selective sweeps. Extreme forms of the latter may result in runs of homozygosity (ROH). In human gene mapping, long ROHs are the basis for homozygosity mapping (HM) with length measured in terms of Mb (10(6) base pairs physical distance). LD varies greatly over the human genome so that long ROHs tend to occur preferentially in regions of high LD and ROHs of the same length in different regions are not strictly comparable. Thus, in human gene mapping, LD appears as a confounder that needs to be taken into account in the interpretation of ROHs. The effect of varying LD can be mitigated by working on a scale of centimorgans (cM, genetic distance) instead of Mb. We demonstrate this effect for HapMap 3 data on chromosome 19 and show examples with different ROH lengths depending on whether physical or genetic lengths are used. These results suggest that HM should preferably be done on genetic rather than physical distances.

Transposable elements (TEs) and repetitive sequences are ubiquitously present in eukaryotic genomes which are in general epigenetically silenced by DNA methylation and/or histone 3 lysine 9 methylation (H3K9me). RNA-directed DNA methylation (RdDM) is the major pathway that initiates de novo DNA methylation in Arabidopsis and sets up a self-reinforcing silencing loop between DNA methylation and H3K9me. However, a key issue is the requirement of a basal level transcript from the target loci to initiate the RNA-based silencing. How the heterochromatic silenced loci are transcribed remains largely unknown. Here, we show that JMJ24, a JmjC domain-containing protein counteracts H3K9me to promote basal level transcription of endogenous silenced loci in Arabidopsis. JMJ24 functionally resembles the fission yeast JmjC protein Epe1. The transcript promoted by JMJ24 is, at least in part, processed to small RNA to initiate the RdDM. Genome-wide transcriptome profiling indicates that transcript levels of TEs are more likely regulated by JMJ24, compared with protein-coding genes. Our data suggest that JMJ24 plays a conserved role in promoting basal level transcription of endogenous silenced loci to reinforce the silencing. We also provide evidence of a physical association between JMJ24 and RNA-dependent RNA polymerase 2 (RDR2), which represents an evolved property of the RNA silencing pathway.

Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.