Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion

Roberts syndrome is an autosomal recessive disorder characterized by craniofacial anomalies, tetraphocomelia and loss of cohesion at heterochromatic regions of centromeres and the Y chromosome. We identified mutations in a new human gene, ESCO2, associated with Roberts syndrome in 15 kindreds. The ESCO2 protein product is a member of a conserved protein family that is required for the establishment of sister chromatid cohesion during S phase and has putative acetyltransferase activity.     

Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity

Multiple organs cooperate to regulate appetite, metabolism, and glucose and fatty acid homeostasis. Here, we identified and characterized lymphatic vasculature dysfunction as a cause of adult-onset obesity. We found that functional inactivation of a single allele of the homeobox gene Prox1 led to adult-onset obesity due to abnormal lymph leakage from mispatterned and ruptured lymphatic vessels. Prox1 heterozygous mice are a new model for adult-onset obesity and lymphatic vascular disease.     

Insect antifeedant properties of withanolides and related steroids from Solanaceae

Summary Physalis peruviana shrubs were not attacked by larvae ofSpodoptera littoralis. It was demonstrated that withanolide E, a steroid isolated fromP. peruviana, as well as several related steroids, have insect antifeedant properties.     

Femtosecond X-ray protein nanocrystallography

X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (～200?nm to 2?μm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.     

Ocean-like water in the Jupiter-family comet 103P/Hartley 2

For decades, the source of Earth's volatiles, especially water with a deuterium-to-hydrogen ratio (D/H) of (1.558?±?0.001)?×?10(-4), has been a subject of debate. The similarity of Earth's bulk composition to that of meteorites known as enstatite chondrites suggests a dry proto-Earth with subsequent delivery of volatiles by local accretion or impacts of asteroids or comets. Previous measurements in six comets from the Oort cloud yielded a mean D/H ratio of (2.96?±?0.25)?×?10(-4). The D/H value in carbonaceous chondrites, (1.4?±?0.1)?×?10(-4), together with dynamical simulations, led to models in which asteroids were the main source of Earth's water, with ≤10 per cent being delivered by comets. Here we report that the D/H ratio in the Jupiter-family comet 103P/Hartley 2, which originated in the Kuiper belt, is (1.61?±?0.24)?×?10(-4). This result substantially expands the reservoir of Earth ocean-like water to include some comets, and is consistent with the emerging picture of a complex dynamical evolution of the early Solar System.     

A phosphatase cascade by which rewarding stimuli control nucleosomal response

Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.     

Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia

Primary ciliary dyskinesia most often arises from loss of the dynein motors that power ciliary beating. Here we show that DNAAF3 (also known as PF22), a previously uncharacterized protein, is essential for the preassembly of dyneins into complexes before their transport into cilia. We identified loss-of-function mutations in the human DNAAF3 gene in individuals from families with situs inversus and defects in the assembly of inner and outer dynein arms. Knockdown of dnaaf3 in zebrafish likewise disrupts dynein arm assembly and ciliary motility, causing primary ciliary dyskinesia phenotypes that include hydrocephalus and laterality malformations. Chlamydomonas reinhardtii PF22 is exclusively cytoplasmic, and a PF22-null mutant cannot assemble any outer and some inner dynein arms. Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway. These results support the existence of a conserved, multistep pathway for the cytoplasmic formation of assembly competent ciliary dynein complexes.     

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.     

T helper 17 cells: discovery, function, and physiological trigger

In the few years since their discovery, T helper 17 cells (T_H17) have been shown to play an important role in host defense against infections, and in tissue inflammation during autoimmunity. T_H17 cells produce IL-17, IL-21, IL-10, and IL-22 cytokines, and thus have broad effects on a variety of tissues. Notably, the requirement for the immunosuppressive cytokine TGF-β along with the pro-inflammatory cytokine IL-6 for T_H17 differentiation supports the intimate relationship between the T_H17 subset and FOXP3⁺ regulatory T cells. Here, we discuss current knowledge on effector functions and differentiation of the T_H17 lineage. Furthermore, we now know of a physiological stimulus for T_H17 differentiation: innate immune recognition of cells undergoing apoptosis as a direct result of infection induces unique development of this subset. As our knowledge of T_H17 and T regulatory cells grows, we are building on a new framework for the understanding of effector T cell differentiation and the biology of CD4⁺ T cell adaptive immune responses.     

‘Tetrazolium oxidase’ identified with the heme-oxidases of human tissues

Résumé Des bandes blanches jusqu'ici mystérieuse, apparaissent quand on teint des traces électrophorétiques avec des réactions de tétrazolium pour faire apparaÎtre diverses enzymes. Ces bandes se révèlent comme étant de l'hémoglobine et d'autres hémo-protéines se trouvant dans le sérum et dans des parties du tissue qui arrÊtent la réduction du tétrazolium. Ces bandes peuvent donc troubler le dessin électrophorétique.