Role of Chk1 in the differentiation program of hematopoietic stem cells

Hematopoietic stem cells (HSC) isolated from umbilical cord blood (UCB) were treated with ionizing radiation (IR) and sensitivity and IR induced checkpoints activation were investigated. No difference in the sensitivity and in the activation of DNA damage pathways was observed between CD133+ HSC and cells derived from them after ex vivo expansion. Chk1 protein was very low in freshly isolated CD133+ cells, and undetectable in ex vivo expanded UCB CD133+ cells. Chk1 was expressed only on day 3 of the ex vivo expansion. This pattern of Chk1 expression was corroborated in CD133+ cells isolated from peripheral blood apheresis collected from an healthy donor. Treatment with a specific Chk1 inhibitor resulted in a strong reduction in the percentage of myeloid precursors (CD33+) and an increase in the percentage of lymphoid precursors (CD38+) compared to untreated cells, suggesting a possible role for Chk1 in the differentiation program of UCB CD133+ HSC.     

Transiting extrasolar planetary candidates in the Galactic bulge

More than 200 extrasolar planets have been discovered around relatively nearby stars, primarily through the Doppler line shifts owing to reflex motions of their host stars, and more recently through transits of some planets across the faces of the host stars. The detection of planets with the shortest known periods, 1.2-2.5 days, has mainly resulted from transit surveys which have generally targeted stars more massive than 0.75 M(o), where M(o) is the mass of the Sun. Here we report the results from a planetary transit search performed in a rich stellar field towards the Galactic bulge. We discovered 16 candidates with orbital periods between 0.4 and 4.2 days, five of which orbit stars of masses in the range 0.44-0.75 M(o). In two cases, radial-velocity measurements support the planetary nature of the companions. Five candidates have orbital periods below 1.0 day, constituting a new class of ultra-short-period planets, which occur only around stars of less than 0.88 M(o). This indicates that those orbiting very close to more-luminous stars might be evaporatively destroyed or that jovian planets around stars of lower mass might migrate to smaller radii.     

Kelletinin I and kelletinin A from the marine molluscBuccinulum corneum are inhibitors of eukaryotic DNA polymeraseα

Summary The inhibitory effect of esters of p-hydroxybenzoic acid (kelletinins I and A), extracted from the marine gastropodBuccinulum corneum, have been tested on eukaryotic and prokaryotic enzymes of DNA metabolism such as DNA polymerases and , DNA polymerase I, Exo III, pancreatic DNAse I, micrococcal DNAse andE. coli RNA polymerase. Kelletinin I and kelletinin A inhibit preferentially DNA polymerase. The inhibitory effect of kelletinin I involves the hydroxyl group of p-hydroxybenzoic acid.     

From pluripotency to forebrain patterning: an in vitro journey astride embryonic stem cells

Embryonic stem cells (ESCs) have been used extensively as in vitro models of neural development and disease, with special efforts towards their conversion into forebrain progenitors and neurons. The forebrain is the most complex brain region, giving rise to several fundamental structures, such as the cerebral cortex, the hypothalamus, and the retina. Due to the multiplicity of signaling pathways playing different roles at distinct times of embryonic development, the specification and patterning of forebrain has been difficult to study in vivo. Research performed on ESCs in vitro has provided a large body of evidence to complement work in model organisms, but these studies have often been focused more on cell type production than on cell fate regulation. In this review, we systematically reassess the current literature in the field of forebrain development in mouse and human ESCs with a focus on the molecular mechanisms of early cell fate decisions, taking into consideration the specific culture conditions, exogenous and endogenous molecular cues as described in the original studies. The resulting model of early forebrain induction and patterning provides a useful framework for further studies aimed at reconstructing forebrain development in vitro for basic research or therapy.     

Tumor suppressive pathways in the control of neurogenesis

The generation of specialized neural cells in the developing and postnatal central nervous system is a highly regulated process, whereby neural stem cells divide to generate committed neuronal progenitors, which then withdraw from the cell cycle and start to differentiate. Cell cycle checkpoints play a major role in regulating the balance between neural stem cell expansion and differentiation. Loss of tumor suppressors involved in checkpoint control can lead to dramatic alterations of neurogenesis, thus contributing to neoplastic transformation. Here we summarize and critically discuss the existing literature on the role of tumor suppressive pathways and their regulatory networks in the control of neurogenesis and transformation.     

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.     

Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism

In degenerative disorders of the central nervous system (CNS), transplantation of neural multipotent (stem) precursor cells (NPCs) is aimed at replacing damaged neural cells. Here we show that in CNS inflammation, NPCs are able to promote neuroprotection by maintaining undifferentiated features and exerting unexpected immune-like functions. In a mouse model of chronic CNS inflammation, systemically injected adult syngeneic NPCs use constitutively activated integrins and functional chemokine receptors to selectively enter the inflamed CNS. These undifferentiated cells survive repeated episodes of CNS inflammation by accumulating within perivascular areas where reactive astrocytes, inflamed endothelial cells and encephalitogenic T cells produce neurogenic and gliogenic regulators. In perivascular CNS areas, surviving adult NPCs induce apoptosis of blood-borne CNS-infiltrating encephalitogenic T cells, thus protecting against chronic neural tissue loss as well as disease-related disability. These results indicate that undifferentiated adult NPCs have relevant therapeutic potential in chronic inflammatory CNS disorders because they display immune-like functions that promote long-lasting neuroprotection.     

Simulating micrometre-scale crystal growth from solution

Understanding crystal growth is essential for controlling the crystallization used in industrial separation and purification processes. Because solids interact through their surfaces, crystal shape can influence both chemical and physical properties. The thermodynamic morphology can readily be predicted, but most particle shapes are actually controlled by the kinetics of the atomic growth processes through which assembly occurs. Here we study the urea-solvent interface at the nanometre scale and report kinetic Monte Carlo simulations of the micrometre-scale three-dimensional growth of urea crystals. These simulations accurately reproduce experimentally observed crystal growth. Unlike previous models of crystal growth, no assumption is made that the morphology can be constructed from the results for independently growing surfaces or from an a priori specification of surface defect concentration. This approach offers insights into the role of the solvent, the degree of supersaturation, and the contribution that extended defects (such as screw dislocations) make to crystal growth. It also connects observations made at the nanometre scale, through in situ atomic force microscopy, with those made at the macroscopic level. If extended to include additives, the technique could lead to the computer-aided design of crystals.