Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5

Mitogen-activated protein (MAP) kinases are essential regulators in immune responses, and their activities are modulated by kinases and phosphatases. MAP kinase phosphatase (MKP) is a family of dual-specificity phosphatases whose function is evolutionarily conserved. A number of mammalian MKPs have been identified so far, but their specific physiological functions in negative regulation of MAP kinases have not been genetically defined. Here we examine innate and adaptive immune responses in the absence of MKP5. JNK activity was selectively increased in Mkp5 (also known as Dusp10)-deficient mouse cells. Mkp5-deficient cells produced greatly enhanced levels of pro-inflammatory cytokines during innate immune responses and exhibited greater T-cell activation than their wild-type counterparts. However, Mkp5-deficient T cells proliferated poorly upon activation, which resulted in increased resistance to experimental autoimmune encephalomyelitis. By contrast, Mkp5-deficient CD4(+) and CD8(+) effector T cells produced significantly increased levels of cytokines compared with wild-type cells, which led to much more robust and rapidly fatal immune responses to secondary infection with lymphocytic choriomeningitis virus. Therefore, MKP5 has a principal function in both innate and adaptive immune responses, and represents a novel target for therapeutic intervention of immune diseases.     

Melting of iron at the physical conditions of the Earth's core

Seismological data can yield physical properties of the Earth's core, such as its size and seismic anisotropy. A well-constrained iron phase diagram, however, is essential to determine the temperatures at core boundaries and the crystal structure of the solid inner core. To date, the iron phase diagram at high pressure has been investigated experimentally through both laser-heated diamond-anvil cell and shock-compression techniques, as well as through theoretical calculations. Despite these contributions, a consensus on the melt line or the high-pressure, high-temperature phase of iron is lacking. Here we report new and re-analysed sound velocity measurements of shock-compressed iron at Earth-core conditions. We show that melting starts at 225 +/- 3 GPa (5,100 +/- 500 K) and is complete at 260 +/- 3 GPa (6,100 +/- 500 K), both on the Hugoniot curve-the locus of shock-compressed states. This new melting pressure is lower than previously reported, and we find no evidence for a previously reported solid-solid phase transition on the Hugoniot curve near 200 GPa (ref. 16).     

Germline KRAS mutations cause Noonan syndrome

Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage-specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.     

Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in ～50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.     

Cycling or not cycling: cell cycle regulatory molecules and adult neurogenesis

The adult brain most probably reaches its highest degree of plasticity with the lifelong generation and integration of new neurons in the hippocampus and olfactory system. Neural precursor cells (NPCs) residing both in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles continuously generate neurons that populate the dentate gyrus and the olfactory bulb, respectively. The regulation of NPC proliferation in the adult brain has been widely investigated in the past few years. Yet, the intrinsic cell cycle machinery underlying NPC proliferation remains largely unexplored. In this review, we discuss the cell cycle components that are involved in the regulation of NPC proliferation in both neurogenic areas of the adult brain.     

Using human pluripotent stem cells to untangle neurodegenerative disease mechanisms

Human pluripotent stem cells, including embryonic (hES) and induced pluripotent stem cells (hiPS), retain the ability to self-renew indefinitely, while maintaining the capacity to differentiate into all cell types of the nervous system. While human pluripotent cell-based therapies are unlikely to arise soon, these cells can currently be used as an inexhaustible source of committed neurons to perform high-throughput screening and safety testing of new candidate drugs. Here, we describe critically the available methods and molecular factors that are used to direct the differentiation of hES or hiPS into specific neurons. In addition, we discuss how the availability of patient-specific hiPS offers a unique opportunity to model inheritable neurodegenerative diseases and untangle their pathological mechanisms, or to validate drugs that would prevent the onset or the progression of these neurological disorders.     

Earthworms (Annelida: Oligochaeta) from islands of Kien Hai District,Kien Giang Province,Vietnam, with descriptions of two new species and one subspecies

An earthworm inventory was conducted on three islands (Hon Tre, Lai Son and An Son) in the southernmost part of Vietnam. A total of 13 species and subspecies belonging to four genera and two families were collected from 49 sampling sites. The genus Metaphire Sims & Easton, 1972 is dominant with six species and subspecies, Metaphire anomala (Michaelsen, 1907), Metaphire bahli (Gates, 1945), Metaphire houlleti (Perrier, 1872), Metaphire mangophila (Nguyen, 2011), Metaphire kiengiangensis Nguyen & Trinh, 2015, Metaphire peguana laisonensis subsp. nov. Two new species, Polypheretima dorsotheca sp. anov. and Polypheretima insularis sp. nov., and a new subspecies Metaphire peguana laisonensis subsp. nov. are described. Additionally, Amynthas alteradamae (Michaelsen, 1934) and Amynthas tertiadamae (Michaelsen, 1934) are re-described based on fresh material. An identification key to species is also provided.

http://zoobank.org/urn:lsid:zoobank.org:pub:4EA4C2C0-BEC2-45BF-8B72-388302A53F51