Mutant glycyl-tRNA synthetase (Gars) ameliorates SOD1G93A motor neuron degeneration phenotype but has little affect on Loa dynein heavy chain mutant mice

Background: In humans, mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system, and clinical phenotypes ranging from Charcot-Marie-Tooth neuropathy to a severe infantile form of spinal muscular atrophy. GARS is ubiquitously expressed and may have functions in addition to its canonical role in protein synthesis through catalyzing the addition of glycine to cognate tRNAs. Methodology/Principal findings: We have recently described a new mouse model with a point mutation in the Gars gene resulting in a cysteine to arginine change at residue 201. Heterozygous Gars^{C201R/+} mice have locomotor and sensory deficits. In an investigation of genetic mutations that lead to death of motor and sensory neurons, we have crossed the Gars^{C201R/+} mice to two other mutants: the TgSOD1^{G93A} model of human amyotrophic lateral sclerosis and the Legs at odd angles mouse (Dync1h1^{Loa}) which has a defect in the heavy chain of the dynein complex. We found the Dync1h1^{Loa/+}; Gars^{C201R/+} double heterozygous mice are more impaired than either parent, and this is may be an additive effect of both mutations. Surprisingly, the Gars^{C201R} mutation significantly delayed disease onset in the SOD1^{G93A}; Gars^{C201R/+} double heterozygous mutant mice and increased lifespan by 29% on the genetic background investigated. Conclusions/Significance: These findings raise intriguing possibilities for the study of pathogenetic mechanisms in all three mouse mutant strains

Resonant Lifetime of Core-Excited Organic Adsorbates from First Principles

We investigate by first-principles simulations the resonant electron-transfer lifetime from the excited state of an organic adsorbate to a semiconductor surface, namely isonicotinic acid on rutile TiO$_2$(110). The molecule-substrate interaction is described using density functional theory, while the effect of a truly semi-infinite substrate is taken into account by Green's function techniques. Excitonic effects due to the presence of core-excited atoms in the molecule are shown to be instrumental to understand the electron-transfer times measured using the so-called core-hole-clock technique. In particular, for the isonicotinic acid on TiO$_2$(110), we find that the charge injection from the LUMO is quenched since this state lies within the substrate band gap. We compute the resonant charge-transfer times from LUMO+1 and LUMO+2, and systematically investigate the dependence of the elastic lifetimes of these states on the alignment among adsorbate and substrate states.Comment: 24 pages, 6 figures, to appear in Journal of Physical Chemistry

Constraints for hypothetical interactions from a recent demonstration of the Casimir force and some possible improvements

The Casimir force is calculated in the configuration of a spherical lens and a disc of finite radius covered by $Cu$ and $Au$ thin layers which was used in a recent experiment. The correction to the Casimir force due to finiteness of the disc radius is shown to be negligible. Also the corrections are discussed due to the finite conductivity, large-scale and short-scale deviations from the perfect shape of the bounding surfaces and the temperature correction. They were found to be essential when confronting the theoretical results with experimental data. Both Yukawa-type and power-law hypothetical forces are computed which may act in the configuration under consideration due to the exchange of light and/or massless elementary particles between the atoms of the lens and the disc. New constraints on the constants of these forces are determined which follow from the fact that they were not observed within the limits of experimental errors. For Yukawa-type forces the new constraints are up to 30 times stronger than the best ones known up today. A possible improvement of experimental parameters is proposed which gives the possibility to strengthen constraints on Yukawa-type interactions up to $10^4$ times and on power-law interactions up to several hundred times.Comment: 15 pages, 3 figures, subm. to Phys. Rev.

Mitochondrial DNA footprints from Western Eurasia in modern Mongolia

Mongolia is located in a strategic position at the eastern edge of the Eurasian Steppe. Nomadic populations moved across this wide area for millennia before developing more sedentary communities, extended empires, and complex trading networks, which connected western Eurasia and eastern Asia until the late Medieval period. We provided a fine-grained portrait of the mitochondrial DNA (mtDNA) variation observed in present-day Mongolians and capable of revealing gene flows and other demographic processes that took place in Inner Asia, as well as in western Eurasia. The analyses of a novel dataset (N = 2,420) of mtDNAs highlighted a clear matrilineal differentiation within the country due to a mixture of haplotypes with eastern Asian (EAs) and western Eurasian (WEu) origins, which were differentially lost and preserved. In a wider genetic context, the prevalent EAs contribution, larger in eastern and central Mongolian regions, revealed continuous connections with neighboring Asian populations until recent times, as attested by the geographically restricted haplotype-sharing likely facilitated by the Genghis Khan’s so-called Pax Mongolica. The genetic history beyond the WEu haplogroups, notably detectable on both sides of Mongolia, was more difficult to explain. For this reason, we moved to the analysis of entire mitogenomes (N = 147). Although it was not completely possible to identify specific lineages that evolved in situ, two major changes in the effective (female) population size were reconstructed. The more recent one, which began during the late Pleistocene glacial period and became steeper in the early Holocene, was probably the outcome of demographic events connected to western Eurasia. The Neolithic growth could be easily explained by the diffusion of dairy pastoralism, as already proposed, while the late glacial increase indicates, for the first time, a genetic connection with western Eurasian refuges, as supported by the unusual high frequency and internal sub-structure in Mongolia of haplogroup H1, a well-known post-glacial marker in Europe. Bronze Age events, without a significant demographic impact, might explain the age of some mtDNA haplogroups. Finally, a diachronic comparison with available ancient mtDNAs made it possible to link six mitochondrial lineages of present-day Mongolians to the timeframe and geographic path of the Silk Route

Mitochondrial genomes from modern and ancient Turano-Mongolian cattle reveal an ancient diversity of taurine maternal lineages in East Asia

Turano-Mongolian cattle are a group of taurine cattle from Northern and Eastern Asia with distinct morphological traits, which are known for their ability to tolerate harsh environments, such as the Asian steppe and the Tibetan plateau. Through the analysis of 170 mitogenomes from ten modern breeds, two sub-lineages within T3 (T3119 and T3055) were identified as specific of Turano-Mongolian cattle. These two T3 sub-lineages, together with the previously identified T4, were also present in six Neolithic samples, dated to ~3900 years BP, which might represent the earliest domestic taurine stocks from Southwest Asia. The rare haplogroup Q, found in three Tibetan cattle, testifies for the legacy of ancient migrations from Southwest Asia and suggests that the isolated Tibetan Plateau preserved unique prehistoric genetic resources. These findings confirm the geographic substructure of Turano-Mongolian cattle breeds, which have been shaped by ancient migrations and geographic barriers

New Population and Phylogenetic Features of the Internal Variation within Mitochondrial DNA Macro-Haplogroup R0

BACKGROUND: R0 embraces the most common mitochondrial DNA (mtDNA) lineage in West Eurasia, namely, haplogroup H (approximately 40%). R0 sub-lineages are badly defined in the control region and therefore, the analysis of diagnostic coding region polymorphisms is needed in order to gain resolution in population and medical studies. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced the first hypervariable segment (HVS-I) of 518 individuals from different North Iberian regions. The mtDNAs belonging to R0 (approximately 57%) were further genotyped for a set of 71 coding region SNPs characterizing major and minor branches of R0. We found that the North Iberian Peninsula shows moderate levels of population stratification; for instance, haplogroup V reaches the highest frequency in Cantabria (north-central Iberia), but lower in Galicia (northwest Iberia) and Catalonia (northeast Iberia). When compared to other European and Middle East populations, haplogroups H1, H3 and H5a show frequency peaks in the Franco-Cantabrian region, declining from West towards the East and South Europe. In addition, we have characterized, by way of complete genome sequencing, a new autochthonous clade of haplogroup H in the Basque country, named H2a5. Its coalescence age, 15.6+/-8 thousand years ago (kya), dates to the period immediately after the Last Glacial Maximum (LGM). CONCLUSIONS/SIGNIFICANCE: In contrast to other H lineages that experienced re-expansion outside the Franco-Cantabrian refuge after the LGM (e.g. H1 and H3), H2a5 most likely remained confined to this area till present days

Assessing temporal and geographic contacts across the Adriatic Sea through the analysis of genome-wide data from Southern Italy

Southern Italy was characterised by a complex prehistory that started with different Palaeolithic cultures, later followed by the Neolithization and the demic dispersal from the Pontic-Caspian Steppe during the Bronze Age. Archaeological and historical evidences point to a link between Southern Italians and the Balkans still present in modern times. To shed light on these dynamics, we analysed around 700 South Mediterranean genomes com-bined with informative ancient DNAs. Our findings revealed high affinities of South-Eastern Italians with modern Eastern Peloponnesians, and a closer affinity of ancient Greek genomes with those from specific regions of South Italy than modern Greek genomes. The higher similarity could be associated with a Bronze Age component ultimately originating from the Caucasus with high Iranian and Anatolian Neolithic ancestries. Furthermore, extremely differentiated allele frequencies among Northern and Southern Italy revealed putatively adapted SNPs in genes involved in alcohol metabolism, nevi features and immunological traits

Uniparental Genetic Heritage of Belarusians: Encounter of Rare Middle Eastern Matrilineages with a Central European Mitochondrial DNA Pool

Ethnic Belarusians make up more than 80% of the nine and half million people inhabiting the Republic of Belarus. Belarusians together with Ukrainians and Russians represent the East Slavic linguistic group, largest both in numbers and territory, inhabiting East Europe alongside Baltic-, Finno-Permic- and Turkic-speaking people. Till date, only a limited number of low resolution genetic studies have been performed on this population. Therefore, with the phylogeographic analysis of 565 Y-chromosomes and 267 mitochondrial DNAs from six well covered geographic sub-regions of Belarus we strove to complement the existing genetic profile of eastern Europeans. Our results reveal that around 80% of the paternal Belarusian gene pool is composed of R1a, I2a and N1c Y-chromosome haplogroups – a profile which is very similar to the two other eastern European populations – Ukrainians and Russians. The maternal Belarusian gene pool encompasses a full range of West Eurasian haplogroups and agrees well with the genetic structure of central-east European populations. Our data attest that latitudinal gradients characterize the variation of the uniparentally transmitted gene pools of modern Belarusians. In particular, the Y-chromosome reflects movements of people in central-east Europe, starting probably as early as the beginning of the Holocene. Furthermore, the matrilineal legacy of Belarusians retains two rare mitochondrial DNA haplogroups, N1a3 and N3, whose phylogeographies were explored in detail after de novo sequencing of 20 and 13 complete mitogenomes, respectively, from all over Eurasia. Our phylogeographic analyses reveal that two mitochondrial DNA lineages, N3 and N1a3, both of Middle Eastern origin, might mark distinct events of matrilineal gene flow to Europe: during the mid-Holocene period and around the Pleistocene-Holocene transition, respectively

Brane world corrections to Newton's law

We discuss possible variations of the effective gravitational constant with length scale, predicted by most of alternative theories of gravity and unified models of physical interactions. After a brief general exposition, we review in more detail the predicted corrections to Newton's law of gravity in diverse brane world models. We consider various configurations in 5 dimensions (flat, de Sitter and AdS branes in Einstein and Einstein-Gauss-Bonnet theories, with and without induced gravity and possible incomplete graviton localization), 5D multi-brane systems and some models in higher dimensions. A common feature of all models considered is the existence of corrections to Newton's law at small radii comparable with the bulk characteristic length: at such radii, gravity on the brane becomes effectively multidimensional. Many models contain superlight perturbation modes, which modify gravity at large scale and may be important for astrophysics and cosmology.Comment: Brief review, 16 pages, 92 references. Some description and references adde

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought