The Himalayas: Barrier and conduit for gene flow

The Himalayan mountain range is strategically located at the crossroads of the major cultural centers in Asia, the Middle East and Europe. Although previous Y‐chromosome studies indicate that the Himalayas served as a natural barrier for gene flow from the south to the Tibetan plateau, this region is believed to have played an important role as a corridor for human migrations between East and West Eurasia along the ancient Silk Road. To evaluate the effects of the Himalayan mountain range in shaping the maternal lineages of populations residing on either side of the cordillera, we analyzed mitochondrial DNA variation in 344 samples from three Nepalese collections (Newar, Kathmandu and Tamang) and a general population of Tibet. Our results revealed a predominantly East Asian‐specific component in Tibet and Tamang, whereas Newar and Kathmandu are both characterized by a combination of East and South Central Asian lineages. Interestingly, Newar and Kathmandu harbor several deep‐rooted Indian lineages, including M2, R5, and U2, whose coalescent times from this study (U2, >40 kya) and previous reports (M2 and R5, >50 kya) suggest that Nepal was inhabited during the initial peopling of South Central Asia. Comparisons with our previous Y‐chromosome data indicate sex‐biased migrations in Tamang and a founder effect and/or genetic drift in Tamang and Newar. Altogether, our results confirm that while the Himalayas acted as a geographic barrier for human movement from the Indian subcontinent to the Tibetan highland, it also served as a conduit for gene flow between Central and East Asia. Am J Phys Anthropol 151:169–182, 2013. © 2013 Wiley Periodicals, Inc.     

Mitochondrial Dysfunction—A Pharmacological Target in Alzheimer's Disease

Increasing evidences suggest that mitochondrial dysfunction plays an important role in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). Alterations of mitochondrial efficiency and function are mainly related to alterations in mitochondrial content, amount of respiratory enzymes, or changes in enzyme activities leading to oxidative stress, mitochondrial permeability transition pore opening, and enhanced apoptosis. More recently, structural changes of the network are related to bioenergetic function, and its consequences are a matter of intensive research. Several mitochondria-targeting compounds with potential efficacy in AD including dimebon, methylene blue, piracetam, simvastatin, Ginkgo biloba, curcumin, and omega-3 polyunsaturated fatty acids have been identified. The majority of preclinical data indicate beneficial effects, whereas most controlled clinical trials did not meet the expectations. Since mitochondrial dysfunction represents an early event in disease progression, one reason for the disappointing clinical results could be that pharmacological interventions might came too late. Thus, more studies are needed that focus on therapeutic strategies starting before severe disease progress.     

Construction of a Gammaretrovirus with a Novel Tropism and Wild-Type Replication Kinetics Capable of Using Human APJ as Entry Receptor

We have constructed a replication-competent gammaretrovirus (SL3-AP) capable of using the human G-protein-coupled receptor hAPJ as its entry receptor. The envelope protein of the virus was made by insertion of the 13-amino-acid peptide ligand for hAPJ, flanked by linker sequences, into one of the variable loops of the receptor binding domain of SL3-2, a murine leukemia virus (MLV) that uses the xenotropic-polytropic virus receptor Xpr1 and which has a host range limited to murine cells. This envelope protein can utilize hAPJ as well as murine Xpr1 for entry into host cells with equal efficiencies. In addition, the SL3-AP virus replicates in cells expressing either of its receptors, hAPJ and murine Xpr1, and causes resistance to superinfection and downregulation of hAPJ in infected cells. Thus, SL3-AP is the first example of a retargeted replication-competent retrovirus, with replication characteristics and receptor interference properties similar to those of natural isolates.     

Interferon-γ receptors are expressed at synapses in the rat superficial dorsal horn and lateral spinal nucleus

Summary Interferon-γ can facilitate the spinal nociceptive flexor reflex and elicit neuropathic pain-related behavior in rats and mice. Immunoreactivity for the interferon-γ receptor (IFN-γR) occurs in the superficial layers of the dorsal horn and the lateral spinal nucleus in the rat and mouse spinal cord, as well as in subsets of neurons in the dorsal root ganglia. The aim of the present study was to examine the cellular localization and origin of the IFN-γR in the spinal cord. As viewed by confocal microscopy, the immunopositivity for the IFN-γR was co-localized with that of the presynaptic marker synaptophysin and with neuronal nitric oxide synthase in the lateral spinal nucleus, whereas only a minor overlap with these molecules was observed in laminae I and II of the dorsal horn. There was no co-localization of the IFN-γR with markers for astrocytes and microglial cells. Ultrastructurally, the IFN-γR was found predominantly in axon terminals in the lateral spinal nucleus but also at postsynaptic sites in dendrites in laminae I and II. The IFN-γR expressed in neurons in dorsal root ganglia was transported in axons both centrally and peripherally. Hemisection of the spinal cord caused no reduction in immunolabelling of the IFN-γR in the dorsal horn or the lateral spinal nucleus. Since rhizotomy does not effect the immunolabelling in the lateral spinal nucleus, our observation indicates that the presynaptic receptors in this nucleus are derived from intrinsic neurons. The localization of the IFN-γR in the spinal cord differed from that of the AMPA glutamate receptor subunits 2 and 3 and the substance P receptor (NK1). Our results, showing localization of IFN-γR to pre- and postsynaptic sites in the dorsal horn and lateral spinal nucleus indicate that IFN-γ can modulate nociception at the spinal cord level.     

Orphan selenoproteins

Selenoproteins contain selenium in stoichiometric amounts. Most are synthesized by a process that decodes UGA codons as selenocysteine. Twelve animal selenoproteins have been characterized, and biochemical functions have been described for all but three. Two of these “orphan” selenoproteins are discussed in this paper. Selenoprotein P is an extracellular glycoprotein that contains multiple selenocysteines. It binds heparin and associates with endothelial cells. Two isoforms have been identified. Plasma concentration of selenoprotein P correlates with protection against diquat liver injury, suggesting that the protein protects against oxidant injury. Selenoprotein W is a small intracellular protein that contains one selenocysteine. It binds glutathione and has been suggested to function in oxidant defense. The postulated oxidant defense properties of these selenoproteins are consistent with the facile thiol-redox properties of selenocysteine. It can be predicted that more proteins will be discovered that take advantage of the chemical properties of selenium. BioEssays 21:231–237, 1999. © 1999 John Wiley & Sons, Inc.     

Apneic effects of cholecystokinin in unanaesthetized fetal sheep

The effects on breathing movements and sleep state of cholecystokinin octapeptide (CCK-8) and its antagonist, proglumide, have been studied in unanaesthetised fetal lambs of 124-142 days gestation. CCK-8 when given into a lateral cerebral ventricle as bolus injections of 10-500 ng caused dose-related periods of apnea ranging from 63-214 min. When given as a 100 ng bolus followed by a 50 ng/h infusion for 2 h there was a prolonged period of apnea lasting 331 +/- 56 min. There was no effect of CCK-8 when given in higher doses (1-50 micrograms). The antagonist proglumide reversed the apnea induced by CCK-8 infusion, but had no effect when given alone, nor did it affect the normal fetal depressive response to hypoxia. Neither CCK-8 nor proglumide had any effect on electrocortical activity. We conclude that CCK has no role in the inhibitory mechanisms causing the apnea associated with high voltage electrocortical activity or hypoxia in the fetus. Furthermore CCK does not appear to be involved in the regulation of sleep state in the fetal lamb.     

Hereditary minisatellite mutations among the offspring of Estonian Chernobyl cleanup workers

A single accidental event such as the fallout released from the Chernobyl reactor in 1986 can expose millions of people to non-natural environmental radiation. Ionizing radiation increases the frequency of germline mutations in experimental studies, but the genetic effects of radiation in humans remain largely undefined. To evaluate the hereditary effects of low radiation doses, we compared the minisatellite mutation rates of 155 children born to Estonian Chernobyl cleanup workers after the accident with those of their siblings born prior to it. All together, 94 de novo paternal minisatellite mutations were found at eight tested loci (52 and 42 mutants among children born after and before the accident, respectively). The minisatellite mutation rate was nonsignificantly increased among children born after the accident (0.042 compared to 0.036, OR 1.33, 95% CI 0.80-2.20). Furthermore, there was some indication of an increased mutation rate among offspring born after the accident to workers who had received doses of 20 cSv or above compared with their siblings born before the accident (OR 3.0, 95% CI 0.97-9.30). The mutation rate was not associated with the father's age (OR 1.04, 95% CI 0.94-1.15) or the sex of the child (OR 0.95, 95% CI 0.50-1.79). Our results are consistent with both no effect of radiation on minisatellite mutations and a slight increase at dose levels exceeding 20 cSv.     

Land-use history of the Axlarp area in the Småland uplands,southern Sweden: palaeoecological and archaeological investigations

The results of pollen analysis, magnetic measurements (SIRM), and archaeological and historical investigations, in the Axlarp area are presented. With respect to natural conditions and the distribution of prehistoric features, this area is typical of the higher parts of the Småland uplands, which, agriculturally, is a marginal region of southern Sweden. The study shows that farming in the Axlarp area began at ca. 700 B.C. (dates in calibrated/calendar years). The period 700 B.C.-A.D. 500 was characterized by shifting cultivation of Hordeum and Triticum and much pasture. Between A.D. 500 and A.D. 1200 farming declined but some pasturage was still practised, possibly on a seasonal basis. Two farms were established in the Middle Ages, probably between A.D. 1200–1300. Cereals were sown in stone-cleared fields and pastoral farming and hay making was carried out. One farm was deserted during the 15th or early 16th century and the other developed into the hamlet Axlarp whose farmers practised a three-course cropping system. Land-use history as recorded in the pollen diagram can be related to activities associated with these farms. Cereals grown after A.D. 1200 included Hordeum and Avena, and possibly Triticum and Secale. There are no indications of slash-and-burn cultivation in the area.     

VIP (Vasoactive Intestinal Polypeptide)-immunoreactive neurons in the retina of the rat

Summary Immunoreactive vasoactive intestinal polypeptide (VIP) was detected in a population of amacrine cells in the retina of the rat. Processes of these cells reach both the inner and outer half of the inner plexiform layer where they form sublayers. The VIP neurons are different from previously known amacrine cell types.     

High-resolution crossover maps for each bivalent of Zea mays using recombination nodules

Recombination nodules (RNs) are closely correlated with crossing over, and, because they are observed by electron microscopy of synaptonemal complexes (SCs) in extended pachytene chromosomes, RNs provide the highest-resolution cytological marker currently available for defining the frequency and distribution of crossovers along the length of chromosomes. Using the maize inbred line KYS, we prepared an SC karyotype in which each SC was identified by relative length and arm ratio and related to the proper linkage group using inversion heterozygotes. We mapped 4267 RNs on 2080 identified SCs to produce high-resolution maps of RN frequency and distribution on each bivalent. RN frequencies are closely correlated with both chiasma frequencies and SC length. The total length of the RN recombination map is about twofold shorter than that of most maize linkage maps, but there is good correspondence between the relative lengths of the different maps when individual bivalents are considered. Each bivalent has a unique distribution of crossing over, but all bivalents share a high frequency of distal RNs and a severe reduction of RNs at and near kinetochores. The frequency of RNs at knobs is either similar to or higher than the average frequency of RNs along the SCs. These RN maps represent an independent measure of crossing over along maize bivalents.