Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity

Agenesis of the corpus callosum (AgCC), a failure to develop the large bundle of fibres that connect the cerebral hemispheres, occurs in 1:4000 individuals. Genetics, animal models and detailed structural neuroimaging are now providing insights into the developmental and molecular bases of AgCC. Studies using neuropsychological, electroencephalogram and functional MRI approaches are examining the resulting impairments in emotional and social functioning, and have begun to explore the functional neuroanatomy underlying impaired higher-order cognition. The study of AgCC could provide insight into the integrated cerebral functioning of healthy brains, and may offer a model for understanding certain psychiatric illnesses, such as schizophrenia and autism.     

Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study

BackgroundObservational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.ConclusionsA genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.     

Trichuris vulpis (Froelich, 1789) infection in a child: a case report

We present a human infection with the canine whipworm, Trichuris vulpis, in a child suffering from rhinitis with a diagnosis of rhinitis. T. vulpis eggs resemble those of T. trichiura but they can be differentiated based on their morphological features and egg size, using micrometry with an ocular micrometer. T. vulpis eggs measured an average of 90 μm by 44 μm (range 86-99 μm by 38-47 μm). Prevalence of hookworms (28.1%), Toxocara canis (11.8%), and Trichuris vulpis (3.5%) was found in 292 fecal samples of dogs collected at the peri-domicile, which showed that the risk of infection was not only fortuitous. The treatment of canine whipworm infections is similar to that of T. trichiura infection. We recommend differentiation of the 2 species for their epidemiological and prevention implications.     

Survival and population persistence in the critically endangered Tuamotu kingfisher

A wide range of threats affect populations of Pacific island birds and conservationists have been challenged to identify factors upon which to focus management. The Tuamotu kingfisher (Todiramphus gambieri) is one of the most endangered vertebrate species in the world, yet little has been published about basic biology or causes of the population decline. We used 4 years of mark-resight and territory resource information to model survival in juvenile and adult Tuamotu kingfishers. Annual survival of adult males (ϕ = 0.77) was similar to congeneric species, whereas survival of adult females (ϕ = 0.40) and juveniles (ϕ = 0.12) was much lower. The best-supported survival model indicated adult female survival was positively related to territory size, whereas adult male survival was negatively related to atoll forest within territories. We used parameter estimates from survival models in a life-stage simulation analysis to evaluate the relative influence of vital rates and territory habitats on population processes. Results indicated that adult female and juvenile survival had the greatest impact on Tuamotu kingfisher populations, accounting for 58% and 32% of variation in the finite rate of population increase, respectively. Nocturnal predation by rats (Rattus spp.) on incubating kingfishers may explain the lower survival of females than males, whereas juvenile birds may be especially vulnerable to predation by cats (Felis catus). Thus, conservation management for Tuamotu kingfishers should include use of metal guards on cavity trees to protect nests and incubating females, and control predator access during fledging periods. © 2012 The Wildlife Society.     

Tetrameric Structure of the GlfT2 Galactofuranosyltransferase Reveals a Scaffold for the Assembly of Mycobacterial Arabinogalactan

Biosynthesis of the mycobacterial cell wall relies on the activities of many enzymes, including several glycosyltransferases (GTs). The polymerizing galactofuranosyltransferase GlfT2 (Rv3808c) synthesizes the bulk of the galactan portion of the mycolyl-arabinogalactan complex, which is the largest component of the mycobacterial cell wall. We used x-ray crystallography to determine the 2.45-Å resolution crystal structure of GlfT2, revealing an unprecedented multidomain structure in which an N-terminal β-barrel domain and two primarily α-helical C-terminal domains flank a central GT-A domain. The kidney-shaped protomers assemble into a C₄-symmetric homotetramer with an open central core and a surface containing exposed hydrophobic and positively charged residues likely involved with membrane binding. The structure of a 3.1-Å resolution complex of GlfT2 with UDP reveals a distinctive mode of nucleotide recognition. In addition, models for the binding of UDP-galactofuranose and acceptor substrates in combination with site-directed mutagenesis and kinetic studies suggest a mechanism that explains the unique ability of GlfT2 to generate alternating β-(1→5) and β-(1→6) glycosidic linkages using a single active site. The topology imposed by docking a tetrameric assembly onto a membrane bilayer also provides novel insights into aspects of processivity and chain length regulation in this and possibly other polymerizing GTs.     

A sulfoximine-based inhibitor of human asparagine synthetase kills l-asparaginase-resistant leukemia cells

An adenylated sulfoximine transition-state analogue 1, which inhibits human asparagine synthetase (hASNS) with nanomolar potency, has been reported to suppress the proliferation of an l-asparagine amidohydrolase (ASNase)-resistant MOLT-4 leukemia cell line (MOLT-4R) when l-asparagine is depleted in the medium. We now report the synthesis and biological activity of two new sulfoximine analogues of 1 that have been studied as part of systematic efforts to identify compounds with improved cell permeability and/or metabolic stability. One of these new analogues, an amino sulfoximine 5 having no net charge at cellular pH, is a better hASNS inhibitor (K_I¹ = 8 nM) than 1 and suppresses proliferation of MOLT-4R cells at 10-fold lower concentration (IC₅₀ = 0.1 mM). More importantly, and in contrast to the lead compound 1, the presence of sulfoximine 5 at concentrations above 0.25 mM causes the death of MOLT-4R cells even when ASNase is absent in the culture medium. The amino sulfoximine 5 exhibits different dose-response behavior when incubated with an ASNase-sensitive MOLT-4 cell line (MOLT-4S), supporting the hypothesis that sulfoximine 5 exerts its effect by inhibiting hASNS in the cell. Our work provides further evidence for the idea that hASNS represents a chemotherapeutic target for the treatment of leukemia, and perhaps other cancers, including those of the prostate.     

A radical approach to beating hypoxia: depressed free radical release from heart fibres of the hypoxia-tolerant epaulette shark (<Emphasis Type="Italic">Hemiscyllum ocellatum</Emphasis>)

Hypoxia and warm ischemia are primary concerns in ischemic heart disease and transplant and trauma. Hypoxia impacts tissue ATP supply and can induce mitochondrial dysfunction that elevates reactive species release. The epaulette shark, Hemiscyllum ocellatum, is remarkably tolerant of severe hypoxia at temperatures up to 34°C, and therefore provides a valuable model to study warm hypoxia tolerance. Mitochondrial function was tested in saponin permeabilised ventricle fibres using high-resolution respirometry coupled with purpose-built fluorospectrometers. Ventricular mitochondrial function, stability and reactive species production of the epaulette shark was compared with that of the hypoxia-sensitive shovelnose ray, Aptychotrema rostrata. Fibres were prepared from each species acclimated to normoxic water conditions, or following a 2 h, acute hypoxic exposure at levels representing 40% of each species’ critical oxygen tension. Although mitochondrial respiratory fluxes for normoxia-acclimated animals were similar for both species, reactive species production in the epaulette shark was approximately half that of the shovelnose ray under normoxic conditions, even when normalised to tissue oxidative phosphorylation flux. The hypoxia-sensitive shovelnose ray halved oxidative phosphorylation flux and cytochrome c oxidase flux was depressed by 34% following hypoxic stress. In contrast, oxidative phosphorylation flux of the epaulette shark ventricular fibres isolated from acute hypoxia exposed the animals remained similar to those from normoxia-acclimated animals. However, uncoupling of respiration revealed depressed electron transport systems in both species following hypoxia exposure. Overall, the epaulette shark ventricular mitochondria showed greater oxidative phosphorylation stability and lower reactive species outputs with hypoxic exposure, and this may protect cardiac bioenergetic function in hypoxic tropical waters.     

Serotonergic effects on feeding, but not hypothalamus-pituitary-adrenal secretion, are altered in ovine pregnancy

In ovine pregnancy, as in human pregnancy, hypothalamus-pituitary-adrenal activity is chronically increased. These studies were designed to test the hypotheses that expression of serotonergic genes and responsiveness to serotonin are increased in pregnancy. We tested the stimulatory effect of an acute, intracerebroventricular injection of the serotonin reuptake inhibitor fluoxetine on plasma ACTH and cortisol in ewes during late pregnancy or postpartum. We also tested the effect of lower-dose, longer-term stimulation by intracerebroventricular infusion of fluoxetine in pregnant and nonpregnant ewes over 6 days. Overall, we found that the stimulatory effect of fluoxetine on ACTH and cortisol was not significantly different between late-gestation and nonpregnant ewes, although the effect of acute fluoxetine administration was inversely related to plasma progesterone concentrations. Also, there were no differences in hypothalamic expression of the glucocorticoid and mineralocorticoid receptors, corticotropin-releasing hormone, AVP, the serotonin reuptake transporter, or the serotonin [5-hydroxytryptamine (5-HT)] receptors 5-HT(1A) and 5-HT(2A) with pregnancy or fluoxetine treatment. However, chronic fluoxetine infusion reduced food intake in the nonpregnant, but not pregnant, ewes. Expression of proopiomelanocortin mRNA in the hypothalamus was reduced in pregnant compared with nonpregnant ewes. Our results indicate that pregnancy does not increase responsiveness of ACTH and cortisol to serotonergic stimulation but, rather, that progesterone reduces the ACTH response. In addition, we found a reduced ability of serotonin to inhibit feeding in the pregnant ewes, consistent with a reduction in anorexic mechanisms in the pregnant state.     

The Expansion of mtDNA Haplogroup L3 within and out of Africa

Although fossil remains show that anatomically modern humans dispersed out of Africa into the Near East ～100 to 130 ka, genetic evidence from extant populations has suggested that non-Africans descend primarily from a single successful later migration. Within the human mitochondrial DNA (mtDNA) tree, haplogroup L3 encompasses not only many sub-Saharan Africans but also all ancient non-African lineages, and its age therefore provides an upper bound for the dispersal out of Africa. An analysis of 369 complete African L3 sequences places this maximum at ～70 ka, virtually ruling out a successful exit before 74 ka, the date of the Toba volcanic supereruption in Sumatra. The similarity of the age of L3 to its two non-African daughter haplogroups, M and N, suggests that the same process was likely responsible for both the L3 expansion in Eastern Africa and the dispersal of a small group of modern humans out of Africa to settle the rest of the world. The timing of the expansion of L3 suggests a link to improved climatic conditions after ～70 ka in Eastern and Central Africa rather than to symbolically mediated behavior, which evidently arose considerably earlier. The L3 mtDNA pool within Africa suggests a migration from Eastern Africa to Central Africa ～60 to 35 ka and major migrations in the immediate postglacial again linked to climate. The largest population size increase seen in the L3 data is 3-4 ka in Central Africa, corresponding to Bantu expansions, leading diverse L3 lineages to spread into Eastern and Southern Africa in the last 3-2 ka.