Mitochondrial DNA evidence supports northeast Indian origin of the aboriginal Andamanese in the Late Paleolithic

In view of the geographically closest location to Andaman archipelago,Myanmar was suggested to be the origin place of aboriginal Andamanese.However,for lacking any genetic information from this region,which has prevented to resolve the dispute on whether the aboriginal Andamanese were originated from mainland India or Myanmar.To solve this question and better understand the origin of the aboriginal Andamanese,we screened for haplogroups M31(from which Andaman-specific lineage M31a1 branched off)and M32 among 846mitochondrial DNAs(mtDNAs)sampled across Myanmar.As a result,two Myanmar individuals belonging to haplogroup M31 were identified,and completely sequencing the entire mtDNA genomes of both samples testified that the two M31 individuals observed in Myanmar were probably attributed to the recent gene flow from northeast India populations.Since no root lineages of haplogroup M31 or M32 were observed in Myanmar,it is unlikely that Myanmar may serve as the source place of the aboriginal Andamanese.To get further insight into the origin of this unique population,the detailed phylogenetic and phylogeographic analyses were performed by including additional 7 new entire mtDNA genomes and 113 M31 mtDNAs pinpointed from South Asian populations,and the results suggested that Andaman-specific M31a1 could in fact trace its origin to northeast India.Time estimation results further indicated that the Andaman archipelago was likely settled by modern humans from northeast India via the land-bridge which connected the Andaman archipelago and Myanmar around the Last Glacial Maximum(LGM),a scenario in well agreement with the evidence from linguistic and palaeoclimate studies.     

Autophagy Protects Monocytes from Wolbachia Heat Shock Protein 60–Induced Apoptosis and Senescence

Monocyte dysfunction by filarial antigens has been a major mechanism underlying immune evasion following hyporesponsiveness during patent lymphatic filariasis. Recent studies have initiated a paradigm shift to comprehend the immunological interactions of Wolbachia and its antigens in inflammation, apoptosis, lymphocyte anergy, etc. Here we showed that recombinant Wolbachia heat shock protein 60 (rWmhsp60) interacts with TLR-4 and induces apoptosis in monocytes of endemic normal but not in chronic patients. Higher levels of reactive oxygen species (ROS) induced after TLR-4 stimulation resulted in loss of mitochondrial membrane potential and caspase cascade activation, which are the plausible reason for apoptosis. Furthermore, release in ROS owing to TLR-4 signaling resulted in the activation of NF-κB p65 nuclear translocation which leads to inflammation and apoptosis via TNF receptor pathway following the increase in IL-6 and TNF-α level. Here for the first time, we report that in addition to apoptosis, rWmhsp60 antigen in filarial pathogenesis also induces molecular senescence in monocytes. Targeting TLR-4, therefore, presents a promising candidate for treating rWmhsp60-induced apoptosis and senescence. Strikingly, induction of autophagy by rapamycin detains TLR-4 in late endosomes and subverts TLR-4-rWmhsp60 interaction, thus protecting TLR-4–mediated apoptosis and senescence. Furthermore, rapamycin-induced monocytes were unresponsive to rWmhsp60, and activated lymphocytes following PHA stimulation. This study demonstrates that autophagy mediates the degradation of TLR-4 signaling and protects monocytes from rWmhsp60 induced apoptosis and senescence.     

Toxicity of Acalypha indica (Euphorbiaceae) and Achyranthes aspera (Amaranthaceae) leaf extracts to Aedes aegypti (Diptera: Culicidae)

Alternative control strategies for the dengue vector Aedes aegypti L. (Diptera: Culicidae) include botanical insecticides. They are believed to pose little threat to the environment or to human health and may provide practical substitutes for synthetic insecticides. In this study, we determined the biological activities of methanol extracts of Acalypha indica L. (Euphorbiaceae) and Achyranthes aspera L (Amaranthaceae) leaves individually and in combination as botanical insecticides against Ae. aegypti. Based on LC₅₀ values for 4th instar Ae. aegypti, the combined extracts showed the strongest larvicidal activity (277 ppm). A. aspera and A. indica extracts individually gave similar results (409 and 420 ppm, respectively). Respective LC₅₀ values for pupae were 326 ppm, 456 ppm, and 467 ppm. In studies of smoke toxicity, 64% of females exposed to negative control smoke (no extract) blood fed on chicken, whereas 17% blood fed when exposed to smoke containing A. aspera extract and to positive control smoke (0.2% d-allethrin). In the field, treatment of water storage tanks (≈ 0.5 m³) with combined plant extract reduced larval and pupal populations by 97% and 81%, respectively, after 5 days. Given the results of this study, further evaluation of the combined (A. indica + A. aspera) extract as a mosquito larvicide is warranted. Mosquito coils with A. aspera extract also show promise as a practical and potentially economical means for mitigating mosquito blood feeding.     

Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells

The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis.     

Functional Dichotomy between NKG2D and CD28-Mediated Co-Stimulation in Human CD8+ T Cells

Both CD28 and NKG2D can function as co-stimulatory receptors in human CD8⁺ T cells. However, their independent functional contributions in distinct CD8⁺ T cell subsets are not well understood. In this study, CD8⁺ T cells in human peripheral blood- and lung-derived lymphocytes were analyzed for CD28 and NKG2D expression and function. We found a higher level of CD28 expression in PBMC-derived naïve (CD45RA⁺CD27⁺) and memory (CD45RA⁻CD27⁺) CD8⁺ T cells (CD28^Hi), while its expression was significantly lower in effector (CD45RA⁺CD27⁻) CD8⁺ T cells (CD28^Lo). Irrespective of the differences in the CD28 levels, NKG2D expression was comparable in all three CD8⁺ T cell subsets. CD28 and NKG2D expressions followed similar patterns in human lung-resident GILGFVFTL/HLA-A2-pentamer positive CD8⁺ T cells. Co-stimulation of CD28^Lo effector T cells via NKG2D significantly increased IFN-γ and TNF-α levels. On the contrary, irrespective of its comparable levels, NKG2D-mediated co-stimulation failed to augment IFN-γ and TNF-α production in CD28^Hi naïve/memory T cells. Additionally, CD28-mediated co-stimulation was obligatory for IL-2 generation and thereby its production was limited only to the CD28^Hi naïve/memory subsets. MICA, a ligand for NKG2D was abundantly expressed in the tracheal epithelial cells, validating the use of NKG2D as the major co-stimulatory receptor by tissue-resident CD8⁺ effector T cells. Based on these findings, we conclude that NKG2D may provide an expanded level of co-stimulation to tissue-residing effector CD8⁺ T cells. Thus, incorporation of co-stimulation via NKG2D in addition to CD28 is essential to activate tumor or tissue-infiltrating effector CD8⁺ T cells. However, boosting a recall immune response via memory CD8⁺ T cells or vaccination to stimulate naïve CD8⁺ T cells would require CD28-mediated co-stimulation.     

Identification of functional cAMP-dependent protein kinase in a 'neurite minus' mouse neuroblastoma cell line

We have characterized and quantitated the level of cAMP-dependent protein kinase in the NS-20, N1E-115, N-18 and N1A-103 mouse neuroblastoma clonal cell lines, and we have correlated the occurrence of functional cAMP-dependent protein kinase with the dibutyryl cAMP-induced differentiated functions in these cells. Our results demonstrate the presence of functional cAMP-dependent protein kinase in extracts of all four cell lines examined, including the 'neurite minus' N1A-103 cell line. Dibutyryl cAMP induced neurite outgrowth and acetylcholinesterase activity in the NS-20, N1E-115 and N-18 neuroblastoma cell lines, but not in the N1A-103 cell line. However, dibutyryl cAMP caused a 2-3-fold increase in the R1 regulatory subunit protein and cAMP-phosphodiesterase activity in the 'neurite minus' N1A-103 cells in a manner similar to that of the other three 'neurite positive' cell lines. These results suggest that the biochemical lesion(s) subserving the neurite-minus phenotype of the N1A-103 cells may be distal to the activation of cAMP-dependent protein kinase and is in a biochemical pathway distinct from the induction of R1 regulatory subunit protein and cAMP-phosphodiesterase activity.     

Multiple maternal origins of chickens: out of the Asian jungles

Domestic chickens have long been important to human societies for food, religion, entertainment, and decorative uses, yet the origins and phylogeography of chickens through Eurasia remain uncertain. Here, we assessed their origins and phylogeographic history by analyzing the mitochondrial DNA hypervariable segment I (HVS-I) for 834 domestic chickens (Gallus gallus domesticus) across Eurasia as well as 66 wild red jungle fowls (Gallus gallus) from Southeast Asia and China. Phylogenetic analyses revealed nine highly divergent mtDNA clades (A-I) in which seven clades contained both the red jungle fowls and domestic chickens. There was no breed-specific clade in the chickens. The clades A, B, and E are distributed ubiquitously in Eurasia, while the other clades were restricted to South and Southeast Asia. Clade C was mainly distributed in Japan and Southeast China, while clades F and G were exclusive to Yunnan, China. The geographic distribution of clade D was closely related to the distribution of the pastime of cock fighting. Statistical tests detect population expansion within each subclade. These distinct distribution patterns and expansion signatures suggest that different clades may originate from different regions, such as Yunnan, South and Southwest China and/or surrounding areas (i.e., Vietnam, Burma, and Thailand), and the Indian subcontinent, respectively, which support the theory of multiple origins in South and Southeast Asia.     

The influence of lipoic acid on adriamycin-induced hyperlipidemic nephrotoxicity in rats

Glutamate, a major excitatory amino acid neurotransmitter is also an endogenous excitotoxin. The present study examined the prolonged and delayed effects of glutamate excitotoxicity on mitochondrial lipid peroxidation and antioxidant parameters in different brain regions, namely, cerebral hemisphere, cerebellum, brain stem and diencephalon. Wistar rats (male) were exposed to monosodium glutamate (MSG) (4 mg × g body wt^–1, i.p.) for 6 consecutive days and sacrificed on 30th and 45th day after last MSG dose. MSG treatment markedly decreased the mitochondrial manganese superoxide-dismutase (Mn-SOD), catalase and reduced glutathione (GSH) content, and increased the lipid peroxidation (LPx), uric acid and glutathione peroxidase (GPx) activity. These results indicate that oxidative stress produced by glutamate in vulnerable brain regions may persist for longer periods and mitochondrial function impairment is an important mechanism of excitatory amino acid mediated neurotoxicity in chronic neurodegeneration.