A late neolithic expansion of Y chromosomal haplogroup O2a1-M95 from east to west

The origin and dispersal of Y-Chromosomal haplogroup O2a1-M95, distributed across the Austro Asiatic speaking belt of East and South Asia, are yet to be fully understood. Various studies have suggested either an East Indian or Southeast Asian origin of O2a1-M95. We addressed the issue of antiquity and dispersal of O2a1-M95 by sampling 8748 men from India, Laos, and China and compared them to 3307 samples from other intervening regions taken from the literature. Analyses of haplogroup frequency and Y-STR data on a total 2413 O2a1-M95 chromosomes revealed that the Laos samples possessed the highest frequencies of O2a1-M95 (74% with >0.5) and its ancestral haplogroups (O2*-P31, O*-M175) as well as a higher proportion of samples with 14STR-median haplotype (17 samples in 14 populations), deep coalescence time (5.7 ± 0.3 Kya) and consorted O2a1-M95 expansion evidenced from STR evolution. All these suggested Laos to carry a deep antiquity of O2a1-M95 among the study regions. A serial decrease in expansion time from east to west: 5.7 ± 0.3 Kya in Laos, 5.2 ± 0.6 in Northeast India, and 4.3 ± 0.2 in East India, suggested a late Neolithic east to west spread of the lineage O2a1-M95 from Laos

Trans-Blood Brain Barrier Delivery of Dopamine-Loaded Nanoparticles Reverses Functional Deficits in Parkinsonian Rats

Sustained and safe delivery of dopamine across the blood brain barrier (BBB) is a major hurdle for successful therapy in Parkinson’s disease (PD), a neurodegenerative disorder. Therefore, in the present study we designed neurotransmitter dopamine-loaded PLGA nanoparticles (DA NPs) to deliver dopamine to the brain. These nanoparticles slowly and constantly released dopamine, showed reduced clearance of dopamine in plasma, reduced quinone adduct formation, and decreased dopamine autoxidation. DA NPs were internalized in dopaminergic SH-SY5Y cells and dopaminergic neurons in the substantia nigra and striatum, regions affected in PD. Treatment with DA NPs did not cause reduction in cell viability and morphological deterioration in SH-SY5Y, as compared to bulk dopamine-treated cells, which showed reduced viability. Herein, we report that these NPs were able to cross the BBB and capillary endothelium in the striatum and substantia nigra in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Systemic intravenous administration of DA NPs caused significantly increased levels of dopamine and its metabolites and reduced dopamine-D2 receptor supersensitivity in the striatum of parkinsonian rats. Further, DA NPs significantly recovered neurobehavioral abnormalities in 6-OHDA-induced parkinsonian rats. Dopamine delivered through NPs did not cause additional generation of ROS, dopaminergic neuron degeneration, and ultrastructural changes in the striatum and substantia nigra as compared to 6-OHDA-lesioned rats. Interestingly, dopamine delivery through nanoformulation neither caused alterations in the heart rate and blood pressure nor showed any abrupt pathological change in the brain and other peripheral organs. These results suggest that NPs delivered dopamine into the brain, reduced dopamine autoxidation-mediated toxicity, and ultimately reversed neurochemical and neurobehavioral deficits in parkinsonian rats