Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age.

We have examined the role of somatic mitochondrial DNA (mtDNA) mutations in human ageing by quantitating the accumulation of the common 4977 nucleotide pair (np) deletion (mtDNA4977) in the cortex, putamen and cerebellum. A significant increase in the mtDNA4977 deletion was seen in elderly individuals. In the cortex, the deleted to total mtDNA ratio ranged from 0.00023 to 0.012 in 67-77 year old brains and up to 0.034 in subjects over 80. In the putamen, the deletion level ranged from 0.0016 to 0.010 in 67 to 77 years old up to 0.12 in individuals over the age of 80. The cerebellum remained relatively devoid of mtDNA deletions. Similar changes were observed with a different 7436 np deletion. These changes suggest that somatic mtDNA deletions might contribute to the neurological impairment often associated with ageing.     

Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases

Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.     

神经系统疾病中的兴奋型毒性问题：新的治疗学挑战

该书由意大利学者Carlo Ferrarese和美国学者M．Flint Beal共同主编。两位主编的初衷是基于目前全球对于老年神经退行性疾病治疗现状的尴尬：现行的药物只能缓解症状，而不能针对病因根治。治疗手段的局限是源于我们对这些疾病时神经细胞死亡的原因和机制不很了解。     

Antibiotics from higher plants.Thalictrum rugosum. Thalrugosamine,a newBisbenzylisoquinoline alkaloid active vsMycobacterium smegmatis

Zusammenfassung Charakterisierung und Strukturaufklärung eines neuen Alkaloides, Thalrugosamin ausThalictrum rugosum.

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Acknowledgment. The authors are indebted to the Warren-Teed Division of Rohm and Haas and the NIH (No. AI 09846) for financial support,Rodger White (Warren-Teed) andFrank W. Denison (Abbott Laboratories) for biological data andRueyping Leu for expert technical assistance.     

On the role of the Agulhas system in ocean circulation and climate

The Atlantic Ocean receives warm, saline water from the Indo-Pacific Ocean through Agulhas leakage around the southern tip of Africa. Recent findings suggest that Agulhas leakage is a crucial component of the climate system and that ongoing increases in leakage under anthropogenic warming could strengthen the Atlantic overturning circulation at a time when warming and accelerated meltwater input in the North Atlantic is predicted to weaken it. Yet in comparison with processes in the North Atlantic, the overall Agulhas system is largely overlooked as a potential climate trigger or feedback mechanism. Detailed modelling experiments--backed by palaeoceanographic and sustained modern observations--are required to establish firmly the role of the Agulhas system in a warming climate.     

Neurons with dual axons in the substantia gelatinosa (SG) of the adult cat lumbosacral spinal cord

Summary A small percentage of SG neurons possessing two separate and complete axons were observed in the lumbosacral spinal cord of the adult cat. Since they are found in small numbers and are structurally similar to single axon SG cells, dual axon cells may represent a developmental aberrancy rather than a functionally distinct cell type.This research was supported by U.S.P.H.S. grant No.NS-16642-01.     

Insights into hominid evolution from the gorilla genome sequence

Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution.     

A high-resolution map of human evolutionary constraint using 29 mammals

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ～4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ～60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.     

Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease

Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.     

Solacasine,a new steroidal alkaloid fromSolanum pseudocapsicum possessing antimicrobial activity

Summary Systematic fractionation of alcohol extracts ofSolanum pseudocapsicum. showed that solacasine is the main antibacterial constituent. Based on physiochemical studies, a structure is proposed.The authors are grateful to Dr.R. Foltz, Battelle's Columbus Laboratories, and Mr.E. Fairchild of our laboratories for the mass spectral data, to Mr.Ruey-Ping Leu for the microbiological data, and to the NIH for grant No. AI-09846 in partial support of this work.