References 1. Courchesne E, Yeung-Courchesne R, Press GA, et al. Hypoplasia of cerebellar vermal lobules VI md VII in autism. N Engl J Med 1988;318:1349-1354 2. Mirakanii JW, Courchesne E, Press GA. et al. Keduced cerehellar hemisphere size and its relationship to neural hypoplasia in autism. Arch Neurol 1989;46:689-694 3 . Courchesne E. Neuroanatomic imaging in autism. Pediatrics 1991;87:781-790 4. Courchesne E, Saitoh 0. Yeung-Courchesne R, et al. Abnormality of crrebellar vernii;in lobules V1 and VII in patients with infantile autism: identification of hypoplastic and hyperplasric subgroups with MR imaging. Am J Radio1 1994;162:123-130 5. Ritvo ER, Garber HJ. Cerebellar hypoplasia and autism. N Engl J Med 1988;3 19: 1 152 6. Kleiman MD, Neff S. liosinan NP. The brain in infantile autism: are posterior fotsa structures abnormal? Neurology 1992: 42:753-760 7. Piven J. Nehme E. Simon J, et RI. Magnetic resonance imaging in autism: measurement of the cerebellum. pons, and fourth ventriclr. Biol Psychiatry 1992;31:491-504 8. Schaefer GB. Thompson J N Jr. Bodensteiner JB. et al. Agerelated changes in rhe relative growth of the posterior fossa. J Child

The authors show that genes can be separated into distinct low or high expression abundance groups. Histone marks reveal that this switch-like transition from low to high expression goes hand-in-hand with a change in chromatin status.

No abstract

Several groups have identified mitochondrial complex I deficiency in Parkinson's disease (PD) substantia nigra and in platelets. A search for any mitochondrial DNA (mtDNA) mutation underlying this defect has not yet produced any consistent result. We have made use of a mtDNA-less (p0) cell line to determine if the complex I deficiency follows the genomic transplantation of platelet mtDNA. From a preselected group of PD patients with low platelet complex I activity, 7 patients were used for detailed study. All 7 patients were used for mixed cybrid analysis and demonstrated a selective 25% deficiency of complex I activity. Individual clonal analysis of A549 p0/PD platelet fusion cybrids from 1 of the patients expressed combined complex I and IV deficiencies with 25% and 20% decreased activities in the PD clones, respectively. Histocytochemical, immunocytochemical, and cellular functional imaging studies of these clones showed the cells within the clones were heterogeneous with respect to cytochrome c oxidase (COX) function, COX I content, and mitochondrial respiratory chain activity. These results are in agreement with a previous study and support the proposition that an mtDNA abnormality may underlie the mitochondrial defect in at least a proportion of PD patients. This p0 technology may serve as a means to identify the subgroup of PD patients in whom an mtDNA defect may contribute to development of the disease.

Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.

Mitochondria play a critical role in cellular energy metabolism. The identification of a respiratory chain defect in Parkinson's disease (PD) provides not only a direct link with toxin models of parkinsonism but also insight into the mechanisms involved in etiology and pathogenesis. The presence of the complex I deficiency in PD substantia nigra and platelets suggests the involvement of a systemic cause. Genomic transplantation studies have been undertaken that in volve the transfer to a novel nuclear background of mitochondrial DNA (mtDNA) from PD patients with a complex I defect, followed by both mixed and clonal expansion of the resulting cybrids. The mixed cybrids with the PD mtDNA expressed the complex I defect present in the original PD donor platelets. Clonal expansion of one such mixed cybrid culture produced a spectrum of clones with complex I and complex IV activities, ranging from severe deficiency to normal range, a pattern typical of a heteroplasmic mtDNA mutation. Histochemical, immunohistochemical, and func tional assessments of Δψ ηι all showed a pattern in the PD clones typical of that produced by a mtDNA mutation. Patients with focal dystonia and a platelet complex I defect were used as disease controls for the cybrid studies. The mitochondrial abnormality was eradicated by transfer of dystonia mtDNA to a control nuclear background in both mixed and clonal cybrids, with no evidence of clonal heterogeneity. These results help to validate our findings in the PD patients and suggest that the complex I deficiency in dystonia is not due to an abnormality of mtDNA. We hypothesize that the mtDNA defect alone may be the cause of PD in a proportion of patients and may contribute to pathogenesis in others. Identification of the mtDNA genotype responsible for PD may allow the testing of neuroprotective strategies in appropriate patients. Schapira AHV, Gu M, Taanman J-W, Tabrizi SJ, Seaton T, Cleeter M, Cooper JM. Mitochondria in the etiology and pathogenesis of Parkinson's disease.

No abstract

In inducing photoperiodic conditions, plants produce a signal dubbed “florigen” in leaves. Florigen moves through the phloem to the shoot apical meristem (SAM) where it induces flowering. In Arabidopsis, the FLOWERING LOCUS T (FT) protein acts as a component of this phloem-mobile signal. However whether the transportable FT mRNA also contributes to systemic florigen signalling remains to be elucidated. Using non-conventional approaches that exploit virus-induced RNA silencing and meristem exclusion of virus infection, we demonstrated that the Arabidopsis FT mRNA, independent of the FT protein, can move into the SAM. Viral ectopic expression of a non-translatable FT mRNA promoted earlier flowering in the short-day (SD) Nicotiana tabacum Maryland Mammoth tobacco in SD. These data suggest a possible role for FT mRNA in systemic floral signalling, and also demonstrate that cis-transportation of cellular mRNA into SAM and meristem exclusion of pathogenic RNAs are two mechanistically distinct processes.