Publications

Fetal growth restriction (FGR) affects 5-10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map.

Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital ablation of the microRNA-synthesizing enzyme, Dicer, in Kiss1 cells, causes late-onset hypogonadotropic hypogonadism in both sexes, but is compatible with pubertal initiation and preserved Kiss1 neuronal populations at the infantile/juvenile period. Yet, failure to complete puberty and attain fertility is observed only in females.

The mechanisms linking systemic infection to hyperinflammation and immune dysfunction in sepsis are poorly understood. Extracellular histones promote sepsis pathology, but their source and mechanism of action remain unclear. Here, we show that by controlling fungi and bacteria captured by splenic macrophages, neutrophil-derived myeloperoxidase attenuates sepsis by suppressing histone release. In systemic candidiasis, microbial capture via the phagocytic receptor SIGNR1 neutralizes myeloperoxidase by facilitating marginal zone infiltration and T cell death-dependent histone release.

Understanding the neural mechanisms underlying sleep state transitions is a fundamental goal of neurobiology and important for the development of new treatments for insomnia and other sleep disorders. Yet, brain circuits controlling this process remain poorly understood. Here we identify a population of sleep-active glutamatergic neurons in the ventrolateral medulla (VLM) that project to the preoptic area (POA), a prominent sleep-promoting region, in mice.

Delayed oligodendrocyte (OL) maturation caused by hypoxia (Hx)-induced neonatal brain injury results in hypomyelination and leads to neurological disabilities. Previously, we characterized Sirt1 as a crucial regulator of OL progenitor cell (OPC) proliferation in response to Hx. We now identify Sirt2 as a critical promoter of OL differentiation during both normal white matter development and in a mouse model of Hx. Importantly, we find that Hx reduces Sirt2 expression in mature OLs and that Sirt2 overexpression in OPCs restores mature OL populations.

Sex differences occur in the structure and function of the rat cerebral cortex and hippocampus, which can change from the juvenile period through old age. Although the evidence is incomplete, it appears that in at least some portions of the cortex these differences develop due to the rise of ovarian hormones at puberty and are potentially not dependent on the perinatal rise in testosterone, which is essential for sexual differentiation of the hypothalamus and sexual behavior.

Rationale DNA damage accumulation is a hallmark of vascular smooth muscle cell (VSMC) ageing. Importantly, VSMC DNA damage accumulation and ageing has been implicated in the progression of cardiovascular disease (CVD), including atherosclerosis and vascular calcification. Chemotherapy drugs used in the treatment of many cancers are known to induce DNA damage in cardiovascular cells and accelerate CVD. Histone deacetylase (HDAC) inhibitors are drugs being investigated for novel treatments of many cancers.

We aimed to determine the possible role of CAG somatic expansions on the clinical expression of intermediate allele (IA) carriers of the HTT gene, responsible for Huntington disease (HD). We performed exon one sequencing analysis of the HTT gene on peripheral blood DNA in a Spanish cohort of asymptomatic IA carriers (n=55), symptomatic IA carriers (n=86) and HD subjects (n=124). Additionally, we investigated different brain regions of an individual carrying an HTT allele with 33 CAGs, with neurocognitive symptoms.

Epigenetic mechanisms are altered in the striatum of HD patients and mouse models, but how they might contribute to pathogenesis, including cognitive deficits, is unclear. Epigenetic regulation is critical to learning and memory processes, through transcriptional control of gene program promoting neural plasticity. We asked whether memory-associated epigenetic and transcriptional responses were impaired in HD R6/1 mice. To this end, we trained R6/1 mice (and control mice) in an aquatic navigation task, the double H maze, which allows assessing striatum-dependent memory (e.g.

RESULTS Microscopic analysis revealed that the full-length _HTT_ mRNA (_FL-HTT_) was retained in RNA nuclear clusters together with the incompletely spliced _HTT1a_ transcript. These clusters were not observed in zQ175 HD mouse model where, instead, _FL-Htt_ and _Htt1a_ mRNAs were detected as mostly cytoplasmic molecules. Immunohistochemistry showed a progressive appearance of aggregated HTT in nuclei in the cortex, striatum, hippocampus and cerebellum. HTRF indicated that the level of exon 1 HTT was highest in the cerebellum.