A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling.

Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.

Organic carbon burial is paced by a ~173-ka obliquity cycle in the middle to high latitudes.

Earth's climate system is complex and inherently nonlinear, which can induce some extraneous cycles in paleoclimatic proxies at orbital time scales. The paleoenvironmental consequences of these extraneous cycles are debated owing to their complex origin. Here, we compile high-resolution datasets of total organic carbon (TOC) and stable carbon isotope (δ13Corg) datasets to investigate organic carbon burial processes in middle to high latitudes. Our results document a robust cyclicity of ~173 thousand years (ka) in both TOC and δ13Corg The ~173-ka obliquity-related forcing signal was amplified by internal climate feedbacks of the carbon cycle under different geographic and climate conditions, which control a series of sensitive climatic processes. In addition, our new and compiled records from multiple proxies confirm the presence of the obliquity amplitude modulation (AM) cycle during the Mesozoic and Cenozoic and indicate the usefulness of the ~173-ka cycle as geochronometer and for paleoclimatic interpretation.

Drug rings database with web interface. A tool for identifying alternative chemical rings in lead discovery programs.

This paper describes the development of a drug rings database and Web-based search tools. The database contains ring structures from both corporate and commercial databases, along with characteristic descriptors including frequency of occurrence as an indicator of synthetic accessibility and calculated property and geometric parameters. Analysis of the rings in several major databases is described, with illustrations of applications of the database in lead discovery programs where bioisosteres and geometric isosteres are sought.

Dominance and submission: the ventrolateral prefrontal cortex and responses to status cues.

Status hierarchies constitute a fundamental organizing principle of human society. However, little is known about the neural systems that process nonverbal cues that indicate status. Preliminary neuropsychological work has suggested a role for the ventrolateral and ventromedial prefrontal cortex (VLPFC/VMPFC) and the superior temporal cortex (STC). We used functional magnetic resonance imaging to delineate the nature of these roles. Analyses revealed signal changes in the right VLPFC in connection with two primary functions attributed to status cues. Status cues moderate behavior and the right VLPFC showed increased signal for high-status relative to neutral and low-status cues. The VLPFC also showed increased signal for high-status cues displayed by individuals of the opposite gender to the perceiver; this may be relevant to the role status cues play in moderating mate choice behavior. Connectivity results indicated significant positive connectivity between the VLPFC and both the VMPFC and the STC. We suggest that the VLPFC retrieves information from these regions when processing hierarchy cues to facilitate socially adaptive behavior.