Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

Medial Expression of TNF-α and TNF Receptors Precedes the Development of Atherosclerotic Lesions in Apolipoprotein E/LDL Receptor Double Knockout Mice

TNF-α is present in atherosclerotic lesions, activates endothelial adhesion molecule expression, stimulates the release of proinflammatory cytokines and matrix metalloproteinases and promotes smooth muscle cell proliferation and migration. Taken together these observations suggest that TNF-α may be functionally involved in early atherosclerosis development. To further evaluate this hypothesis we compared vascular TNF-α and TNF receptor expression in atherosclerosis-susceptible apoE-/-/LDL receptor-/- mice and control C57BL/6 mice. The aortas of 8 week old apoE-/-/LDLreceptor-/- mice displayed immunoreactivity for TNF-α as well as TNF p55 and p75 receptors (2.1 ± 1.6%, 5.6 ± 1.5% and 3.6 ± 1.3% of total media area, respectively), but did not have any detectable lesions. A marginal increase in TNF-α and TNF receptor immunoreactivity was observed at 12 weeks and atherosclerotic plaques were detected in 1 out of 5 animals. At 16 weeks TNF-α expression in the media was increased more than four-fold as compared with 8 week old mice, and atherosclerosis was widespread. TNF-α immunoreactivity was also observed in all plaques. In addition, at the same age a tendency towards increased TNF-α mRNA levels was detected in the double knockout mice compared to age-matched controls. A further increase in TNF-α and TNF receptor immunoreactivity as well as plaque size was observed at 20 weeks. With only a few exceptions, no TNF-α or TNF receptor immunoreactivity was detected in C57BL/6 control mice. These findings demonstrate that medial TNF-α and TNF receptor expression precedes lesion formation in apoE-/-/LDL receptor-/- mice

Medial expression of TNF alpha and TNF receptors precedes the development of atherosclerotic lesions in apolipoprotein E/LDL receptor double knockout mice

TNF-alpha is present in atherosclerotic lesions, activates endothelial adhesion molecule expression, stimulates the release of proinflammatory cytokines and matrix metalloproteinases and promotes smooth muscle cell proliferation and migration. Taken together these observations suggest that TNF-alpha may be functionally involved in early atherosclerosis development. To further evaluate this hypothesis we compared vascular TNF-alpha and TNF receptor expression in atherosclerosis-susceptible apoE-/-/LDL receptor-/- mice and control C57BL/6 mice. The aortas of 8 week old apoE-/-/LDLreceptor-/- mice displayed immunoreactivity for TNF-alpha as well as TNF p55 and p75 receptors (2.1 +/-1.6%, 5.6 +/- 1.5% and 3.6 +/- 1.3% of total media area, respectively), but did not have any detectable lesions. A marginal increase in TNF-alpha and TNF receptor immunoreactivity was observed at 12 weeks and atherosclerotic plaques were detected in 1 out of 5 animals. At 16 weeks TNF-alpha expression in the media was increased more than four-fold as compared with 8 week old mice, and atherosclerosis was widespread. TNF-alpha immunoreactivity was also observed in all plaques. In addition, at the same age a tendency towards increased TNF-alpha mRNA levels was detected in the double knockout mice compared to age-matched controls. A further increase in TNF-alpha and TNF receptor immunoreactivity as well as plaque size was observed at 20 weeks. With only a few exceptions, no TNF-alpha or TNF receptor immunoreactivity was detected in C57BL/6 control mice. These findings demonstrate that medial TNF-alpha and TNF receptor expression precedes lesion formation in apoE-/-/LDL receptor-/- mice

Complement C1q Reduces Early Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

We explored the role of the classic complement pathway in atherogenesis by intercrossing C1q-deficient mice (C1qa(−/−)) with low-density lipoprotein receptor knockout mice (Ldlr(−/−)). Mice were fed a normal rodent diet until 22 weeks of age. Aortic root lesions were threefold larger in C1qa(−/−)/Ldlr(−/−) mice compared with Ldlr(−/−) mice (3.72 ± 1.0% aortic root versus 1.1 ± 0.4%; mean ± SEM, P < 0.001). Furthermore, the cellular composition of lesions in C1qa(−/−)/Ldlr(−/−) was more complex, with an increase in vascular smooth muscle cells. The greater aortic root lesion size in C1qa(−/−)/Ldlr(−/−) mice occurred despite a significant reduction in C5b-9 deposition per lesion unit area, suggesting the critical importance of proximal pathway activity. Apoptotic cells were readily detectable by cleaved caspase-3 staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electron microscopy in C1qa(−/−)/Ldlr(−/−), whereas apoptotic cells were not detected in Ldlr(−/−) mice. This is the first direct demonstration of a role for the classic complement pathway in atherogenesis. The greater lesion size in C1qa(−/−)/Ldlr(−/−) mice is consistent with the emerging homeostatic role for C1q in the disposal of dying cells. This study suggests the importance of effective apoptotic cell removal for containing the size and complexity of early lesions in atherosclerosis