Reconstruction and Simulation of Neocortical Microcircuitry.

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm(3) containing ~31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ~8 million connections with ~37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies. PAPERCLIP: VIDEO ABSTRACT.

The urine-to-plasma urea concentration ratio is associated with eGFR and eGFR decline over time in a population cohort.

BACKGROUND: Evaluation of renal function and of factors associated with its decline are important public health issues. Besides markers of glomerular function [e.g. glomerular filtration rate (GFR)], those of tubular functions are rarely evaluated. Urea, the most abundant urinary solute, is markedly concentrated in urine when compared with plasma. We explored the urine-to-plasma ratio of urea concentrations (U/P urea ratio) as a marker of tubular functions. METHODS: We evaluated the relationship of the U/P urea ratio with eGFR at baseline in 1043 participants (48 ± 17 years) from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) population-based cohort, using mixed regression. In 898 participants, we assessed the relation between U/P urea ratio and renal function decline between two study waves 3 years apart. We studied U/P ratios for osmolarity, Na, K and uric acid for comparison. RESULTS: In a transversal study at baseline, estimated GFR (eGFR) was positively associated with U/P-urea ratio [ßscaled = 0.08, 95% CI (0.04; 0.13)] but not with the U/P ratio of osmolarity. Considering separately participants with renal function >90 or ≤90 mL/min × 1.73 m2, this association was observed only in those with reduced renal function. In the longitudinal study, eGFR declined at a mean rate of 1.2 mL/min per year. A significant association was observed between baseline U/P urea ratio and eGFR decline [ßscaled = 0.08, 95% CI (0.01; 0.15)]. A lower baseline U/P urea ratio was associated with a greater eGFR decline. CONCLUSION: This study provides evidence that the U/P urea ratio is an early marker of kidney function decline in the general adult population. Urea is easy to measure with well-standardized techniques and at low cost. Thus, the U/P urea ratio could become an easily available tubular marker for evaluating renal function decline.

PhenoExplorer: An Interactive Web-based Platform for Exploring (Epi)Genome-Wide Associations Using a Swiss Population-based Study.

The recent advent of high-throughput sequencing technologies has allowed exploring the contribution of thousands of genomic, epigenomic, transcriptomic, or proteomic variants to complex phenotypic traits. Here, we sought to conduct large-scale (Epi)Genome-Wide Association Studies (GWAS/EWAS) to investigate the associations between genomic (Single Nucleotide Polymorphism; SNP) and epigenomic (Cytosine-Phospho-Guanine; CpG) markers, with multiple phenotypic traits in a population-based context. We used data from SKIPOGH, a family- and population-based cohort conducted in the cities of Lausanne, Geneva, and Bern (N=1100). We used 7,577,572 SNPs, 420,444 CpGs, and 825 phenotypes, including anthropometric, clinical, blood, urine, metabolite, and metal measures. GWAS analyses assessed the associations between SNPs and metabolites and metals (N=279), using regression models adjusted for age, sex, recruitment center, and familial structure, whereas EWAS analyses explored the relations between CpGs and 825 phenotypes, additionally adjusting for the seasonality of blood sampling and technical nuisance. Following the implementation of GWAS and EWAS analyses, we developed a web-based platform, PhenoExplorer, aimed at providing an open access to the obtained results. Of the 279 phenotypes included in GWAS, 103 displayed significant associations with 2804 SNPs (2091 unique SNPs) at Bonferroni threshold, whereas 109 of the 825 phenotypes included in EWAS analyses were associated with 4893 CpGs (2578 unique CpGs). All of the obtained GWAS and EWAS results were eventually made available using the in-house built web-based PhenoExplorer platform, with the purpose of providing an open-access to the tested associations. In conclusion, we provide a comprehensive outline of GWAS and EWAS associations performed in a Swiss population-based study. Further, we set up a web-based PhenoExplorer platform with the purpose of contributing to the overall understanding of the role of molecular variants in regulating complex phenotypes.

Renal handling of zinc in chronic kidney disease patients and the role of circulating zinc levels in renal function decline.

BACKGROUND: Zinc deficiency is commonly encountered in chronic kidney disease (CKD). The aims of this study were to assess whether zinc deficiency was related to increased renal excretion of zinc and to the progression of CKD. METHODS: Plasma and 24-h urinary zinc levels, urinary electrolytes and uromodulin were measured in 108 CKD patients and 81 individuals without CKD. Serum creatinine values were collected for 3 years to calculate the yearly change in estimated glomerular filtration rate (eGFR). Multivariable regression analysis was performed to assess the association between baseline zinc levels and yearly change in eGFR. RESULTS: CKD patients had lower circulating zinc levels and higher 24-h urinary zinc excretion than non-CKD participants (612.4 ± 425.9 versus 479.2 ± 293.0 µg/day; P = 0.02). Fractional excretion (FE) of zinc was higher and it significantly increased at more advanced CKD stages. Zinc FE was correlated negatively with 24-h urinary uromodulin excretion (r=-0.29; P < 0.01). Lower baseline plasma zinc levels were associated with a faster yearly decline of renal function in age, gender, diabetes and hypertension adjusted models, but this relationship was no longer significant when baseline eGFR or proteinuria were included. CONCLUSIONS: Zinc levels are lower in CKD, and not compensated by reduced renal zinc excretion. The inverse association between urinary zinc excretion and uromodulin possibly points to an impaired tubular activity, which could partly account for zinc imbalance in CKD. These data suggest that zinc status is associated with renal function decline, but further studies elucidating the underlying mechanisms and the potential role of zinc supplements in CKD are needed.

A versatile clearing agent for multi-modal brain imaging.

Extensive mapping of neuronal connections in the central nervous system requires high-throughput µm-scale imaging of large volumes. In recent years, different approaches have been developed to overcome the limitations due to tissue light scattering. These methods are generally developed to improve the performance of a specific imaging modality, thus limiting comprehensive neuroanatomical exploration by multi-modal optical techniques. Here, we introduce a versatile brain clearing agent (2,2'-thiodiethanol; TDE) suitable for various applications and imaging techniques. TDE is cost-efficient, water-soluble and low-viscous and, more importantly, it preserves fluorescence, is compatible with immunostaining and does not cause deformations at sub-cellular level. We demonstrate the effectiveness of this method in different applications: in fixed samples by imaging a whole mouse hippocampus with serial two-photon tomography; in combination with CLARITY by reconstructing an entire mouse brain with light sheet microscopy and in translational research by imaging immunostained human dysplastic brain tissue.

Brain-resident microglia predominate over infiltrating myeloid cells in activation, phagocytosis and interaction with T-lymphocytes in the MPTP mouse model of Parkinson disease.

Parkinson disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra (SN). Recent evidence suggests that innate and adaptive immune responses can influence dopaminergic cell death in animal models of PD. However, the precise role of mononuclear phagocytes, key players in damaged tissue clearance and cross-talk with cells of adaptive immune system, remains open in PD. Mononuclear phagocytes in the brain occur as brain-resident microglia and as brain-infiltrating myeloid cells. To elucidate their differential contribution in the uptake of dopaminergic cell debris and antigen presentation capacity, we labeled nigral dopaminergic neurons retrogradely with inert rhodamine-conjugated latex retrobeads before inducing their degeneration by subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. We used green fluorescent protein (GFP)-expressing bone marrow chimeric mice to differentiate brain-infiltrating from brain-resident myeloid cells. We found that half of both endogenous (GFP-) and exogenous (GFP+) microglia (Iba1+) in the SN incorporated the tracer from degenerating dopaminergic neurons 1d after MPTP intoxication. In absolute numbers, endogenous microglia were much more activated to macrophages compared to exogenous myeloid cells at 1d after MPTP. Mainly the endogenous, tracer-phagocytosing microglia expressed the major histocompatibility complex (MHC) class II molecule for antigen presentation. Additionally, T-lymphocytes (Iba1-/GFP+/CD3+), which infiltrate the MPTP-lesioned SN, were mainly in direct contact with MHCII+ endogenous microglia. Our data suggest that brain-resident microglia are predominantly implicated in the removal of dopaminergic cell debris and the cross-talk with infiltrating T-lymphocytes in the SN in the MPTP mouse model of PD.