9 research outputs found
Proton gradients and pH oscillations emerge from heat flow at the microscale
Proton gradients are essential for biological systems. They not only drive the synthesis of ATP, but initiate molecule degradation and recycling inside lysosomes. However, the high mobility and permeability of protons through membranes make pH gradients very hard to sustain in vitro. Here we report that heat flow across a water-filled chamber forms and sustains stable pH gradients. Charged molecules accumulate by convection and thermo- phoresis better than uncharged species. In a dissociation reaction, this imbalances the reaction equilibrium and creates a difference in pH. In solutions of amino acids, phosphate, or nucleotides, we achieve pH differences of up to 2 pH units. The same mechanism cycles biomolecules by convection in the created proton gradient. This implements a feedback between biomolecules and a cyclic variation of the pH. The finding provides a mechanism to create a self-sustained proton gradient to drive biochemical reactions
Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria
Photochemical Microscale Electrophoresis Allows Fast Quantification of Biomolecule Binding
Intricate spatiotemporal patterns
emerge when chemical reactions
couple to physical transport. We induce electrophoretic transport
by a confined photochemical reaction and use it to infer the binding
strength of a second, biomolecular binding reaction under physiological
conditions. To this end, we use the photoactive compound 2-nitrobenzaldehyde,
which releases a proton upon 375 nm irradiation. The charged photoproducts
locally perturb electroneutrality due to differential diffusion, giving
rise to an electric potential Φ in the 100 μV range on
the micrometer scale. Electrophoresis of biomolecules in this field
is counterbalanced by back-diffusion within seconds. The biomolecule
concentration is measured by fluorescence and settles proportionally
to expÂ(−μ/<i>D</i> Φ). Typically, binding
alters either the diffusion coefficient D or the electrophoretic mobility
μ. Hence, the local biomolecule fluorescence directly reflects
the binding state. A fit to the law of mass action reveals the dissociation
constant of the binding reaction. We apply this approach to quantify
the binding of the aptamer TBA15 to its protein target human-α-thrombin
and to probe the hybridization of DNA. Dissociation constants in the
nanomolar regime were determined and match both results in literature
and in control experiments using microscale thermophoresis. As our
approach is all-optical, isothermal and requires only nanoliter volumes
at nanomolar concentrations, it will allow for the fast screening
of biomolecule binding in low volume multiwell formats
Subcellular distribution of 14-3-3 proteins in the unicellular green alga Chlamydomonas reinhardtii
Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability (Nature Communications, (2021), 12, 1, (24), 10.1038/s41467-020-19366-9)
The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article
Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria