Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction

Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts’ increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR

The Pediatric Cell Atlas:Defining the Growth Phase of Human Development at Single-Cell Resolution

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan

Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction

Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts' increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR

OptGraft: A computational procedure for transferring a binding site onto an existing protein scaffold

One of the many challenging tasks of protein design is the introduction of a completely new function into an existing protein scaffold. In this study, we introduce a new computational procedure OptGraft for placing a novel binding pocket onto a protein structure so as its geometry is minimally perturbed. This is accomplished by introducing a two-level procedure where we first identify where are the most appropriate locations to graft the new binding pocket into the protein fold by minimizing the departure from a set of geometric restraints using mixed-integer linear optimization. On identifying the suitable locations that can accommodate the new binding pocket, CHARMM energy calculations are employed to identify what mutations in the neighboring residues, if any, are needed to ensure that the minimum energy conformation of the binding pocket conserves the desired geometry. This computational framework is benchmarked against the results available in the literature for engineering a copper binding site into thioredoxin protein. Subsequently, OptGraft is used to guide the transfer of a calcium-binding pocket from thermitase protein (PDB: 1thm) into the first domain of CD2 protein (PDB:1hng). Experimental characterization of three de novo redesigned proteins with grafted calcium-binding centers demonstrated that they all exhibit high affinities for terbium (Kd ∼ 22, 38, and 55 μM) and can selectively bind calcium over magnesium

Investigation of Air Quality Index and PM10 and PM2.5 in Arak

Background and purpose: In this study, the air quality index and concentration of particles such as PM10 and PM2.5 were investigated in Arak. Materials and Methods: To determine the concentration of PM10 and PM2.5, 60 samples were collected by laser TSI model 8520 in summer and winter 2012. The collection site was around Arak city center. Results: during the sampling period, as a matter of PM10, the cleanest and the most polluted month were December and June with the average of 34.33 µg m-3 and 100.1 µg m-3, respectively. The concentration of PM2.5 was 12.93 and 53.17 µg m-3 for December and June, respectively. Meanwhile, in terms of air quality index (AQI), in 98.3% and 70% of cases, the concentrations of PM10 and PM2.5, respectively were less than normal (AQI100). Conclusion: The concentration of PM10 in the study period was less than Environmental Protection Agency (EPA) 2006 guideline. Meanwhile, the concentrations of PM2.5 in 30% of air samples were greater than EPA guideline. The average PM2.5/PM10 ratio during the sampling period was 0.41 compared to range 0.15 to 0.25 reported by EPA

Evaluation of Ground Water Fluoride Concentration in Hamadan Province West of IRAN(2012)

Background and purpose: Fluoride is one of the drinking water contaminants regulated by EPA. This ion, in low doses in the mouth reduces tooth decay without health risk and at much higher doses causes health complications and can be toxic. The major sources of exposure to fluoride are drinking water, food, dental products, and pesticides. The biggest contributor to exposure for most people in Iran is drinking water. This study was carried out to determine groundwater fluoride concentration of Hamadan province located in the west of Iran in 2012. Materials and Methods: Ground water samples were collected from 192 sampling point, during dry and wet seasons. Fluoride concentration was determined in the water samples using UV-Spectrophotometry method (DR 5000) and SPADNS Fluoride Reagent Solution. Results: The fluoride concentration of ground water of examined regions varied between 0 to 1.78 mg/l. Mean concentration of fluoride samples and standard deviation were 0.574 and 0.351 mg/l respectively. The results showed that 49% of fluoride concentration samples were less than the standard value according to National standards of IRAN and WHO guideline. Conclusion: According to low level of fluoride concentration in this province, fluoride supplements such as mouth washes, consumption of fluoride containing foods and water fluoridation are recommended to reduce caries development

Ultrafast Hydrogen Exchange Reveals Specific Structural Events during the Initial Stages of Folding of Cytochrome <i>c</i>

Many proteins undergo a sharp decrease in chain dimensions during early stages of folding, prior to the rate-limiting step in folding. However, it remains unclear whether compact states are the result of specific folding events or a general hydrophobic collapse of the poly peptide chain driven by the change in solvent conditions. To address this fundamental question, we extended the temporal resolution of NMR-detected H/D exchange labeling experiments into the microsecond regime by adopting a microfluidics approach. By observing the competition between H/D exchange and folding as a function of labeling pH, coupled with direct measurement of exchange rates in the unfolded state, we were able to monitor hydrogen-bond formation for over 50 individual backbone NH groups within the initial 140 microseconds of folding of horse cytochrome <i>c</i>. Clusters of solvent-shielded amide protons were observed in two α-helical segments in the C-terminal half of the protein, while the N-terminal helix remained largely unstructured, suggesting that proximity in the primary structure is a major factor in promoting helix formation and association at early stages of folding, while the entropically more costly long-range contacts between the N- and C-terminal helices are established only during later stages. Our findings clearly indicate that the initial chain condensation in cytochrome <i>c</i> is driven by specific interactions among a subset of α-helical segments rather than a general hydrophobic collapse

The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA.

The capacity for T cells to become activated and clonally expand during pathogen invasion is pivotal for protective immunity. Our understanding of how T cell receptor (TCR) signaling prepares cells for this rapid expansion remains limited. Here we provide evidence that the E3 ubiquitin ligase Cullin-4b (Cul4b) regulates this process. The abundance of total and neddylated Cul4b increased following TCR stimulation. Disruption of Cul4b resulted in impaired proliferation and survival of activated T cells. Additionally, Cul4b-deficient CD4+ T cells accumulated DNA damage. In T cells, Cul4b preferentially associated with the substrate receptor DCAF1, and Cul4b and DCAF1 were found to interact with proteins that promote the sensing or repair of damaged DNA. While Cul4b-deficient CD4+ T cells showed evidence of DNA damage sensing, downstream phosphorylation of SMC1A did not occur. These findings reveal an essential role for Cul4b in promoting the repair of damaged DNA to allow survival and expansion of activated T cells