Hemerythrin‐like proteins have generally been studied for their ability to reversibly bind oxygen through their binuclear nonheme iron centers. However, in recent years, it has become increasingly ...evident that some members of the hemerythrin‐like superfamily also participate in many other biological processes. For instance, the binuclear nonheme iron site of YtfE, a hemerythrin‐like protein involved in the repair of iron centers in Escherichia coli, catalyzes the reduction of nitric oxide to nitrous oxide, and the human F‐box/LRR‐repeat protein 5, which contains a hemerythrin‐like domain, is involved in intracellular iron homeostasis. Furthermore, structural data on hemerythrin‐like domains from two proteins of unknown function, PF0695 from Pyrococcus furiosus and NMB1532 from Neisseria meningitidis, show that the cation‐binding sites, typical of hemerythrin, can be absent or be occupied by metal ions other than iron. To systematically investigate this functional and structural diversity of the hemerythrin‐like superfamily, we have collected hemerythrin‐like sequences from a database comprising fully sequenced proteomes and generated a cluster map based on their all‐against‐all pairwise sequence similarity. Our results show that the hemerythrin‐like superfamily comprises a large number of protein families which can be classified into three broad groups on the basis of their cation‐coordinating residues: (a) signal‐transduction and oxygen‐carrier hemerythrins (H‐HxxxE‐HxxxH‐HxxxxD); (b) hemerythrin‐like (H‐HxxxE‐H‐HxxxE); and, (c) metazoan F‐box proteins (H‐HExxE‐H‐HxxxE). Interestingly, all but two hemerythrin‐like families exhibit internal sequence and structural symmetry, suggesting that a duplication event may have led to the origin of the hemerythrin domain.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Human organoids recapitulating the cell-type diversity and function of their target organ are valuable for basic and translational research. We developed light-sensitive human retinal organoids with ...multiple nuclear and synaptic layers and functional synapses. We sequenced the RNA of 285,441 single cells from these organoids at seven developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable “developed” state at a rate similar to human retina development in vivo. Transcriptomes of organoid cell types converged toward the transcriptomes of adult peripheral retinal cell types. Expression of disease-associated genes was cell-type-specific in adult retina, and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in human retinas.
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•Light-sensitive, multilayered human retinal organoids with functional synapses•285,441 transcriptomes from light-responsive human retinas and retinal organoids•Organoid cell types converge to adult peripheral retinal cell types•Linking retinal diseases to human retinal and retinal organoid cell types
Light-sensitive, multilayered human retinal organoids with functional synapses are developed and benchmarked against human retinas obtained under conditions that preserve retinal integrity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Internal structure similarity in proteins can be observed at the domain and subdomain levels. From an evolutionary perspective, structurally similar elements may arise divergently by gene duplication ...and fusion events but may also be the product of convergent evolution under physicochemical constraints. The characterization of proteins that contain repeated structural elements has implications for many fields of protein science including protein domain evolution, structure classification, structure prediction, and protein engineering. FiRES (Find Repeated Elements in Structure) is an algorithm that relies on a topology‐independent structure alignment method to identify repeating elements in protein structure. FiRES was tested against two hand curated databases of protein repeats: MALIDUP, for very divergent duplicated domains; and RepeatsDB for short tandem repeats. The performance of FiRES was compared to that of lalign, RADAR, HHrepID, CE‐symm, ReUPred, and Swelfe. FiRES was the method that most accurately detected proteins either with duplicated domains (accuracy = 0.86) or with multiple repeated units (accuracy = 0.92). FiRES is a new methodology for the discovery of proteins containing structurally similar elements. The FiRES web server is publicly available at http://fires.ifc.unam.mx. The scripts, results, and benchmarks from this study can be downloaded from https://github.com/Claualvarez/fires.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The efficacy of chemotherapy is reduced by dysfunctional tumor vasculature, which may limit chemotherapy delivery to tumors. Preclinical studies have shown that moderate aerobic exercise improves ...tumor vascular function and increases chemotherapy efficacy in mouse models, but the effect of exercise on human tumor vasculature has not yet been determined. Here, we demonstrate that exercise remodels the tumor vasculature, accelerates the regression, and delays the regrowth of pancreatic ductal adenocarcinoma in a patient-derived xenograft mouse model treated with gemcitabine. By evaluating pancreatic adenocarcinoma specimens from patients treated with preoperative chemotherapy or chemoradiation therapy, we also demonstrate for the first time that tumor vascular remodeling occurs in association with exercise in humans. Future studies will evaluate whether exercise-induced vascular remodeling improves gemcitabine or other chemotherapy efficacy in patients, as this study evaluated only changes in tumor vascular structure.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this ...improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES‐bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine‐1‐phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Intracellular pathogenic bacteria evade the immune response by replicating within host cells. Legionella pneumophila, the causative agent of Legionnaires' Disease, makes use of numerous effector ...proteins to construct a niche supportive of its replication within phagocytic cells. The L. pneumophila effector SidK was identified in a screen for proteins that reduce the activity of the proton pumping vacuolar-type ATPases (V-ATPases) when expressed in the yeast Saccharomyces cerevisae. SidK is secreted by L. pneumophila in the early stages of infection and by binding to and inhibiting the V-ATPase, SidK reduces phagosomal acidification and promotes survival of the bacterium inside macrophages. We determined crystal structures of the N-terminal region of SidK at 2.3 Å resolution and used single particle electron cryomicroscopy (cryo-EM) to determine structures of V-ATPase:SidK complexes at ~6.8 Å resolution. SidK is a flexible and elongated protein composed of an α-helical region that interacts with subunit A of the V-ATPase and a second region of unknown function that is flexibly-tethered to the first. SidK binds V-ATPase strongly by interacting via two α-helical bundles at its N terminus with subunit A. In vitro activity assays show that SidK does not inhibit the V-ATPase completely, but reduces its activity by ~40%, consistent with the partial V-ATPase deficiency phenotype its expression causes in yeast. The cryo-EM analysis shows that SidK reduces the flexibility of the A-subunit that is in the 'open' conformation. Fluorescence experiments indicate that SidK binding decreases the affinity of V-ATPase for a fluorescent analogue of ATP. Together, these results reveal the structural basis for the fine-tuning of V-ATPase activity by SidK.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although ecological restoration is widely used to combat environmental degradation, very few studies have evaluated the cost-effectiveness of this approach. We examine the potential impact of forest ...restoration on the value of multiple ecosystem services across four dryland areas in Latin America, by estimating the net value of ecosystem service benefits under different reforestation scenarios. The values of selected ecosystem services were mapped under each scenario, supported by the use of a spatially explicit model of forest dynamics. We explored the economic potential of a change in land use from livestock grazing to restored native forest using different discount rates and performed a cost—benefit analysis of three restoration scenarios. Results show that passive restoration is cost-effective for all study areas on the basis of the services analyzed, whereas the benefits from active restoration are generally outweighed by the relatively high costs involved. These findings were found to be relatively insensitive to discount rate but were sensitive to the market value of carbon. Substantial variation in values was recorded between study areas, demonstrating that ecosystem service values are strongly context specific. However, spatial analysis enabled localized areas of net benefits to be identified, indicating the value of this approach for identifying the relative costs and benefits of restoration interventions across a landscape.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Aminoacyl‐tRNA synthetases (aaRSs) establish the genetic code. Each aaRS covalently links a given canonical amino acid to a cognate set of tRNA isoacceptors. Glycyl tRNA aminoacylation is unusual in ...that it is catalyzed by different aaRSs in different lineages of the Tree of Life. We have investigated the phylogenetic distribution and evolutionary history of bacterial glycyl tRNA synthetase (bacGlyRS). This enzyme is found in early diverging bacterial phyla such as Firmicutes, Acidobacteria, and Proteobacteria, but not in archaea or eukarya. We observe relationships between each of six domains of bacGlyRS and six domains of four different RNA‐modifying proteins. Component domains of bacGlyRS show common ancestry with (i) the catalytic domain of class II tRNA synthetases; (ii) the HD domain of the bacterial RNase Y; (iii) the body and tail domains of the archaeal CCA‐adding enzyme; (iv) the anti‐codon binding domain of the arginyl tRNA synthetase; and (v) a previously unrecognized domain that we call ATL (Ancient tRNA latch). The ATL domain has been found thus far only in bacGlyRS and in the universal alanyl tRNA synthetase (uniAlaRS). Further, the catalytic domain of bacGlyRS is more closely related to the catalytic domain of uniAlaRS than to any other aminoacyl tRNA synthetase. The combined results suggest that the ATL and catalytic domains of these two enzymes are ancestral to bacGlyRS and uniAlaRS, which emerged from common protein ancestors by bricolage, stepwise accumulation of protein domains, before the last universal common ancestor of life.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Based on a combination of Electron Spin Resonance (ESR) dating of quartz, luminescence dating of K-feldspar and palaeomagnetism, this study presents the first chronostratigraphic framework for the ...Pleistocene fluvial deposits of the lower Moulouya river in the Triffa basin (NE Morocco). K-feldspar pIRIR225 and pIRIR290 signals of all samples are saturated, suggesting fluvial deposition at least as early as the Middle Pleistocene (∼0.39–0.80 Ma). Consequently, further chronological information was obtained with ESR dating of quartz grains from the ancient Pleistocene fluvial deposits. As for ESR, the multiple centres approach provides equivalent dose values derived from the Al and Ti centres that mostly agree within 1σ-error, suggesting complete signal resetting from the former during fluvial transport. ESR dating results yield Calabrian deposition ages for all river profiles from ∼1.1 to ∼1.5 Ma. These ages are remarkably consistent with the palaeomagnetic results: the occurrence of mostly reversed polarity in the deposits indicates a Matuyama age (>0.78 Ma). While low incision rates in the Triffa basin (0.025 ± 0.003 mm/a) related to thrusting activity during the Calabrian could be inferred, the fluvial record points to an acyclic and discontinuous sedimentation pattern over the last ∼1.3 Ma. It thereby probably rules out climate as the main driver for fluvial aggradation in the lowermost sedimentary basin. At a regional scale, several indicators point to transient fluvial response resulting from major Quaternary tectonic activity along the Beni Snassen gorge, located directly upstream of the investigated basin. We suggest that a capture event at the margin of the uplifting Beni Snassen massif occurred between 1.04 and 1.36 Ma at the latest and subsequently led to the creation of the gorge.
•First numerical ages were obtained for the fluvial deposits in the lower Moulouya.•Equivalent dose values of the Al and Ti centres mostly agree within 1σ.•ESR chronology is remarkably consistent with palaeomagnetic results.•Discontinuous sedimentation pattern over the second half of the Quaternary.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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