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Glomeruli are highly sophisticated filters and glomerular disease is the leading cause of kidney failure. Morphological change in glomerular podocytes and the underlying basement membrane are frequently observed in disease, irrespective of the underlying molecular etiology. Standard electron microscopy techniques have enabled the identification and classification of glomerular diseases based on two-dimensional information, however complex three-dimensional ultrastructural relationships between cells and their extracellular matrix cannot be easily resolved with this approach. We employed serial block face-scanning electron microscopy to investigate Alport syndrome, the commonest monogenic glomerular disease, and compared findings to other genetic mouse models of glomerular disease ( Myo1e− / −, Ptpro− / − ). These analyses revealed the evolution of basement membrane and cellular defects through the progression of glomerular injury. Specifically we identified sub-podocyte expansions of the basement membrane with both cellular and matrix gene defects and found a corresponding reduction in podocyte foot process number. Furthermore, we discovered novel podocyte protrusions invading into the glomerular basement membrane in disease and these occurred frequently in expanded regions of basement membrane. These findings provide new insights into mechanisms of glomerular barrier dysfunction and suggest that common cell-matrix-adhesion pathways are involved in the progression of disease regardless of the primary insult.

Phospholipase A 2 receptor (PLA 2 R) is a member of the mannose receptor family found in podocytes in human kidney. PLA 2 R is the target of the autoimmune disease, membranous nephropathy, characterised by production of anti-PLA 2 R autoantibodies which bind to the podocyte. However the function of PLA 2 R in health and in disease remains unclear. To gain insight into the molecular mechanisms of PLA 2 R function, we searched for its endogenous binding partners. Proteomic analysis identified annexinA2 as a potential interactor with the extracellular domains of PLA 2 R. We confirmed that PLA 2 R binds to annexinA2-S100A10 (A2t) complex with specific high affinity to the S100A10 component. The binding occured within the PLA 2 R NC3 fragment and was increased in acidic pH. Furthermore Ca 2+ promoted the association of the PLA 2 R-A2t complex with phospholipid membranes in vitro . Within the podocyte, all three proteins were enriched in the plasma membrane and organelle membrane compartments. PLA 2 R co-localised with S100A10 at the cell surface and in extracellular vesicles. This novel interaction between PLA 2 R and the A2t complex offers insights into the role of PLA 2 R in podocytes and how autoantibodies might disrupt PLA 2 R function. The ability of podocytes to secrete vesicles containing PLA 2 R provides a route for engagement of PLA 2 R with the immune system.

Background Mutations in podocyte and basement membrane genes are associated with a growing spectrum of glomerular disease affecting adults and children. Investigation of familial cases has helped to build understanding of both normal physiology and disease. Methods We investigated a consanguineous family with a wide clinical phenotype of glomerular disease using clinical, histological, and new genetic studies. Results We report striking variability in severity of nephropathy within an X-linked Alport syndrome (XLAS) family. Four siblings each carried a mutant COL4A5 allele, p.(Gly953Val) and p.(Gly1033Arg). Two boys had signs limited to hematuria and mild/moderate proteinuria. In striking contrast, a sister presented with end-stage renal disease (ESRD) at 8 years of age and an infant brother presented with nephrotic syndrome, progressing to ESRD by 3 years of age. Both were subsequently found to have homozygous variants in MYO1E , p.(Lys118Glu) and p.(Thr876Arg). MYO1E is a gene implicated in focal segmental glomerulosclerosis and it encodes a podocyte-expressed non-muscle myosin. Bioinformatic modeling demonstrated that the collagen IV-alpha3,4,5 extracellular network connected via known protein–protein interactions to intracellular myosin 1E. Conclusions COL4A5 and MYO1E mutations may summate to perturb common signaling pathways, resulting in more severe disease than anticipated independently. We suggest screening for MYO1E and other non- COL4 ‘podocyte gene’ mutations in XLAS when clinical nephropathy is more severe than expected for an individual’s age and sex.

Alport syndrome is caused by mutations in the genes COL4A3, COL4A4 or COL4A5 and is characterised by progressive glomerular disease, sensorineural hearing loss and ocular defects. Occurring in less than 1:5000, Alport syndrome is a rare genetic disorder but still accounts for > 1% of the prevalent population receiving renal replacement therapy. There is also increasing awareness about the risk of chronic kidney disease in individuals with heterozygous mutations in Alport syndrome genes. The mainstay of current therapy is the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, yet potential new therapies are now entering clinical trials. The 2017 International Workshop on Alport Syndrome in Glasgow was a pre-conference workshop ahead of the 50th anniversary meeting of the European Society for Pediatric Nephrology. It focussed on updates in clinical practice, genetics and basic science and also incorporated patient perspectives. More than 80 international experts including clinicians, geneticists, researchers from academia and industry, and patient representatives took part in panel discussions and breakout groups. This report summarises the workshop proceedings and the relevant contemporary literature. It highlights the unique clinician, patient and researcher collaborations achieved by regular engagement between the groups.

Phospholipase A receptor (PLA R) is a member of the mannose receptor family found in podocytes in human kidney. PLA R is the target of the autoimmune disease, membranous nephropathy, characterised by production of anti-PLA R autoantibodies which bind to the podocyte. However the function of PLA R in health and in disease remains unclear. To gain insight into the molecular mechanisms of PLA R function, we searched for its endogenous binding partners. Proteomic analysis identified annexinA2 as a potential interactor with the extracellular domains of PLA R. We confirmed that PLA R binds to annexinA2-S100A10 (A2t) complex with specific high affinity to the S100A10 component. The binding occured within the PLA R NC3 fragment and was increased in acidic pH. Furthermore Ca promoted the association of the PLA R-A2t complex with phospholipid membranes in vitro. Within the podocyte, all three proteins were enriched in the plasma membrane and organelle membrane compartments. PLA R co-localised with S100A10 at the cell surface and in extracellular vesicles. This novel interaction between PLA R and the A2t complex offers insights into the role of PLA R in podocytes and how autoantibodies might disrupt PLA R function. The ability of podocytes to secrete vesicles containing PLA R provides a route for engagement of PLA R with the immune system.

The Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2), is the latest atmospheric reanalysis of the modern satellite era produced by NASA’s Global Modeling and Assimilation Office (GMAO). MERRA-2 assimilates observation types not available to its predecessor, MERRA, and includes updates to the Goddard Earth Observing System (GEOS) model and analysis scheme so as to provide a viable ongoing climate analysis beyond MERRA’s terminus. While addressing known limitations of MERRA, MERRA-2 is also intended to be a development milestone for a future integrated Earth system analysis (IESA) currently under development at GMAO. This paper provides an overview of the MERRA-2 system and various performance metrics. Among the advances in MERRA-2 relevant to IESA are the assimilation of aerosol observations, several improvements to the representation of the stratosphere including ozone, and improved representations of cryospheric processes. Other improvements in the quality of MERRA-2 compared with MERRA include the reduction of some spurious trends and jumps related to changes in the observing system and reduced biases and imbalances in aspects of the water cycle. Remaining deficiencies are also identified. Production of MERRA-2 began in June 2014 in four processing streams and converged to a single near-real-time stream in mid-2015. MERRA-2 products are accessible online through the NASA Goddard Earth Sciences Data Information Services Center (GES DISC).

Proteasomes: Ubiquitin binding via Rpn 13 The 26S proteasome is a multisubunit complex that selectively degrades ubiquitin conjugated proteins. Two studies show that a known component of the proteasome, Rpn13 functions as a novel ubiquitin binding receptor. Structural studies reveal a novel mode of ubiquitin recognition. Rpn 13 is also a receptor for a deubiquitinating enzyme, suggesting a linkage between ubiquitin chain recognition and disassembly. The 26S proteasome is a multisubunit complex that selectively degrades ubiquitin conjugated proteins. Two studies (this Letter and the Article Dikic doi:10.1038/nature06926) show that a known component of the proteasome, Rpn13, functions as a novel ubiquitin binding receptor, and structural studies reveal a novel mode of ubiquitin recognition. Rpn13 is also a receptor for a deubiquitinating enzyme, suggesting a linkage between ubiquitin chain recognition and disassembly. Targeted protein degradation is largely performed by the ubiquitin–proteasome pathway, in which substrate proteins are marked by covalently attached ubiquitin chains that mediate recognition by the proteasome. It is currently unclear how the proteasome recognizes its substrates, as the only established ubiquitin receptor intrinsic to the proteasome is Rpn10/S5a (ref. 1 ), which is not essential for ubiquitin-mediated protein degradation in budding yeast 2 . In the accompanying manuscript we report that Rpn13 (refs 3–7 ), a component of the nine-subunit proteasome base, functions as a ubiquitin receptor 8 , complementing its known role in docking de-ubiquitinating enzyme Uch37/UCHL5 (refs 4–6 ) to the proteasome. Here we merge crystallography and NMR data to describe the ubiquitin-binding mechanism of Rpn13. We determine the structure of Rpn13 alone and complexed with ubiquitin. The co-complex reveals a novel ubiquitin-binding mode in which loops rather than secondary structural elements are used to capture ubiquitin. Further support for the role of Rpn13 as a proteasomal ubiquitin receptor is demonstrated by its ability to bind ubiquitin and proteasome subunit Rpn2/S1 simultaneously. Finally, we provide a model structure of Rpn13 complexed to diubiquitin, which provides insights into how Rpn13 as a ubiquitin receptor is coupled to substrate deubiquitination by Uch37.

The uptake of water by atmospheric aerosols has a pronounced effect on particle light scattering properties, which in turn are strongly dependent on the ambient relative humidity (RH). Earth system models need to account for the aerosol water uptake and its influence on light scattering in order to properly capture the overall radiative effects of aerosols. Here we present a comprehensive model–measurement evaluation of the particle light scattering enhancement factor f(RH), defined as the particle light scattering coefficient at elevated RH (here set to 85 %) divided by its dry value. The comparison uses simulations from 10 Earth system models and a global dataset of surface-based in situ measurements. In general, we find a large diversity in the magnitude of predicted f(RH) amongst the different models, which can not be explained by the site types. Based on our evaluation of sea salt scattering enhancement and simulated organic mass fraction, there is a strong indication that differences in the model parameterizations of hygroscopicity and model chemistry are driving at least some of the observed diversity in simulated f(RH). Additionally, a key point is that defining dry conditions is difficult from an observational point of view and, depending on the aerosol, may influence the measured f(RH). The definition of dry also impacts our model evaluation, because several models exhibit significant water uptake between RH = 0 % and 40 %. The multisite average ratio between model outputs and measurements is 1.64 when RH = 0 % is assumed as the model dry RH and 1.16 when RH = 40 % is the model dry RH value. The overestimation by the models is believed to originate from the hygroscopicity parameterizations at the lower RH range which may not implement all phenomena taking place (i.e., not fully dried particles and hysteresis effects). This will be particularly relevant when a location is dominated by a deliquescent aerosol such as sea salt. Our results emphasize the need to consider the measurement conditions in such comparisons and recognize that measurements referred to as dry may not be dry in model terms. Recommendations for future model–measurement evaluation and model improvements are provided.

KMT2A -rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A -R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A -R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. Silencing SET specifically abolished the clonogenic ability of KMT2A -R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10 . Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A -R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3β, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A -R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.

The syntheses of trans‐[Ru(C≡CC6H4‐4‐CHO)(C≡CC6H4‐4‐R)(dppe)2] (R=H (9 a), NO2 (9 b), CHO (9 c), C≡CC6H3‐3,5‐Et2 (9 d), (E)‐CHCHC6H4‐4‐tBu (9 e); dppe=1,2‐bis(diphenylphosphino)ethane), trans‐[Ru(C≡CC6H4‐4‐R)Cl(dppe)2] (R=C≡CC6H3‐3,5‐Et2 (11 a), (E)‐CHCHC6H4‐4‐tBu (11 b), (E)‐CHCHC6H4‐4‐NO2 (11 c)), 1,2,4,5‐trans‐[(dppe)2(RC6H4C≡C)RuC≡CC6H4‐4‐(E)‐CHCH]4C6H2 (R=H (14 a), C≡CC6H3‐3,5‐Et2 (14 b), (E)‐CHCHC6H4‐4‐tBu (14 c)), 1‐I‐3,5‐trans‐[(L2)2(R)RuC≡CC6H4‐4‐(E)‐CHCH]2C6H3 (L2=1,1‐bis(diphenylphosphino)methane (dppm)), R=Cl (15 a); L2=dppe, R=C≡CPh (15 b), R=C≡CC6H4‐4‐NO2 (15 c)), 1‐Me3SiC≡C‐3,5‐trans‐[(L2)2(R)RuC≡CC6H4‐4‐(E)‐CHCH]2C6H3 (L2=dppm, R=Cl (16 a); L2=dppe, R=C≡CPh (16 b)), 1‐HC≡C‐3,5‐trans‐[(dppe)2(R)RuC≡CC6H4‐4‐(E)‐CHCH]2C6H3 (R=Cl (17 a), R=C≡CPh (17 b)), and 1,3,5‐trans‐[(dppe)2(3,5‐R2‐C6H3C≡C)RuC≡CC6H4‐4‐(E)‐CHCH]3C6H3 (R=(E)‐CHCHC6H4‐4‐C≡C‐trans‐[Ru(C≡CPh)(dppe)2] (18)) are reported together with those of the precursor alkynes 1‐RC≡C‐3,5‐Et2C6H3 (R=SiMe3 (2), H (3), C6H4‐4‐C≡CSiMe3 (5), C6H4‐4‐C≡CH (6)). The identities of 9 c, 9 d, 9 e, 11 a, and trans‐[RuC≡CC6H4‐4‐(E)‐CHCHC6H4‐4‐tBu2(dppe)2] (12 and 12′) were confirmed by single‐crystal X‐ray diffraction studies. The electrochemical properties of 9 a–e, 11 a–b, 14 a–c, 15 a–c, 16 b, 17 a, 17 b, and 18 were assessed by cyclic voltammetry; the studies reveal that potentials for the fully/quasi‐reversible metal‐centered oxidation processes decrease upon introduction of solubilizing alkyl substituents and increase upon increasing acceptor substituent strength; other structural variations have little impact. UV/Vis‐NIR spectroscopic studies on these complexes reveal lowest‐energy metal–ligand charge transfer (MLCT) bands that redshift upon increasing the acceptor substituent strength, blueshift on alkyl incorporation, and gain in intensity on progression from linear to star complexes. Low‐temperature UV/Vis‐NIR spectroelectrochemical studies of 14 a–c show the appearance of an intense low‐energy band at 7400–7900 cm−1 that is redshifted upon π‐system lengthening and alkyl substituent incorporation. The cubic nonlinear optical properties of 9 d, 9 e, 14 a–c, 15 a–c, 16 b, 17 a, b, and 18 were assayed by femtosecond Z‐scan studies at benchmark wavelengths (750 and 800 nm) in the near‐IR region, with nonlinearity increasing upon nitro incorporation; the values for the E‐ene‐linked dendrimers in these studies are much larger than yne‐linked analogues. Compounds 9 d, 9 e, 14 a–c, and 18 were further examined by broad‐spectral‐range femtosecond Z‐scan studies; the cruciform complexes have appreciable multiphoton absorption cross‐sections, with maximal values close to two and three times the wavelength of the linear optical absorption maxima. Super stars: (4‐Formylphenylethynyl)ruthenium complexes (see figure) are shown to undergo “chemistry‐on‐complex” Horner–Wadsworth–Emmons coupling to afford a range of tri‐ and tetraruthenium‐functionalized star molecules and a nonaruthenium dendrimer. The products are nonlinear optical (NLO)‐active, with linear optical properties that are redox‐switchable.