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Haploinsufficiency drives Darwinian evolution. Siblings, while alike in many aspects, differ due to monoallelic differences inherited from each parent. In cancer, solid tumors exhibit aneuploid genetics resulting in hundreds to thousands of monoallelic gene-level copy-number alterations (CNAs) in each tumor. Aneuploidy patterns are heterogeneous, posing a challenge to identify drivers in this high-noise genetic environment. Here, we developed Shifted Weighted Annotation Network (SWAN) analysis to assess biology impacted by cumulative monoallelic changes. SWAN enables an integrated pathway-network analysis of CNAs, RNA expression, and mutations via a simple web platform. SWAN is optimized to best prioritize known and novel tumor suppressors and oncogenes, thereby identifying drivers and potential druggable vulnerabilities within cancer CNAs. Protein homeostasis, phospholipid dephosphorylation, and ion transport pathways are commonly suppressed. An atlas of CNA pathways altered in each cancer type is released. These CNA network shifts highlight new, attractive targets to exploit in solid tumors.

Context. The origin of the slow solar wind is still an open issue. One possibility that has been suggested is that upflows at the edge of an active region can contribute to the slow solar wind. Aims. We aim to explain how the plasma upflows are generated, which mechanisms are responsible for them, and what the upflow region topology looks like. Methods. We investigated an upflow region using imaging data with the unprecedented temporal (3 s) and spatial (2 pixels = 236 km) resolution that were obtained on 30 March 2022 with the 174 channel of the Extreme-Ultraviolet Imager (EUI)/High Resolution Imager (HRI) on board Solar Orbiter. During this time, the EUI and Earth-orbiting satellites (Solar Dynamics Observatory, Hinode, and the Interface Region Imaging Spectrograph, IRIS) were located in quadrature (∼92), which provides a stereoscopic view with high resolution. We used the Hinode/EIS (Fe XII) spectroscopic data to find coronal upflow regions in the active region. The IRIS slit-jaw imager provides a high-resolution view of the transition region and chromosphere. Results. For the first time, we have data that provide a quadrature view of a coronal upflow region with high spatial resolution. We found extended loops rooted in a coronal upflow region. Plasma upflows at the footpoints of extended loops determined spectroscopically through the Doppler shift are similar to the apparent upward motions seen through imaging in quadrature. The dynamics of small-scale structures in the upflow region can be used to identify two mechanisms of the plasma upflow: Mechanism I is reconnection of the hot coronal loops with open magnetic field lines in the solar corona, and mechanism II is reconnection of the small chromospheric loops with open magnetic field lines in the chromosphere or transition region. We identified the locations in which mechanisms I and II work., Astronomy & Astrophysics, 673, ISSN:0004-6361, ISSN:1432-0746

BackgroundThe kidney vasculature is exquisitely structured to orchestrate renal function. Structural profiling of the vasculature in intact rodent kidneys, has provided insights into renal haemodynamics and oxygenation, but has never been extended to the human kidney beyond a few vascular generations. We hypothesised that synchrotron-based imaging of a human kidney would enable assessment of vasculature across the whole organ.MethodsAn intact kidney from a 63-year-old male was scanned using hierarchical phase-contrast tomography (HiP-CT), followed by semi-automated vessel segmentation and quantitative analysis. These data were compared to published micro-CT data of whole rat kidney.ResultsThe intact human kidney vascular network was imaged with HiP-CT at 25 μm voxels, representing a 20-fold increase in resolution compared to clinical CT scanners. Our comparative quantitative analysis revealed the number of vessel generations, vascular asymmetry and a structural organisation optimised for minimal resistance to flow, are conserved between species, whereas the normalised radii are not. We further demonstrate regional heterogeneity in vessel geometry between renal cortex, medulla, and hilum, showing how the distance between vessels provides a structural basis for renal oxygenation and hypoxia.ConclusionsThrough the application of HiP-CT, we have provided the first quantification of the human renal arterial network, with a resolution comparable to that of light microscopy yet at a scale several orders of magnitude larger than that of a renal punch biopsy. Our findings bridge anatomical scales, profiling blood vessels across the intact human kidney, with implications for renal physiology, biophysical modelling, and tissue engineering.SIGNIFICANCE STATEMENTHigh-resolution, three-dimensional, renal vasculature models are currently highly reliant on data obtained from rodent kidneys. Obtaining this information in a human kidney is difficult, given its size and scale. Here, we overcome this challenge through synchrotron-based imaging to profile the vasculature of an intact human kidney. Organ-wide vascular network metrics are shown to be largely conserved between human and rat kidneys. Regional and spatial heterogeneities between cortical, medullary, and hilar vascular architecture are revealed, highlighting a structural basis for renal oxygen gradients in humans. This is, to our knowledge, the first time the vasculature of a human kidney has been mapped in its entirety, with implications for understanding how the hierarchy of individual blood vessel segments collectively scales to renal function.

BackgroundHyperglycemia is common during acute myocardial infarction, irrespective of diabetic status, and portends excess mortality. The mechanisms of this adverse outcome remain unelucidated.ObjectivesTo test the hypothesis that elevated glucose, at the time of reperfusion following myocardial ischemia, is directly injurious to the heart through induction of sodium/glucose-linked transporter 1 (SGLT1) activity.MethodsEx-vivo, Langendorff rodent models of 35minute global ischemia and 2hour reperfusion injury were utilised, with variable glucose and reciprocal mannitol concentrations maintaining equivalent osmolarity across groups during reperfusion. Infarct size was assessed by tri-phenyltetrazolium staining. SGLT1 expression was determined in rodents by rtPCR, RNAscope and immunohistochemistry and in human with single-cell transcriptomic analysis.Ex-vivo, functional involvement of SGLT1 was determined using three, structurally distinct pharmacological inhibitors: phlorizin, canagliflozin and mizagliflozin.ResultsIn non-diabetic rodent hearts there was a J-shaped dose-response relationship between reperfusion-glucose concentration and infarct size, an association ameliorated in diabetic heart. Single-cell transcriptomic analysis revealed human myocardial SGLT1 expression equivalent to that seen in rodents at both an RNA and protein level. Diabetic rodent heart SGLT1 expression was significantly reduced compared to non-diabetic, and pharmacological SGLT1 inhibition abrogated excess injury associated with high glucose in non-diabetic heart.ConclusionElevated glucose during reperfusion exacerbated myocardial infarction in non-diabetic heart, but this exacerbation was attenuated in diabetic rat heart where SGLT1 expression is suppressed. Inhibiting non-diabetic heart SGLT1 abrogates the excess injury associated with elevated glucose, thus highlighting SGLT1 as a potential clinical translational target to improve outcomes in acute myocardial infarction associated with hyperglycemia.

The MEaSUREs Calibrated Enhanced-Resolution Passive Microwave Daily Equal-Area Scalable Earth Grid 2.0 Brightness Temperature (CETB) Earth System Data Record (ESDR) includes conventional- and enhanced-resolution radiometer brightness temperature (TB) images on standard, compatible grids from calibrated satellite radiometer measurements collected over a multi-decade period. Recently, the CETB team processed the first 4 years of enhanced resolution Soil Moisture Active Passive (SMAP) L-band (1.41 GHz) radiometer TB images. The CETB processing employs the radiometer form of the Scatterometer Image Reconstruction (rSIR) algorithm to create enhanced resolution images, which are posted on fine resolution grids. In this paper, we evaluate the effective resolution of the SMAP TB image products using coastline and island crossings. We similarly evaluate the effective resolution of the SMAP L1C_TB_E enhanced resolution product that is based on Backus-Gilbert processing. We present a comparison of the spatial resolution of the rSIR and L1C_TB_E enhanced resolution products with conventionally-processed (gridded) SMAP data. We find that the effective resolution of daily CETB rSIR SMAP TB images is slightly finer than that of L1C_TB_E and about 30% finer than conventionally processed data.

The solar chromosphere hosts a wide variety of transients, including dynamic fibrils (DFs) that are characterised as elongated, jet-like features seen in active regions, often through Hα diagnostics. So far, these features have been difficult to identify in coronal images, primarily due to their small size and the lower spatial resolution of the current extreme-ultraviolet (EUV) imagers. Here we present the first unambiguous signatures of DFs in coronal EUV data using high-resolution images from the Extreme Ultraviolet Imager (EUI) on board Solar Orbiter. Using the data acquired with the 174 Å High Resolution Imager (HRIEUV) of EUI, we find many bright dot-like features (with a size of 0.3-0.5 Mm) that move up and down (often repeatedly) in the core of an active region. In a space-time map, these features produce parabolic tracks akin to the chromospheric observations of DFs. Properties such as their speeds (14 km s-1), lifetime (332 s), deceleration (82 m s-2), and lengths (1293 km) are also reminiscent of the chromospheric DFs. The EUI data strongly suggest that these EUV bright dots are basically the hot tips (of the cooler chromospheric DFs) that could not be identified unambiguously before because of a lack of spatial resolution., Astronomy & Astrophysics, 670, ISSN:0004-6361, ISSN:1432-0746

Lipopolysaccharide (LPS) is a known inducer of inflammatory signaling which triggers generation of reactive oxygen species (ROS) and cell death in responsive cells like THP-1 promonocytes and freshly isolated human monocytes. A key LPS-responsive metabolic pivot point is the 9.5 megadalton mitochondrial pyruvate dehydrogenase complex (PDC), which provides pyruvate dehydrogenase (E1), lipoamide-linked transacetylase (E2) and lipoamide dehydrogenase (E3) activities to produce acetyl-CoA from pyruvate. While phosphorylation-dependent decreases in PDC activity following LPS treatment or sepsis have been deeply investigated, redox-linked processes have received less attention. Data presented here demonstrate that LPS-induced reversible oxidation within PDC occurs in PDCE2 in both THP-1 cells and primary monocytes. Knockout of PDCE2 by CRISPR and expression of FLAG-tagged PDCE2 in THP-1 cells demonstrated that LPS-induced glutathionylation is associated with wild type PDCE2 but not mutant protein lacking the lipoamide-linking lysine residues. Moreover, the mitochondrially-targeted electrophile MitoCDNB elevates ROS similar to LPS but does not cause PDCE2 glutathionylation. However, both LPS and MitoCDNB together are synergistic for PDCE2 glutathionylation, ROS production, and cell death. These results suggest that glutathionylation on PDCE2 lipoamide sulfurs is a specific modification associated with LPS and cell death which is not recapitulated by a general rise in mitochondrial ROS, but is enhanced after LPS treatment by rising oxidative stress exerted by MitoCDNB that impairs reductase systems.HighlightsPDCE2 is oxidized and glutathionylated (-SSG) during acute inflammation in monocytesPDCE2 knockout cells exhibit decreased ROS production during acute inflammationLipopolysaccharide-induced PDCE2-SSG occurs in THP1 cells and fresh monocytesLipoamide-deficient PDCE2 exhibits lower LPS-induced PDCE2-SSG and ROS productionMitoCDNB leads to ROS production but not PDCE2-SSG, but is synergistic with LPSGraphical Abstract

Sun-as-a-star coronal plasma composition, derived from full-Sun spectra, and the F10.7 radio flux (2.8 GHz) have been shown to be highly correlated (r = 0.88) during solar cycle 24. However, this correlation becomes nonlinear during increased solar magnetic activity. Here, we use co-temporal, high spatial resolution, multi-wavelength images of the Sun to investigate the underlying causes of the non-linearity between coronal composition (FIP bias) and F10.7 solar index correlation. Using the Karl G. Jansky Very Large Array (JVLA), Hinode/EIS (EUV Imaging Spectrometer), and the Solar Dynamic Observatory (SDO), we observed a small active region, AR 12759, throughout the solar atmosphere from the photosphere to the corona. Results of this study show that the magnetic field strength (flux density) in active regions plays an important role in the variability of coronal abundances, and it is likely the main contributing factor to this non-linearity during increased solar activity. Coronal abundances above cool sunspots are lower than in dispersed magnetic plage regions. Strong magnetic concentrations are associated with stronger F10.7 cm gyroresonance emission. Considering that as the solar cycle moves from minimum to maximum, the size of sunspots and their field strength increase with gyroresonance component, the distinctly different tendencies of radio emission and coronal abundances in the vicinity of sunspots is the likely cause of saturation of Sun-as-a-star coronal abundances during solar maximum, while the F10.7 index remains well correlated with the sunspot number and other magnetic field proxies., Comment: 15 pages, 5 figures, 2 tables, accepted for publication in The Astrophysical Journal

BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4 functions on transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interacts with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 recruitment to acetylated histones/chromatin. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation–dependent regulatory mechanism of BRD4 and highlight targeting PRMT2/4 for better antitumor effect of BET inhibitors and DNA damaging agents.

Studies of the structural and molecular features of the lymphatic vasculature, which clears fluid, macromolecules and leukocytes from the tissue microenvironment, have largely relied on animal models, with limited information in human organs beyond traditional immunohistochemical assessment. Here, we use three-dimensional imaging and single-cell RNA-sequencing to study lymphatics in the human kidney. We found a hierarchical arrangement of lymphatic vessels within human kidneys, initiating along specialised nephron epithelium in the renal cortex and displaying a distinct, kidney-specific transcriptional profile. In chronic transplant rejection we found kidney allograft lymphatic expansion alongside a loss of structural hierarchy, with human leukocyte antigen-expressing lymphatic vessels infiltrating the medulla, presenting a putative target for alloreactive antibodies. This occurred concurrently with lymphatic vessels invading and interconnecting tertiary lymphoid structures at early stages of lymphocyte colonisation. Analysis of intercellular signalling revealed upregulation of co-inhibitory molecule-mediated CD4+T cell-lymphatic crosstalk in rejecting kidneys, potentially acting to limit local alloimmune responses. Overall, we delineate novel structural and molecular features of human kidney lymphatics and reveal perturbations to their phenotype and transcriptome in the context of alloimmunity.SUMMARYLymphatics regulate fluid balance and immune cell accumulation but are under-studied in human organs such as the kidney. Jafree and colleagues profiled human kidney lymphatics using three-dimensional imaging and single-cell RNA-sequencing, revealing structural and transcriptional perturbations in rejecting kidney transplants.

Quasiperiodically driven fermionic systems can support topological phases not realized in equilibrium. The fermions are localized in the bulk, but support quantized energy currents at the edge. These phases were discovered through an abstract classification, and few microscopic models exist. We develop a coupled layer construction for tight-binding models of these phases in $d\in\{1,2\}$ spatial dimensions, with any number of incommensurate drive frequencies $D$. The models exhibit quantized responses associated with synthetic two- and four-dimensional quantum Hall effects in the steady state. A numerical study of the phase diagram for $(d+D) = (1+2)$ shows: (i) robust topological and trivial phases separated by a sharp phase transition; (ii) charge diffusion and a half-integer energy current between the drives at the transition; and (iii) a long-lived topological energy current which remains present when weak interactions are introduced., Comment: 15 pages, 11 figures; (v2) published version

The glomerulus mediates kidney ultrafiltration through specialised epithelial cells called podocytes which line a basement membrane shared with blood capillary endothelium. Cell-cell crosstalk is critical for glomerular function, but its investigation in childhood glomerular diseases has received little attention.WT1encodes a transcription factor expressed in podocytes, whose heterozygous variants cause devastating kidney disease in childhood. We used single-cell RNA sequencing and ligand-receptor interaction analysis to resolve the glomerular transcriptional landscape of mice that carry an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell type in early disease, with disrupted angiogenic signalling preceding glomerular capillary loss. Comparative analyses with additional murine and human glomerular disease datasets identified unique transcriptional changes in WT1 glomerular disease, reflecting a non-immunological pathology, whilst revealing a common injury signature across multiple glomerular diseases. Collectively, this work advocates vascular-based therapies over immunosuppressive drugs in the treatment of WT1 glomerular disease.

Background Osteoarthritis (OA) is the most prevalent form of joint disease and commonly affects the hip. Hip OA is associated with a high socioeconomic burden. Intra-articular hyaluronic acid (HA) injection may be of benefit but quality evidence for HA use in hip OA is lacking. The purpose of this study was to assess the safety and efficacy of ultrasound guided injection of a high molecular weight, non-animal derived, stabilised HA (NASHA) in patients with mild to moderate hip OA. Methods This single site study is an analysis of prospectively collected outcome data for 87 consecutive patients over a 2-year period who received a single HA (Durolane) injection for symptomatic hip OA. Inclusion criteria were male or female patients over 18-years of age with mild to moderate hip OA on x-ray. Patients with severe hip OA were excluded. The primary outcome measure was a modified Harris Hip Score (mHHS) questionnaire at baseline and 6-weeks with a minimal clinically important difference (MCID) of 10 points. All adverse events were recorded and assessed. Results Data from 87 patients, 49 women and 38 men with mean age of 54 (SD = 10.8) were analysed. At baseline, mean mHHS was 58.47 (SD 14.31). At the 6 week follow up, mean mHHS improved to 71.30 (SD 16.46), a difference of 12.83 (p Conclusion A single injection of HA (NASHA) in the setting of hip joint OA was both safe and efficacious in this 87 patient cohort. Improvement in pain and function as measured with mHHS was statistically significant and reached the MCID of 10. Trial registration The study was retrospectively registered on the 1st of February 2021 in the Australian New Zealand Clinical Trials Registry with registry number ACTRN12621000098831. All research was performed in accordance with the Declaration of Helsinki.

Image reconstruction from discrete samples is fundamental in remote sensing. The reconstruction problem is more complicated when the sample locations are irregularly spaced and employ different aperture functions. Further, not all 2-D sampling configurations permit full image reconstruction of band-limited signals. In this article, 2-D signal reconstruction from irregular samples with variable apertures is considered using theory and examples. Exact reconstruction requires that the signal be band-limited and the sampling matrix be invertable. The results are sensitive to the sample locations and noise in the measurements. Illustrative examples are provided using simulation and actual data from the L-band Soil Moisture Active Passive (SMAP) radiometer. The general approach can be employed with other sensors.

The genus Moerckia Gottsche belongs to the order Pallaviciniales, the phylogeny of which has been insufficiently studied. We re-evaluate the phylogenetic position of M. blyttii and the importance o...

Plasma ultrafiltration in the kidney occurs across glomerular capillaries, which are surrounded by epithelial cells called podocytes. Podocytes have a unique shape maintained by a complex cytoskeleton, which becomes disrupted in glomerular disease resulting in defective filtration and albuminuria. Lack of endogenous thymosin β4 (TB4), an actin sequestering peptide, exacerbates glomerular injury and disrupts the organisation of the podocyte actin cytoskeleton, however, the potential of exogenous TB4 therapy to improve podocyte injury is unknown. Here, we have used Adriamycin (ADR), a toxin which injures podocytes and damages the glomerular filtration barrier leading to albuminuria in mice. Through interrogating single-cell RNA-sequencing data of isolated glomeruli we demonstrate that ADR injury results in reduced levels of podocyte TB4. Administration of an adeno-associated viral vector encoding TB4 increased the circulating level of TB4 and prevented ADR-induced podocyte loss and albuminuria. ADR injury was associated with disorganisation of the podocyte actin cytoskeleton in vitro, which was ameliorated by treatment with exogenous TB4. Collectively, we propose that systemic gene therapy with TB4 prevents podocyte injury and maintains glomerular filtration via protection of the podocyte cytoskeleton thus presenting a novel treatment strategy for glomerular disease.

Summary Congenital lower urinary tract disorders are a family of diseases affecting both urinary storage and voiding as well as upstream kidney function. Current treatments include surgical reconstruction but many children still fail to achieve urethral continence or progress to chronic kidney disease. New therapies can only be achieved through undertaking research studies to enhance our understanding of congenital lower urinary tract disorders. Animal models form a critical component of this research, a corner of the triangle composed of human in-vitro studies and clinical research. We describe the current animal models for two rare congenital bladder disorders, posterior urethral valves (PUV) and bladder exstrophy (BE). We highlight important areas for researchers to consider when deciding which animal model to use to address particular research questions and outline the strengths and weaknesses of current models available for PUV and BE. Finally, we present ideas for refining animal models for PUV and BE in the future to stimulate future researchers and help them formulate their thinking when working in this field.

Wide area multilateration algorithms suffer from stability issues related to the fact that the reference points are nearly coplanar. This paper presents a method to add elevation angle measurements to a multilateration problem and thereby reduce the error perpendicular to the plane where the measurements are taken. The resulting measurement error is significantly reduced for co- planar and nearly coplanar reference points.

Disjunct distributions in bryophytes are well known, but when it comes to the mechanisms that have shaped these distributions, especially for apparently sterile species, the historical processes leading to inter-continental disjunctions remain enigmatic. In this study, we developed microsatellite markers to investigate the spatial distribution and extent of genotypic diversity of 147 Anastrophyllum alpinum samples collected from three populations each in Nepal and Scotland (UK). For a more general insight into genetic differences, sequence divergence in A. alpinum and eight other globally rare and disjunct oceanic-montane liverworts was also assessed. A nested allele distribution of Scottish populations of A. alpinum within the allele range of the Nepalese populations, and lower levels of genetic diversity within Scottish samples indicate that the Scottish populations likely have their origins in the Sino-Himalaya. The evidence for long-distance dispersal was supported by a lack of sequence divergence in chloroplast DNA between Scottish and Nepalese populations, with only a single substitution detected from 5160 bp of plastid sequence. Low levels of sequence divergence were also detected in species with similar distributions. While Scottish populations of A. alpinum do not appear to produce spores, they do still harbour a considerable genetic diversity. This indicates that sexual reproduction has been important at some point in their history. However, the current absence of evidence for sexual reproduction needs to be taken into account when designing conservation actions for these montane species, to ensure population maintenance and ability to track suitable climate and habitat space.

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1 , NOP10 , or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with DKC1 p.Glu206Lys and two children with homozygous NOP10 p.Thr16Met. Females with heterozygous DKC1 p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin–NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin–NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.

Small spacecraft require systems to facilitate safe preflight and launch operations. These include access ports to test software, charge batteries, and monitor spacecraft health after assembly, as well as inhibits to prevent inadvertent operation during servicing, integration, transport, and launch. For CubeSats, the requirements for these features are primarily governed by the CubeSat Design Specification (CDS). The size, weight, and cost of existing, off-the-shelf access port, inhibit, and remove-before-flight implementations can be prohibitive for low-budget, miniaturized spacecraft. This article aims to reduce the size, weight, and cost of CDS-required servicing and safety features. This is achieved by integrating these features into a single system using off-the-shelf, consumer-scale electrical components, including a type-B universal serial bus (USB) mini connector and an FTDI USB to multiserial protocol integrated circuit.

Background Total serum 25-hydroxyvitamin D [25(OH)D] is considered the best marker of vitamin D status and used routinely in clinical practice. However, 25(OH)D is predominantly bound to vitamin D-binding protein (VDBP), and it has been reported that the free-25(OH)D and 25(OH)D loosely bound to albumin fraction correlates better with clinical outcomes. Methods We assessed total-25(OH)D, measured free-25(OH)D, and calculated free-25(OH)D and their relationship with VDBP and biomarkers of mineral metabolism in 61 children (22 CKD 2–3, 18 dialysis, and 21 post-transplant). Results Total-25(OH)D concentrations were comparable across the three groups (p = 0.09), but free- and bioavailable-25(OH)D (free- and albumin-25(OH)D) were significantly lower in the transplant group (both: p = 0.01). Compared to CKD and dialysis patients, the transplant group had significantly higher VDBP concentrations (p = 0.03). In all three groups, total-25(OH)D concentrations were positively associated with measured free-, calculated free-, and bioavailable-25(OH)D. Multivariable regression analysis showed that total-25(OH)D was the only predictor of measured free-25(OH)D concentrations in the dialysis group (β = 0.9; R2 = 90%). In the transplant group, measured free-25(OH)D concentrations were predicted by both total-25(OH)D and VDBP concentrations (β = 0.6, − 0.6, respectively; R2 = 80%). Correlations between parathyroid hormone with total-25(OH)D and measured and calculated free-25(OH)D were only observed in the transplant group (all: p Conclusions In transplanted patients, VDBP concentrations were significantly higher compared to CKD and dialysis patients, and consequently, free-25(OH)D concentrations were lower, despite a comparable total-25(OH)D concentration. We suggest that free-25(OH)D measures may be required in children with CKD, dialysis, and transplant, with further research required to understand its association with markers of mineral metabolism.

The octanol–water partition coefficients (Kow) of the aristolochic acids, AA I and AA II, were determined using the traditional shake-flask method as a function of pH and ionic strength. These compounds have been implicated in the etiology of Balkan endemic nephropathy, but evidence of a plausible exposure pathway remains elusive, and research is constrained by the absence of critical physical–chemical parameters on these compounds. Apparent Kow values were determined across a range of pH and ionic strength conditions. The results show that the apparent Kow decreased by approximately four orders of magnitude as pH increased from 2 to 9. The pH dependence was well described by a simple model that calculated the apparent Kow based on the ionization fractions and intrinsic Kow values for the neutral and ionized species. Higher ionic strength solutions resulted in higher Kow values at high pH, but had no effect at low pH. These results suggest that transport of aristolochic acids will be highly dependent on pH and ionic strength, with significant aqueous-phase transport at neutral to slightly alkaline conditions, with the highest mobility occurring under low ionic strength conditions, and the possibility of significant partitioning to nonpolar phases, such as soil organic matter or plant material, at low pH. Much of the region where BEN is prevalent is a karst environment, and pH values are generally above 8, thus leaching and groundwater transport are favored, which can suggest possible exposure routes.

The kidney contains a network of lymphatic vessels that clear fluid, small molecules, and cells from the renal interstitium. Through modulating immune responses and via crosstalk with surrounding renal cells, lymphatic vessels have been implicated in the progression and maintenance of kidney disease. In this Review, we provide an overview of the development, structure, and function of lymphatic vessels in the healthy adult kidney. We then highlight the contributions of lymphatic vessels to multiple forms of renal pathology, emphasizing CKD, transplant rejection, and polycystic kidney disease and discuss strategies to target renal lymphatics using genetic and pharmacologic approaches. Overall, we argue the case for lymphatics playing a fundamental role in renal physiology and pathology and treatments modulating these vessels having therapeutic potential across the spectrum of kidney disease.

The striking nonlinear effects exhibited by cavity QED systems make them a powerful tool in modern condensed matter and atomic physics. A recently discovered example is the quantized pumping of energy into a cavity by a strongly-coupled, periodically-driven spin. We uncover a remarkable feature of these energy pumps: they coherently translate, or boost, a quantum state of the cavity in the Fock basis. Current optical cavity and circuit QED experiments can realize the required Hamiltonian in a rotating frame. Boosting thus enables the preparation of highly-excited non-classical cavity states in near-term experiments., 6 pages, 4 figures + 6 pages, 6 figures; (v2) Clarifications on experimental considerations, including an additional appendix on the lab frame evolution

Gaining insight into different cell behaviors is key to better understanding different pathologies. These behaviors may be explained in part through close observation of 3D cell morphology. Therefore, the objective of this research was to develop a machine learning (ML) framework that can predict 3D subcellular morphological variation of endothelial cells (ECs) to generate digital twins. ECs were cultured and their membrane, nucleus, and focal adhesion (FA) sites were stained and imaged with confocal microscopy. The multicellular confocal z stacks were segmented resulting in a total of 60 single-cell stacks. Fifty randomly picked cells were augmented 20-fold to train the ML framework, and the remaining 10 were used for an independent test of prediction accuracy. The ML framework was based on an open-source conditional generative adversarial network (cGAN), which was expanded to make 3D predictions using membrane only as input to predict nucleus and FA morphology. After training the framework, the results on the independent test showed an average prediction accuracy of ~87% for nucleus and ~70% for FA sites. The predictions were used to build a digital twin of each EC and compared to their respective ground truth, showing an average ~79% global accuracy and ~84% accuracy in FA-Nucleus distribution. The results presented show the effectiveness of the developed ML framework to generate digital twins of ECs using limited amount of data. These digital twins can be used to couple EC morphology with different behaviors. The ML framework can be potentially expanded to predict morphology of other subcellular structures as well as to study other types of cells.

Urban settlements are rapidly growing outward and upward, with consequences for resource use, greenhouse gas emissions, and ecosystem and public health, but rates of change are uneven around the world. Understanding trajectories and predicting consequences of global urban expansion requires quantifying rates of change with consistent, well-calibrated data. Microwave backscatter data provides important information on upward urban growth – essentially the vertical built-up area. We developed a multi-sensor, multi-decadal, gridded (0.05° lat/lon) data set of global urban microwave backscatter, 1993–2020. Comparison of backscatter from two C-band sensors (ERS and ASCAT) and one Ku-band sensor (QuikSCAT) are made at four invariant non-urban sites (~3500 km2) to evaluate instrument stability and multi-decadal pattern. For urban areas, there was a strong linear correlation (overall R2 = 0.69) between 2015 ASCAT urban backscatter and a continental-scale gridded product of building volume, across 8450 urban grid cells (0.05° × 0.05°) in Europe, China, and the USA. This urban backscatter data set provides a time series characterizing global urban change over the past three decades.

Plasma ultrafiltration in the kidney occurs across glomerular capillaries, which are surrounded by epithelial cells called podocytes. Podocytes have a unique shape maintained by a complex cytoskeleton, which becomes disrupted in glomerular disease resulting in defective filtration and albuminuria. Lack of endogenous thymosin β4 (TB4), an actin sequestering peptide, exacerbates glomerular injury and disrupts the organisation of the podocyte actin cytoskeleton, however, the potential of exogenous TB4 therapy to improve podocyte injury is unknown. Here, we have used Adriamycin (ADR), a toxin which injures podocytes and damages the glomerular filtration barrier leading to albuminuria in mice. Through interrogating single-cell RNA-sequencing data of isolated glomeruli we demonstrate that ADR injury results in reduced levels of podocyte TB4. Administration of an adeno-associated viral vector encoding TB4 increased the circulating level of TB4 and prevented ADR-induced podocyte loss and albuminuria. ADR injury was associated with disorganisation of the podocyte actin cytoskeleton in vitro, which was ameliorated by treatment with exogenous TB4. Collectively, we propose that systemic gene therapy with TB4 prevents podocyte injury and maintains glomerular filtration via protection of the podocyte cytoskeleton thus presenting a novel treatment strategy for glomerular disease.

Basement membranes (BMs) are complex macromolecular networks underlying all continuous layers of cells. Essential components include collagen IV and laminins, which are affected by human genetic variants leading to a range of debilitating conditions including kidney, muscle, and cerebrovascular phenotypes. We investigated the dynamics of BM assembly in human pluripotent stem cell-derived kidney organoids. We resolved their global BM composition and discovered a conserved temporal sequence in BM assembly that paralleled mammalian fetal kidneys. We identified the emergence of key BM isoforms, which were altered by a pathogenic variant in COL4A5. Integrating organoid, fetal, and adult kidney proteomes, we found dynamic regulation of BM composition through development to adulthood, and with single-cell transcriptomic analysis we mapped the cellular origins of BM components. Overall, we define the complex and dynamic nature of kidney organoid BM assembly and provide a platform for understanding its wider relevance in human development and disease.

Riccardia fuscovirens Lindb. is lectotypified and the lectotype is described. It is morphologically very similar to Aneura pinguis and provisionally regarded as synonym to it.

Here, we present a study of the phenomena of decayless kink oscillations in a system of active-region (AR) coronal loops. Using high-resolution observations from two different instruments, namely the Extreme Ultraviolet Imager (EUI) on board Solar Orbiter and the Atmospheric Imaging Assembly (AIA) on board the Solar Dynamics Observatory, we follow these AR loops for an hour each on three consecutive days. Our results show significantly more resolved decayless waves in the higher resolution EUI data compared with the AIA data. Furthermore, the same system of loops exhibits many of these decayless oscillations on Day 2, while we detect very few oscillations on Day 3 , and find none at all on Day 1. Analysis of photospheric magnetic field data reveals that, most of the time, these loops were rooted in sunspots, where supergranular flows are generally absent. This suggests that supergranular flows, which are often invoked as drivers of decayless waves, are not necessarily driving such oscillations in our observations. Similarly, our findings also cast doubt on other possible drivers of these waves, such as a transient driver or mode conversion of longitudinal waves near the loop footpoints. In conclusion, our analysis suggests that none of the commonly suspected sources proposed to drive decayless oscillations in active-region loops seem to be operating in this event, and therefore the search for that elusive wave driver needs to continue., Astronomy & Astrophysics, 666, ISSN:0004-6361, ISSN:1432-0746

Background: Greater trochanteric pain syndrome (GTPS) is a debilitating chronic condition, most prevalent in postmenopausal women. A positive association between high estrogen levels and tendon health may exist, and postmenopausal women have reduced estrogen. Menopausal hormone therapy (MHT) may reduce the incidence of tendon abnormality, particularly when combined with exercise. Purpose: To determine the effect of MHT and exercise on tendon pain and function in postmenopausal women with GTPS. Study Design: Randomized controlled clinical trial; Level of evidence, 1. Methods: Postmenopausal women (N = 132; n = 12, lost to follow-up) with GTPS were randomized into MHT and placebo transdermal cream groups combined with tendon-specific or sham exercise. All groups received education about avoiding gluteal tendon compression and load management throughout 12 weeks of intervention. The primary outcome was the Victorian Institute of Sport Assessment for gluteal tendinopathy (VISA-G), and secondary outcomes were measured at baseline and at 12 and 52 weeks. The Global Rating of Change was assessed at 12 and 52 weeks. A linear mixed-effects model was used to assess differences. Body mass index (BMI) was included as a covariate. Results: All participant groups improved over time (baseline vs 12 weeks, P < .001; baseline vs 52 weeks, P < .001). There was no difference among exercise groups measured by all outcomes (VISA-G: baseline, P = .97, mean difference [MD] = 0.10; 12 weeks, P = .49, MD = 2.15; 52 weeks, P = .32, MD = −3.08). There was a significant interaction effect between cream and BMI; therefore, the population was stratified by BMI levels (Conclusion: MHT or placebo combined with tendon-specific or sham exercise plus education reduced pain and increased function for this population. For women with a BMI Registration: ACTRN12614001157662 (Australian New Zealand Clinical Trials Registry).

As the cells that line the vasculature, endothelial cells are continually exposed to fluid shear stress by blood flow. Recent studies suggest that the morphological response of endothelial cells to fluid shear stress depends on the endothelial cell type. Thus, the present study characterizes the morphological response of human dermal microvascular endothelial cells (HMEC-1) and nuclei to steady, laminar, and unidirectional fluid shear stress. Cultured HMEC-1 monolayers were exposed to shear stress of 0.3 dyn/cm

Understanding cell behaviors can provide new knowledge on the development of different pathologies. Focal adhesion (FA) sites are important sub-cellular structures that are involved in these processes. To better facilitate the study of FA sites, deep learning (DL) can be used to predict FA site morphology based on limited datasets (e.g., cell membrane images). However, calculating the accuracy score of these predictions can be challenging due to the discrete/point pattern like nature of FA sites. In the present work, a new image similarity metric, discrete protein metric (DPM), was developed to calculate FA prediction accuracy. This metric measures differences in distribution (d), shape/size (s), and angle (a) of FA sites between the predicted image and its ground truth image. Performance of the DPM was evaluated by comparing it to three other commonly used image similarity metrics: Pearson correlation coefficient (PCC), feature similarity index (FSIM), and Intersection over Union (IoU). A sensitivity analysis was performed by comparing changes in each metric value due to quantifiable changes in FA site location, number, aspect ratio, area, or orientation. Furthermore, accuracy score of DL-generated predictions was calculated using all four metrics to compare their ability to capture variation across samples. Results showed better sensitivity and range of variation for DPM compared to the other metrics tested. Most importantly, DPM had the ability to determine which FA predictions were quantitatively more accurate and consistent with qualitative assessments. The proposed DPM hence provides a method to validate DL-generated FA predictions and can be extended to evaluating other predicted or segmented discrete structures of biomedical relevance.

Double-strand breaks (DSBs) are one of the most toxic forms of DNA damage and represent a major source of genomic instability. Members of the bromodomain and extra-terminal (BET) protein family are characterized as epigenetic readers that regulate gene expression. However, evidence suggests that BET proteins also play a more direct role in DNA repair. Here, we establish a cell-free system using Xenopus egg extracts to elucidate the gene expression-independent functions of BET proteins in DSB repair. We identify the BET protein BRD4 as a critical regulator of homologous recombination and describe its role in stimulating DNA processing through interactions with the SWI/SNF chromatin remodeling complex and resection machinery. These results establish BRD4 as a multifunctional regulator of chromatin binding that links transcriptional activity and homology-directed repair.