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Roundabout guidance receptor 2 (ROBO2) plays an important role during early kidney development. ROBO2 is expressed in podocytes, inhibits nephrin-induced actin polymerization, down-regulates nonmuscle myosin IIA activity, and destabilizes kidney podocyte adhesion. However, the role of ROBO2 during kidney injury, particularly in mature podocytes, is not known. Herein, we report that loss of ROBO2 in podocytes [Robo2 conditional knockout (cKO) mouse] is protective from glomerular injuries. Ultrastructural analysis reveals that Robo2 cKO mice display less foot process effacement and better-preserved slit-diaphragm density compared with wild-type littermates injured by either protamine sulfate or nephrotoxic serum (NTS). The Robo2 cKO mice also develop less proteinuria after NTS injury. Further studies reveal that ROBO2 expression in podocytes is up-regulated after glomerular injury because its expression levels are higher in the glomeruli of NTS injured mice and passive Heymann membranous nephropathy rats. Moreover, the amount of ROBO2 in the glomeruli is also elevated in patients with membranous nephropathy. Finally, overexpression of ROBO2 in cultured mouse podocytes compromises cell adhesion. Taken together, these findings suggest that kidney injury increases glomerular ROBO2 expression that might compromise podocyte adhesion and, thus, loss of Robo2 in podocytes could protect from glomerular injury by enhancing podocyte adhesion that helps maintain foot process structure. Our findings also suggest that ROBO2 is a therapeutic target for podocyte injury and podocytopathy.

Some flexible appendages, such as solar panels, communication antenna and other large structures are mounted on the base of the space robot. The structure flexibilities will cause vibration during the operation of manipulators. Due to complicated dynamic coupling among manipulators, the rigid base and flexible appendages, it is very challenging to control the end-effector to track inertial trajectories, especially when the target states are constantly changing. This paper proposes a vibration suppression method for autonomous target capturing during the preimpact phase without controlling the base. Firstly, we derive the rigid-flexible coupling dynamics of a space robot system with flexible appendages. Then, the relationship among joint rates, elastic motion and the end-effector velocities is established by using the linear momentum and angular momentum conservation equations. Secondly, a closed-loop control system is designed based on the dynamic coupling model. And the control system is composed of target motion prediction, autonomous trajectory planning, energy-based joint controllers and so on. Thirdly, the energy-based joint control is detailed, which is proved to be stable by Lyapunov direct method. Finally, simulations of a planar space robot with two flexible appendages and a 3D space robot with single flexible appendage are provided to verify the effectiveness of the presented approach. The effectiveness of energy-based joint control for vibration suppression is verified by a single-degree-of-freedom space robot experimental system. The simulation and experimental results show that the space manipulator can successfully capture the moving target while suppressing the structure vibration.

Slit guidance ligand 2 (SLIT2) is a large, secreted protein that binds roundabout (ROBO) receptors on multiple cell types, including neurons and kidney podocytes. SLIT2-ROBO–mediated signaling regulates neuronal migration and ureteric bud (UB) outgrowth during kidney development as well as glomerular filtration in adult kidneys. Additionally, SLIT2 binds Gremlin, an antagonist of bone morphogenetic proteins (BMPs), and BMP–Gremlin signaling also regulates UB formation. However, direct cross-talk between the ROBO2–SLIT2 and BMP–Gremlin signaling pathways has not been established. Here, we report the discovery of negative feedback between the SLIT2 and BMP–Gremlin signaling pathways. We found that the SLIT2–Gremlin interaction inhibited both SLIT2–ROBO2 signaling in neurons and Gremlin antagonism of BMP activity in myoblasts and fibroblasts. Furthermore, BMP2 down-regulated SLIT2 expression and promoter activity through canonical BMP signaling. Gremlin treatment, BMP receptor inhibition, and SMAD family member 4 (SMAD4) knockdown rescued BMP-mediated repression of SLIT2. BMP2 treatment of nephron progenitor cells derived from human embryonic stem cells decreased SLIT2 expression, further suggesting an interaction between the BMP2–Gremlin and SLIT2 pathways in human kidney cells. In conclusion, our study has revealed direct negative cross-talk between two pathways, previously thought to be unassociated, that may regulate both kidney development and adult tissue maintenance.

The real-world large industry has gradually become a data-rich environment with the development of information and sensor technology, making the technology of data-driven fault diagnosis acquire a thriving development and application. The success of these advanced methods depends on the assumption that enough labeled samples for each fault type are available. However, in some practical situations, it is extremely difficult to collect enough data, e.g., when the sudden catastrophic failure happens, only a few samples can be acquired before the system shuts down. This phenomenon leads to the few-shot fault diagnosis aiming at distinguishing the failure attribution accurately under very limited data conditions. In this paper, we propose a new approach, called Feature Space Metric-based Meta-learning Model (FSM3), to overcome the challenge of the few-shot fault diagnosis under multiple limited data conditions. Our method is a mixture of general supervised learning and episodic metric meta-learning, which will exploit both the attribute information from individual samples and the similarity information from sample groups. The experiment results demonstrate that our method outperforms a series of baseline methods on the 1-shot and 5-shot learning tasks of bearing and gearbox fault diagnosis across various limited data conditions. The time complexity and implementation difficulty have been analyzed to show that our method has relatively high feasibility. The feature embedding is visualized by t-SNE to investigate the effectiveness of our proposed model.

Prognostics, which usually means the prediction of the field reliability or the Remaining Useful Life (RUL), is the basis of Prognostic and Health Management (PHM). Research in this paper focuses on remaining useful life prediction of aircraft engine in the same gradual degradation mode. As the gradual degradation with same failure mechanism has some regularity in macro, there would be certain relation between an arbitrary point of the degradation process and the correspondent RUL. This paper tries to learn this certain relation via neural network and the learned network, which reflects the relation, can be partly perceived as degradation pattern. The main prognostic idea of degradation pattern learning is firstly proposed and illustrated. And then an improved back propagation neural network is designed and analyzed as the implementation technique, in whose loss function an adjacent difference item is added. Next details of implementation via adjacent difference neural network are elaborated. Finally, the proposed approach is validated by two experiments respectively using different aircraft engine degradation datasets. Results of the experiments show a relatively good prediction accuracy, which verifies the correctness, effectiveness and practicability of the idea.

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT.

We report a female patient with a de novo balanced translocation, 46,X,t(X;2)(p11.2;q37)dn, who exhibits seizures, capillary abnormality, developmental delay, infantile hypotonia, and obesity. The 2q37 breakpoint observed in association with the seizure phenotype is of particular interest, because it lies near loci implicated in epilepsy in humans and mice. Fluorescence in situ hybridization mapping of the translocation breakpoints showed that no known genes are disrupted at Xp11.2, whereas diacylglycerol kinase delta (DGKD) is disrupted at 2q37. Expression studies in Drosophila and mouse suggest that DGKD is involved in central nervous system development and function. Electroencephalographic assessment of Dgkd mutant mice revealed abnormal epileptic discharges and electrographic seizures in three of six homozygotes. These findings implicate DGKD disruption by the t(X;2)(p11.2;q37)dn in the observed phenotype and support a more general role for DGKD in the etiology of seizures.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a very common lethal monogenetic disease with significant morbidities and a high likelihood of progression to renal failure for which there is no proven disease-specific therapy currently available for clinical use. Human ADPKD cystic epithelia have proliferative abnormalities mediated by EGFR over-expression and mispolarization leading autocrine response to EGF family ligands. We now show that apical localization of EGFR complexes in normal fetal and ADPKD epithelia is associated with heterodimerization of EGFR(HER-1) with HER-2(neu/ErbB2), while basal membrane localization in normal adult renal epithelia is associated with EGFR(HER-1) homodimers. Since ADPKD epithelial cells have reduced migratory function, this was used as a bioassay to evaluate the ability of compounds to rescue the aberrant human ADPKD phenotype. General tyrosine kinase inhibition by herbimycin and specific inhibition of HER-2(neu/ErbB2) by AG825 or pretreatment with ErbB2 siRNA reversed the migration defect of ADPKD epithelia. Selective inhibition of EGFR(HER-1) showed partial rescue. Increased ADPKD cell migration after inhibition of p38MAP kinase but not of PI3-kinase implicated p38MAPK downstream of HER-2(neu/ErbB2) stimulation. Daily administration of AG825 to PKD1 null heterozygous mice significantly inhibited the development of renal cysts. These studies implicate HER2(neu/ErbB2) as an effector of apical EGFR complex mispolarization and that its inhibition should be considered a candidate for clinical therapy of ADPKD.

We recently identified a mutation in the I-kappa B kinase associated protein (IKBKAP) gene as the major cause of familial dysautonomia (FD), a recessive sensory and autonomic neuropathy. This alteration, located at base pair 6 of the intron 20 donor splice site, is present on99.5% of FD chromosomes and results in tissue-specific skipping of exon 20. A second FD mutation, a missense change in exon 19 (R696P), was seen in only four patients heterozygous for the major mutation. Here, we have further characterized the consequences of the major mutation by examining the ratio of wild-type to mutant (WT:MU) IKBKAP transcript in EBV-transformed lymphoblast lines, primary fibroblasts, freshly collected blood samples, and postmortem tissues from patients with FD. We consistently found that WT IKBKAP transcripts were present, albeit to varying extents, in all cell lines, blood, and postmortem FD tissues. Further, a corresponding decrease in the level of WT protein is seen in FD cell lines and tissues. The WT:MU ratio in cultured lymphoblasts varied with growth phase but not with serum concentration or inclusion of antibiotics. Using both densitometry and real-time quantitative polymerase chain reaction, we found that relative WT:MU IKBKAP RNA levels were highest in cultured patient lymphoblasts and lowest in postmortem central and peripheral nervous tissues. These observations suggest that the relative inefficiency of WT IKBKAP mRNA production from the mutant alleles in the nervous system underlies the selective degeneration of sensory and autonomic neurons in FD.Therefore, exploration of methods to increase the WT:MU IKBKAP transcript ratio in the nervous system offers a promising approach for developing an effective therapy for patients with FD.

Apparently balanced chromosomal rearrangements in individuals with major congenital anomalies represent natural experiments of gene disruption and dysregulation. These individuals can be studied to identify novel genes critical in human development and to annotate further the function of known genes. Identification and characterization of these genes is the goal of the Developmental Genome Anatomy Project (DGAP). DGAP is a multidisciplinary effort that leverages the recent advances resulting from the Human Genome Project to increase our understanding of birth defects and the process of human development. Clinically significant phenotypes of individuals enrolled in DGAP are varied and, in most cases, involve multiple organ systems. Study of these individuals' chromosomal rearrangements has resulted in the mapping of 77 breakpoints from 40 chromosomal rearrangements by FISH with BACs and fosmids, array CGH, Southern-blot hybridization, MLPA, RT-PCR, and suppression PCR. Eighteen chromosomal breakpoints have been cloned and sequenced. Unsuspected genomic imbalances and cryptic rearrangements were detected, but less frequently than has been reported previously. Chromosomal rearrangements, both balanced and unbalanced, in individuals with multiple congenital anomalies continue to be a valuable resource for gene discovery and annotation.

Purpose Vesico-ureteral reflux (VUR) is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter. VUR is a major contributing factor to end-stage renal disease in paediatric patients. We aim to identify genetic factors contributing to VUR. Material and Methods In a collaborative study we investigated a man with a de novo translocation, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for the SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, two novel ROBO2 intracellular missense variants were identified that segregate with CAKUT and VUR in two unrelated families. SLIT-ROBO signalling is involved in the development of the ureteric bud. To investigate the involvement of 12 other functional candidate genes (mostly involved in ureteric budding) and two reported loci in VUR, we performed a linkage study in four large, Dutch, multi-generational families with multiple affected individuals. Results We were unable to detect linkage to any of the genes and loci and could exclude the GDNF, RET, SLIT2, SPRY1, PAX2, AGTR2, UPK1A and UPK3A genes and the 1p13 and 20p13 loci from linkage to VUR. Conclusions Mutations in ROBO2 contribute to the development of VUR in a small subset of patients. Our results provide further evidence that there appears to be genetic heterogeneity in VUR.