CHD1L: a new candidate gene for congenital anomalies of the kidneys and urinary tract (CAKUT)

Background. Recently, we identified a microduplication in chromosomal band 1q21.1 encompassing the CHD1L/ALC1 gene encoding a chromatin-remodelling enzyme in congenital anomalies of the kidneys and urinary tract (CAKUT) patient. Methods. To explore the role of CHD1L in CAKUT, we screened 85 CAKUT patients for mutations in the CHD1L gene and performed functional analyses of the three heterozygous missense variants detected. In addition, we quantitatively determined CHD1L expression in multiple human fetal and adult tissues and analysed expression of CHD1L protein in human embryonal, adult and hydronephrotic kidney sections. Results. Two of three novel heterozygous missense variants identified in three patients were not found in >400 control chromosomes. All variants lead to amino acid substitutions in or near the CHD1L macro domain, a poly-ADP-ribose (PAR)-binding module interacting with PAR polymerase 1 (PARP1), and showed decreased interaction with PARP1 by pull-down assay of transfected cell lysates. Quantitative messenger RNA analysis demonstrated high CHD1L expression in human fetal kidneys, and levels were four times higher than in adult kidneys. In the human embryo at 7-11 weeks gestation, CHD1L immunolocalized in the early ureteric bud and the S- and comma-shaped bodies, critical stages of kidney development. In normal postnatal sections, CHD1L was expressed in the cytoplasm of tubular cells in all tubule segments. CHD1L expression appeared higher in the hydronephrotic kidney of one patient with a hypofunctional CHD1L variant than in normal kidneys, recapitulating high fetal levels. Conclusion. Our data suggest that CHD1L plays a role in kidney development and may be a new candidate gene for CAKU

CHERI Concentrate: Practical Compressed Capabilities

We present CHERI Concentrate, a new fat-pointer compression scheme applied to CHERI, the most developed capability-pointer system at present. Capability fat-pointers are a primary candidate for enforcing fine-grained and non-bypassable security properties in future computer systems, although increased pointer size can severely affect performance. Thus, several proposals for capability compression have been suggested but these did not support legacy instruction sets, ignored features critical to the existing software base, and also introduced design inefficiencies to RISC-style processor pipelines. CHERI Concentrate improves on the state-of-the-art region-encoding efficiency, solves important pipeline problems, and eases semantic restrictions of compressed encoding, allowing it to protect a full legacy software stack. We analyze and extend logic from the open-source CHERI prototype processor design on FPGA to demonstrate encoding efficiency, minimize delay of pointer arithmetic, and eliminate additional load-to-use delay. To verify correctness of our proposed high-performance logic, we present a HOL4 machine-checked proof of the decode and pointer-modify operations. Finally, we measure a 50%-75% reduction in L2 misses for many compiled C-language benchmarks running under a commodity operating system using compressed 128-bit and 64-bit formats, demonstrating both compatibility with and increased performance over the uncompressed, 256-bit format

CHERI JNI: Sinking the Java Security Model into the C

Java provides security and robustness by building a high- level security model atop the foundation of memory protection. Unfortunately, any native code linked into a Java program – including the million lines used to implement the standard library – is able to bypass both the memory protection and the higher-level policies. We present a hardware-assisted implementation of the Java native code interface, which extends the guarantees required for Java’s security model to native code. Our design supports safe direct access to buffers owned by the JVM, including hardware-enforced read-only access where appropriate. We also present Java language syntax to declaratively describe isolated compartments for native code. We show that it is possible to preserve the memory safety and isolation requirements of the Java security model in C code, allowing native code to run in the same process as Java code with the same impact on security as running equivalent Java code. Our approach has a negligible impact on performance, compared with the existing unsafe native code interface. We demonstrate a prototype implementation running on the CHERI microprocessor synthesized in FPGA.Defense Advanced Research Projects Agency Google, Inc. Isaac Newton Trust Thales E-Securit

Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells

Phenoxodiol is a novel isoflav-3-ene, currently undergoing clinical trials, that has a broad in vitro activity against a number of human cancer cell lines. Phenoxodiol alone inhibited DU145 and PC3 in a dose- and time-dependent manner with IC50 values of 8±1 and 38±9 μM, respectively. The combination of phenoxodiol and cisplatin was synergistic in DU145, and additive in PC3, as assessed by the Chou–Talalay method. Carboplatin was also synergistic in combination with phenoxodiol in DU145 cells. The activity of the phenoxodiol and cisplatin combination was confirmed in vivo using a DU145 xenograft model in nude mice. Pharmacokinetic data from these mice suggest that the mechanism of synergy may occur through a pharmacodynamic mechanism. An intracellular cisplatin accumulation assay showed a 35% (P<0.05) increase in the uptake of cisplatin when it was combined in a ratio of 1 μM: 5 μM phenoxodiol, resulting in a 300% (P<0.05) increase in DNA adducts. Taken together, our results suggest that phenoxodiol has interesting properties that make combination therapy with cisplatin or carboplatin appealing

Renal malformations associated with mutations of developmental genes: messages from the clinic

Renal tract malformations (RTMs) account for about 40% of children with end-stage renal failure. RTMs can be caused by mutations of genes normally active in the developing kidney and lower renal tract. Moreover, some RTMs occur in the context of multi-organ malformation syndromes. For these reasons, and because genetic testing is becoming more widely available, pediatric nephrologists should work closely with clinical geneticists to make genetic diagnoses in children with RTMs, followed by appropriate family counseling. Here we highlight families with renal cysts and diabetes, renal coloboma and Fraser syndromes, and a child with microdeletion of chromosome 19q who had a rare combination of malformations. Such diagnoses provide families with often long-sought answers to the question “why was our child born with kidney disease”. Precise genetic diagnoses will also help to define cohorts of children with RTMs for long-term clinical outcome studies

Loss of endogenous thymosin β4 accelerates glomerular disease

Glomerular disease is characterized by morphologic changes in podocyte cells accompanied by inflammation and fibrosis. Thymosin $\beta_4$ regulates cell morphology, inflammation, and fibrosis in several organs and administration of exogenous thymosin $\beta_4$ improves animal models of unilateral ureteral obstruction and diabetic nephropathy. However, the role of endogenous thymosin $\beta_4$ in the kidney is unknown. We demonstrate that thymosin β4 is expressed prominently in podocytes of developing and adult mouse glomeruli. Global loss of thymosin $\beta_4$ did not affect healthy glomeruli, but accelerated the severity of immune-mediated nephrotoxic nephritis with worse renal function, periglomerular inflammation, and fibrosis. Lack of thymosin $\beta_4$ in nephrotoxic nephritis led to the redistribution of podocytes from the glomerular tuft toward the Bowman capsule suggesting a role for thymosin $\beta_4$ in the migration of these cells. Thymosin $\beta_4$ knockdown in cultured podocytes also increased migration in a wound-healing assay, accompanied by F-actin rearrangement and increased RhoA activity. We propose that endogenous thymosin $\beta_4$ is a modifier of glomerular injury, likely having a protective role acting as a brake to slow disease progression

Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis

Research UK Innovation and Project; Cancer Research U

Kelluvien asuntojen infratarkastelu

Tämän insinöörityön tavoitteena on tuottaa ratkaisu kelluvien asuntojen sähkö-, vesi- ja viemäriverkostolle. Ratkaisussa otetaan huomioon sen toimivuus pohjoismaisissa olosuhteissa ympäri vuoden. Erityishuomiota vaativat vedenpinnan korkeuserot jotka voivat olla rasitteeksi vesi- ja viemäröintikanavalle ja liitoksille sekä rakenteiden jäätymisen tuomat haasteet eristyksille. Insinöörityössä selvitetään onko kohteessa mahdollista liittää asuntojen viemäröintikanava suoraan kunnallisverkkoon tai vaihtoehtoisesti rannalle sijoitettavaan omaan umpisäiliöön josta se tyhjennetään loka-autolla. Tutkimusmenetelmä on vertaileva case tutkimus ja tavoitteena on tuottaa mahdollisimman kustannustehokas ja toimiva suunnitelma yrityskäyttöön. Insinöörityössä keskitytään yhteen ratkaisuun joka ei välttämättä sellaisenaan sovellu käytettäväksi muihin vastaaviin asumismuotoihin

Urinary isoflavonoid excretion is inversely associated with the ratio of protein to dietary fibre intake in young women

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