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Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at [G.sub.2]/M. We explored the relative importance of the PT DNA damage response (DDR) in kidney fibrosis by genetically inactivating ataxia telangiectasia and Rad3-related (ATR), which is a sensor and upstream initiator of the DDR. In human chronic kidney disease, ATR expression inversely correlates with DNA damage. ATR was upregulated in approximately 70% of Lotus tetragonolobus lectin-positive ([LTL.sup.+]) PT cells in cisplatin-exposed human kidney organoids. Inhibition of ATR resulted in greater PT cell injury in organoids and cultured PT cells. PT-specific Atr- knockout ([ATR.sup.RPTC-/-]) mice exhibited greater kidney function impairment, DNA damage, and fibrosis than did WT mice in response to kidney injury induced by either cisplatin, bilateral ischemia-reperfusion, or unilateral ureteral obstruction. [ATR.sup.RPTC-/-] mice had more cells in the [G.sub.2]/M phase after injury than did WT mice after similar treatments. In conclusion, PT ATR activation is a key component of the DDR, which confers a protective effect mitigating the maladaptive repair and consequent fibrosis that follow kidney injury., Introduction Acute kidney injury (AKI) occurs in approximately 13% of hospitalized patients and is associated with high mortality, especially in critically ill patients (1). AKI also predisposes patients to chronic [...]

For the evaluation of novel therapeutic agents for diabetic kidney disease (DKD), it is desirable to examine their efficacy in animal models by using the glomerular filtration rate (GFR) as an index. For this purpose, animal models that demonstrate a short‐term GFR decline because of disease progression are required. Therefore, we aimed to develop such an animal model of DKD by using obese type 2 diabetic spontaneously diabetic Torii (SDT) fatty rats treated with salt loading by drinking water containing sodium chloride with or without unilateral nephrectomy. As a result, we have found that 0.3% salt loading with unilateral nephrectomy or 0.8% salt loading alone caused a rapid GFR decline, hypertension and rapid development of tubulointerstitial fibrosis. Moreover, the addition of losartan to a mixed diet suppressed the GFR decline in SDT fatty rats treated with 0.3% salt loading with unilateral nephrectomy. These results suggest that the model of SDT fatty rats treated with 0.3% salt loading and unilateral nephrectomy could be used as a hypertensive DKD model for evaluating therapeutic agents based on suppression of GFR decline. [ABSTRACT FROM AUTHOR]

Coarse-grained molecular dynamics simulations were performed to elucidate the capillary flow process of liquid state capillary underfill (CUF), a sealing resin material. First, we ran a wettability simulation with the CUF consisting of a monomer with small and large fillers. We observed that a certain amount of the monomer spreads ahead on the substrate, while many fillers are left inside the droplet. This was confirmed by subsequent mean square deviation (MSD), which showed that the monomer had a higher MSD, 25–45 σ2, than the small and large fillers, which were 0.4–1.4 σ2 and 0.02–0.2 σ2, respectively. When one part of large fillers was replaced with small fillers, small fillers helped accelerate the wetting dynamics because they could move fast. However, when the small filler ratio was high (20%), the MSD of small fillers decreased. Next, we performed a capillary flow simulation in which the CUF flowed between parallel walls and observed that it formed a ridgeline at the upper wall edge. Small fillers contributed to a decreased flow time. However, when the small filler ratio was even higher, the flow time increased. Then, the small fillers slowed themselves down, as shown in the MSD. This is due to an increase in monomer interactions and less space to move. We also found that the bleed length decreased with an increase in the small filler ratio. This study clarified the effects of filler usage on the flow time and bleed length and contributed to new insight into the capillary actions and material design relevant to CUF. [ABSTRACT FROM AUTHOR]

Background Inhibiting enteropeptidase, a gut serine protease regulating protein digestion, suppresses food intake and ameliorates obesity and diabetes in mice. However, the effects of enteropeptidase inhibition on kidney parameters are largely unknown. Here, we evaluated the chronic effects of an enteropeptidase inhibitor, SCO-792, on kidney function, albuminuria and kidney pathology in spontaneously hypercholesterolaemic (SHC) rats, a rat chronic kidney disease (CKD) model. Methods SCO-792, an orally available enteropeptidase inhibitor, was administered [0.03% and 0.06% (w/w) in the diet] to 20-week-old SHC rats showing albuminuria and progressive decline in glomerular filtration rate (GFR) for five weeks. The effects of SCO-792 and the contribution of amino acids to these effects were evaluated. Results SCO-792 increased the faecal protein content, indicating that SCO-792 inhibited enteropeptidase in SHC rats. Chronic treatment with SCO-792 prevented GFR decline and suppressed albuminuria. Moreover, SCO-792 improved glomerulosclerosis and kidney fibrosis. Pair feeding with SCO-792 (0.06%) was less effective in preventing GFR decline, albuminuria and renal histological damage than SCO-792 treatment, indicating the enteropeptidase-inhibition-dependent therapeutic effects of SCO-792. SCO-792 did not affect the renal plasma flow, suggesting that its effect on GFR was mediated by an improvement in filtration fraction. Moreover, SCO-792 increased hydrogen sulphide production capacity, which has a role in tissue protection. Finally, methionine and cysteine supplementation to the diet abrogated SCO-792-induced therapeutic effects on albuminuria. Conclusions SCO-792-mediated inhibition of enteropeptidase potently prevented GFR decline, albuminuria and kidney fibrosis; hence, it may have therapeutic potential against CKD. [ABSTRACT FROM AUTHOR]

The tensile-fatigue behavior of sintered-copper die-attach materials was investigated by focusing on sintering-pressure dependence. Specimens for fatigue tests were prepared by sintering copper oxide paste made from copper oxide particles with a mean diameter of 200 nm in hydrogen atmosphere under low (4 MPa) and high (13 MPa) pressures at 623 K for 15 min. The tensile-fatigue test was conducted using micro-load testing equipment in air at room temperature. The fatigue tests were conducted under pulsating load conditions. The fatigue strength of the high-pressure specimens was higher than that of the low-pressure specimens when comparing them within the nominal stress range $\Delta \sigma $. The fracture at the narrow neck part and the dimpled fracture at the peripheral part of the voids were observed in both types of specimens from fractographic studies. The $\Delta \sigma $ was converted to the total strain range $\Delta \varepsilon _{t}$ by using finite element analysis (FEA). It was confirmed that the fatigue strength of the high-pressure specimens was higher than that of the low-pressure specimens even when comparing them within $\Delta \varepsilon _{t}$. The strain distributions at the neck part and peripheral voids were calculated through FEA using a microporous structure model to clarify the cause of the fatigue lifetime difference between the low-pressure and high-pressure specimens. The calculated strain in the low-pressure specimens was locally concentrated at some of the narrow necks and could be linked to perpendicular cracks with a high strain level, whereas that in the high-pressure specimens was broadly distributed between the voids with a low strain level. This difference in strain distribution seemed to be the cause of the difference in the fatigue lifetime between the low-pressure and high-pressure specimens. [ABSTRACT FROM AUTHOR]

The effect of loading type on the fatigue lifetime of sintered-silver die attach was investigated. The fatigue lifetime was measured by fatigue testing with micro-load testing equipment. The fatigue tests were conducted under displacement control with (reversed loading (stress ratio ${R}= -1$), pulsating-tensile loading (${R} =0$), and pulsating-compression loading (${R} = -\infty $)) at room temperature. The strain of the fatigue test was estimated by strain-displacement relation obtained from previous tensile test using the strain gauge. Sintered-silver specimens were made from prebaked microscale silver paste and pressurized at 10 MPa for 10 minutes in air atmosphere at 573 K. The fatigue lifetime of reversed-loading case was 1000 cycles, that of pulsating-tensile-loading case was 4000 cycles, and the pulsating-compression-loading case remained unbroken. This suggests that compression load does not contribute to the destruction of the sintered silver. These measured fatigue lifetimes were aligned in a row when these are organized by maximum stress (tensile stress range). For fatigue lifetime evaluation of sintered silver, evaluation focusing on tensile stress seems to be important. [ABSTRACT FROM AUTHOR]

Macro- and micro-deformation properties of sintered copper die-attach material were evaluated. The macro-deformation properties are the properties, including the contribution of voids, and the micro-deformation properties are the properties, excluding the contribution of voids. Macro-deformation properties were evaluated by tensile tests at room temperature along with finite-element analysis (FEA). The specimens for these tests were made by sintering copper-oxide nano particles in the form of paste in a hydrogen atmosphere under low and high pressures. The micro-deformation properties were estimated by tensile test and FEA using a model that reproduces the micro-porous structure obtained from processing focused-ion beam scanning electron microscope data. The micro-stress/strain curve estimated for sintered copper was found to lie above the sintered silver and below the bulk copper. The porosity dependency of the macro-deformation properties of sintered copper was calculated using FEA models and the estimated micro-deformation property. The results obtained show that the macro-deformation properties of sintered copper are higher than those of sintered silver with similar porosity. This suggests that sintered copper die-attach material requires a lower sintering pressure than for sintered silver to achieve the same strength. [ABSTRACT FROM PUBLISHER]

Effects of pressurization and thermal-processing conditions on the deformation properties of sintered-silver sheets, excluding the contribution of the voids, (hereinafter, referred to as “micro-deformation properties”) were evaluated. Three types of thin-plate specimen sintered under the different conditions were prepared and these micro-deformation properties were compared. The first type was pressurized at 10 MPa for 10 min in the atmosphere at 573 K, the second type was annealed at 573 K for six hours before pressure processing and pressurized at 10 MPa for 10 min in the atmosphere at 573 K, and the third type was not pressurized and sintering in the atmosphere at 573 K for 10 min. The micro-deformation properties of these specimens were estimated by tensile testing and finite-element analysis (FEA) using a model that reproduces the microporous-structure. The microporous-structure models were made from serial cross-sectional images obtained by focused-ion-beam scanning electron microscope. These estimation results indicate that the micro-deformation properties of sintered-silver sheets do not depend on pressure, but on thermal-process conditions. The estimated micro-deformation properties were compared with those determined by nanoindentation tests and the validity of the estimated micro-deformation properties was confirmed. A deformation property of non-pressurized specimens was predicted by using the estimated micro-deformation properties and the microporous structures obtained from the pressurized specimens. The predicted deformation properties corresponded to experimental one. It is therefore concluded that if the deformation properties and microporous-structure of a sintered-silver specimen under a certain condition are determined, it is possible to predict the porosity dependency of deformation properties by FEA. [ABSTRACT FROM PUBLISHER]

Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19 KO) had higher parasitemia and died earlier than wild-type ( WT) controls. Interestingly, p19 KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17 KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19 KO and 17 KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites. [ABSTRACT FROM AUTHOR]

After a brain insult, ATP is released from injured cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor necrosis factor (TNF). The release of TNF appears to be dependent on the P2X[sub7] receptor. The inhibitors 1,4-diamino-2, 3-dicyano-1, 4-bis[2-amino-phenylthio] butadiene (U0126), anthra[1,9-cd] pyrazol-6(2H)-one (SP600125), and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) IH-imidazole (SB203580), which target MEK (mitogen- activated protein kinase kinase), INK (c-Jun N-terminal kinase), and p38, respectively, all potently suppress the production of TNF in ATP-stimulated microglia, whereas the production of TNF mRNA is strongly inhibited by U0126 and SP600125. SB203580 did not affect the increased levels of TNF mRNA but did prevent TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38 [but not extracellular signal-regulated kinase (ERK)] could be inhibited by brilliant blue G, a P2X[sub7] receptor blocker, and by genistein and 4-amino-5-br(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-D]pyrimidine, which are general and src-family-specific tyrosine ki- nase inhibitors, respectively. Most important, we found that treatment of the microglia in neuron-microglia cocultures with the P2X[sub7] agonist 2'-3'-O(benzoyl-benzoyl) ATP led to significant reductions in glutamate-induced neuronal cell death, and that either TNF-α converting enzyme inhibitor or anti-TNF readily suppressed the protective effect implied by this result. Together, these findings indicate that both FRK and JNK are involved in the regulation of TNF mRNA expression, that p38 is involved in the nucleocytoplasmic transport of TNF mRNA, and that a PTK (protein tyrosine kinase), possibly a member of the src family, acts downstream of the P2X[sub7] receptor to activate INK and p38. Finally, our data suggest that P2X[sub7] receptor-activated microglia protect neurons... [ABSTRACT FROM AUTHOR]

Abstract: The oxygen-depolarized cathode has become attractive by reducing energy consumption and also CO2 emissions. The initial gas-diffusion electrode was for a three-compartment cell in which the alkaline electrolyte was separated from the oxygen feeder. During the electrolysis, the electrolyte penetrated into the hydrophobic gas-diffusion layer. Thus the pores in the diffusion layer were flooded with the electrolyte and the performance decreased. We proposed a new gas-diffusion electrode (GDE) having a large pore radius for a two-compartment cell in which the GDE was pressed on the membrane, and the electrolyte was transported through the GDE. The previous electrode was used for a three-compartment cell, which contained the anolyte, catholyte and oxygen-feeder compartments. First, a model analysis was made to simulate the cathodic overpotential curves of the GDE''s for the two-compartment and three-compartment cells. Experiments were made using a half cell for the cathodic polarization curve and a zero-gap cell for testing the increased durability. The two-compartment cell with Ag–CC (carbon cloth) had the highest performance among the GDE''s. However, the decrease in performance during a longer period, such as 600 days, was considered to be due to catalyst aggregation and not flooding the pores based on the cathodic potential curve and the SEM images. [Copyright &y& Elsevier]

Objective: The primary objective of this study was to investigate the parenting attitudes towards children with autism spectrum disorders in early childhood in Japan., Design: This study was a cohort study. The participants were enrolled from January 2011 to March 2014. We obtained the prevalence of autism spectrum disorders at 3 years of age, parenting attitudes and other factors from questionnaires. We divided the participants into two groups, an autism spectrum disorders group and a non-autism spectrum disorders group, and compared the parenting attitudes., Setting: This study used data from a Japanese birth cohort study: the Japan Environment and Children's Study, conducted across 15 regional centres in Japan., Participants: The full dataset of the Japan Environment and Children's Study comprised 104 059 records. We excluded 17 889 records because the answer for the autism spectrum disorders in the questionnaire was blank. As a result, we analysed the remaining 82 411 mother-child pairs., Main Outcome Measures: The primary outcome variable was parenting attitudes at 3.5 years of age, which was assessed using a questionnaire. We asked respondents 16 questions related to parenting attitudes, and they answered based on their behaviours. The independent variable was the prevalence of autism spectrum disorders at 3 years of age., Results: Of the 82 411 participants, the children with autism spectrum disorders at 3 years of age were 372 (0.45%). In most questions about parenting attitudes, the autism spectrum disorders group had unfavourable responses. The difference was particularly noticeable when the parents taught their children social discipline. Unfavourable parenting attitudes were 16.6% in the autism spectrum disorders group and 0.8% in the non-autism spectrum disorders group in the question item with the largest difference between the two groups, a significant difference., Conclusions: Parents of children with autism spectrum disorders tended to have unfavourable attitudes, suggesting the importance of parental training., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Microglia perform both neuroprotective and neurotoxic functions in the brain, with this depending on their state of activation and their release of mediators. Upon P2X(7) receptor stimulation, for example, microglia release small amounts of TNF, which protect neurons, whereas LPS causes massive TNF release leading to neuroinflammation. Here we report that, in rat primary cultured microglia, nicotine enhances P2X(7) receptor-mediated TNF release, whilst suppressing LPS-induced TNF release but without affecting TNF mRNA expression via activation of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs). In microglia, nicotine elicited a transient increase in intracellular Ca(2+) levels, which was abolished by specific blockers of alpha7 nAChRs. However, this response was independent of extracellular Ca(2+) and blocked by U73122, an inhibitor of phospholipase C (PLC), and xestospongin C, a blocker of the IP(3) receptor. Repeated experiments showed that currents were not detected in nicotine-stimulated microglia. Moreover, nicotine modulation of LPS-induced TNF release was also blocked by xestospongin C. Upon LPS stimulation, inhibition of TNF release by nicotine was associated with the suppression of JNK and p38 MAP kinase activation, which regulate the post-transcriptional steps of TNF synthesis. In contrast, nicotine did not alter any MAP kinase activation, but enhanced Ca(2+) response in P2X(7) receptor-activated microglia. In conclusion, microglial alpha7 nAChRs might drive a signaling process involving the activation of PLC and Ca(2+) release from intracellular Ca(2+) stores, rather than function as conventional ion channels. This novel alpha7 nAChR signal may be involved in the nicotine modification of microglia activation towards a neuroprotective role by suppressing the inflammatory state and strengthening the protective function., ((c) 2006 Wiley-Liss, Inc.)