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Is there any difference in clinical outcomes between a human chorionic gonadotrophin (HCG)-only trigger and a dual trigger combining gonadotrophin-releasing hormone agonist (GnRHa) and HCG in a progestin-primed ovarian stimulation (PPOS) protocol?This retrospective cohort study included women younger than 40 years old with a normal ovarian reserve who underwent IVF/intracytoplasmic sperm injection treatment with a PPOS protocol. Participants were allocated to two groups according to the triggering medicines. The clinical outcomes were compared, with cumulative live birth rate (CLBR) being the primary outcome.In total, 1066 women were included, 565 in the HCG-only group and 501 in the dual trigger group. Demographic parameters were comparable between the groups. Fewer oocytes were retrieved in the HCG-only trigger group (dual trigger 12.56 ± 7.12 versus HCG-only trigger 11.62 ± 6.02, P = 0.020). No significant difference was observed in the numbers of two-pronuclear embryos (7.12 ± 4.90 versus 6.76 ± 4.45, P = 0.208) and high-quality embryos (4.01 ± 3.70 versus 3.96 ± 3.32, P = 0.815). The CLBR after one complete cycle was also similar (40.72% versus 43.72%, P = 0.354). Multivariate logistic analysis confirmed that the trigger method had no association with CLBR (odds ratio [OR] 0.763, 95% confidence interval [CI] 0.578-1.005, P = 0.055) in the PPOS-treated patients.Compared with the HCG-only trigger group, comparable embryological and clinical outcomes were achieved, although more oocytes were retrieved in the dual trigger group. This suggests that there may be no extra benefit from dual triggering, and that it should not be recommended for routine use in the general population undergoing PPOS protocols.

SUMMARY Seismic full waveform inversion (FWI) can produce high-resolution subsurface models by using the complete information of the observed data, but its computational cost can be prohibitively large, particularly for realistically sized 3-D problems. Due to its relatively fast convergence rate, it would be beneficial when Gauss–Newton algorithms could be employed for such problems, but the approximate Hessian matrix required for Gauss–Newton schemes would be too large to be kept in computer memory. Therefore, compact FWI (CFWI) was introduced, with which the number of inversion model parameters can be reduced substantially, and thus the amenable properties of Gauss–Newton inversion schemes can be exploited. Here, we extend the CFWI technology to 3-D problems. Since the spatial coverage of sources and receivers is generally sparser in 3-D (compared with 2-D problems), the total number of model parameters can become very large, and adequate model parametrization is particularly important for 3-D problems. Furthermore, we introduce gradient constrained CFWI (GC-CFWI). This is a novel development that allows the number of model parameters to be further reduced significantly. CFWI employs hierarchical model parametrizations that can be, for example, based on spatial Fourier transforms or wavelet transforms. Only those parameters of such a hierarchical parametrization are retained that exhibit a sufficiently high formal resolution. With GC-CFWI, it is further checked which of these parameters are expected to be changed significantly during a single CFWI iteration. Only parameters with a potentially significant adjustment are retained in the inversion parameter space. We have performed numerical experiments to analyse the performance of CFWI and GC-CFWI for 3-D acoustic FWI problems. For that purpose, we have considered a crosshole geometry including four boreholes and a surface deployment of sources and receivers. As parametrizations, we have considered the Fourier-based Hartley transform and the Haar wavelet transform. For both set-ups, the number of inversion model parameters could be reduced to about 20 per cent for the crosshole model and to about 10 per cent for the surface-based acquisition using CFWI. With GC-CFWI, a further reduction of about 50 per cent for both experimental set-ups could be achieved. The different results for the crosshole and surface-based set-ups indicate that an optimal model parametrization is tightly coupled to the experimental layout.

Surface-enhanced Raman scattering (SERS) is a rapid and promising detection technique for trace molecules. A central goal of research in this area is to achieve the highly sensitive detection of molecules built on a systematic understanding of enhancement mechanisms. Herein, we develop a Ag cluster@rGO composite nanostructure, which utilizes strong molecular adsorption to achieve ultrahigh SERS sensitivity. Ag clusters are prepared without additional reducing agents, leaving a low carbon footprint in the fabrication process. Finite-difference time-domain (FDTD) simulations show strong electromagnetic field enhancements generated at the edges and interstices of Ag clusters due to the specificity of their structure. Density Functional Theory (DFT) calculations show that the HOMO-LUMO energy gap value is significantly reduced when Ag cluster@rGO forms a composite system with the target molecule, which enables efficient charge transfer between the substrate and molecules, resulting in charge transfer enhancement. A detection limit of 10

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is a rare histopathologic pattern of glomerular injury with limited studies in pediatric patients. Characteristics and outcomes of children with MPGN have also remained to be further explored. METHODS: We retrospectively reviewed the clinicopathological features, genetic findings, treatments and outcomes in 17 pediatric patients pathologically diagnosed with MPGN from 2007 to 2020 in the Children’s National Medical Center in China. RESULTS: Median age at disease onset was 9.9 years (IQR, 5.6–11.9 years). Most of the patients (12/17) had nephrotic range of proteinuria, and nephritic-nephrotic syndrome was the most common clinical presentation (35.2%). Secondary causes were identified in eight patients including hepatitis B virus (HBV) infection (n=4), methylmalonic acidemia (MMA, n=2), rheumatoid arthritis (RA, n=1) and Aymé-Gripp Syndrome (n=1). The nine patients with primary MPGN were further identified as immune-complex mediated MPGN (n=8), and unclassifiable MPGN (U-MGPN, n=1). Genetic analyses identified pathogenic variants of MMACHC gene in two cases of MMA and established the diagnosis for Aymé-Gripp syndrome in one case with a de novo variant of MAF gene. Comparing study between the complete or partial remission group (n=8) and non-response group (n=9) showed a significant difference in the timing of renal biopsy (P

Helical structures are ubiquitous in natural and engineered systems across multiple length scales, while they often exhibit nearly uniform radius and pitch. Utilization of biomimetic structure design to develop stretchable and robust 3D helical structures that are shape-preserving and heat-tolerant is of great interest. Herein, we devise flexible 3D helixes by supramolecular self-assembly and high voltage electric field orientation of molecular chains. The 3D helixes not only inherit buffering mechanics with exceptional shape-retention ability against cyclic stretching but also exhibit excellent heat-resistant quality. The results of the experimental tests confirm that the helix can recover its original shape without obvious residual strain and basically withstand after 2000 cycles under force loading of 10 cN. Such robust biomimetic materials hold great prospects in the fields of artificial muscles, wearable materials, and so on.

The fixation of the catalyst interface is an important consideration for the design of practical applications. However, the electronic structure of MoS2 is sensitive to its embedding environment, and the catalytic performance of MoS2 catalysts may be altered significantly by the type of binding agents and interfacial structure. Interfacial engineering is an effective method for designing efficient catalysts, arising from the close contact between different components, which facilitates charge transfer and strong electronic interactions. Here, we have developed a layer-by-layer (LbL) strategy for the preparation of interfacial MoS2-based catalyst structures with two types of conducting polymers on various substrates. We demonstrate how the assembled partners in the LbL structure can significantly impact the electronic structures in MoS2. As the number of bilayers grows, using polypyrrole as a binder remarkably increases the catalytic efficacy as compared to using polyaniline. On the one hand, the ratio of S22- (or S2-), which is related to the remaining active hydrogen evolution reaction (HER) species, is further increased. On the other hand, density functional theory calculations indicate that the interfacial charge transport from the conducting polymers to MoS2 may boost the HER activity of the interfacial structure of the conducting polymer/MoS2 by decreasing the adsorption free energy of the intermediate H* at the S sites in the basal plane of MoS2. The optimized catalytic efficacy of the (conducting polymer/MoS2)n assembly peaks is obtained with 16 assembly cycles. In preparing interfacial catalytic structures, the LbL-based strategy exhibits several key advantages, including the flexibility of choosing assembly partners, the ability to fine-tune the structures with precision at the nanometer scale, and planar homogeneity at the centimeter scale. We expect that this LbL-based catalyst immobilization strategy will contribute to the fundamental understanding of the scalability and control of highly efficient electrocatalysts at the interface for practical applications.

Transitional metal sulfide ultrathin structures present various advantageous functional properties and hold great promise in energy conversion reactions, but their facile and large-scale preparation are still challenging. Herein, a facile strategy is developed for the preparation of ultrathin MoS2 nanosheets via an organic matrix-facilitated deposition followed by ultrasonic exfoliation strategy. MoS2 nanosheets with lateral dimensions around 100 nm and thickness around 10–20 nm are facilely obtained. They present the typical multiple absorbance indicating the unique band structure characteristics of MoS2 2D nanosheets. Furthermore, the electronic structures of the ultrathin MoS2 nanosheets can be tuned via controlling their immediate environment in assemblies. In the layer-by-layer interfacial assemblies of (PEDOT:PSS/MoS2)n multilayers, the catalytic efficiency of MoS2 nanosheets is enhanced by a charge transfer process as corroborated by DFT simulation. The catalytic capabilities of the assemblies are optimized by the well-controlled layer-by-layer process and present effective and stable electrochemical HER properties. We expect that this fabrication strategy of 2D MoS2 nanosheets promote the research of functional materials based on MoS2 nanosheets and can be extended to the preparation of other nanosheet materials.

Over the recent 20 years, numerous researches have focused on the lithium-ion batteries anodes of MOx 3d-metal oxides which have a high specific capacity. For example, the specific capacity of CuO material as an anode is ∼670 mAh g−1. Unfortunately, serious capacity degradation limits their promising applicability. To improve cyclic stability, PPy is covered on CuO surface to prepare CuO@PPy core–shell hybrid materials by chemical polymerisation. Pyrrole amount plays an important role on control the PPy shell thickness. After PPy coating, the lithium-ion battery cycling stability and coulombic efficiency have been improved greatly, and CP-5 sample has the best cyclic stability and coulombic efficiency. The capacity retention of bare CuO is only 27.9% after 200 cycles. By contrast, the capacity retention of CP-5 sample is ∼100%. The flexible conducting polymers shell (PPy) lead to improved cyclic stability. These results give a strategy to solve MOx 3d-metal oxide capacity degradation as Lithium-ion batteries anode.

Ubiquitination regulates immune signaling, and multiple E3 ubiquitin ligases have been studied in the context of their role in immunity. Despite this progress, the physiological roles of the Pellino E3 ubiquitin ligases, especially Pellino2, in immune regulation remain largely unknown. Accordingly, this study aimed to elucidate the role of Pellino2 in murine dendritic cells (DCs). In this study, we reveal a critical role of Pellino2 in regulation of the proinflammatory response following TLR9 stimulation. Pellino2-deficient murine DCs show impaired secretion of IL-6 and IL-12. Loss of Pellino2 does not affect TLR9-induced activation of NF-κB or MAPKs, pathways that drive expression of IL-6 and IL-12. Furthermore, DCs from Pellino2-deficient mice show impaired production of type I IFN following endosomal TLR9 activation, and it partly mediates a feed-forward loop of IFN-β that promotes IL-12 production in DCs. We also observe that Pellino2 in murine DCs is downregulated following TLR9 stimulation, and its overexpression induces upregulation of both IFN-β and IL-12, demonstrating the sufficiency of Pellino2 in driving these responses. This suggests that Pellino2 is critical for executing TLR9 signaling, with its expression being tightly regulated to prevent excessive inflammatory response. Overall, this study highlights a (to our knowledge) novel role for Pellino2 in regulating DC functions and further supports important roles for Pellino proteins in mediating and controlling immunity., Key Points Pellino2 mediates TLR9-induced cytokine production in dendritic cells.Pellino2 does not play a role in TLR9 signaling in macrophages.Pellino2 is a limiting factor for TLR9 signaling in dendritic cells.

Determining the etiology of end-stage renal disease (ESRD) constitutes a great challenge in the context of renal transplantation. Evidence is lacking on the genetic findings for adult renal transplant recipients through exome sequencing (ES). Adult patients on kidney transplant waitlist were recruited from 2017 to 2019. Trio-ES was conducted for the families who had multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early onset or extrarenal features. Pathogenic variants were confirmed in 62 from 115 families post sequencing for 421 individuals including 195 health family members as potential living donors. Seventeen distinct genetic disorders were identified confirming the priori diagnosis in 33 (28.7%) families, modified or reclassified the clinical diagnosis in 27 (23.5%) families, and established a diagnosis in two families with ESRD of unknown etiology. In 14.8% of the families, we detected promising variants of uncertain significance in candidate genes associated with renal development or renal disease. Furthermore, we reported the secondary findings of oncogenes in 4.4% of the patients and known single-nucleotide polymorphisms associated with pharmacokinetics in our cohort to predict the drug levels of tacrolimus and mycophenolate. The diagnostic utility of the genetic findings has provided new clinical insight in most families that help with preplanned renal transplantation.

Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is a protein with roles in early development, activation of the transcription factor NF-κB, and production of mitochondrial reactive oxygen species (mROS) that facilitates clearance of intracellular bacteria like Salmonella. ECSIT is also an important assembly factor for mitochondrial complex I. Unlike the murine form of Ecsit (mEcsit), we demonstrate here that human ECSIT (hECSIT) is highly labile. To explore whether the instability of hECSIT affects functions previously ascribed to its murine counterpart, we created a potentially novel transgenic mouse in which the murine Ecsit gene is replaced by the human ECSIT gene. The humanized mouse has low levels of hECSIT protein, in keeping with its intrinsic instability. Whereas low-level expression of hECSIT was capable of fully compensating for mEcsit in its roles in early development and activation of the NF-κB pathway, macrophages from humanized mice showed impaired clearance of Salmonella that was associated with reduced production of mROS. Notably, severe cardiac hypertrophy was manifested in aging humanized mice, leading to premature death. The cellular and molecular basis of this phenotype was delineated by showing that low levels of human ECSIT protein led to a marked reduction in assembly and activity of mitochondrial complex I with impaired oxidative phosphorylation and reduced production of ATP. Cardiac tissue from humanized hECSIT mice also showed reduced mitochondrial fusion and more fission but impaired clearance of fragmented mitochondria. A cardiomyocyte-intrinsic role for Ecsit in mitochondrial function and cardioprotection is also demonstrated. We also show that cardiac fibrosis and damage in humans correlated with low expression of human ECSIT. In summary, our findings identify a role for ECSIT in cardioprotection, while generating a valuable experimental model to study mitochondrial dysfunction and cardiac pathophysiology.

The present study aimed at evaluating the mechanism by which functionality of hepatic stellate cells (HSCs) is modulated by bone marrow stromal cells (BMSCs). Induction of apoptosis in HSCs was found to be caused by directly co-culturing HSCs with BMSCs, where the expression of α-smooth muscle actin (α-SMA) increased significantly in HSCs, along with an increase in their proliferation rate. Additionally, expression of Hes1 and Notch1 in HSCs co-cultured with BMSCs increased significantly at both protein and mRNA levels. Blocking of the notch signaling pathway (NSP) either by Notch1 siRNA or by DAPT treatment increased the proliferation rate while decreasing apoptosis and led to activation of the NF-κB signaling pathway in HSCs co-cultured with BMSCs. These effects were found to be reversed in HSCs overexpressing IκB S32/S36 mutants. The Notch signaling-mediated cell-cell contact was partially involved in the significant inhibition of proliferation of HSCs by BMSCs. Additionally, the NF-κB pathway was found to be responsible for NSP-mediated inhibition of growth of HSCs in the co-culture system. Thus, BMSCs might have a potential therapeutic significance in treating hepatic fibrosis.

In this study, stable composite multilayers incorporating magnetic montmorillonite (MMT) and weak polyelectrolyte were prepared under the assistance of a magnetic field. We reported a facile method for fabrication of covalently cross-linked Layer-by-Layer (LbL) multilayers using a photosensitive cross-linking agent 4,4′-diazostilbene-2,2′-disulfonic acid disodium salt that carried double azido groups. The multilayers after cross-linking presented improved stability against extreme solution conditions (basic solution pH = 14), and over 78.15% of magnetic MMT remained on the substrate, in clear contrast with the non-cross-linked multilayers, for which less than 8% of the magnetic MMT remained. The results of UV–Vis spectroscopy and scanning electron microscopy (SEM) measurements supported the improvement in the stability of the multilayers. Moreover, the assistance of the external magnetic field improved the LbL assembly efficiency and the cross-linking step achieved the molecular retarded release. When gauze was used as the substrate, the mass loading under the magnetic field was approximately 0.976 mg/cm2, which was 4.2 times the amount deposited on gauze without an external magnetic field. After interfacial modification of gauze using LbL multilayers, the static contact angle transformed from hydrophobic (111.25°) to perfect hydrophilic. When we employed aspirin as the target drug, it took 23 h for the cross-linked multilayers to achieve saturated release, as opposed to 9 h for the non-cross-linked multilayers.

The fixation of the catalyst interface is an important consideration for the design of practical applications. However, the electronic structure of MoS

Hsp70 is an evolutionarily conserved chaperone involved in maintaining protein homeostasis during normal growth and upon exposure to stresses. Mutations in the β6/β7 region of the substrate-binding domain (SBD) disrupt the SBD hydrophobic core resulting in impairment of the heat-shock response and prion propagation in yeast. To elucidate the mechanisms behind Hsp70 loss of function due to disruption of the SBD, we undertook targeted mutational analysis of key residues in the β6/β7 region. We demonstrate the critical functional role of the F475 residue across yeast cytosolic Hsp70-Ssa family. We identify the size of the hydrophobic side chain at 475 as the key factor in maintaining SBD stability and functionality. The introduction of amino acid variants to either residue 475, or close neighbor 483, caused instability and cleavage of the Hsp70 SBD and subsequent degradation. Interestingly, we found that Hsp70-Ssa cleavage may occur through a vacuolar carboxypeptidase (Pep4)-dependent mechanism rather than proteasomal. Mutations at 475 and 483 result in compromised ATPase function, which reduces protein re-folding activity and contributes to depletion of cytosolic Hsp70 in vivo. The combination of reduced functionality and stability of Hsp70-Ssa results in yeast cells that are compromised in their stress response and cannot propagate the [PSI+ ] prion.

Summary Seismic Full Waveform Inversion (FWI) has the potential to produce high-resolution subsurface images, but the computational resources required for realistically sized problems can be prohibitively large. In terms of computational costs, Gauss-Newton algorithms are more attractive than the commonly employed conjugate gradient methods, because the former have favorable convergence properties. However, efficient implementations of Gauss-Newton algorithms require an excessive amount of computer memory for larger problems. To address this issue, we introduce Compact Full Waveform Inversion (CFWI). Here, a suitable inverse model parameterization is sought that allows representing all subsurface features, potentially resolvable by a particular source-receiver deployment, but using only a minimum number of model parameters. In principle, an inverse model parameterization, based on the Eigenvalue decomposition, would be optimal, but this is computationally not feasible for realistic problems. Instead, we present two alternative parameter transformations, namely the Haar and the Hartley transformations, with which similarly good results can be obtained. By means of a suite of numerical experiments, we demonstrate that these transformations allow the number of model parameters to be reduced to only a few percent of the original parameterization without any significant loss of spatial resolution. This facilitates efficient solutions of large-scale FWI problems with explicit Gauss-Newton algorithms.

Background and Objectives: Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. Establishing the genetic diagnosis appears particularly important to NDI for early detection and differential diagnosis.Method: We utilized a Chinese multicenter registry to investigate genotype and phenotype in children with NDI from 2014 to 2019. The structural locations of the pathogenic mutations from this study and the literature, as well as population variants retried from gnomAD were analyzed. Results: A total of 10 boys from 9 families carried mutations in AVPR2 (8/10) or AQP2 (2/10). Another 7 relatives of the families were diagnosed by sequencing for partial or subclinical NDI. Patients presented with dehydration, polyuria-polydipsia, and severe hypernatremia with a median age at diagnosis of 1.0 month (IQR 0.16, 18). Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane regions of AVPR2, and enrichment of diagnostic mutations by autosomal dominant inheritance (AD) in the C terminal region of AQP2. The pathogenic mutations are significantly more likely to be buried inside the domain comparing the population variants. Through structural analysis and in silico prediction, the eight mutations identified in this study were considered as presumably disease causative. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment of hypernatremic dehydration in neonates should not choose the isotonic saline as a rehydration fluid.Conclusion: Genetic analysis presumably confirmed the diagnosis of NDI in every patient of the studied cohort. A plea of early identifying NDI confirmed by phenotype and genotype, and consequently optimize the treatment.

We have investigated the problem of designing the forward operator and its exact adjoint for two-way wave-equation least-squares migration. We study the problem in the time domain and pay particular attention to the individual operators that are required by the algorithm. We derive our algorithm using the language of linear algebra and establish a simple path to design forward and adjoint operators that pass the dot-product test. We also found that the exact adjoint operator is not equal to the classic reverse time migration algorithm. For instance, one must pay particular attention to boundary conditions to compute the exact adjoint that accurately passes the dot-product test. Forward and adjoint operators are adopted to solve the so-called least-squares reverse time migration problem via the method of conjugate gradients. We also examine a preconditioning strategy to invert extended images.

Invasive pulmonary aspergillosis (IPA) is a severe life-threatening condition. Diagnosis of fungal disease in general, and especially that caused by Aspergillus fumigatus is problematic. A. fumigatus secretes siderophores to acquire iron during infection, which are also essential for virulence. We describe the chemoacetylation of ferrated fusarinine C to diacetylated fusarinine C (DAFC), followed by protein conjugation, which facilitated triacetylfusarinine C (TAFC)-specific monoclonal antibody production with specific recognition of the ferrated form of TAFC. A single monoclonal antibody sequence was ultimately elucidated by a combinatorial strategy involving protein LC-MS/MS, cDNA sequencing and RNAseq. The resultant murine IgG2a monoclonal antibody was secreted in, and purified from, mammalian cell culture (5 mg) and demonstrated to be highly specific for TAFC detection by competitive ELISA (detection limit: 15 nM) and in a lateral flow test system (detection limit: 3 ng), using gold nanoparticle conjugated- DAFC-bovine serum albumin for competition. Overall, this work reveals for the first time a recombinant TAFC-specific monoclonal antibody with diagnostic potential for IPA diagnosis in traditional and emerging patient groups (e.g., COVID-19) and presents a useful strategy for murine Ig sequence determination, and expression in HEK293 cells, to overcome unexpected limitations associated with aberrant or deficient murine monoclonal antibody production.

A large accumulation of carbon dioxide emission have attracted much attention recently. The existing researches mainly focused on such impact factors of carbon dioxide emission as population, economy, technology and others. However, there is little specific guidance for the subdivision of demographic factors. This paper employed STIRPAT (Stochastic Impacts by Regression on Population, Affluence and Technology) model to examine the impact of population size, per capita consumption, energy intensity, urbanization and aging population on CO 2 emissions by adopting panel data of 30 provinces from 1997 to 2012. Taking the climate change as a control variable, we can get the result that the population size, per capita consumption and energy intensity have strong explanatory power on CO 2 emissions in the three regions. The urbanization level has a positive influence on carbon emissions in the western region and has a negative effect in the central region, while it is not statistically significant in the eastern region. Aging population increases emissions in the eastern region, while decreases emissions in the central region and the western region.

To examine the screening history of invasive cervical cancer (ICC) cases in Alberta, Canada to identify areas for improvement of the population-based cervical cancer screening program.Retrospective review of ICC cases diagnosed in 2 cities in Alberta between 2007 and 2012. Cancer morphology and staging were elicited from the Alberta Cancer Registry; cancer screening history and Pap test results were extracted from the Provincial Cervical Cancer Screening database. Women were classified as adequately screened, underscreened, and unscreened depending on time from last screening Pap test to diagnosis.Of the 280 cases that occurred in women eligible for screening, 125 (44.6%) were adequately screened, 18 (6.4%) were underscreened, and 137 (49%) were unscreened. Among the adequately screened, 71 (56.8%) had normal Pap test results, but 48 (38%) had less than 3 previous Pap tests (p = .003). Cancer stages I to II were diagnosed in 48.8% and 44.1% of adequately screened and unscreened women and cancer stages III to IV in 30.6% and 66.1% in each group, respectively (p = .0058). Squamous cell carcinoma (SCC) was diagnosed in 189 women (67.5%). The proportion of SCCs was similar in adequately screened and unscreened women.The proportion of SCCs and advanced stages of ICC seems to be decreased. The results of quality improvement initiatives such as enhanced surveillance of high-grade Pap test results and histology-cytology correlation will be monitored and are expected to result in better outcomes for adequately screened women.

Hsp70 is a highly conserved molecular chaperone critical for the folding of new and denatured proteins. While traditional models state that cells respond to stress by upregulating inducible HSPs, this response is relatively slow and is limited by transcriptional and translational machinery. Recent studies have identified a number of post-translational modifications (PTMs) on Hsp70 that act to fine-tune its function. We utilized mass spectrometry to determine whether yeast Hsp70 (Ssa1) is differentially modified upon heat shock. We uncovered four lysine residues on Ssa1, K86, K185, K354 and K562 that are deacetylated in response to heat shock. Mutation of these sites cause a substantial remodeling of the Hsp70 interaction network of co-chaperone partners and client proteins while preserving essential chaperone function. Acetylation/deacetylation at these residues alter expression of other heat-shock induced chaperones as well as directly influencing Hsf1 activity. Taken together our data suggest that cells may have the ability to respond to heat stress quickly though Hsp70 deacetylation, followed by a slower, more traditional transcriptional response.

Background: A school-based program with quadrivalent human papillomavirus (HPV) vaccination was implemented in Alberta in 2008. We assessed the impact of this program on Pap test cytology results using databases of province-wide vaccination and cervical cancer screening. Methods: We conducted a nested case-control study involving a cohort of women in Alberta born between 1994 and 1997 who had at least 1 Pap test between 2012 and 2015. Women with negative cytology results were controls. Women with low-grade (atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion) and high-grade (atypical squamous cells, cannot rule out a high-grade lesion; or high-grade squamous intraepithelial lesion) cervical abnormalities were cases. Exposure status was assigned according to records of HPV vaccination. Odds ratios (ORs) for abnormal cytology results by vaccination status were adjusted for neighbourhood income, laboratory service, rural versus urban residency, and age. Results: The total study population was 10 204. Adjusting for age, vaccinated women had a higher screening rate than unvaccinated women (13.0% v. 11.4%, p Interpretation: Quadrivalent HPV vaccination significantly reduced high-grade cervical abnormalities but required 3 doses. Vaccination against HPV was associated with screening uptake. Population-based vaccination and screening programs should work together to optimize cervical cancer prevention.

Human cystatin C (HCC) amyloid angiopathy (HCCAA) is characterized by tissue deposition of amyloid fibrils in blood vessels, which can lead to recurrent hemorrhagic stroke. Wild-type HCC forms part of the amyloid deposits in brain arteries of elderly people with amyloid angiopathy. A point mutation causing a glutamine to a leucine substitution at residue 68 in the HCC polypeptide chain greatly increases the amyloidogenic propensity of HCC and causes a more severe cerebral hemorrhage and premature death in young adults. In this study, we used molecular dynamics simulations to assess the importance of disulfide bridge formation upon the stability of chicken cystatin and how this may influence the propensity for amyloid formation. We found that disulfide bridge formation between Cys95 and Cys115 in human cystatin played a critical role in overall protein stability. Importantly, Cys95-Cys115 influenced cystatin structure in regions of the protein that play key roles in the protein-folding transitions that occur, which enable amyloid fibril formation. We hypothesized that correct disulfide bridge formation is a critical step in stabilizing cystatin toward its native conformation. Disrupting Cys95-Cys115 disulfide bridge formation within cystatin appears to significantly enhance the amyloidogenic properties of this protein. In addition, by combining in silico studies with our previous experimental results on Eps1, a molecular chaperone of the PDI family, we proposed that age-related HCCAA, may possess a different pathogenic mechanism compared with its amyloidogenic counterpart, the early onset amyloidogenic cystatin-related CAA.

Background WT1 mutations cause a wide spectrum of renal and extrarenal manifestations concerning urogenital development and the development of tumors. Methods We retrospectively collected the information on the genotype and phenotype of WT1 nephropathy from the multicenter registry since 2014 to 2019. All patients were stratified by renal function decline status or by sequence timing. Rapid progressive group was defined as rapidly developing into ERSD within 12 months since disease onset. Early sequencing group was defined as gene mutation identified before ERSD. Results Thirty-three (3.5%) cases were identified with a WT1 mutation in patients with steroid resistant nephrotic syndrome (SRNS), proteinuria and chronic kidney disease (CKD) 3–5 stage of unknown origin. ESRD developed in twenty patients at a median age of 4.3 years old. Comparing study between the rapid progressive group (n = 8) and non-rapid progressive group (n = 25) showed no significant difference in age of onset, gender, syndrome phenotype, genotype and proteinuria except for initial estimated glomerular filtration rate (eGFR) (p = 0.021) or sequencing timing (p = 0.003). In multivariable logistic regression analysis, the delayed sequencing was associated with rapid renal function decline, even after adjusting for established clinical factors including syndromic phenotype, genotype, age onset and eGFR at initial stage (p = 0.019). The renal survival analysis did not show a significantly better outcome in early sequencing group than in delayed sequencing group (p > 0.05). Conclusion Screening for WT1 mutations should be performed in children with Wilms’ tumor, proteinuria/SRNS or CKD. Early diagnosis of WT1 nephropathy through clinical and genetic findings is warranted.

LiV3O8 attracts much research interest because it is a high theoretical specific capacity and low cost cathode material of lithium ion battery and is also a good candidate for the anode material of aqueous lithium ion battery. Therefore, it is worth of further investigation on preparing LiV3O8 materials. However, when preparing LiV3O8 materials, impurities such as L0.3V2O5 are usually accompanied. Besides, the calcination temperature and time when preparing LiV3O8 materials in different literatures are diverse. To solve this problem, the LiV3O8 crystal are prepared and the optimum calcination conditions and the optimum stoichiometry of Li:V are systematic studied. The optimum calcination temperature and time is chosen at 400 °C for 5 h. The best stoichiometry of Li:V is 1.15:3. The LiV3O8 material prepared in this study has a good purity and no impurity is found. When act as cathode of LIBs, the LiV3O8 crystal has relatively high discharge capacity as 220–240 mAh g−1.

Human cystatin C (HCC) is a 120-amino acid protein that belongs to the cystatin super family. It is expressed in all nucleated human cells and is found in almost all tissues and body fluids. HCC pl...

To evaluate the association between leptin level, adiponectin level, gestational weight gain, maternal constitutional factors, and the weights at birth and at 1 year of age in infants born to women with gestational diabetes mellitus (GDM).Fifty-one women with GDM were recruited from June 2011 to September 2011. Leptin and adiponectin levels in maternal and cord blood were measured and their correlations with infant’s birth weight and weight after 1 year were evaluated using Pearson correlation analysis. The weight correlations were also determined with maternal constitutional factors.The neonatal birth weight positively correlates with cord blood leptin (r=0.316, p=0.024) and adiponectin (r=0.855, p=0.026) levels. One-year-old infant’s weight correlates only with the cord blood adiponectin level (r=0.753, p=0.036). The infant’s birth weight had positive correlations with maternal constitutional factors such as prepregnancy weight (r=0.340, p=0.015), prepregnancy BMI (r=0.289, p=0.040), prepartum weight (r=0.404, p=0.003), prepartum BMI (r=0.348, p=0.012), and gestational weight gain (r= 0.280, p=0.047).The infant’s birth weight is closely associated with cord blood levels of both leptin and adiponectin and with pregravid and prepartum maternal obesity. The 1-year weight of infants born to GDM mothers is only associated with levels of adiponectin in cord blood.

The allosteric coupling of the highly conserved nucleotide- and substrate-binding domains of Hsp70 has been studied intensively. In contrast, the role of the disordered, highly variable C-terminal region of Hsp70 remains unclear. In many eukaryotic Hsp70s, the extreme C-terminal EEVD motif binds to the tetratricopeptide-repeat domains of Hsp70 co-chaperones. Here, we discovered that the TVEEVD sequence of Saccharomyces cerevisiae cytoplasmic Hsp70 (Ssa1) functions as a SUMO-interacting motif. A second C-terminal motif of ∼15 amino acids between the α-helical lid and the extreme C terminus, previously identified in bacterial and eukaryotic organellar Hsp70s, is known to enhance chaperone function by transiently interacting with folding clients. Using structural analysis, interaction studies, fibril formation assays, and in vivo functional assays, we investigated the individual contributions of the α-helical bundle and the C-terminal disordered region of Ssa1 in the inhibition of fibril formation of the prion protein Ure2. Our results revealed that although the α-helical bundle of the Ssa1 substrate-binding domain (SBDα) does not directly bind to Ure2, the SBDα enhances the ability of Hsp70 to inhibit fibril formation. We found that a 20-residue C-terminal motif in Ssa1, containing GGAP and GGAP-like tetrapeptide repeats, can directly bind to Ure2, the Hsp40 co-chaperone Ydj1, and α-synuclein, but not to the SUMO-like protein SMT3 or BSA. Deletion or substitution of the Ssa1 GGAP motif impaired yeast cell tolerance to temperature and cell-wall damage stress. This study highlights that the C-terminal GGAP motif of Hsp70 is important for substrate recognition and mediation of the heat shock response.

Hsp70 is a highly conserved chaperone that in addition to providing essential cellular functions and aiding in cell survival following exposure to a variety of stresses is also a key modulator of prion propagation. Hsp70 is composed of a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). The key functions of Hsp70 are tightly regulated through an allosteric communication network that coordinates ATPase activity with substrate-binding activity. How Hsp70 conformational changes relate to functional change that results in heat shock and prion-related phenotypes is poorly understood. Here, we utilised the yeast [PSI +] system, coupled with SBD-targeted mutagenesis, to investigate how allosteric changes within key structural regions of the Hsp70 SBD result in functional changes in the protein that translate to phenotypic defects in prion propagation and ability to grow at elevated temperatures. We find that variants mutated within the β6 and β7 region of the SBD are defective in prion propagation and heat-shock phenotypes, due to conformational changes within the SBD. Structural analysis of the mutants identifies a potential NBD:SBD interface and key residues that may play important roles in signal transduction between domains. As a consequence of disrupting the β6/β7 region and the SBD overall, Hsp70 exhibits a variety of functional changes including dysregulation of ATPase activity, reduction in ability to refold proteins and changes to interaction affinity with specific co-chaperones and protein substrates. Our findings relate specific structural changes in Hsp70 to specific changes in functional properties that underpin important phenotypic changes in vivo. A thorough understanding of the molecular mechanisms of Hsp70 regulation and how specific modifications result in phenotypic change is essential for the development of new drugs targeting Hsp70 for therapeutic purposes. Electronic supplementary material The online version of this article (10.1007/s00018-017-2698-3) contains supplementary material, which is available to authorized users.