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Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (

Descoperirea de noi biomarkeri sau paneluri de biomarkeri pentru diagnosticarea precoce a cancerului ovarian este una dintre marile provocări ale medicinei moderne. Folosirea determinării de CA125 (biomarkerul cel mai des folosit) a fost îmbunătăţită luând în considerare valorile în dinamică, disponibile în contextul screening-ului. În prezent, cea mai mare sensibilitate a testelor screening efectuate pentru diagnosticul precoce de cancer ovarian a fost de 96% şi a fost obţinută folosind un panel de biomarkeri serici compus din apolipoproteina A1, transtiretina, transferina şi CA125. Lucrarea de faţă prezintă diferite tipuri de compuşi proteici din ser, propuşi ca biomarkeri pentru detectarea cancerului ovarian, care sunt studiaţi în prezent. Studiile viitoare vor trebui conduse în scopul găsirii unui nou panel de markeri tumorali cantitativ, reproductibil, rapid şi cu sensibilitate şi specificitate chiar mai mari decât cele obţinute până acum, pentru diagnosticarea precoce a cancerului ovarian.

Development of porous alumina has been the objective of numerous studies in recent decades, due to the intrinsic properties of aluminium oxide, such as high melting point, low thermal conductivity, chemical inertness and corrosion resistance which, in addition to a high surface area and permeability, make aluminas being used for many different industrial and technical applications. The crystallographic and textural stability of alumina acquires significant importance in those processes involving high temperatures; however, most of the synthesis methods yield metastable oxides of little interest in high-temperature processes due to the transformation to alpha phase, with the consequent reduction in surface area. The present article reviews diverse procedures for obtaining porous alumina with high specific surface area, including methods and strategies for preparing high surface alpha-alumina. Within this framework, the paper analyzes the results obtained through bioreplica of lignocellulosic materials. This technology allows preparing aluminas with the complex structural hierarchy of the lignocellulosic templates.En las últimas décadas el desarrollo de alúminas porosas viene siendo objeto de numerosas investigaciones por las propiedades intrínsecas que tiene el óxido de aluminio, como elevado punto de fusión, baja conductividad térmica, inercia química y resistencia a la corrosión, a las que se unen una elevada superficie específica y permeabilidad, que hacen que encuentren aplicación en multitud de sectores industriales y técnicos. En aquellos procesos en los que intervengan temperaturas altas, la estabilidad cristalográfica y textural de las alúminas adquiere una importancia significativa; sin embargo, la mayoría de los métodos de preparación conducen hacia la generación de óxidos metaestables, que no encuentran aplicabilidad en procesos de elevada temperatura debido a su transformación hacia la fase alfa, con la consiguiente reducción de superficie. El presente artículo realiza una revisión de distintas vías de obtención de alúmina porosa de elevada superficie específica, incluyendo los métodos y estrategias que han tenido por objeto la síntesis de alfa-alúmina de alta superficie. Dentro de este marco, el trabajo analiza los resultados obtenidos hasta el momento a través de la bio-réplica de lignocelulósicos, tecnología que permite mimetizar con exactitud la compleja jerarquía estructural de las máscaras hasta diferentes niveles.

We discuss a mixed-action approach in which sea quarks are regularised using non-perturbatively O(a) improved Wilson fermions, while a fully-twisted tmQCD action is used for valence quarks. In this setup, automatic O(a) improvement is preserved for valence observables, apart from small residual O(a) effects from the sea. A strategy for matching sea and valence is set up, and carried out for Nf = 2 + 1 CLS ensembles with open boundary conditions at several simulation points. The scaling of basic light-quark observables such as the pseudoscalar meson decay constant is studied, as well as the isospin splitting of pseudoscalar meson masses.

We study the scaling with the number of colors Nc of the weak amplitudes mediating kaon mixing and decay, in the limit of light charm masses (mu = md = ms = mc). The amplitudes are extracted directly on the lattice for Nc = 3 - 7 (with preliminar results for Nc = 8 and 17) using twisted mass QCD. It is shown that the (sub-leading) 1 /Nc corrections to B^k are small and that the naive Nc → ∞ limit, B^k = 3/4, seems to be recovered. On the other hand, the O (1/Nc) corrections in K → ππ amplitudes (derived from K → π matrix elements) are large and fully anti-correlated in the I = 0 and I = 2 channels. This may have some implications for the understanding of the ΔI = 1/2 rule.

The culture of strain LA21, a non-mucoid strain of Azotobacter vinelandii derivative of ATCC 9046, revealed that alginate is not necessary for aggregate formation. In fact, the non-mucoid strain LA21 developed aggregates significantly larger than those of the mucoid strain (ATCC 9046), which suggests that alginate has a detrimental effect on the aggregate size, due to its properties as a surface active agent. Treating the aggregates with a protease caused a decrease in the equivalent diameter of the structures, suggesting the participation of extracellular proteins in the aggregation. Key words: Aggregation; Azotobacter vinelandii; alginate; mutant strain; mucoid.El cultivo de la cepa LA21, una cepa no-mucoide de Azotobacter vinelandii, derivada de la cepa parental ATCC9046, reveló que el alginato no es necesario para la formación de los agregados celulares. De hecho, la cepa mutante desarrolló agregados significativamente más grandes que los generados por la cepa parental mucoide (ATCC9046), lo cual sugiere que el alginato ejerce un efecto negativo sobre el tamaño de agregación debido a sus propiedades como agente tensoactivo. Al tratar los agregados con proteasas se produjo una disminución en el diámetro equivalente de las estructuras, sugiriendo la participación de proteínas extracelulares en el proceso de agregación de la bacteria. Palabras clave: agregación; Azotobacter vinelandii; alginato; cepa mutante; mucoide.

The determination of quark masses from lattice QCD simulations requires a non-perturbative renormalization procedure and subsequent scale evolution to high energies, where a conversion to the commonly used MS¯$\overline {{\rm{MS}}} $ scheme can be safely established. We present our results for the non-perturbative running of renormalized quark masses in Nf = 3 QCD between the electroweak and a hadronic energy scale, where lattice simulations are at our disposal. Recent theoretical advances in combination with well-established techniques allows to follow the scale evolution to very high statistical accuracy, and full control of systematic effects.

The interdependence of green density and particle size and their influence on the reaction sintering behaviour of zircon - dolomite powder mixtures were investigated. Powder size was controlled by attrition-milling for different times and was defined as the average size obtained by laser particle size analysis. Green compact density was shown to be related to the powder particle size distribution for identical consolidation conditions. Both the green density and the degree of powder agglomeration affect the sinter behaviour over the entire process. The experimental results showed that compacts with similar green density and which contained fewer coarse particles had a better sintering behaviour. The most important controlling parameters are characteristics of the raw materials as particle or agglomerate particle size and particle size distribution, homogeneity and compaction of the raw materials and sintering temperature.Se ha estudiado la interdependencia entre la densidad en verde y el tamaño de partícula en la sinterización reactiva de mezclas de circón – dolomita. El tamaño del polvo se ha determinado con un analizador de partícula por láser y se ha controlado variando el tiempo de molienda en un molino de atrición. Se ha observado que para un mismo método de consolidación la densidad de los compactos, en verde, esta relacionada con la distribución de tamaño de partícula. La densidad en verde y el grado de aglomeración influyen sobre la sinterización de la mezcla de polvos. Los datos experimentales indican que compactos con similar densidad en verde y menor número de aglomerados presentan un mejor comportamiento durante la sinterización. Se ha probado que los parámetros significativos en el proceso son el tamaño de partícula y/o aglomerado y características de la mezcla tales como homogeneidad y grado de compactación.

Abstract Background Studies of recent hospital outbreaks caused by multiresistant P.aeruginosa (MRPA) have often failed to identify a specific environmental reservoir. We describe an outbreak due to a single clone of multiresistant (MR) Pseudomonas aeruginosa (PA) and evaluate the effectiveness of the surveillance procedures and control measures applied. Methods Patients with MRPA isolates were prospectively identified (January 2006-May 2008). A combined surveillance procedure (environmental survey, and active surveillance program in intensive care units [ICUs]) and an infection control strategy (closure of ICU and urology wards for decontamination, strict compliance with cross-transmission prevention protocols, and a program restricting the use of carbapenems in the ICUs) was designed and implemented. Results Three hundred and ninety patients were identified. ICU patients were the most numerous group (22%) followed by urology patients (18%). Environmental surveillance found that 3/19 (16%) non-ICU environmental samples and 4/63 (6%) ICU samples were positive for the MRPA clonal strain. In addition, active surveillance found that 19% of patients were fecal carriers of MRPA. Significant changes in the trends of incidence rates were noted after intervention 1 (reinforcement of cleaning procedures): -1.16 cases/1,000 patient-days (95%CI -1.86 to -0.46; p = 0.003) and intervention 2 (extensive decontamination): -1.36 cases/1,000 patient-days (95%CI -1.88 to -0.84; p < 0.001) in urology wards. In addition, restricted use of carbapenems was initiated in ICUs (January 2007), and their administration decreased from 190-170 DDD/1,000 patient-days (October-December 2006) to 40-60 DDD/1,000 patient-days (January-April 2007), with a reduction from 3.1 cases/1,000 patient-days in December 2006 to 2.0 cases/1,000 patient-days in May 2007. The level of initial carbapenem use rose again during 2008, and the incidence of MRPA increased progressively once more. Conclusions In the setting of sustained MRPA outbreaks, epidemiological findings suggest that patients may be a reservoir for further environmental contamination and cross-transmission. Although our control program was not successful in ending the outbreak, we think that our experience provides useful guidance for future approaches to this problem.

Abstract Background The oxygen transfer rate (OTR) and dissolved oxygen tension (DOT) play an important role in determining alginate production and its composition; however, no systematic study has been reported about the independent influence of the OTR and DOT. In this paper, we report a study about alginate production and the evolution of the molecular mass of the polymer produced by a wild-type A. vinelandii strain ATCC 9046, in terms of the maximum oxygen transfer rate (OTRmax) in cultures where the dissolved oxygen tension (DOT) was kept constant. Results The results revealed that in the two dissolved oxygen conditions evaluated, strictly controlled by gas blending at 0.5 and 5% DOT, an increase in the agitation rate (from 300 to 700 rpm) caused a significant increase in the OTRmax (from 17 to 100 mmol L-1 h-1 for DOT of 5% and from 6 to 70 mmol L-1 h-1 for DOT of 0.5%). This increase in the OTRmax improved alginate production, as well as the specific alginate production rate (SAPR), reaching a maximal alginate concentration of 3.1 g L-1 and a SAPR of 0.031 g alg g biom-1 h-1 in the cultures at OTRmax of 100 mmol L-1 h-1. In contrast, the mean molecular mass (MMM) of the alginate isolated from cultures developed under non-oxygen limited conditions increased by decreasing the OTRmax, reaching a maximal of 550 kDa at an OTRmax of 17 mmol L-1 h-1 . However, in the cultures developed under oxygen limitation (0.5% DOT), the MMM of the polymer was practically the same (around 200 kDa) at 300 and 700 rpm, and this remained constant throughout the cultivation. Conclusions Overall, our results showed that under oxygen-limited and non oxygen-limited conditions, alginate production and its molecular mass are linked to the OTRmax, independently of the DOT of the culture.

Abstract Several aspects of alginate and PHB synthesis in Azotobacter vinelandii at a molecular level have been elucidated in articles published during the last ten years. It is now clear that alginate and PHB synthesis are under a very complex genetic control. Genetic modification of A. vinelandii has produced a number of very interesting mutants which have particular traits for alginate production. One of these mutants has been shown to produce the alginate with the highest mean molecular mass so far reported. Recent work has also shed light on the factors determining molecular mass distribution; the most important of these being identified as; dissolved oxygen tension and specific growth rate. The use of specific mutants has been very useful for the correct analysis and interpretation of the factors affecting polymerization. Recent scale-up/down work on alginate production has shown that oxygen limitation is crucial for producing alginate of high molecular mass, a condition which is optimized in shake flasks and which can now be reproduced in stirred fermenters. It is clear that the phenotypes of mutants grown on plates are not necessarily reproducible when the strains are tested in lab or bench scale fermenters. In the case of PHB, A. vinelandii has shown itself able to produce relatively large amounts of this polymer of high molecular weight on cheap substrates, even allowing for simple extraction processes. The development of fermentation strategies has also shown promising results in terms of improving productivity. The understanding of the regulatory mechanisms involved in the control of PHB synthesis, and of its metabolic relationships, has increased considerably, making way for new potential strategies for the further improvement of PHB production. Overall, the use of a multidisciplinary approach, integrating molecular and bioengineering aspects is a necessity for optimizing alginate and PHB production in A. vinelandii.

The proton transfer associated with the synthesis of protic ionic liquids (PILs) is often incomplete, meaning that the parent compounds may coexist with the ionic species. However, PILs are proposed for many applications as pure compounds without analysis of their ionicity. This work focuses on tris(2-hydroxyethyl)ammonium-based PILs with lactate, hydrogen succinate, hydrogen malate, and dihydrogen citrate anions. The interest of these anions lies in their low toxicity and capacity to disrupt the hydrogen-bonding network inherent to biopolymers. To improve current synthesis methods of this kind of PILs, which frequently lead to impurities derived from decomposition of reactants, working in the absence of solvents and at moderate temperatures is proposed. Through NMR studies, the ionicity of these systems was found to be low, from 20% to 86%, so the widely used term "ionic liquid" is not rigorous and must be used with caution. The un-ionized acid and base species coexist with the corresponding ionic forms, and this has to be considered in the studies involving these chemicals. The thermal characterization of the PILs was carried out. The influence of the anion on the thermal stability was found to be low. Isothermal thermogravimetric analysis showed that mass loss of these PILs starts at temperatures close to 350 K., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Lignin is a very attractive and abundant biopolymer with the potential to be a biorenewable source of a large number of value-added organic chemicals. The current state-of-the-art methods fail to provide efficient valorization of lignin in this regard without the involvement of harsh conditions and auxiliary substances that compromise the overall sustainability of the proposed processes. Making an original approach from the set of mildest temperature and pressure conditions, this work identifies and explores the capacity of an aqueous solution of the nonvolatile ionic liquid 1-ethyl-3-methylimidazolium acetate ([C 2 mim][OAc]) to partially depolymerize technical lignin (Indulin AT) by means of a treatment consisting in the simple contact at ambient temperature and pressure. Among a considerable number of valuable phenolic molecules that were identified in the resulting fluid, vanillin (yield of about 3 g/kg) and guaiacol (yield of about 1 g/kg) were the monophenolic compounds obtained in a higher concentration. The properties of the post-treatment solids recovered remain similar to those of the original lignin, although with a relatively lower abundance of guaiacyl units (in agreement with the generation of guaiacyl-derived phenolic molecules, such as vanillin and guaiacol). The assistance of the treatment with UV irradiation in the presence of nanoparticle catalysts does not lead to an improvement in the yields of phenolic compounds.

Study Question: Can machine learning predict the number of oocytes retrieved from controlled ovarian hyperstimulation (COH)?, Summary Answer: Three machine-learning models were successfully trained to predict the number of oocytes retrieved from COH., What Is Known Already: A number of previous studies have identified and built predictive models on factors that influence the number of oocytes retrieved during COH. Many of these studies are, however, limited in the fact that they only consider a small number of variables in isolation., Study Design, Size, Duration: This study was a retrospective analysis of a dataset of 11,286 cycles performed at a single centre in France between 2009 and 2020 with the aim of building a predictive model for the number of oocytes retrieved from ovarian stimulation. The analysis was carried out by a data analysis team external to the centre using the Substra framework. The Substra framework enabled the data analysis team to send computer code to run securely on the centre's on-premises server. In this way, a high level of data security was achieved as the data analysis team did not have direct access to the data, nor did the data leave the centre at any point during the study., Participants/materials, Setting, Methods: The Light Gradient Boosting Machine algorithm was used to produce three predictive models: one that directly predicted the number of oocytes retrieved and two that predicted which of a set of bins provided by two clinicians the number of oocytes retrieved fell into. The resulting models were evaluated on a held-out test set and compared to linear and logistic regression baselines. In addition, the models themselves were analysed to identify the parameters that had the biggest impact on their predictions., Main Results and the Role of Chance: On average, the model that directly predicted the number of oocytes retrieved deviated from the ground truth by 4.21 oocytes. The model that predicted the first clinician's bins deviated by 0.73 bins whereas the model for the second clinician deviated by 0.62 bins. For all models, performance was best within the first and third quartiles of the target variable, with the model underpredicting extreme values of the target variable (no oocytes and large numbers of oocytes retrieved). Nevertheless, the erroneous predictions made for these extreme cases were still within the vicinity of the true value. Overall, all three models agreed on the importance of each feature which was estimated using Shapley Additive Explanation (SHAP) values. The feature with the highest mean absolute SHAP value (and thus the highest importance) was the antral follicle count, followed by basal AMH and FSH. Of the other hormonal features, basal TSH, LH, and testosterone levels were similarly important and baseline LH was the least important. The treatment characteristic with the highest SHAP value was the initial dose of gonadotropins., Limitations, Reasons for Caution: The models produced in this study were trained on a cohort from a single centre. They should thus not be used in clinical practice until trained and evaluated on a larger cohort more representative of the general population., Wider Implications of Findings: These predictive models for the number of oocytes retrieved from COH may be useful in clinical practice, assisting clinicians in optimizing COH protocols for individual patients. Our work also demonstrates the promise of using the Substra framework for allowing external researchers to provide clinically relevant insights on sensitive fertility data in a fully secure, trustworthy manner and opens a number of exciting avenues for accelerating future research., Study Funding/competing Interest(s): This study was funded by the French Public Bank of Investment as part of the Healthchain Consortium. T.Fe., C.He., J.C., C.J., C.-A.P., and C.Hi. are employed by Apricity. C.Hi. has received consulting fees and honoraria from Vitrolife, Merck Serono, Ferring, Cooper Surgical, Dibimed, Apricity, and Fairtility and travel support from Fairtility and Vitrolife, participates on an advisory board for Merck Serono, was the founder and organizer of the AI Fertility conference, has stock in Aria Fertility, TMRW, Fairtility, Apricity, and IVF Professionals, and received free equipment from Planar in exchange for first user feedback. C.J. has received a grant from BPI. J.C. has also received a grant from BPI, is a member of the Merck AI advisory board, and is a board member of Labelia Labs. C.He has a contract for medical writing of this manuscript by CHU Nantes and has received travel support from Apricity. A.R. haș received honoraria from Ferring and Organon. T.Fe. has received a grant from BPI., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

A non-dissolving pretreatment consisting in the direct contact of cellulose and the ionic liquid tetra( n -butyl)phosphonium acetate, or its fluid mixtures with other phosphonium ionic liquids or with molecular liquids such as ethanol or DMSO, causes a reduction in the crystallinity of the popular microcrystalline cellulose-type Avicel PH-101 under mild conditions. At the same time, the degree of polymerization and the thermal stability of the pretreated Avicel remain essentially unaltered with respect to the untreated Avicel. The diminution of the crystallinity has been related to the increase of the reactivity of the pretreated Avicel samples via analysis of the kinetics of their enzymatic hydrolysis. For selected samples, this improved reactivity has been confirmed through their effective carboxymethylation under a simplified and milder reaction procedure.

The extension of blockchain use for nonfinancial domains has revealed opportunities to the health care sector that answer the need for efficient and effective data and information exchanges in a secure and transparent manner. Blockchain is relatively novel in health care and particularly for data analytics, although there are examples of improvements achieved. We provide a systematic review of blockchain uses within the health care industry, with a particular focus on the in vitro fertilization (IVF) field. Blockchain technology in the fertility sector, including data sharing collaborations compliant with ethical data handling within confines of international law, allows for large-scale prospective cohort studies to proceed at an international scale. Other opportunities include gamete donation and matching, consent sharing, and shared resources between different clinics., (Copyright © 2020. Published by Elsevier Inc.)

Artificial intelligence (AI) systems have been proposed for reproductive medicine since 1997. Although AI is the main driver of emergent technologies in reproduction, such as robotics, Big Data, and internet of things, it will continue to be the engine for technological innovation for the foreseeable future. What does the future of AI research look like?, (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The present methodology teaches the investigator how to measure and use the LAV as a surrogate of chronic elevations in Left Ventricular diastolic pressure through echocardiography, as well as to obtain measurements of the Aorta and PA diameter in mice. Mice older than 10 d of age can be analyzed using the present technique. The technique is composed of 3 main steps: set-up, image acquisition, and image analysis. The set-up step consists of getting the mouse anesthetized with 1% isoflurane, shaving it, and taping it in a supine position to a heated EKG board where the image acquisition will take place. The image acquisition step consists of learning to identify the cardiac structures and obtaining all the required images with its correspondent probe and axis in order to be able to calculate volumes and diameters. The image analysis step consists of measuring the previously acquired images with the aid of computer software. Advantages of the proposed technique include a fast (15 min) procedure that would allow the researcher to evaluate interventions in a non-invasive, non-terminal approach and therefore follow the same mouse over time; each mouse can be used as its own control. This fact plus having the same operator perform all the acquisition and analysis for the entire experiment minimizes the limitation of operator-dependency. The present methodology is useful for mouse researchers in cardiovascular and pulmonary medicine.

Orosomucoid-like (ORMDL)3 has been strongly linked with asthma in genetic association studies. Because allergen challenge induces lung ORMDL3 expression in wild-type mice, we have generated human ORMDL3 zona pellucida 3 Cre (hORMDL3(zp3-Cre)) mice that overexpress human ORMDL3 universally to investigate the role of ORMDL3 in regulating airway inflammation and remodeling. These hORMDL3(zp3-Cre) mice have significantly increased levels of airway remodeling, including increased airway smooth muscle, subepithelial fibrosis, and mucus. hORMDL3(zp3-Cre) mice had spontaneously increased airway responsiveness to methacholine compared to wild-type mice. This increased airway remodeling was associated with selective activation of the unfolded protein response pathway transcription factor ATF6 (but not Ire1 or PERK). The ATF6 target gene SERCA2b, implicated in airway remodeling in asthma, was strongly induced in the lungs of hORMDL3(zp3-Cre) mice. Additionally, increased levels of expression of genes associated with airway remodeling (TGF-β1, ADAM8) were detected in airway epithelium of these mice. Increased levels of airway remodeling preceded increased levels of airway inflammation in hORMDL3(zp3-Cre) mice. hORMDL3(zp3-Cre) mice had increased levels of IgE, with no change in levels of IgG, IgM, and IgA. These studies provide evidence that ORMDL3 plays an important role in vivo in airway remodeling potentially through ATF6 target genes such as SERCA2b and/or through ATF6-independent genes (TGF-β1, ADAM8).

Unlabelled: Inflammasome activation plays a central role in the development of drug-induced and obesity-associated liver disease. However, the sources and mechanisms of inflammasome-mediated liver damage remain poorly understood. Our aim was to investigate the effect of NLRP3 inflammasome activation on the liver using novel mouse models. We generated global and myeloid cell-specific conditional mutant Nlrp3 knock-in mice expressing the D301N Nlrp3 mutation (ortholog of D303N in human NLRP3), resulting in a hyperactive NLRP3. To study the presence and significance of NLRP3-initiated pyroptotic cell death, we separated hepatocytes from nonparenchymal cells and developed a novel flow-cytometry-based (fluorescence-activated cell sorting; FACS) strategy to detect and quantify pyroptosis in vivo based on detection of active caspase 1 (Casp1)- and propidium iodide (PI)-positive cells. Liver inflammation was quantified histologically by FACS and gene expression analysis. Liver fibrosis was assessed by Sirius Red staining and quantitative polymerase chain reaction for markers of hepatic stellate cell (HSC) activation. NLRP3 activation resulted in shortened survival, poor growth, and severe liver inflammation; characterized by neutrophilic infiltration and HSC activation with collagen deposition in the liver. These changes were partially attenuated by treatment with anakinra, an interleukin-1 receptor antagonist. Notably, hepatocytes from global Nlrp3-mutant mice showed marked hepatocyte pyroptotic cell death, with more than a 5-fold increase in active Casp1/PI double-positive cells. Myeloid cell-restricted mutant NLRP3 activation resulted in a less-severe liver phenotype in the absence of detectable pyroptotic hepatocyte cell death., Conclusions: Our data demonstrate that global and, to a lesser extent, myeloid-specific NLRP3 inflammasome activation results in severe liver inflammation and fibrosis while identifying hepatocyte pyroptotic cell death as a novel mechanism of NLRP3-mediated liver damage., (© 2014 by the American Association for the Study of Liver Diseases.)

The inflammasome is a cytoplasmic multiprotein complex that promotes proinflammatory cytokine maturation in response to host- and pathogen-derived signals. Missense mutations in cryopyrin (NLRP3) result in a hyperactive inflammasome that drives overproduction of the proinflammatory cytokines IL-1β and IL-18, leading to the cryopyrin-associated periodic syndromes (CAPS) disease spectrum. Mouse lines harboring CAPS-associated mutations in Nlrp3 have elevated levels of IL-1β and IL-18 and closely mimic human disease. To examine the role of inflammasome-driven IL-18 in murine CAPS, we bred Nlrp3 mutations onto an Il18r-null background. Deletion of Il18r resulted in partial phenotypic rescue that abolished skin and visceral disease in young mice and normalized serum cytokines to a greater extent than breeding to Il1r-null mice. Significant systemic inflammation developed in aging Nlrp3 mutant Il18r-null mice, indicating that IL-1 and IL-18 drive pathology at different stages of the disease process. Ongoing inflammation in double-cytokine knockout CAPS mice implicated a role for caspase-1-mediated pyroptosis and confirmed that CAPS is inflammasome dependent. Our results have important implications for patients with CAPS and residual disease, emphasizing the need to explore other NLRP3-mediated pathways and the potential for inflammasome-targeted therapy.

IL-6 is a known downstream target of IL-1β and is consistently increased in serum from patients with NLRP3 inflammasome-mediated conditions. Therefore, IL-6 could be a therapeutic target in the treatment of IL-1β-provoked inflammation. IL-6 was increased in serum with accompanying neutrophilia in tissues of an inducible mouse model of Muckle-Wells syndrome. However, an IL-6-null background failed to provide phenotypic rescue and did not significantly impact inflammatory cytokine levels. In a second model of IL-1β-driven inflammation, NLRP3 activation by monosodium urate crystals similarly increased IL-6. Consistent with our Muckle-Wells syndrome model, ablation of IL-6 did not impact an acute neutrophilic response in this in vivo evaluation of gouty arthritis. Taken together, our results indicate that IL-6 is a reliable marker of inflammation, with no direct role in inflammasome-mediated disease.

NLRP3 nucleates the inflammasome, a protein complex responsible for cleavage of prointerleukin-1beta (IL-1beta) to its active form. Mutations in the NLRP3 gene cause the autoinflammatory disease spectrum cryopyrin-associated periodic syndromes (CAPS). The central role of IL-1beta in CAPS is supported by the response to IL-1-targeted therapy. We developed two Nlrp3 mutant knockin mouse strains to model CAPS to examine the role of other inflammatory mediators and adaptive immune responses in an innate immune-driven disease. These mice had systemic inflammation and poor growth, similar to some human CAPS patients, and demonstrated early mortality, primarily mediated by myeloid cells. Mating these mutant mice to various gene mutant backgrounds showed that the mouse disease phenotype required an intact inflammasome, was only partially dependent on IL-1beta, and was independent of T cells. These data suggest that CAPS are true inflammasome-mediated diseases and provide insight for more common inflammatory disorders.

Patents are a major source of information in drug discovery and, when properly processed and analyzed, can yield a wealth of information on competitors activities, R&D trends, emerging fields, collaborations, among others. This review discusses the current state-of-the-art in textual data analysis and exploration methods as applied to patent analysis.:, (© 2005 Elsevier Ltd . All rights reserved.)

Studies of twenty-five patients with loculated leptomeningeal tumor metastases diagnosed by CT and/or MR were analyzed retrospectively. Medulloblastoma was the most frequent primary tumor (8/25, 32%). Four subgroups of loculated patterns were identified. Type A included mass(es) limited to the subarachnoid space without obvious direct parenchymal infiltration; this pattern occurred in 12 patients, of whom five had associated diffuse pattern. Type B was characterized by mass(es) still predominantly in the subarachnoid space but with minor transpinal parenchymal infiltration; this pattern was found in five patients. Type C comprised subarachnoid mass(es) with marked transpinal extension mimicking parenchymal lesion; this pattern was observed in three patients. Type D consisted of subarachnoid mass(es) growing along the perineural CSF space; this pattern was noted in two patients. Additionally, two patients presented with combined A and C patterns, and one patient had a combined B and C pattern. More than half the patients (14/25, 56%) presented with a single lesion. The most frequent locations were the suprasellar cistern, ventricular walls, and lateral recesses of the fourth ventricle, Gd-DTPA-enhanced T1-weighted MR images appeared best for demonstrating the site and extent of disease. Recognition of the loculated patterns of leptomeningeal metastases, which are less common than the diffuse pattern, is important to radiologists and clinicians for correct diagnosis and proper management of patients with this disease.

Studies of twenty-five patients with loculated leptomeningeal tumor metastases diagnosed by CT and/or MR were analyzed retrospectively. Medulloblastoma was the most frequent primary tumor (8/25, 32%). Four subgroups of loculated patterns were identified. Type A included mass(es) limited to the subarachnoid space without obvious direct parenchymal infiltration; this pattern occurred in 12 patients, of whom five had associated diffuse pattern. Type B was characterized by mass(es) still predominantly in the subarachnoid space but with minor transpinal parenchymal infiltration; this pattern was found in five patients. Type C comprised subarachnoid mass(es) with marked transpinal extension mimicking parenchymal lesion; this pattern was observed in three patients. Type D consisted of subarachnoid mass(es) growing along the perineural CSF space; this pattern was noted in two patients. Additionally, two patients presented with combined A and C patterns, and one patient had a combined B and C pattern. More than half the patients (14/25, 56%) presented with a single lesion. The most frequent locations were the suprasellar cistern, ventricular walls, and lateral recesses of the fourth ventricle, Gd-DTPA-enhanced T1-weighted MR images appeared best for demonstrating the site and extent of disease. Recognition of the loculated patterns of leptomeningeal metastases, which are less common than the diffuse pattern, is important to radiologists and clinicians for correct diagnosis and proper management of patients with this disease.

The MR findings in six cases of paranasal sinus mucoceles are described. Two basic MR appearances were encountered: either moderate to marked signal hypointensity in the expanded sinuses on T1- and T2-weighted images (four patients) or moderate to marked signal hyperintensity on T1- and T2-weighted images (two patients). These patterns appear to represent inspissated or hydrated sinus contents, respectively. CT correlation revealed hyperdense mucoceles in the decreased MR signal group and hypo- or isodense mucoceles in the increased MR signal group. Superimposed allergic Aspergillus sinusitis was also present in two patients with hypointense mucoceles on MR.