The Transmuted Exponentiated Additive Weibull Distribution: Properties and Applications

A new generalization of the transmuted additive Weibull distribution is proposed by using the quadratic rank transmutation map, the so-called transmuted exponentiated additive Weibull distribution. It retains the characteristics of a good model. It is more flexible, being able to analyze more complex data; it includes twenty-seven sub-models as special cases and it is interpretable. Several mathematical properties of the new distribution as closed forms for ordinary and incomplete moments, quantiles, and moment generating function are presented, as well as the MLEs. The usefulness of the model is illustrated by using two real data sets

Ghost-arc geochemical anomaly at a spreading ridge caused by supersized flat subduction

The Southern Atlantic-Southwest Indian ridges (SASWIR) host mid-ocean ridge basalts with a residual subduction-related geochemical fingerprint (i.e., a ghost-arc signature) of unclear origin. Here, we show through an analysis of plate kinematic reconstructions and seismic tomography models that the SASWIR subduction-modified mantle source formed in the Jurassic close to the Georgia Islands slab (GI) and remained near-stationary in the mantle reference frame. In this analysis, the GI lies far inboard the Jurassic Patagonian-Antarctic Peninsula active margin. This was formerly attributed to a large-scale flat subduction event in the Late Triassic-Early Jurassic. We propose that during this flat slab stage, the subduction-modified mantle areas beneath the Mesozoic active margin and surrounding sutures zones may have been bulldozed inland by >2280 km. After the demise of the flat slab, this mantle anomaly remained near-stationary and was sampled by the Karoo mantle plume 183 Million years (Myr) ago and again since 55 Myr ago by the SASWIR. We refer to this process as asthenospheric anomaly telescoping. This study provides a hitherto unrecognized geodynamic effect of flat subduction, the viability of which we support through numerical modeling.G. M. G. and C. R. N. recognize the support given by CONICET and the funding given by the Universidad Nacional de la Patagonia San Juan Bosco (Grant number: CIUNPAT no. 1399). S. Z. and J. L. acknowledge the funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 777778. S.Z. acknowledges the funding of Project PID2020-113463RB-C32 funded by MCIN/AEI /10.13039/501100011033 and the funding of Generalitat de Catalunya via the 2021 SGR 01049.Peer ReviewedPostprint (published version

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

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A new approach for the treatment of CLL using chlorambucil/hydroxychloroquine-loaded anti-CD20 nanoparticles

Current approaches for the treatment of chronic lymphocytic leukemia (CLL) have greatly improved the prognosis for survival, but some patients remain refractive to these therapeutic regimens. Hence, in addition to reducing the long-term sideeffects of therapeutics for all leukemia patients, there is an urgent need for novel therapeutic strategies for difficult-to-treat leukemia cases. Due to the cytotoxicity of drugs, the major challenge currently is to deliver the therapeutic agents to neoplastic cells while preserving the viability of non-malignant cells. In this study, we propose a therapeutic approach in which high doses of hydroxychloroquine and chlorambucil were loaded into biodegradable polymeric nanoparticles coated with an anti-CD20 antibody.We first demonstrated the ability of the nanoparticles to target and internalize in tumor B-cells. Moreover, these nanoparticles could kill not only p53-mutated/deleted leukemia cells expressing a low amount of CD20, but also circulating primary cells isolated from chronic lymphocytic leukemia patients. The safety of these nanoparticles was also demonstrated in healthy mice, and their therapeutic effects were shown in a new model of aggressive leukemia. These results showed that anti-CD20 nanoparticles containing hydroxychloroquine and chlorambucil can be effective in controlling aggressive leukemia and provided a rationale for adopting this approach for the treatment of other B-cell disorders. [Figure not available: see fulltext.

Infrapatellar fat pad gene expression and protein production in patients with and without osteoarthritis

Osteoarthritis (OA) is one of the most common joint disorders. Evidence suggests that the infrapatellar fat pad (IFP) is directly involved in OA pathology. However, a comparison between OA versus non-OA IFP is still missing. Thus, the aim of this study was to compare IFP molecular, adipocytes and extracellular matrix characteristics of patients affected by OA, and patients undergoing anterior cruciate ligament (ACL) reconstruction. We hypothesized that not only inflammation but also changes in adipocytes and extracellular matrix (ECM) composition might be involved in OA pathogenesis. Fifty-three patients were enrolled. IFP biopsies were obtained, evaluating: (a) lymphocytic infiltration and vascularization; (b) adipocytes area and number; (c) adipo-cytokines and extracellular matrix gene expression levels; (d) IL-6 and VEGF protein production; (e) collagen fibers distribution. OA IFP was more inflamed and vascularized compared to ACL IFP. OA IFP adipocytes were larger and numerically lower (1.3-fold) than ACL IFP adipocytes. An increase of gene expression of typical white adipose tissue genes was observed in OA compared to ACL IFP. Collagen-types distribution was different in the OA IFP group compared to controls, possibly explaining the change of the biomechanical characteristics found in OA IFP. Statistical linear models revealed that the adipocyte area correlated with BMI in the OA group. In conclusion, inflammation and fibrotic changes of OA IFP could represent novel therapeutic targets to counteract OA

Browning formation markers of subcutaneous adipose tissue in relation to resting energy expenditure, physical activity and diet in humans

© 2017 Walter de Gruyter GmbH, Berlin/Boston. Regular exercise and diet may contribute to white adipose tissue (WAT) conversion into a brown adipose-like phenotype that may increase resting energy expenditure (REE), leading to weight loss. We examined the relationship between REE, physical activity (PA) participation and diet with browning formation markers of subcutaneous WAT in healthy men. We assessed REE, diet and body composition of 32 healthy men [age (years): 36.06 ± 7.36, body mass index (BMI): 27.06 ± 4.62 (kg/m 2 )]. Participants also underwent measurements of PA [metabolic equivalent (MET)-min/week] using the International Physical Activity Questionnaire (IPAQ), while they undertook a subcutaneous fat biopsy from the abdominal region to assess the mRNA expressions of uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), peroxisome proliferator-activated receptor alpha (PPARα) and peroxisome proliferator-activated receptor gamma (PPARγ). We found no associations between the UCP1, PGC-1α, PPARα and PPARγ mRNAs with REE, PA levels and diet (p > 0.05). However, the PGC-1α, PPARα and PPARγ mRNAs were more expressed in individuals displaying moderate rather than low PA levels (p < 0.05). Furthermore, PGC-1α, PPARα and PPARγ mRNAs were negatively correlated with fat mass percentage (p < 0.05). PGC-1α and PPARα mRNAs were also negatively correlated with BMI, while PGC-1α mRNA was inversely associated with waist-to-hip ratio (p < 0.05). REE, PA levels and diet are not associated with browning formation indices of subcutaneous adipose tissue in healthy adult men.This study was supported by funding from the European Union 7th Framework Program (FP7-PEOPLE-2012-IRSES grant 319010; FP7-PEOPLE-2013-IRSES grant 612547). A.V. was supported by funding from the Education and Lifelong Learning Programme of the Greek Ministry of Education, Co-financed by Greece and the European Union (NSRF 2007–2013, IRAKLITOS II, grant 162).Published versio

Human white-fat thermogenesis: Experimental and meta-analytic findings

© 2020 The Authors. Published by Taylor & Francis. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1080/23328940.2020.1769530White adipose tissue (WAT) thermogenic activity may play a role in whole-body energy balance and two of its main regulators are thought to be environmental temperature (Tenv) and exercise. Low Tenv may increase uncoupling protein one (UCP1; the main biomarker of thermogenic activity) in WAT to regulate body temperature. On the other hand, exercise may stimulate UCP1 in WAT, which is thought to alter body weight regulation. However, our understanding of the roles (if any) of Tenv and exercise in WAT thermogenic activity remains incomplete. Our aim was to examine the impacts of low Tenv and exercise on WAT thermogenic activity, which may alter energy homeostasis and body weight regulation. We conducted a series of four experimental studies, supported by two systematic reviews and meta-analyses. We found increased UCP1 mRNA (p = 0.03; but not protein level) in human WAT biopsy samples collected during the cold part of the year, a finding supported by a systematic review and meta-analysis (PROSPERO review protocol: CRD42019120116). Additional clinical trials (NCT04037371; NCT04037410) using Positron Emission Tomography/Computed Tomography (PET/CT) revealed no impact of low Tenv on human WAT thermogenic activity (p > 0.05). Furthermore, we found no effects of exercise on UCP1 mRNA or protein levels (p > 0.05) in WAT biopsy samples from a human randomized controlled trial (Clinical trial: NCT04039685), a finding supported by systematic review and meta-analytic data (PROSPERO review protocol: CRD42019120213). Taken together, the present experimental and meta-analytic findings of UCP1 and SUVmax, demonstrate that cold and exercise may play insignificant roles in human WAT thermogenic activity. Abbreviations: WAT:White adipose tissue; Tenv: Environmental temperature; UCP1: Uncoupling protein one; BAT: Brown adipose tissue; BMI:Body mass index; mRNA: Messenger ribonucleic acid; RCT: Randomized controlled trial; WHR: Waist-to-hip ratio; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses; PET/CT: Positron Emission Tomography and Computed Tomography; REE: Resting energy expenditure; 18F-FDG: F18 fludeoxyglucose; VO2peak:Peak oxygen consumption; 1RM: One repetition maximum; SUVmax: Maximum standardized uptake value; Std: Standardized mean difference.This work was supported by funding from the European Union 7th Framework Program FP7-PEOPLE-2012-IRSES grant no. [319010]; FP7-PEOPLE-2013-IRSES grant no. [612547] and Horizon 2020 ICI-THROUGH grant no [645710].Published versio

Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity

<p>Abstract</p> <p>Background</p> <p>Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten. Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. By studying and comparing mucosal expression of genes associated with intestinal barrier function, as well as innate and adaptive immunity in CD compared with GS, we sought to better understand the similarities and differences between these two gluten-associated disorders.</p> <p>Methods</p> <p>CD, GS and healthy, gluten-tolerant individuals were enrolled in this study. Intestinal permeability was evaluated using a lactulose and mannitol probe, and mucosal biopsy specimens were collected to study the expression of genes involved in barrier function and immunity.</p> <p>Results</p> <p>Unlike CD, GS is not associated with increased intestinal permeability. In fact, this was significantly reduced in GS compared with controls (<it>P </it>= 0.0308), paralleled by significantly increased expression of claudin (CLDN) 4 (<it>P </it>= 0.0286). Relative to controls, adaptive immunity markers interleukin (IL)-6 (<it>P </it>= 0.0124) and IL-21 (<it>P </it>= 0.0572) were expressed at higher levels in CD but not in GS, while expression of the innate immunity marker Toll-like receptor (TLR) 2 was increased in GS but not in CD (<it>P </it>= 0.0295). Finally, expression of the T-regulatory cell marker FOXP3 was significantly reduced in GS relative to controls (<it>P </it>= 0.0325) and CD patients (<it>P </it>= 0.0293).</p> <p>Conclusions</p> <p>This study shows that the two gluten-associated disorders, CD and GS, are different clinical entities, and it contributes to the characterization of GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.</p

Resveratrol Acts Not through Anti-Aggregative Pathways but Mainly via Its Scavenging Properties against Aβ and Aβ-Metal Complexes Toxicity

It has been recently suggested that resveratrol can be effective in slowing down Alzheimer's disease (AD) development. As reported in many biochemical studies, resveratrol seems to exert its neuro-protective role through inhibition of β-amyloid aggregation (Aβ), by scavenging oxidants and exerting anti-inflammatory activities. In this paper, we demonstrate that resveratrol is cytoprotective in human neuroblastoma cells exposed to Aβ and or to Aβ-metal complex. Our findings suggest that resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties