This study is based on an investigation of the transport phenomenon, specifically the quantification of arsenic diffusion in carrots within a temperature range of 89 °C–99 °C using a thin plate ...model. Studying the diffusion of arsenic in carrots is important due to its toxicity, as it can concentrate during cooking. The World Health Organization considers arsenic as one of the ten chemical substances of public health concern. In this study, biennial hybrid carrots of the Nantesa variety were cooked whole with their epidermis in an aqueous solution containing diarsenic trioxide with an As concentration of 5 mgL−1 at 89 °C, 94 °C, and 99 °C. The cooking times of the carrots at different temperatures were based on a specific degree of tenderness, with a value of ≤3 kg m−2. The evaluated data showed consistency with increasing temperature. The calculated effective diffusion coefficients at temperatures of 89 °C, 94 °C, and 99 °C were 5.84E-09 m2s-1, 1.08E-08 m2s-1, and 2.51E-08 m2s-1 for the flesh (DL), and 1.601E-11 m2s-1, 2.15E-11 m2s-1, and 4.39E-11 m2s-1 for the epidermis (DE), respectively. The activation energy for diffusion was determined to be 159.54 kJmol−1 for the and 110.68 kJmol−1 for the epidermis. Similar behaviours were observed in different radial positions of the carrot, where the arsenic content decreased from the periphery to the centre, consistent with studies on diffusion phenomena with other solutes in food. The novelty was the detailed quantification of arsenic diffusion in the Nantes-type hybrid carrot matrix. This study is limited to a specific concentration of 5 mgL−1 of arsenic solution. The findings of this study may have significant implications for public health and food safety.
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that facilitate IL-1β production. Although these are gain-of-function variants ...characterized by hypersensitivity to cell priming, patients with CAPS and animal models of the disease may present inflammatory flares without identifiable external triggers. Here we find that CAPS-associated NLRP3 variants are forming constitutively active inflammasome, which induce increased basal cleavage of gasdermin D, IL-18 release and pyroptosis, with a concurrent basal pro-inflammatory gene expression signature, including the induction of nuclear receptors 4 A. The constitutively active NLRP3-inflammasome of CAPS is responsive to the selective NLRP3 inhibitor MCC950 and its activation is regulated by deubiquitination. Despite their preactivated state, the CAPS inflammasomes are responsive to activation of the NF-κB pathway. NLRP3-inflammasomes with CAPS-associated variants affect the immunometabolism of the myeloid compartment, leading to disruptions in lipids and amino acid pathways and impaired glycolysis, limiting IL-1β production. In summary, NLRP3 variants causing CAPS form a constitutively active inflammasome inducing pyroptosis and IL-18 release without cell priming, which enables the host's innate defence against pathogens while also limiting IL-1β-dependent inflammatory episodes through immunometabolism modulation.
Bisphenols such as bisphenol A (BPA), S (BPS), C (BPC), F (BPF), AF (BPAF), tetrabromobisphenol, nonylphenol, and octylphenol are plasticizers used worldwide to manufacture daily-use articles. ...Exposure to these compounds is related to many pathologies of public health importance, such as infertility. Using a protector compound against the reproductive toxicological effects of bisphenols is of scientific interest. Melatonin and vitamins have been tested, but the results are not conclusive. To this end, this systematic review and meta-analysis compared the response of reproductive variables to melatonin and vitamin administration as protectors against damage caused by bisphenols. We search for controlled studies of male rats exposed to bisphenols to induce alterations in reproduction, with at least one intervention group receiving melatonin or vitamins (B, C, or E). Also, molecular docking simulations were performed between the androgen (AR) and estrogen receptors (ER), melatonin, and vitamins. About 1234 records were initially found; finally, 13 studies were qualified for review and meta-analysis. Melatonin plus bisphenol improves sperm concentration and viability of sperm and increases testosterone serum levels compared with control groups; however, groups receiving vitamins plus bisphenols had lower sperm concentration, total testis weight, and testosterone serum levels than the control. In the docking analysis, vitamin E had the highest negative MolDock score, representing the best binding affinity with AR and ER, compared with other vitamins and melatonin in the docking. Our findings suggest that vitamins could act as an endocrine disruptor, and melatonin is most effective in protecting against the toxic effects of bisphenols.
: Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory ...diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes.
To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative.
NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants.
A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses.
We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.
Introduction
Upadacitinib (UPA) is an oral, selective Janus kinase inhibitor that has demonstrated favorable efficacy with an acceptable safety profile across a global, phase 3 program in rheumatoid ...arthritis (RA). This phase 2 open-label extension investigated the efficacy and safety of UPA through 6 years of treatment.
Methods
Patients from two phase 2b trials (BALANCE-1 and -2) enrolled in BALANCE-EXTEND (NCT02049138) and received open-label UPA 6 mg twice daily (BID). Dose increases to 12 mg BID were required for patients with < 20% improvement in swollen or tender joint counts at weeks 6 or 12 and permitted for those not achieving Clinical Disease Activity Index (CDAI) low disease activity (LDA; CDAI 2.8 to ≤ 10). Dose reduction to UPA 6 mg BID was permitted only for safety or tolerability reasons. After January 2017, the 6/12 mg BID doses were replaced by 15/30 mg once-daily extended-release equivalents. Efficacy and safety were monitored up to 6 years of UPA treatment; outcomes included rates of achievement of LDA or remission. Data were analyzed for patients who received the lower UPA dose throughout; titrated up to the higher UPA dose from weeks 6 or 12; or titrated to the higher UPA dose and back down.
Results
Overall, 493 patients entered BALANCE-EXTEND (‘Never titrated’,
n
= 306; ‘Titrated up’,
n
= 149; ‘Titrated up and down’,
n
= 38), and 223 patients (45%) completed the 6-year study. Total cumulative exposure was 1863 patient-years. Rates of LDA and remission were maintained through 6 years. Overall, 87%/70%/73% of patients in the ‘Never titrated’/‘Titrated up’/‘Titrated up and down’ groups achieved CDAI LDA at week 312, while the respective rates of Disease Activity Score 28 with C-reactive protein meeting LDA and remission criteria were 85%/69%/70% and 72%/46%/63%. Improvements in patient-reported outcomes were similar among the three groups. No new safety signals were identified.
Conclusions
In this open-label extension of two phase 2 studies, UPA demonstrated sustained efficacy and an acceptable safety profile through 6 years of treatment in patients who completed the study. These data support a favorable long-term benefit–risk profile of UPA in patients with RA.
Trial Registration
Trial registration number: NCT02049138.
Major geologic and climatic changes during the Quaternary exerted a major role in shaping past and contemporary distribution of genetic diversity and structure of aquatic organisms in southern South ...America. In fact, the northern glacial limit along the Pacific coast, an area of major environmental changes in terms of topography, currents, and water salinity, represents a major biogeographic transition for marine and freshwater species. We used mitochondrial DNA sequences (D-loop) to investigate the consequences of Quaternary glacial cycles over the pattern of genetic diversity and structure of G. maculatus (Pisces: Galaxiidae) along two biogeographical provinces in the Chilean coast. Extreme levels of genetic diversity and strong phylogeographic structure characterize the species suggesting a low amount of influence of the last glacial cycle over its demography. However, we recognized contrasting patterns of genetic diversity and structure between main biogeographical areas here analyzed. Along the Intermediate Area (38°-41° S) each estuarine population constitutes a different unit. In contrast, Magellanic populations (43°-53° S) exhibited low levels of genetic differentiation. Contrasting patterns of genetic diversity and structure recorded in the species between the analyzed biogeographic areas are consistent with the marked differences in abiotic factors (i.e., different coastal configurations, Quaternary glacial histories, and oceanographic regimes) and to inherent characteristics of the species (i.e., salt-tolerance, physiology, and reproductive behavior).
This study investigated whether the coadministration of vitamin E (VitE) diminishes the harmful effects provoked by plasticizer bisphenol S (BPS) in the serum metabolites related to hepatic and renal ...metabolism, as well as the endocrine pancreatic function in diabetic male Wistar rats. Rats were divided into five groups (
= 5-6); the first group was healthy rats (Ctrl group). The other four groups were diabetic rats induced with 45 mg/kg bw of streptozotocin: Ctrl-D (diabetic control); VitE-D (100 mg/kg bw/d of VitE); BPS-D (100 mg/kg bw/d of BPS); The animals from the VitE + BPS-D group were administered 100 mg/kg bw/d of VitE + 100 mg/kg bw/d of BPS. All compounds were administered orally for 30 days. Body weight, biochemical assays, urinalysis, glucose tolerance test, pancreas histopathology, proximate chemical analysis in feces, and the activity of antioxidants in rat serum were assessed. The coadministration of VitE + BPS produced weight losses, increases in 14 serum analytes, and degeneration in the pancreas. Therefore, the VitE + BPS coadministration did not have a protective effect versus the harmful impact of BPS or the diabetic metabolic state; on the contrary, it partially aggravated the damage produced by the BPS. VitE is likely to have an additive effect on the toxicity of BPS.
Background & Aims: Molecular evolutionary analysis based on coalescent theory can provide important insights into epidemiologic processes worldwide. This approach was combined with analyses of the ...hepatitis C virus (HCV) epidemiologic-historical background and HCV-related hepatocellular carcinoma (HCC) in different countries. Methods: The HCV gene sequences of 131 genotype 1b (HCV-1b) strains from Japan, 38 HCV-1a strains from the United States, 33 HCV-1b strains from Spain, 27 HCV-3a strains from the former Soviet Union (FSU), 47 HCV-4a strains from Egypt, 25 HCV-5a strains from South Africa, and 24 HCV-6a strains from Hong Kong isolated in this study and previous studies were analyzed. Results: The coalescent analysis indicated that a transition from constant size to rapid exponential growth (spread time) occurred in Japan in the 1920s (HCV-1b), but not until the 1940s for the same genotype in Spain and other European countries. The spread time of HCV-1a in the United States was estimated to be in the 1960s; HCV-3a in the FSU, HCV-5a in South Africa, and HCV-6a in Hong Kong in the 1960s, mid-1950s, and late 1970s, respectively. Three different linear progression curves were determined by analysis of the relationship between HCV seroprevalence and HCC mortality in different geographic regions; a steep ascent indicated the greatest progression to HCC in Japan, a near horizontal line indicated the least progression in the United States and the FSU, and an intermediate slope was observed in Europe. Conclusions: These findings strongly suggest that the initial spread time of HCV is associated with the progression dynamics of HCC in each area, irrespective of genotype.
A facile one-step synthesis of 1H-benzoxazine-2,4-diones from heterocyclic anhydrides and TMSA was described. This paper determines their antimicrobial activity against nine human bacterial pathogens ...by the broth microdilution method; antioxidant activity by DPPH• inactivation and a ferric-reducing power assay; and toxicity by a brine shrimp, Artemia salina, assay. The 1H-benzoxazine-2,4-dione yields were in the range of 57 to 98%. The novel compound 1H-pyrazino2,3-1,3oxazine-2,4-dione 4c showed the highest antioxidant capacity (DPPH 35.4% and FRAP 0.063 µmol TEs/µmol).
This research proposes a generic methodology for dimensionality reduction upon time–frequency representations applied to the classification of different types of biosignals. The methodology directly ...deals with the highly redundant and irrelevant data contained in these representations, combining a first stage of irrelevant data removal by variable selection, with a second stage of redundancy reduction using methods based on linear transformations. The study addresses two techniques that provided a similar performance: the first one is based on the selection of a set of the most relevant time–frequency points, whereas the second one selects the most relevant frequency bands. The first methodology needs a lower quantity of components, leading to a lower feature space; but the second improves the capture of the time-varying dynamics of the signal, and therefore provides a more stable performance. In order to evaluate the generalization capabilities of the methodology proposed it has been applied to two types of biosignals with different kinds of non-stationary behaviors: electroencephalographic and phonocardiographic biosignals. Even when these two databases contain samples with different degrees of complexity and a wide variety of characterizing patterns, the results demonstrate a good accuracy for the detection of pathologies, over 98
%.
The results open the possibility to extrapolate the methodology to the study of other biosignals.
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