Differential RNA editing by adenosine deaminases that act on RNA (ADARs) has been implicat-ed in several neurological disorders, including Parkinson’s disease (PD). Here, we report results of an RNAi screen of genes differentially regulated in adr-2 mutants, normally encoding the only catalytically active ADAR in Caenorhabditis elegans, ADR-2. Subsequent analysis of candidate genes that alter the misfolding of human α-synuclein (α-syn) and dopaminergic neurodegenera-tion, two PD pathologies, reveal that reduced expression of xdh-1, the ortholog of human xanthine dehydrogenase (XDH), is protective against α-synuclein-induced dopaminergic neurodegenera-tion. Further RNAi experiments show that WHT-2, the worm ortholog of the human ABCG2 transporter and a predicted interactor of XDH-1, is the rate-limiting factor in the ADR-2, XDH-1, WHT-2 system for dopaminergic neuroprotection. Proteomic analysis indicates that the editing of one nucleotide in wht-2 RNA leads to the substitution of threonine with alanine at residue 124 in the WHT-2 protein, changing its structure. Thus, we propose a model where wht-2, is edited by ADR-2 which promotes optimal export of uric acid, a known substrate of WHT-2 and a product of XDH-1 activity. In the absence of editing, uric acid export is limited provoking a reduction in xdh-1 transcription to limit uric acid production and maintain cellular homeostasis. In turn, ele-vation of uric acid is protective against dopaminergic neuronal cell death. These data indicate that modifying specific targets of RNA editing may represent a promising therapeutic strategy for PD.

Cellular Vehicle-to-Everything (C-V2X) is a communication technology that supports various safety, mobility, and environmental applications given its higher reliability properties compared to other communication technologies. The performance of these C-V2X-enabled Intelligent Transportation System (ITS) applications is affected by the performance of the C-V2X communication technology (mainly packet loss). Similarly, the performance of the C-V2X communication is dependent on the vehicular traffic density which is affected by the traffic mobility patterns, and vehicle routing strategies. Consequently, it is critical to develop a tool that can simulate, analyze, and evaluate the mutual interactions of the transportation and communication systems at the application level and to the evaluate the benefits of the C-V2X enabled ITS applications. In this paper, we demonstrate the benefits gained when using C-V2X Vehicle-to-Infrastructure (V2I) communication technology in an energy-efficient dynamic routing application. Specifically, we develop a Connected Energy-Efficient Dynamic Routing (C-EEDR) application using C-V2X as a communication medium in an integrated vehicular traffic and communication simulator (INTEGRATION). The results demonstrate that the C-EEDR application achieves fuel savings of up to 16.6% and 14.7% in the IDEAL and C-V2X communication cases, respectively for a peak hour demand on the downtown Los Angeles network considering a 50% level of market penetration of connected vehicles. The results demonstrate that the fuel savings increase with increasing levels of market penetration at lower traffic demand levels (25% and 50% the peak demand). At higher traffic demand levels (75% and 100%) the fuel savings increase with increasing levels of market penetration with maximum benefits at a 50% market penetration rate. Although the communication system is affected by the high density of vehicles at the high traffic demand levels (75% and 100% the peak demand), the C-EEDR application manages to perform reliably producing system-wide fuel consumption savings.The C-EEDR application achieves fuel savings of 15.2% and 11.7% for the IDEAL communication and 14% and 9% for the C-V2X communication at the 75% and 100% market penetration rates, respectively. Finally, the paper demonstrates that the C-V2X communication constraints only affect the performance of the C-EEDR application at the full demand level when the market penetration of connected vehicles exceeds 25%. This degradation, however is minimal (less than a 2.5% reduction in fuel savings).

Background: Acute pancreatitis is a common emergency. Morbidity control requires early detection of disease severity. METHODS: A total of 131 AP patients were analyzed retrospectively. Patients were divided into two groups mild AP (MAP: Ranson score <3) and severe AP (SAP: Ranson score ≥3), according to Ranson’s criteria. Demographic data, hospitalization duration, PNI, CRP, and RDW levels were compared. Any p-value below 0.05 (p<0.05) was accepted as statistically significant. RESULTS: Study included 67 (51.15%) males and 64 (48.85%) females. The age average was 59.74 (19-90) years. 95 (72.52%) patients had MAP, and 36 (27.48%) patients had SAP. Mean hospitalization time, PNI, and CRP differed significantly between the two groups (p=0.010, p<0.05, p<0.05, respectively). The RDW (p=0.380) level difference was insignificant. For SAP prediction; the sensitivity, specificity and cut-off value according to Ranson code cut-off point for PNI were determined as 80.0% (95% CI:54.8-85.8), %72.2 (95% CI:70.5-87.5) and ≤45.6 (gr/L) + (mm3), respectively, and 94.7% (95% CI:57.8-87.9), %75.0 (95% CI:88.1-98.3) and >105,1 mg/L, respectively for CRP. CONCLUSION: PNI and CRP values (but not RDW values) were compatible with the disease severity determined by the Ranson criteria.

It is shown that the representation theory of some finitely presented groups thanks to their $SL_2(\mathbb{C})$ character variety is related to algebraic surfaces. We make use of the Enriques-Kodaira classification of algebraic surfaces and the related topological tools to make such surfaces explicit. We study the connection of $SL_2(\mathbb{C})$ character varieties to topological quantum computing (TQC) as an alternative to the concept of anyons. The Hopf link $H$, whose character variety is a Del Pezzo surface $f_H$ (the trace of the commutator), is the kernel of our view of TQC. Qutrit and two-qubit magic state computing, derived from the trefoil knot in our previous work, may be seen as TQC from the Hopf link. The character variety of some two-generator Bianchi groups as well as that of the fundamental group for the singular fibers $\tilde{E}_6$ and $\tilde{D}_4$ contain $f_H$. A surface birationally equivalent to a $K_3$ surface is another compound of their character varieties.

Background: The demand in the development of cancer nanomedicine has increased due to various limitations in conventional cancer therapy. This study assessed the mRNA transcriptomic profiling of human HepG2 cells exposed to C. roseus-AgNPs. Methods: The proliferative activity of hepatocellular carcinoma (HepG2) and normal human liver (THLE3) cells treated with C. roseus‑AgNPs were measured using MTT assay. The RNA samples were extracted and sequenced using BGIseq500 platform. This is followed by data filtering, mapping, gene expression analysis, DEG analysis, GO analysis, and pathway analysis. Results: The mean IC₅₀ values of C. roseus‑AgNPs on HepG2 was 4.38±1.59 µg/mL while on THLE3 cells was 800±1.55 µg/mL. Transciptomic profiling revealed an alteration of 296 genes. C. roseus‑AgNPs induced the expression of stress-associated genes such as MT, HSP and HMOX-1. Cellular signaling pathways were potentially activated through MAPK, TNF and TGF pathways that responsible for apoptosis and cell cycle arrest. The alteration of ARF6, EHD2, FGFR3, RhoA, EEA1, VPS28, VPS25, TSG101 indicated the uptake of C. roseus-AgNPs via both clathrin-dependent and clathrin-independent endocytosis. Conclusions: This study provides the new insights on gene expression study of biosynthesized AgNPs on cancer cells. The cytotoxicity effect is mediated by the aberrant gene alteration, and more interestingly the unique selective antiproliferative properties indicates the C. roseus‑AgNPs as an ideal anticancer candidate.

Understanding of the decisive role of the interaction mechanism and kinetics in the combustion processes is highly relevant for the elaboration of optimal conditions for obtaining Mo-Cu composite powders. From this perspective, the efficient delivery of the reduction mechanism of copper and molybdenum oxides with combined Mg + C reducing agents at high heating rates is crucial to develop a valuable approach for the combustion synthesis of Mo-Cu composite powders. Herein, we shed light on the mechanism of the reactions in all the studied binary, ternary and quaternary systems contemporaneously demonstrating the effect of the heating rate on the conversion degree. The combination of two highly exothermic and speedy reactions (MoO3+3Mg and CuO+Mg vs MoO3+CuO+4Mg) led to a slow interaction with weak self-heating (dysynergistic effect) due to a change in the reaction mechanism. On the other hand, it has been shown that during the simultaneous utilization of the Mg and C reducing agents, the process begins exclusively with carbothermic reduction, and at relatively high temperatures it continues with magnesiothermic one. The effective activation energy values of the magnesiothermic stages of the studied reactions were determined by Kissinger isoconversional method.

Host ribosome-associated scaffold protein Receptor for Activated C Kinase 1 (RACK1) is utilized by a diverse group of human viruses for Internal Ribosomal Entry Sites (IRES) – mediated translation of viral mRNAs. We recently reported inhibition of herpes virus by small molecules targeting the RACK1 functional site. Here, we tested these molecules against HIV-1 and HCV, as HIV-1 contains two potential IRES sites and HCV translation occurs exclusively through IRES. Compounds significantly downregulated activities of HIV-1- and HCV-related dicistronic reporter constructs in transfected HEK293T cells. The compounds also strongly downregulated production of the HIV-1 capsid protein p24 in HIV-infected cells, as well as production of HIV-1 Gag precursor p55 and p55-derived proteins p24 and p17 in cells infected with the HIV-1 virus. Hepatitis C virus (HCV) IRES activities were also significantly inhibited by RACK1 inhibitor compounds. Since a number of human and plant pathogenic viruses are reported to use IRES, the RACK1 compounds can be established as broad host-targeted antivirals.

Pd-Pt catalysts supported on carbon preheated to 1600°C have been reinvestigated in CHFCl2 hydrodechlorination. An additionally adopted catalyst oxidation at 350-400°C produced an order of magnitude increase in the catalytic activity of Pd/C. This increase is not caused by changes in metal dispersion or possible decontamination of the Pd surface from superficial carbon, but rather by unlocking the active surface, originally inaccessible in metal particles tightly packed in the pores of carbon. Burning carbon from the pore walls attached to the metal changes the pore structure, providing easier access for the reactants to the entire palladium surface. As upon calcination the performance of the rest of the Pd-Pt/C catalysts changes less than for Pd/C, the relation between the turnover frequency and alloy composition does not confirm the Pd-Pt synergy invoked in our previous work. The use of even higher-preheated carbon (1800°C), completely free of micropores, results in a Pd/C catalyst that does not need to be oxidized to achieve high activity and excellent selectivity up to CH2F2 (>90%).

Biochar application to the soil can improve soil quality and nutrient leaching loss. Recent studies have reported that surficial application of biochar to stored swine manure can reduce emissions of odorous compounds and reduce the volatilization loss of ammonia. Our working hypothesis was that the biochar-treated manure application to the soil would decrease nutrient leaching from manure and increase plant-available nutrients. The study objectives were to evaluate the impact of biochar-treated swine manure on soil total C, N, and other major and minor nutrients. Three biochars (i) neutral pH red-oak (RO), (ii) highly alkaline autothermal corn (Zea mays) stover (HAP), and (iii) mild acidic Fe-treated autothermal corn stover (HAPE) were incubated with swine manure for a month. The biochar-manure mixture was applied in triplicate to soil columns with application rate determined by the P₂O₅-P content in manure or manure-biochar mixtures after the incubation. The ammonium (NH₄⁺), nitrate (NO₃^-), and reactive P concentrations in soil column leachates were recorded for eight leaching events. Soil properties and plant-available nutrients were compared between treatments and control manure & soil. Manure-(HAP&HAPE) biochar treatments significantly increased soil organic matter (OM) and increased soil total C, N, and improved soil bulk density. Concentrations of KCl-extractable NH₄⁺ and NO₃^- significantly increased in HAPE column leachates during this 4-week study and in the soil after the experiment. A significant reduction in soil Mehlich3 Cu was also observed for the manure-HAPE mixture compared with the control. Overall, the manure-biochar incubation enabled biochar to sorb nutrients from manure, and the subsequent manure-biochar mixture application to soil improved soil quality and plant nutrient availability in comparison to conventional manure application to soil. This proof-of-the-concept study suggests that biochars could be used to solve both environmental and agronomic challenges and further improve the sustainability of animal and crop production agriculture.

In this paper, 6063 aluminum alloy for common building profiles is used as the research object. By adding a new Al-Ti-C-La composite alloy, the effect of 6063 aluminum alloy on the microstructure and properties of 6063 aluminum alloy is studied. The results show that Al-Ti-C-La composite alloy has obvious effect on grain refinement of 6063 aluminum alloy. With the addition of Al-Ti-C-La composite alloy, the grain size decreased significantly. When the addition amount of Al-Ti-C-La composite alloy is 1%, the grain size is reduced from 482 μm to 121 μm. Rare earth La is mainly distributed near the Mg2Si phase and β-AlFeSi, and complex compounds such as AlFeSiMgLa are formed. After aging for 270 days on the basis of T6 heat treatment, the tensile strength and elongation of 6063 aluminum alloy augmented with the addition of Al-Ti-C-La composite alloy, and the Vickers hardness gradually diminished. When the addition amount of Al-Ti-C-La composite alloy is 1%, the tensile strength, elongation and Vickers hardness of 6063 aluminum alloy reach 177.2 MPa, 17.8% and 60.9 HV, respectively, and the tensile strength is increased by 16.3%. The elongation is increased by 50.8%, the Vickers hardness is reduced by 15.4%, and the fracture of the alloy is mainly ductile fracture.

In this paper, the forecast horizon and solar variability influences on MHFM model based on multiscale decomposition, AR and NN models, are studied. This article follows the works published in [1] showing the performance of the MHFM using 3 multiscale decomposition methods and a forecast horizon equal to 1 hour. Several forecast horizon strategies and his influence on the MHFM performances are investigated. We show that the best strategy for a rRMSE variying from $4.43\%$ to $10.24\%$ is obtained for forecast horizons from $5$ minutes to $6$ hours. In a second part, the solar variability influence on the MHFM is studied. A classification based on a shows that the best performance of MHFM is obtained for clear sky days with a rRMSE of $2.91\%$ and worst for cloudy sky days with a rRMSE of $6.73\%$.

Sumudu transform of the Dixon elliptic function with non zero modulus a ≠ 0 for arbitrary powers sm^N(x,a) ; N ≥ 1 ; sm^N(x,a)cm(x,a) ; N ≥ 0 and sm^N(x,a)cm²(x,a) ; N ≥ 0 is given by product of Quasi C fractions. Next by assuming denominators of Quasi C fraction to 1 and hence applying Heliermann correspondance relating formal power series (Maclaurin series of Dixon elliptic functions) and regular C fraction, Hankel determinants are calculated and showed by taking a = 0 gives the Hankel determinants of regular C fraction. The derived results were back tracked to the Laplace transform of sm(x,a) ; cm(x,a) and sm(x,a)cm(x,a).

Citrus species essential oils (EOs) are significant sources of bioactive compounds and demonstrate diverse therapeutic effects. However, limited documentation exists regarding the phytochemicals associated with their biological activities. This study aims to assess the antioxidant activity, plant inhibitory properties, and brine shrimp cytotoxic effects of EOs derived from three Citrus species: C. sinensis, C. limon, and C. hystrix. Utilizing chemometric analysis and gas chromatography-mass spectrometry (GC-MS) fingerprints, the volatile components contributing to antioxidant activity were elucidated. The peels of the Citrus samples were hydro-distillated to obtain EOs, and subsequently subjected to antioxidant, plant inhibitory, and brine shrimp cytotoxic assays. The results indicated that C. limon EO exhibited the highest antioxidant activity, while C. hystrix and C. sinensis EOs demonstrated pronounced inhibitory effects against Aetrmia salina and Lactuca sativa, respectively. GC-MS analysis facilitated the identification of key compounds in each EO. Principal component analysis (PCA) and hierarchy cluster analysis (HCA) effectively categorized Citrus EOs based on their antioxidant properties, highlighting the proximity of C. limon and C. sinensis. Among the identified compounds, D-limonene, α-Terpineol, Caryophyllene, (+)-3-Carene, β-Pinene, (-)-Spathulenol, trans-p-Mentha-1(7),8-dien-2-ol, and trans-Verbenol were the most discriminating compounds affected the antioxidant activity of C.limon and C. sinensis EOs.

Apis mellifera, especially weak ones, are highly vulnerable to Carpoglyphus lactis mites, which can rapidly infest and consume stored pollen, leading to weakened colonies and potentially colony collapse. This study aimed to ascertain and investigate the prevalence of this mite in honeybee colonies across 9 provinces in the Republic of Korea (ROK). A total of 615 honeybee colonies were collected, from 66 apiaries during the spring and 58 apiaries during the summer of 2023. A 1,242 bp segment of the the Cytochrome c oxidase subunit 1 (COI) gene was amplified using the polymerase chain reaction method. The detection levels of C. lactis in the honeybees were compared between winter and summer. Based on the COI sequence analysis, the nucleotide sequence similarity of C. lactis mites isolated in the ROK with those from China (NC048990.1) was found to be 99.5%, and with those from the United Kingdom (KY922482.1) was 99.3%. This study is the first report of C. lactis in Korean apiaries. The findings in this study demonstrate a significantly higher detection rate in winter, which is 4.1 times greater than that in summer (p &lt; 0.001). Furthermore, the results underscore the usefulness of molecular diagnostic techniques for detecting C. lactis mites.

Radiation therapy is employed in treating various cancer types. However, depending on the type and stage of cancer, its benefits can be limited, and it may cause serious side effects that detrimentally affect the quality of life (QOL) for the patient. Preventing the side effects of radiation therapy can enhance the response to cancer treatment and improve the patient’s QOL. Independently, vitamin C and hydrogen have demonstrated potential in reducing the side effects of anticancer drugs and radiation therapy. Furthermore, both have been postulated to possess direct anticancer properties. However, the effects of their combined therapy remain underexplored. This study investigates the hypothesis that combining vitamin C and hydrogen efficiently prevents radiation-induced injuries. Survival rates were investigated in cancer cell lines (MDA-MB231 and GL261) and normal cells (HUVEC) treated with hydrogen, vitamin C and irradiation. Apoptosis was assessed using the FLICA test, and EMT gene expression was elucidated via the qPCR technique. In the normal cell line, the introduction of vitamin C and hydrogen to the culture medium boosted survival rates, exhibiting a radioprotective effect upon irradiation. In contrast, cancer cells showed a decreased survival rate with the introduction of vitamin C and hydrogen, which was further diminished with irradiation. Treated cancer cells showed signs of apoptosis. Caspase activity in viable cells was reduced by the combination treatment with vitamin C and hydrogen. Additionally, glioblastoma cells treated with this combination showed reduced EMT gene expression. This study reveals that a combined therapy of hydrogen and vitamin C offers radioprotective effects on normal cells and exerts direct anticancer effects on cancer cells, while also amplifying the anticancer effects of radiation. Importantly, this combined therapy attenuated the radiation-induced EMT signature in the GL261 murine glioma cell line, suggesting potential in diminishing treatment resistance and tumor invasion.

Background: We previously reported that human keratinocytes express protease-activated receptor (PAR)-2 and play an important role in activated protein C (APC)-induced cutaneous wound healing. This study investigated the involvement of PAR-2 in the production of gelatinolytic matrix metalloproteinases (MMP)-2 and -9 by APC during cutaneous wound healing. Methods: Full-thickness excisional wounds were made on the dorsum of male C57BL/6 mice. Wounds were treated with APC on days 1, 2, and 3 post-wounding. Cultured neonatal foreskin keratinocytes were treated with APC with or without intact PAR-2 signalling to examine the effects on MMP-2 and MMP-9 production. Murine dermal fibroblasts from PAR2 knock-out (KO) mice were also assessed. MMP-2 and -9 were measured by gelatin zymography, fluorometric assay, and immunohistochemistry. Results: APC accelerated wound healing in WT mice, but had negligible effect in PAR-2 KO mice. APC stimulated murine cutaneous wound healing was associated with differential 0temporal production of MMP-2 and MMP-9, with the latter peaking on Day 1 and the former on Day 6. In-hibition of PAR-2 in human keratinocytes reduced APC-induced MMP-2 activity 25~50, but had little effect on MMP-9. Similarly, APC-induced MMP-2 activation was reduced by 40% in cultured dermal fibroblasts derived from PAR-2 KO mice. Conclusion: This study shows for the first time that PAR-2 is essential for APC-induced MMP-2 production. Considering the important role of MMP-2 in wound healing, this work helps explain the underlying mechanisms of action of APC to promote wound healing through PAR2.

A hydrothermal technique with microwave heating (200 °C, 2 hours, 2 magnetrons, 2.45 GHz) was modified to obtain UV-C luminescent LaPO4: Pr3+ colloidal nanorods for the potential use in X-ray cancer theranostics. For further possible biofunctionalization, a compound of tartaric acid formed under basic conditions was used as a coating and stabilizing agent to provide colloidal properties to the surface of nanoparticles in basic to neutral aqueous media, which was confirmed by zeta potential measurements. In addition, the colloidal properties and clustering processes of synthesized LaPO4:Pr3+ nanorods in aqueous solutions with different pH values were studied in real time using a highly sensitive laser ultramicroscope operating according to the “light-sheet” scheme. A comparative analysis of the transmission electron microscopy, X-ray powder diffraction and high-energy spectroscopy showed the different effects of synthesis parameters on the morphological, crystalline and luminescent properties of the obtained nanorods. Through optimization of the synthesis parameters, stable aqueous solutions of m-LaPO4:Pr3+ nanorods with sizes less than 30 nm and an intensity of UV-C luminescence equal to 5-10% of the unmodified nanofibers were obtained.

Background and Aims: The impact of antibody response after direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV)-infected recipients before and after liver transplantation (LT) is still undetermined. Methods: In this observational cohort study, we aimed to explore the association of changes in anti-HCV antibody titers after pre-LT DAA therapy with allograft injury, including biliary complications (BCs) and acute cellular rejection (ACR). Results: A total of 153 cases were enrolled from January 2015 to February 2021. Serum anti-HCV antibody titers were assessed before and after (day 30) LT. Among all recipients, 31/153 (20.3%) had pre-LT DAA therapy (DAA group) and 122/153 (79.7%) did not undergo pre-LT DAA therapy (DAA-naïve group). Higher incidence of post-LT BCs was observed in the DAA group (P = 0.028). Compared with the DAA-naïve group, the DAA group had a significantly higher mean level of anti-HCV titer upregulation (P = 0.0024); furthermore, among the recipients with BCs (n = 28) and ACR (n = 41), those in the DAA group exhibited significantly higher mean levels of anti-HCV antibody titer upregulation (P < 0.005). Conclusion: In conclusion, we speculated that anti-HCV antibody titer upregulation, which might have been induced by restoration of HCV-specific immune responses with pre-LT DAA therapy, were associated with post-LT allograft injury.

Estrogens play a protective role during early life stages. However, endogenous 17β-estradiol (E2) can accelerate atherosclerosis progression in low-grade inflammatory conditions like established atherosclerosis. Our single-center cohort study assessed sex-specific associations of gonadal hormones with oxidative stress, inflammation, and myocardial injury markers in 111 patients (37% women) diagnosed with acute myocardial infarction (MI) between July 2011 and December 2013. Blood samples were collected within 48 hours of symptom onset, and we measured sex steroids (E2, total testosterone [T]), oxidized low-density lipoproteins, high-sensitive C-reactive protein (CRP), white blood cell counts (WBC), and cardiac enzymes (creatine kinase [CK], the CK Muscle-Brain fraction [CK-MB], and high-sensitive troponin T [hsTnT]). The SYNTAX score gauged coronary disease severity from coronary angiography results. In men with acute MI, peak cardiac enzyme levels were predicted by post-percutaneous coronary intervention (PCI) E2 plasma levels (OR 1.011, p=0.047 - CK; OR 1.018, p=0.013 - CK- MB; OR 1.019, p=0.005 - TnT), peak WBC count (OR 1.487, p=0.015 - CK ; OR 1,709, p=0,005 - CK- MB; OR 1.391, p=0.012 - TnT), and peak CRP plasma levels (OR 1.040, p=0.033 - CK; OR 1.024, p=0.029 - CK-MB; OR 1.063, p=0.006 - TnT). T levels and E2/T ratio were associated with post-PCI CRP in these men (OR 0.980, p = 0.024 - T, OR 1.010, p = 0.076 - CRP). For women, peak WBC was a marker of highest testosterone (OR 1.348, p = 0.062), and only WBC was a significant indicator of myocardial injury extent (OR 1.426, p=0.039 - CK; OR 1.384, p=0.036 - CK-MB; OR 1.299, p=0.048 - TnT). During acute MI, elevated endogenous estradiol levels correlate with myocardial necrosis severity in men, while in women, increased leukocyte levels indicate acute myocardial damage. Elevated plasma T is associated with increased WBC in women. In men, post-PCI plasma CRP specifically indicates endogenous T levels and E2/T ratio during the acute phase.

The visual appearance of humans derives significantly from our skin and hair color. While melanin from epidermal melanocytes protects our skin from the damaging effects of ultraviolet radiation, the biological value of pigmentation in the hair follicle, particularly in the scalp, is less clear. In this study, we explore the heterogeneity of pigment cells in the human scalp anagen hair follicle bulb, a site conventionally viewed to be focused solely on pigment production for transfer to the hair shaft. Using c-KIT/CD117 microbeads, we isolated bulbar c-KIT-positive and c-KIT-negative melanocytes. While both subpopulations expressed MITF, only the c-KIT-positive fraction expressed SOX10. We further localized bulbar melanocyte subpopulations (expressing c-KIT, SOX10, MITF, and DCT) that exhibited distinct/variable expression of downstream differentiation-associated melanosome markers (e.g., gp100 and Melan-A). Localization of a second ‘immature’ SOX10 negative melanocyte population, which was c-KIT/MITF double positive, was identified outside of the melanogenic zone in the most peripheral/proximal matrix. These studies describe an approach to purifying human scalp anagen hair bulb melanocytes, allowing us to identify unexpected levels of melanocyte heterogeneity. The function of the more immature melanocytes in this part of the hair follicle remains to be elucidated. Could they be in-transit migratory cells destined to synthesize mela-nin ultimately or could they contribute to the hair follicle in non-melanogenic ways.

Several studies suggest that children infected with SARS-CoV-2 have fewer clinical manifestations than adults; when they develop symptoms, they rarely progress to severe disease. Different immunological theories have been proposed to explain this phenomenon. In September 2020, 16% of the active COVID-19 cases in Venezuela were children under 19 years. We conducted a cross-sectional study of pediatric patients' immune response and clinical conditions with SARS-CoV-2 infection. The patients were admitted to the COVID-19 area of the emergency department of Dr José Manuel de los Ríos Children's Hospital (2021-2022). The lymphocyte subpopulations were analysed by flow cytometry, and IFNγ, IL-6 and IL-10 serum concentrations were quantified using commercial ELISA assays. The analysis was conducted on 72 patients aged one month and 18 years. The majority, 52.8%, had mild disease, and 30.6 % were diagnosed with MIS-C. The main symptoms reported were fever, cough and diarrhoea. A correlation was found between IL-10 and IL-6 concentrations and age group; lymphocyte subpopulations and nutritional status and steroid use; IL-6 concentrations and clinical severity. The results suggest a different immune response depending on age and nutritional status that should be considered for treating pediatric COVID-19 patients.

In the Czech Republic, the Universal Soil Loss Equation provides the basis for defining the soil protection strategy. Field rainfall simulators were used to define the actual cover-management factor values of the most extensively seeded crops in the Czech Republic. More than 380 simulations between 2016 and 2021 provided data. The methodology focused on multi-seasonal measurements to cover the most important phenological phases. A comparison with the original USDA values for maize showed that it is desirable to redefine the C-factor. 71 fallow plot experiments showed that the rainfall-runoff relation is much easier to replicate than the actual sediment transport. For 30-minute intensive rainfall, the runoff ratio reached 62%, and the coefficient of variation was 25%. On saturated soil, the runoff ratio reached 81% and the coefficient of variation dropped to 12%. Soil protection techniques have a significant effect on runoff reduction. Maize seeded after cover crops and combined with reduced tillage or direct seeding can reduce the runoff ratio to 10-20% for ‘dry’ conditions and to 12-40% for ‘saturated’ conditions. Concerning soil loss, the variations are greater, with the coefficient of variation reaching 42% during fallow plot experiments. The reader should consider associated uncertainties.

Transcription factors (TFs) and microRNAs (miRNAs) are co-actors in genome-scale decoding and regulatory networks, often targeting common genes. In this paper, we describe the algebraic geometry of both TFs and miRNAs thanks to group theory. In TFs, the generator of the group is a DNA-binding domain while, in miRNAs, the generator is the seed of the sequence. For such a generated (infinite) group $\pi$, we compute the $SL(2,\mathbb{C})$ character variety, where $SL(2,\mathbb{C})$ is simultaneously a \lq space-time' (a Lorentz group) and a \lq quantum' (a spin) group. A noteworthy result of our approach is to recognize that optimal regulation occurs when $\pi$ looks like a free group $F_r$ ($r =1$ to $3$) in the cardinality sequence of its subgroups, a result obtained in our previous papers. A non free group structure features a potential disease. A second noteworthy result is about the structure of the Groebner basis $\mathcal{G}$ of the variety. A surface with simple singularities (like the well known Cayley cubic) within $\mathcal{G}$ is a signature of a potential disease even when $G$ looks like a free group $F_r$ in its structure of subgroups. Our methods apply to groups with a generating sequence made of two to four distinct DNA/RNA bases in $\{A,T/U,G,C\}$. Several human TFs and miRNAs are investigated in detail thanks to our approach.

This paper investigates whether currency risk is priced differently in the different sectors (industrial, financial, and basic materials) of equity markets in a sample of developed United States of America (USA) and developing economies (Brazil, India, Poland, and South Africa). The paper makes use of the following techniques: (i) Univariate Autoregressive Fractionally Integrated Moving Average and Exponential General Autoregressive Conditional Heteroskedastic (ARFIMA-EGARCH), (ii) the Markov-Switching method (MS), and (iii) the Canonical Vine Copulas (C-Vine) techniques. Using a sample of daily data made of the foreign exchange rate against the domestic currency and equity market sectors; our findings show that there is an asymmetry effect between equities markets and the foreign exchange rate: there is a heterogeneous, strong, and positive dependence between the two. Higher equities prices are associated with depreciation of local currencies, according to US dollar (USD) exchange rates. In addition, we find that the selected emerging economies are pricing a positive and considerable currency risk. The pricing of currency risk has a varied effect in both regimes representing the states of the economy. In fact, when currency risk pricing has a beneficial impact on certain sectors of the economy, investors predict better returns.

Quadruplex-interactive small molecules have a wide potential application, not only as drugs but also as sensors of quadruplexes structures. The purpose of this work is the synthesis of analogues of the bis-methylquinolinium-pyridine-2,6-dicarboxamide G4 ligand 360A, to identify relevant structure-activity relationships to apply to the design of other G4-interactive small molecules bearing bis-quinoline or bis-isoquinoline moieties. Thermal denaturation experiments revealed that non-methylated derivatives with a relative 1,4 position between the amide linker and the nitrogen of the quinoline ring are moderate G4 stabilizers, with a preference for the hybrid h-Telo G4. Insertion of a positive charge upon methylation of quinoline/isoquinoline nitrogen increases compounds capacity to selectively stabilize G4s compared to duplex DNA, with a preference for parallel structures. Among these, compounds having a relative 1,3-position between the charged methylquinolinium/isoquinolinium nitrogen and the amide linker are the best G4 stabilizers. More interestingly, these ligands showed different capacities to selectively block DNA polymer-ization in a PCR-stop assay and to induce G4 conformation switches of hybrid h-Telo G4. Mo-lecular dynamic simulations with the parallel k-RAS G4 structure showed that the relative spatial orientation of the two methylated quinoline/isoquinoline rings determines the ligands mode and strength of binding to G4s.

Aegilops columnaris Zhuk. is tetraploid grass species (2n=4x=28, UcUcXcXc) closely related to Ae. neglecta and growing in Western Asia and a western part of the Fertile Crescent. Genetic diversity of Ae. columnaris was assessed using C-banding, FISH, nuclear and chloroplast (cp)DNA analyses, and gliadin electrophoresis. Cytogenetically Ae. columnaris was subdivided into two groups, C-I and C-II, showing different karyotype structure, C-banding and FISH patterns. Group C-I was more similar to Ae. neglecta. All types of markers revealed significant heterogeneity of the C-II group, although group C-I was also polymorphic. Two chromosomal groups were consistent with plastogroups identified in a current study based on sequencing of three chloroplast intergenic spacer regions. The similarity of group C-I of Ae. columnaris with Ae. neglecta and their distinctness from C-II indicate that divergence of the C-I group was associated with minor genome modifications. Group C-II could emerge from C-I relatively recently, probably due to introgression from another Aegilops species followed by a reorganization of the parental genomes. Most C-II accessions were collected from the very narrow geographic region, and they might originate from a common ancestor. We suggest that the C-II group is at the initial stage of species divergence and undergoing an extensive speciation process.

Plants are affected by soil environments to the same extent they affect soil functioning through interactions between environmental and genetic factors. Here, five plant species (broad bean, pea, cabbage, fennel, and olive) grown under controlled pot conditions were tested for their ability to differently stimulate the degradation of standard litter. Litter, soil C and N contents and soil microbial abundance were measured. The architecture and morphological traits of roots systems were also evaluated by using specific open-source software (SmartRoot). Soil chemical and microbiological characteristics were significantly influenced by the plant species. Variations in soil C/N dynamics were correlated with the diversity of root traits among species. Early-stage decomposition of the standard litter changed on the basis of the plant species. The results indicated that key soil processes are governed by interactions between plant roots, soil C and N, and the microbial metabolism that stimulate decomposition reactions. This, in turn, can have marked effects on soil chemical and microbiological fertility, both fundamental for sustaining crops, and can promote the development of new approaches for optimizing soil C and N cycling, managing nutrient transport, and sustaining and improving net primary production.

The non-structural protein NS3/4A protease is a critical factor for hepatitis C virus (HCV) maturation that requires activation by NS4A. Synthetic peptide mutants of NS4A were found to inhibit NS3 function. The bridging from peptide inhibitors to heterocyclic peptidomimetics of NS4A has not been in consideration in literature, and therefore, we decided to explore this strategy to develop a new class of NS3 inhibitors. In this report, a structure-based design approach was used to convert the bound form of NS4A into 1H-imidazole-2,5-dicarboxamide derivatives as first generation peptidomimetics. This scaffold mimics the buried amino acid sequence Ile-25` to Arg-28` at the core of NS4A21`-33` needed to activate the NS3 protease. Some of the synthesized MOC compounds were able to compete with and displace NS4A21`-33` for binding to NS3. For instance, N5-(4-guanidinobutyl)-N2-(n-hexyl)-1H-imidazole-2,5-dicarboxamide (MOC-24) inhibited the binding of NS4A21`-33` with a competition IC50 of 1.9 ± 0.12 µM in a fluorescence anisotropy assay, stabilized the denaturation of NS3 by increasing the aggregation temperature by ΔTagg 0.6 ± 0.140 ℃. MOC-24 also inhibited NS3 protease activity in a fluorometric assay. Molecular dynamics simulations rationalized the structure-activity relationship (SAR) differences between the active MOC-24 and the inactive MOC-26. Our data shows that MOC compounds are possibly the first examples of NS4A peptidomimetics that demonstrated promising activities against NS3 proteins.

Transforming growth factor beta (TGF-β) is a determinant for inflammation and fibrosis in cardiac and skeletal muscle in Chagas disease. To determine its regulatory mechanisms, we investigated the response of T. cruzi-infected cardiomyocytes (CM), cardiac fibroblasts (CF) and L6E9 skeletal myoblasts to TGF-β. Cultures of CM, CF and L6E9 were infected with T. cruzi (Y strain) and treated with TGF-β (1–10 ng/mL, 1h or 48 h). Fibronectin (FN) distribution was analyzed by immunofluorescence and Western blot (WB). Phosphorylated SMAD2 (PS2), phospho-p38 (p-p38), and phospho-c-Jun (p-c-Jun) signaling were evaluated by WB. CF and L6E9 showed an increase in FN from 1 ng/mL of TGF-β, while CM displayed FN modulation only after 10 ng/mL treatment. CF and L6E9 showed higher PS2 levels than CM, while p38 is less stimulated in CF than CM and L6E9. After T. cruzi infection, localized FN disorganization was observed in infected CF and L6E9. T. cruzi induced an increase in FN in CF cultures, mainly in uninfected cells. Infected CF cultures treated with TGF-β showed a reduction in PS2 and an increase in p-p38 and p-c-Jun levels. Our data suggest that p38 and c-Jun pathways may be participating in the fibrosis regulatory process mediated by TGF-β after T. cruzi infection.

Various types of electroconductive additives were evaluated for high C-rate capability in an attempt to extend practical application of high-areal-capacity lithium–sulfur batteries that employ an aluminum-foam current collector. Carbon nanofibers (CNFs) were found to be the most effective additive, with the ability to attain a high-sulfur-loading of 40 mg cm−2. A CNF-containing cell exhibited gravimetric capacities of 1094 and 758 mAh gsulfur−1 (46.8 and 32.4 mAh cm−2) at 0.05 and 0.1 C-rate, respectively, in an ether-based electrolyte. Because a CNF-containing slurry exhibits low viscosity even at a high solid ratio, it could be filled into the aluminum foam. Additionally, a lithium–sulfur battery with high-sulfur-loading had an energy density of ~120 Wh kg−1, a value that was calculated from the weight of the components of the cathode, anode, current collectors, electrolyte, and separator. Assuming that the amount of electrolyte decreases and that the energy density of cells accumulate, a theoretical energy density of 522 Wh kg−1 was estimated. Moreover, it was found that even if a high-areal-capacity was achieved, the discharge capacity converged at a high C-rate, unless there was an improvement in ion diffusion in the bulk electrolyte. This is considered a limitation of sulfur cathodes with high-sulfur-loading.

Rotavirus species H (RVH) has been detected in pigs, humans and bats. Moreover, porcine RVHs have been recently identified in several swine-producing countries. Despite their zoonotic impact, genome information of RVHs is still limited. This study aimed to establish a tentative complete genome-based genotyping system for RVHs, by appending genomic sequences from 12 porcine RVHs identified in Japan between 2013 and 2015 to those from human and other porcine RVHs reported in previous studies. Phylogenetic analysis of 11 RNA segments indicated that porcine RVHs could be classified into multiple genotypes. Consequently, the genotype classification for RVHs revealed the existence of genotypes 10G, 6P, 6I, 3R, 4C, 7M, 6A, 2N, 4T, 6E, 3H for the genes VP7, VP4, VP6, VP1, VP2, VP3, NSP1, NSP2, NSP3, NSP4 and NSP5, respectively. Surprisingly, two distinctive types in NSP1 and NSP3 genes were identified from among the twelve porcine RVHs. Our data suggest a potentially novel gene rearrangement event between porcine RVH and rotavirus species C in the NSP3 gene. These findings would provide a new insight in understanding for evolution of RV.

The Mediterranean diet (MedDiet) is recognised to reduce risk of coronary heart disease (CHD), in part, via its anti-inflammatory properties. Diet efficacy via this mechanism is however unclear in patients with diagnosed CHD. This study aimed to determine the effect of MedDiet versus low-fat diet intervention on inflammatory biomarkers and adiposity in a pilot cohort of Australian patients post coronary event. Participants (62±9 years, 83% male) were randomised to the MedDiet (n=34) or low-fat diet (n=31). At 0-, 3- and 6-months, dietary counselling, anthropometry, body composition (Dual-energy X-ray Absorptiometry) and venepuncture was conducted. Participants adhered well to the MedDiet intervention, however, there were no significant changes in body composition or inflammatory biomarkers hs-C-reactive protein or hs-interleukin-6 in the MedDiet compared to the low-fat diet group after 6-months. Adiponectin, an anti-inflammatory adipokine, tended to increase in response to the MedDiet (+1.1±4.2ng/mL, p=0.11) and decrease in response to the low-fat diet (-0.9±3.3ng/mL, p=0.20). In the pooled cohort, participants with greatest improvement in MedDiet adherence score had significantly lower waist circumference and subcutaneous fat levels at 6-months. A clinically significant effect of the MedDiet on inflammation and adiposity in CHD patients may require a larger sample, adjunct exercise intervention and/or caloric restriction.

The pleiotropic biochemical and antioxidant functions of Vitamin C (Vit C) have recently sparked interest in its application in intensive care. Vit C protects important organ systems such as the cardiovascular, neurologic and renal system during inflammation and oxidative stress. Vit C also influences the systems of coagulation and inflammation and its application might prevent the development of organ damage. The current evidence of Vit C’s effect on the pathophysiological reactions during various acute stress events, such as sepsis, shock, trauma, burn and ischemia-reperfusion injury imposes the question, if the application of Vit C might be especially beneficial for cardiac surgery patients, who are routinely exposed to ischemia/reperfusion and subsequent inflammation, systematically affecting different organ systems. This review covers current knowledge about the role of Vit C in cardiac surgery patients with focus on its influence on organ dysfunctions. The relationships between Vit C and clinical health outcomes are reviewed with special emphasis on its application in cardiac surgery. Additionally, this review pragmatically discusses evidence regarding the administration of Vitamin C in every day clinical practice, tackling the issues of safety, monitoring, dosage and most the appropriate application strategy.

C-terminal Src kinase (CSK) is the major inhibitory kinase for Src family kinases (SFKs) through phosphorylation of their C-tail tyrosine site, and regulates various cellular activities in association with SFKs functions. As a cytoplasmic protein, CSK need be recruited to the plasma membrane to regulate SFKs activities. The regulatory mechanism for CSK activity and its subcellular localization remains largely unclear. In this work, we developed a genetically encoded biosensor based on fluorescence resonance energy transfer (FRET) to visualize CSK activity in live cells. The biosensor with optimized substrate peptide confirmed crucial Arg107 site in CSK SH2 domain, and displayed sensitivity and specificity to CSK activity while little responses to co-transfected Src and Fyn. FRET measurements showed CSK having relatively mild level of kinase activity in comparison to Src and Fyn ones in rat airway smooth muscle cells. The biosensor tagged with different submembrane-targeting signals detected CSK activity at both non-lipid raft and lipid raft microregions, while showed higher FRET level at non-lipid ones. Co-transfected receptor-type protein tyrosine phosphatase alpha (PTPα) had inhibitory effect on the CSK FRET response. The biosensor didn’t detect obvious changes of CSK activity between metastatic cancer cells and normal ones. In conclusion, a novel FRET biosensor was generated to monitor CSK activity, and demonstrated CSK activity existing in both non-lipid and lipid raft membrane microregions while more present at non-lipid ones.

The process of sexual reproduction in eukaryotes starts when gametes from two different sexes encounter each other. Paramecium, a unicellular eukaryote, undergoes conjugation and uses a gametic nucleus to enter the sexual reproductive process. The molecules responsible for recognizing mating partners, hypothetically called mating-type substances, are still unclear. We have identified an O3-type mating substance polypeptide and its gene sequence using protein chemistry, molecular genetics, immunofluorescence, RNA inter-ference, and microinjection. The O3-type substance is a polypeptide found in the ciliary membranes, located from the head to the ventral side of cells. The O3-type substance has a kinase-like domain in its N-terminal part located outside the cell and four EF-hand motifs that bind calcium ions in its C-terminal part located inside the cell. RNA interference and immunofluorescence revealed that this polypeptide positively correlated with the expression of mating reactivity. Microinjection of an expression vector incorporating the O3Pc-MSP gene induced additional O3 mating type in the recipient clones of different mating types or syngen. Phylogenetic analysis indicates this gene is widely present in eukaryotes and exhibits high homology among closely related species. The O3Pc-MSP gene had nine silent mutations compared to the complementary mating type of the E3 homologue gene.

Recent years have experienced an increase in construction and demolition waste (C&amp;DW), which is the most significant solid waste stream. C&amp;DW is contributing to exceeding all planetary boundaries and presents a range of other issues. In order to better understand the existing research on C&amp;DW, a global bibliographic analysis was undertaken through seven groups of keyword searches and the results visualised using VOCviewer. The results show that C&amp;DW receives only a modest research attention compared to other areas of waste, and this is despite an exponential increase in C&amp;DW research since 2016. The analyses also show that concrete is the most researched material in terms of C&amp;DW, and that reuse, recycling, and circular economy are so far attracting only proportionally modest research attention. This signals a need for further acceleration of the C&amp;DW research, and specifically for more research on reuse, recycling, and circular economy for materials other than concrete.

In order to obtain the good match between yield strength and low-temperature toughness, the short-time partial austenitization (SPA) process was employed for V-microalloying 0.22C-5.24Mn steel. The initial microstructure after intercritical tempering was dual-phase ferrite and reversed austenite (RA), while the final microstructure was consisted of ferrite, RA and secondary martensite (SM) after subjected to SPA process. (V, Mo)C with disc-like morphology mainly precipitated during intercritial tempering, and the aspect ratio of particle decreased, leading to the appearance of near-spherical morphology. After subjected to SPA process, the resultant multiphase hierarchical microstructure (three layers: out layer of ferrite, interlayer of SM and inner layer RA) enabled high yield strength of 1097 MPa, total elongation of 14%, and impressive impact energy of 33.3 J at -20 °C. The strengthening contribution of (V, Mo)C precipitation was estimated about 108 MPa.

Diversity-generating retroelements (DGRs) are prokaryotic systems providing rapid modification and adaptation of target proteins. In phages, the main targets of DGRs are receptor-binding proteins that are usually parts of tail structures and the variability of such host-recognizing structures enables phage adaptation to changes on the bacterial host surface. Sometimes, more than one target gene containing a hypermutated variable repeat (VR) can be found in phage DGRs. The role of mutagenesis of two functionally different genes is unclear. In this study, several phage genomes that contain DGRs with two target genes were found in the gut virome of healthy volunteer. Bioinformatics analysis of these genes indicated that they encode proteins with different topology; however, both proteins contain the C-type lectin (C-lec) domain with a hypermutated beta-hairpin on its surface. One of the target proteins belongs to a new family of proteins with a specific topology: N-terminal C-lec domain followed by one or more immunoglobulin domains. Proteins from the new family were named tentaclins after TENTACLe+proteIN. The genes encoding such proteins were found in the genomes of prophages and phages from the gut metagenomes. We hypothesized that tentaclins are involved in binding either to bacterial receptors or intestinal/immune cells.

Monitoring snowmelt dynamics in mountains is crucial to understand water releases downstream. Sentinel-1 (S-1) synthetic aperture radar (SAR) has become one of the most widely used techniques to achieve this aim due to its high frequency of acquisitions and all-weather capability. This work aims to understand the possibilities of S-1 SAR imagery to capture snowmelt dynamics and related changes in streamflow response in semiarid mountains. The results proved that S-1 SAR imagery was able not only to capture the final spring melting but also all melting cycles that commonly appear throughout the year in these types of environments. The general change detection approach to identify wet snow was adapted for these regions using as reference the average S-1 SAR image from the previous summer, and a threshold of -3.00 dB. In addition, four different type of melting runoff onsets depending on physical snow condition were identified. When translating that at the catchment scale, distributed melting runoff onset maps were defined to better understand the spatiotemporal evolution of melting dynamics. Finally, a linear connection between melting dynamics and streamflow was found for long-lasting melting cycles, with a determination coefficient (R2) ranging from 0.62 to 0.83 and an average delay between the melting onset and streamflow peak of about 21 days.

The integration of deep learning methods, especially Convolutional Neural Networks (CNN), and Synthetic Aperture Radar Automatic Target Recognition (SAR ATR) has been widely deployed in the field of radar signal processing. Nevertheless, these methods are frequently regarded as black-box models due to the limited visual interpretation of their internal feature representation and parameter organization. In this paper, we propose an innovative approach named C-RISE, which builds upon the RISE algorithm to provide a post-hoc interpretation technique for black-box models used in SAR Images Target Recognition. C-RISE generates saliency maps that effectively visualize the significance of each pixel. Our algorithm outperforms RISE by clustering masks that capture similar fusion features into distinct groups, enabling more appropriate weight distribution and increased focus on the target area. Furthermore, we employ Gaussian blur to process the masked area, preserving the original image structure with optimal consistency and integrity. C-RISE has been extensively evaluated through experiments, and the results demonstrate superior performance over other interpretation methods based on perturbation when applied to neural networks for SAR image target recognition. Furthermore, our approach is highly robust and transferable compared to other interpretable algorithms, including white-box methods.

Revealing the time structure of physical or biological objects is usually performed thanks to the tools of signal processing like the fast Fourier transform, Ramanujan sum signal processing and many other techniques. For space-time topological objects in physics and biology, we propose a type of algebraic processing based on schemes in which the discrimination of singularities within objects is based on the space-time-spin group SL(2,C). Such topological objects possess an homotopy structure encoded in their fundamental group and the related SL(2,C) multivariate polynomial character variety contains a plethora of singularities somehow analogous to the frequency spectrum in time structures. Our approach is applied to an Akbulut cork in exotic R4, to an hyperbolic model of topological quantum computing based on algebraic surfaces and to microRNAs in genetics. Such diverse topics reveal the manifold of possibilities of using the concept of a scheme spectrum.

In the multicenter, non-randomized, exploratory C-reactive protein (CRP) Apheresis in Myocardial Infarction (CAMI-1) study, CRP apheresis after ST-Elevation Myocardial Infarction (STEMI) significantly decreased blood CRP concentrations in humans. Cardiac damage was assessed by Cardiac Magnetic Resonance (CMR1) 3-9 d after onset of STEMI symptoms and quantified by myocardial infarct size (IS; %), left ventricular ejection fraction (LVEF; %), circumferential strain (CS) and longitudinal strain (LS) Compared with the control group (n=34), cardiac damage was significantly lower in the apheresis group (n=32). These findings suggested improved wound healing due to CRP apheresis already within few days after the STEMI event. In the current supplementary data analysis of CAMI-1, we have tested by a follow-up CMR (CMR2) after an average of 88 (65-177) d whether the effect of CRP apheresis is clinically maintained. After this time period wound healing in STEMI is considered complete. Whereas patients with low CRP production and a CRP gradient cut off of &lt;0.6 mg/L/h in the hours after STEMI (9 of 32 patients in the CRP apheresis group) did not significantly benefit from CRP apheresis in CMR2, patients with high CRP production and a CRP gradient cut off of &gt;0.6 mg/L/h (23 of 32 patients in the CRP apheresis group) showed significant treatment benefit. In the latter patients, CMR2 revealed a lower IS (-5.4%; p=0.05), a better LVEF (+6.4%; p=0.03), and an improved CS (-6.1%; p=0.005). No significant improvement, however, was observed for LS (-2.9%; p=0.1). These data suggest a sustained positive effect of CRP apheresis on the heart physiology in STEMI patients with high CRP production well beyond the period of its application. The data demonstrate the sustainability of the CRP removal from plasma which is associated with less scar tissue.

Leucine-rich α-2 glycoprotein1 (LRG1) is a member of the leucine-rich repeat (LRR) family that was implicated in multiple diseases including cancer, aging and heart failure as well as diabetes and obesity. LRG1 plays a key role in diet-induced hepatosteatosis and insulin resistance by mediating the crosstalk between adipocytes and hepatocytes. LRG1 also promotes hepatosteatosis by upregulating de novo lipogenesis in the liver and suppressing fatty acid β oxidation. In this study, we investigated the association of LRG1 with obesity markers including leptin and other adipokines in adolescents (11-14 years; n=425). BMI-for-age classification based on WHO growth charts was used to define obesity. Plasma LRG1 was measured by ELISA while other markers were measured by multiplexing assay. Median (IQR) of LRG1 levels was higher in obese [30 (25, 38) µg/mL] and overweight [30 (24, 39) µg/mL] adolescents, compared to normal-weight participants [27 (22, 35) µg/mL]. The highest tertile of LRG1 had an OR [95%CI] of 2.55 [1.44, 4.53] for obesity. LRG1 was positively correlated to plasma levels of HsCRP (R=0.2), Leptin (R=0.2) and Chemerin (R=0.24) with p<0.001. Additionally, it was positively associated with plasma level of IL6 (R=0.17) and IL10 (R=0.14) but not TNF-α. In conclusion, LRG1 levels are increased in obese kids and associate with increased levels of adipogenic markers. These results suggest the usefulness of LRG1 as an early biomarker for obesity and its related pathologies in adolescents.

The construction of carbon-carbon bonds by direct involvement of two unactivated carbon-hydrogen bonds, without any directing group, ensures an high atom economy of the entire process. Here it is described a simple protocol for the Pd(II)/Cu(II)-promoted intermolecular cross-dehydrogenative coupling (CDC) of 5-arylimidazoles, benzimidazoles, benzoxazole and 4,5-diphenylimidazole at their C-2 position with functionalized styrenes. This specific CDC, known as Fujiwara-Moritani reaction or oxidative Heck coupling, allowed also the C-4 alkenylation of the imidazole nucleus when both 2 and 5 positions are occupied.

The identification and molecular characterization of cellular hierarchies in complex tissues is key to understanding both normal cellular homeostasis and tumorigenesis. The mammary epithelium is a heterogeneous tissue consisting of two main cellular compartments, an outer basal layer containing myoepithelial cells and an inner luminal layer consisting of estrogen receptor-negative (ER⁻) ductal cells and secretory alveolar cells (in the fully functional differentiated tissue) and hormone-responsive estrogen receptor-positive (ER⁺) cells. Recent publications have used single-cell RNA-sequencing (scRNA-seq) analysis to decipher epithelial cell differentiation hierarchies in human and murine mammary glands, and reported the identification of new cell types and states based on the expression of the luminal progenitor cell marker KIT (c-Kit). These studies allow for comprehensive and unbiased analysis of the different cell types that constitute a heterogeneous tissue. Here we discuss scRNA-seq studies in the context of previous research in which mammary epithelial cell populations were molecularly and functionally characterized, and identified c-Kit⁺ progenitors and cell states analogous to those reported in the recent scRNA-seq studies.

Bodybuilders utilize peaking strategies in a bid to fine-tune their aesthetics for competition day. The most prevalent peaking strategies utilized by natural bodybuilders are unreported in the current literature. Eighty-one (M - 59, F - 22) natural bodybuilders were recruited from competitions during the 2016 and 2017 British Natural Bodybuilder Federation seasons. Competitors completed a 34-item questionnaire designed to investigate peaking and contest day strategies. The questionnaire listed commonly utilized peaking strategies and provided additional space for qualitative information. Analysis of the data indicated that carbohydrate (CHO), water and sodium manipulation were the most commonly utilized peak week strategies. The consumption of high glycemic index CHO was the most common competition day strategy. Only 6.2 % of competitors reported following their regular diet the week prior to competition. The CHO manipulation strategies were similar to classical CHO loading, whereby bodybuilders attempt to maximize muscle glycogen concentrations. Furthermore, bodybuilders attempted to remove superfluous water by exploiting the diuretic/polyuria effect associated with water loading/restriction. The potentially deleterious effects of peaking on bodybuilders' health is considered and the efficacy of these strategies to enhance appearance is discussed. The findings of the present investigation are likely to be of interest to bodybuilders and their coaches.

Biological neural network (BNN) is the core brain for creature to accomplish its intelligent behaviors through unique network structure and mechanisms. It also inspires controlling human-designed autonomous agents including robots to generate more advanced intelligent behaviors by mimicking the neural control mechanism of creatures at a deeper and more interactive level. Here, we constructed a whole-brain neural network model of Caenorhabditis elegans (C. elegans), which characterizes the electrochemical processes at the level of cellular synapse. The neural network simulation integrates computational programming and visualization of neurons and synapse connections of C. elegans, containing the specific controllable circuits summarization with their dynamic characteristics within the whole network. To illustrate its particular intelligent control capability in terms of robotics, we introduce the first innovative methodology for applying the BNN model to a 12-legged robot’s movement control based on the established numerical simulation platforms. We accomplished and designed two methods and corresponding encoding processes, one involving orientation control and the other involving locomotion generation, to demonstrate the intelligent control performance of BNN. Both simulation and experiment results indicate that the robot exhibits stronger autonomy and more intelligent moving performance under the control of BNN. We then summarized the contributions for digitalizing the C. elegans’ whole-brain neural network in real-time and utilizing it to control robot in a closed loop to validate its advanced intelligence control ability in terms of a scientific robot.

A change in biological properties of the SARS-CoV-2 virus can enhance its transmissibility and virulence, complicate the disease course, and reduce the effectiveness of anti-viral therapy and vaccination. We have studied 16 genetic lineages of the Omicron variant. The viral reproduction course was analyzed based on plaque morphology in the agar layer and the maximum titer in Vero E6 cells. BALB/c mice and Syrian hamsters were used as animal models. Viral load and infectious SARS-CoV-2 titer were determined in the nasal tissue and lungs. The severity of infectious process was assessed using histological methods. An increased plug size was observed in CH.1.1 and BQ.1.2.1 strains after six passages. This was due to substitutions D614G, H655Y, and N764K in the coronavirus S protein. The same changes in gene variants Gamma and BA.1 were caused by the substitution R682W, which is not present in lineages CH.1.1 and BQ.1.2.1. A similar substitution, namely R682P, was observed in the BA.5.1 strain. We characterized BA.1 (as a reference), BA.5.2, and XBB.3 strains in vivo as representatives of the main circulating genetic lineages. For the BA.1 strain, ID50 was 1.3 and 14 TCD50 in Syrian hamsters and BALB/c mice, respectively. An insignificant increase in the BA.5.2 virulence compared to that of BA.1 was noted (ID50 was 07. and 10 TCD50, respectively). The XBB.3 pathogenicity in laboratory animals is similar to that of BA.1 (ID50 was 1.8 and 15 TCD50, respectively). Experiments showed a consistent decrease in the virulence of Omicron strains compared to previously circulating SARS-CoV-2 variants. A co-evolutionary change in amino acid sequences, affecting the conformation of the coronavirus S protein and its surface epitopes in representatives of different genetic lineages, was noted. The emergence of potential proteolysis sites and alterations of the furin cleavage site have been observed in numerous Omicron coronavirus variants.

SORL1 gene encodes LR11/SorLA, a protein that binds -amyloid precursor protein (bAPP) and drives its intracellular trafficking. SORL1 mutations occurring frequently in a subset of familial cases of Alzheimer’s disease (AD) have been documented but their pathogenic potential is not yet clear and questions remain concerning their putative influence on the physiopathological processing of bAPP. We have assessed the influence of three SORL1 mutations that were described as likely disease-causing and that were associated with either benign (SorLA924) or severe (SorLA141 and SorLA511) AD phenotypes. We examined the influence of wild-type and mutants SorLA in transiently transfected HEK293 cells expressing either wild-type or Swedish mutated bAPP on bAPP expression, secreted Ab and sAPPa levels, intracellular Ab40 and Ab42 peptides, APP-CTFs (C99 and C83) expressions, a-, b- and g-secretases expressions and activities as well as Ab and CTFs-degrading enzymes. These paradigms were studied in control conditions or after pharmacological proteasomal modulation. We also established stably transfected CHO cells expressing wild-type SorLA and established the colocalization of wild-type SorLA and bAPP. Overall, although we mostly confirmed previous data concerning the influence of wild-type SorLA on bAPP processing, we were unable to evidence significant alterations triggered by our set of SorLA mutants, whatever the cells or pharmacological conditions examined. Our study however does not rule out the possibility that other AD-linked SORL1 mutations could indeed affect bAPP processing and that pathogenic mutations examined in the present study could interfere with other cellular pathways/triggers in AD.

Background and Objectives: C-arm free MIS techniques can offer significantly reduced rates of postoperative complications such as blood loss and hospitalization time. Another advantageous long-term aspect is the notably diminished exposure to radiation which is known to cause ma-lignant changes. This study emphasizes that, in some cases of spinal conditions which require a procedural intervention, C-arm free MIS techniques hold stronger indications than open surgeries guided by image intensifier. Materials and Methods: In this research, a retrospective analysis and review of various cervical and thoracic spinal procedures, performed in our hospital, by applying C-arm free techniques. The course of the study explains the basic steps of the procedures and demonstrating postoperative or intra-operative results. For anterior cervical surgery, we performed OPLL resection, while for posterior cervical surgery, we performed posterior fossa decompression for Chiari malformation, minimally invasive cervi-cal pedicle screw fixation (MICEPS) and modified Goel technique with C1 lateral mass screw for atlantoaxial subluxation. Re-garding the thoracic spine, we performed anterior correction for Lenke type 5 scoliosis, and transdiscal screw fixation for DISH fractures. Results: C-arm free techniques are safe procedures that offer precise and high-quality postoperative results by offering sufficient spine alignment and adequate decompression depending on the case. Blood loss, postoperative pain and wound infection are other important aspects of spine surgery that must be always taken into consideration. Conclusions: Navigated C-arm free techniques are safe and precise procedures implemented in the treatment of surgically demanding conditions. They can significantly increase accuracy while decreasing the operative time. They represent the advancement in the field spine surgery and are hailed as the future of the same

Prostate cancer (PC) is the most frequently diagnosed non-skin cancer in the world. Previous studies showed that genomic alterations represent the most common mechanism for molecular alterations that cause the development and progression of PC. Great efforts have been done to identify common protein-coding genetic variations; however, the impact of non-coding variations including regulatory genetic variants is not still well understood. To gain an understanding of the functional impact of genetic variants, particularly, regulatory variants in PC, we developed an integrative pipeline (AGV) that used whole genome/exome sequences, GWAS SNPs, chromosome conformation capture data, and ChIP-Seq signals to investigate the potential impact of genomic variants on the underlying target genes in PC. We identified 646 putative regulatory variants, of which 30 of them significantly altered the expression of at least one protein-coding gene. Our analysis of chromatin interactions data (Hi-C) revealed that the 30 putative regulatory variants may affect 131 coding and non-coding genes. Interestingly, our study showed the 131 protein-coding genes are involved in disease-related pathways including Reactome and MSigDB in which for most of them targeted treatment options are currently available. Together, our results provide a comprehensive map of genomic variants in PC and revealed their potential contribution to prostate cancer progression and development.

Data from ocean color (OC) remote sensing are considered a cost-effective tool for the study of biogeochemical processes globally. Satellite-derived chlorophyll, for instance, is considered an Essential Climate Variable since it is helpful in detecting climate change impacts. Google Earth Engine (GEE) is a planetary scale tool for remote sensing data analysis. Along with OC data, such tools allow an unprecedented spatial and temporal scale analysis of water quality monitoring in a way that has never been done before. Although OC data have been routinely collected at medium (~1 km) and more recently at high (~250 m) spatial resolution, only coarse resolution (≥4 km) data are available in GEE, making them unattractive for applications in the coastal regions. Data reprojection is needed prior to making OC data readily available in the GEE. In this paper, we introduce a simple but practical procedure to reproject and ingest OC data into GEE. The procedure is applicable to OC swath (Level-2) data and is easily adaptable to higher-level products. The results showed consistent distributions between swath and reprojected data, building confidence in the introduced framework. The study aims to start a discussion on making high resolution OC data readily available in GEE.

Human pegivirus (HPgV) is best known for persistent, presumably non-pathogenic, infection and a propensity to co-infect with human immunodeficiency virus or hepatitis C virus. However, unique at-tributes, such as the increased risk of malignancy or immune modulation, have been recently recognized for HPgV. We have identified a unique case of a woman with high levels HPgV infection in two preg-nancies, which occurred 4 years apart, without evidence of human immunodeficiency virus or hepatitis C virus infection. The second pregnancy was complicated by congenital heart disease. A high level of HPgV infection was detected in maternal blood from different trimesters by RT-PCR and identified as HPgV type 1 genotype 2 in both pregnancies. In the second pregnancy, the decidua and intervillous tissue of the placenta were positive for HPgV by PCR but not the chorion or cord blood (from both pregnancies), suggesting no vertical transmission despite high levels of viremia. The HPgV genome sequence was remarkably conserved over the 4 years. Using VirScan, sera antibodies for HPgV were detected in the first trimester of both pregnancies. We observed the same anti-HPgV antibodies against the non-structural NS5 protein in both pregnancies, suggesting a similar non-E2 protein humoral immune response over time. To the best of our knowledge, this is the first report of persistent HPgV infection involving placental tissues with no evidence of vertical transmission. Our results reveal a more elaborate viral-host interaction than previously reported, expand our knowledge about tropism, and opens avenues for exploring the replication sites of this virus.

Background: The fulminant course of COVID-19, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents with a high mortality rate and still lacks a causative treatment. C-reactive protein (CRP) has been shown to increase dramatically during the disease progression and correlates with deleterious outcomes. Selective CRP apheresis can reduce circulating CRP levels fast and effective. Methods: Seven hospitalized patients with documented severe COVID-19 progression, elevated CRP plasma levels (> 100 mg/L) and signs of respiratory failure were treated with CRP apheresis. 2-12 CRP apheresis sessions were performed generally in 24 h time intervals and depending on CRP plasma levels. Results: CRP apheresis reduced CRP plasma levels by up to 84% within a few hours, without exhibiting side effects in any patient. Despite signs of severe lung infiltration in all patients, only one patient died. The other patients showed improvements within the chest x-ray after CRP apheresis and were able to recover regardless of intubation and/or ECMO (4 patients). All remaining six patients were discharged from the hospital in good clinical condition. All patients had comorbidities. Conclusions: This case series presents a mortality rate of only 14%, which is dramatically lower than expected from the presented CRP levels as well as comorbidities and ventilation require-ments. Our clinical observations regarding the here presented seven patients support the hypoth-esis that CRP is a candidate to be therapeutically targeted in the early stage of severe COVID-19.

Rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to 9-tetrahydrocannabinol (9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that 9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg 9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to 9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, 9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACC, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expression of hepatic DGAT1/DGAT2 was sustained at six months, concomitant with mitochondrial dysfunction (i.e., elevated p66shc) and oxidative stress. Interestingly, decreases in miR-203a-3p and miR-29a/b/c, both implicated in dyslipidemia, was also observed in these 9-THC-exposed offspring. Collectively, these findings indicate that prenatal 9-THC exposure results in long-term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms.

Gut microbiota and its metabolites like short chain fatty acids (SCFAs) are linked with pathology of Alzheimer’s disease (AD)- a debilitating public health problem in older adults. However, strategies to beneficially modulate gut microbiota and its sensing signaling pathways remain largely unknown. Here, we screened, validated and established the agonists of free fatty acid receptor 2 (FFAR2) signaling, which senses beneficial signals from SCFAs produced by microbiota in the gut. We demonstrated that inhibition of FFAR2 signaling increases amyloid-beta (Aβ) stimulated neuronal toxicity. Thus, we screened FFAR2 agonists, using in-silico library of more than 144,000 natural compounds, and 15 compounds were selected based on binding with FFAR2 agonist sites. Further, cell culture toxicity and FFAR2 stimulatory experiments demonstrated that Fenchol (a natural compound commonly present in basil) was potent FFAR2 agonist in neuronal cells. Interestingly, we also demonstrated that Fenchol protects Aβ-stimulated neurodegeneration in FFAR2 dependent manner. In addition, Fenchol reduced AD like phenotypes such as Aβ-accumulation and, learning and memory behaviors in Caenorhabditis (C.) elegans. Fenchol increased Aβ-clearance by increasing proteasome/lysosome activity and reduced senescence in neuronal cells. These results demonstrated that the inhibition of FFAR2 signaling promotes Aβ-induced neurodegeneration, while activating it by Fenchol as a natural agonist reverse it by promoting Aβ-clearance and reducing cellular senescence; thus stimulation of FFAR2 signaling can be a therapeutic approach to prevent/ treat AD.

Endometrial Cancer (EC) is the sixth most commonly occurring cancer in women with 380 000 cases in 2018. Sadly, EC morbidity and mortality are continuously increasing, therefore the medical society have a substantial need for an accurate and inexpensive diagnostic test for EC early detection and a prognostic tool for treatment planning and evaluation. Considering experience with different types of cancers C-reactive protein (CRP) appears to be a promising diagnostic and prognostic factor. Aiming to investigate its potential and in view of EC authors, this paper reviewed the following databases for metanalysis, randomized controlled trials and review articles published up to June 2020: Pubmed, Scopus, Google scholar and ClinicalKey. Studies indicate CRP >3.33 mg/l correlate with EC incidence with HR = 2.29 (p<0.05). Moreover, High-sensitivity CRP assay allows to detect CRP in very low concentrations and distinguish patients with endometriosis, soft tissue sarcomas and possibly EC. Preoperational and postoperational CRP, as well as its dynamic change are independent prognostic factors for EC and are more reliable if analyzed together. However, CRP-to-albumin ratio as well as Glasgow Prognostic Scale have greater prognostic value that CRP alone. Additionally, CRP is possibly a mediator of carcinogenesis and cancer progression through activation of inter alia FcgRs/MAPK/ERK, FcgRs/IL-6/AKT/STAT3 and FcgRs/NF-κB/NLRP3 pathways.

Introduction: Coronavirus 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2. The majority of patients have at most mild symptoms, however, a significant proportion develops respiratory failure. COVID-19 may also progress beyond the lungs. Coagulopathy and thromboembolism are prevalent in severe COVID-19 and relate to decreased survival. Coagulation is an intricate balance between clot promoting and dissolving processes in which vitamin K plays a well-known role. We hypothesized that vitamin K status is reduced in patients with severe COVID-19. Methods: Vitamin K status was assessed by measuring desphospho-uncarboxylated matrix Gla protein (dp-ucMGP; inversely related to vitamin K status) and the rate of elastin degradation by measuring desmosine. We included 123 patients who were admitted with COVID-19 and 184 controls. Results: Dp-ucMGP levels were significantly elevated in COVID-19 patients (1,673Å}1,584 pmol/L) compared to controls (536±291 pmol/L; p<0.0005). Dp-ucMGP levels were significantly higher in COVID-19 patients with unfavorable outcome compared to those with less severe disease. Furthermore, dp-ucMGP and desmosine levels were significantly associated (r=0.65; p<0.0005). Conclusions: Vitamin K status was reduced in patients with COVID-19 and related to poor prognosis. Also, low vitamin K status seems to be associated with accelerated elastin degradation. An intervention trial is now needed to assess whether vitamin K administration improves outcome in patients with COVID-19.

The fourth Industrial Revolution, well-known as “Industry 4.0”, based on the integration of information and communication technologies, has introduced significant improvements in manufacturing. However, vision systems still experience various impracticalities in dealing with the effect of complex lighting on the systems platform. Therefore, a machine vision system for automatic identification of pen parts under varying lighting conditions at a digital learning factory is proposed. The developed vision system presents a straightforward approach by effectively minimizing the environmental lighting effect on the identification process. First, the obtained information of the designed vision framework is exported to a program, where a reduction of non-uniform illumination is achieved through the implementation of Retinex image enhancement techniques. Then, the color-based Fuzzy C-means (FCM) algorithm, including improved mark watershed segmentation, is employed for pen parts object classification. Finally, the position features of the selected pen part are reported. The process applied to a total number of 210 upper pen parts (caps) and 241 lower pen parts (tubes) images under different lighting scenarios. Results indicate that average parts identification precision for cap and tube parts is different and equals to 98.64% and 95.26%, respectively. The present methodology provides a promising scheme that can be feasibly adapted for other industrial Color-based object recognition applications.

Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, are responsible for approximately 2.65 million deaths per year. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: 1) Supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; 2) Supplementation above the RDA, but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and 3) Public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.

Indirubin-3′-monoxime (I3M) exhibits anti-proliferative activity in various cancer cells; however, its anti-cancer mechanism remains incompletely elucidated. This study revealed that I3M promotes the expression of death receptor 5 (DR5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in HCT116 p53+/+ cells, resulting in caspase-mediated apoptosis. However, this study demonstrated that HCT116 p53-/- cells are insensitive to I3M-mediated apoptosis, indicating that I3M-induced apoptosis depends on the p53 status of HCT116 cells. Additionally, in HCT116 p53-/- cells, I3M significantly increased Ras expression, while in HCT116 p53+/+ cells, it reduced Ras expression. Furthermore, I3M remarkably increased the production of reactive oxygen species (ROS), which were reduced in transient p53 knockdown, indicating that I3M-mediated apoptosis is promoted by p53-mediated ROS production. Our results also showed that I3M enhanced transcription factor C/EBP homologous protein (CHOP) expression, resulting in endoplasmic reticulum (ER) stress-mediated DR5 expression, which is upregulated by ROS production in HCT116 p53+/+ cells. Moreover, co-treatment with TRAIL synergistically enhanced I3M-induced DR5 expression, thereby triggering TRAIL-induced apoptosis of HCT116 p53+/+ cells, which was interfered by a DR5-specific blocking chimeric antibody. In summary, I3M potently enhances TRAIL-induced apoptosis by upregulating DR5 expression via p53-mediated ROS production in HCT116 p53+/+ cells. However, HCT116 p53-/- cells were resistant to I3M-mediated apoptosis, suggesting that I3M could be a promising anti-cancer candidate against TRAIL-resistant p53+/+ cancer cells.

In this work, several random Boolean networks (RBN) are generated and analyzed from two characteristics: their time evolution diagram and their transition diagram. To do this, its randomness is estimated using three metrics, of which algorithmic complexity is the only one capable of revealing both transitions towards the chaotic regime and the algorithmic contribution of certain states to the transition diagram and their relationship with the order they occupy in the temporal evolution of the respective RBN.

The effect of the antioxidant vitamin C in cancer has been studied for over 30 years with conflict-ing results ranging from total absence of effect, to possible protective effect, to potential therapeutic effect when administered in high doses. The aim of the study was to define the effect of vitamin C in breast cancer and the possible involvement of sphingomyelin metabolism. Therefore, the effect of low and high dose of vitamin C on cells reproducing luminal A type (MCF7) and triple negative type (MB231) of breast cancer was analyzed. The results showed that high dose of vitamin C produced effects only in MCF7 cells such as decreased cell viability, modulation of cell cycle re-lated genes, unexpected change in cell phenotype due to estrogen receptor downregulation, catabo-lism of sphingomyelin with a large increase in ceramide. In conclusion, we demonstrated that high doses of VitC on the one hand reduce the growth of lu-minal A type breast cancer cells and on the other hand induce their phenotypic change towards hormone therapy resistant cells. The effect of vitamin C on therapeutic treatment failure of luminal A breast cancer and the possible involvement of high ceramide levels were discussed.

Organic light-emitting diodes (OLEDs) are energy-efficient; however, the coordinating ligand can affect their stability. Sky-blue phosphorescent Pt(II) complexes with a C^N chelate, fluorinated-dbi (dbi = [1-(2,4-diisopropyldibenzo[b,d]furan-3-yl)-2-phenyl-1H-imidazole]), and acetylactonate (acac)(1)/picolinate (pic)(2) ancillary ligands were synthesized. The molecular structures were characterized using various spectroscopic methods. The Pt(II) coordination sphere in 2 exhibited a distorted square-planar geometry, with several intra- and inter-molecular interactions involving Cπ⋯H/Cπ⋯Cπ stacking. Complex 1 emitted bright sky-blue light (λmax = 485 nm) with a moderate photoluminescent quantum efficiency of 0.37 and short decay time (6.1 µs) compared to those of 2. Time-dependent density functional theory calculations suggested that the electronic transition of 1 arose from ligand(C^N)-centered π–π* transitions combined with metal-to-ligand charge transfer transitions (MLCT), whereas that of 2 arose from MLCT and ligand(C^N)-to-ligand(pic) charge transfer (LLCT), with minimal contribution from the C^N chelate to the lowest unoccupied molecular orbital. Multi-layered phosphorescent OLEDs using 1 as a dopant and a mixed host, 3,3-di(9H-carbazol-9-yl)-1,1-biphenyl:3-di(9H-carbazol-9-yl)-1,1-biphenyl (mCBP)/9-(3’-carbazol-9-yl-5-cyano-biphenyl-3-yl)-9H-carbazole-3-carbonitrile (CNmCBPCN) were successfully fabricated. At a 10% doping of 1, a current efficiency of 13.6 cd A−1 and external quantum efficiency of 8.4 % at 100 cd m−2 were achieved. These results show that the ancillary ligand in phosphorescent Pt(II) complexes must be considered.

Abstract Eye health is crucial and the onset of diseases can reduce vision and affect the quality of life of patients. The main causes of progressive and irreversible vision loss include various pathologies such as cataracts, ocular atrophy, corneal opacity, age-related macular degeneration, uncorrected refractive error, posterior capsular opacification, uveitis, glaucoma, diabetic retinopathy, retinal detachment, undetermined disease and other disorders involving oxidative stress and inflammation. The eyes are constantly exposed to the external environment and, for this reason, must be protected from damage from the outside. Many drugs, including cortisonics and antinflammatory drugs have widely been used to counteract eye disorders. However, recent advances have been obtained via supplementation of patients with natural antioxidants and nutraceuticals. In particular, evidence has been accumulated that polyphenols (mostly deriving from Citrus Bergamia) represent a reliable source of antioxidants able to counteract oxidative stress accompanying early stages of eye diseases. Luteolin, in particular, has been found to protect foto-receptors thereby improving vision in many disease states. Moreover, a consistent anti-inflammatory response was found to occur when curcumin is used alone or in combination with other nutraceuticals. On the other hand, CoQ10 has been demonstrated to produce consistent effect in reducing ocular pressure thereby leding to protection in patients undergoing glaucoma. Finally, both grape seed extract rich in anthocyanosides and polynsatured fatty acids (PUFAs) seem to contribute in the prevention of retinal disorders. Thus, combination of nutraceuticals and anti-oxidants may represent the right solution for a multiaction activity in eye protection to be associated to current drug therapies, and this will be of potential interest in early stages of eye disorders.

Most oral squamous cell carcinomas (OSCCs) arise from oral epithelial dysplasia; however, there is no useful marker for early OSCC detection, likely owing to the inability to continuously observe the carcinoma sequence. We aimed to establish an experimental model to observe changes in the sequential expression pattern of mRNA and protein in the same rat using liquid-based cytology techniques. Cytology specimens were collected from a 4-nitroquinoline 1-oxide-induced rat tongue cancer model at 2, 5, 8, 11, 14, 17, and 21 weeks. We examined candidate biomarker expression using immunocytochemistry and quantitative real-time PCR. The percentage of positively stained nuclei was calculated as the labeling index (LI). All rats had OSCC of the tongue at 21 weeks. Brd4 (Brd4), Myc (c-Myc), and Tp53 (p53) mRNA levels were upregulated during progression from negative for intraepithelial lesion or malignancy to SCC. Brd4- and c-Myc-LI were increased in low- and high-grade squamous intraepithelial lesions and SCC specimens. p53-LI was significantly increased in SCC specimens. Our experimental model allowed the observation of sequential morphological changes and mRNA and protein expression patterns in the same rat during carcinogenesis. By reducing the false negative rate, BRD4 and c-Myc can be useful markers for the early detection of OSCC.

Insulin-like growth factor binding proteins (IGFBPs) are critical modulators of the metabolism. In adults, IGFBPs are associated with obesity and insulin resistance but the association of IGFBPs with metabolic homeostasis in children and adolescents is not fully characterized. In this study we investigated the association of plasma IGFBPs (IGFBP-1, 3 and 7) with weight status, central adiposity and cardiovascular disease markers Hs-CRP and Ox-LDL. A total of 420 adolescents (age 11-14 years) were randomly recruited from public middle schools in Kuwait. IGFBPs were measured using bead-based multiplexing while Hs-CRP and Ox-LDL were measured using ELISA. IGFBP-1 levels were significantly lower in obese and overweight participants compared to normal weight children. Only IGFBP-1 was negatively associated with waist circumference to height (WC/Ht) ratio. IGFBP-1 was negatively correlated with Hs-CRP while IGFBP-3 and IGFBP-7 were negatively correlated with Ox-LDL. These data demonstrate a robust negative association of IGFBP-1, but not IGFBP-3 or -7, with overweight and obesity, and the inflammation marker Hs-CRP. Central adiposity (WC/Ht ratio) was a stronger predictor of IGFBP-1 than BMI-for-age z-score. IGFBP-1 could thus be used as a sensitive predictive diagnostic tool for obesity and its subsequent effects in screening and monitoring of obesity-related metabolic complications in adolescents.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the etiological agent of the current pandemic worldwide. The pathological condition induced by this pathogen is known as COVID-19 disease. SARS-CoV-2 associated pandemic has been defined as a “public health emergency of international concern” by the International Health Regulation Emergency Committee of the World Health Organization. To date, considerable efforts are in progress to develop more advanced strategies against SARS-CoV-2. Despite the numerous scientific studies published, our knowledge regarding this pathogen is still incomplete, as this virus has been identified only recently. Therefore, scientific investigation of the SARS-CoV-2 has been possible only for a short period of time and effective management of the serious forms of this disease is still lacking. Considerable efforts are in progress worldwide with the purpose to develop more advanced strategies against this pathogen. In this review, we have analyzed the structural and the biological SARS-CoV-2 characteristics and those of other well-known RNA viruses, with the aim to identify possible similarities and analogies between all these pathogens, may be a very useful approach. These infectious agents have been widely studied since several years ago and, a large series of scientific reports are available in the literature regarding this topic. Therefore, focusing on the Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) and Influenza viruses (IVs), we have collected their historical data, clinical manifestations, pathogenetic mechanisms and related infections. Taking advantage of the results of our research, we have assembled this narrative review, with the aim to get useful insights and lessons from HIV, HCV and IVs characteristics and, consequently, to transfer the obtained knowledge to the study of SARS-CoV-2 biology. There are well known differences between all these pathogens. In particular, they present a distinct mode of transmission, as SARS-CoV-2 and Influenza viruses are airborne pathogens, whereas HIV and HCV are bloodborne infectious agents. However, these viruses exhibit some potential common clinical manifestations and pathogenetic mechanisms and their understanding may contribute to establishing preventive measures and new therapies against SARS-CoV-2. Accordingly, we have analysed and discussed the following points: 1) the biology, the pathogenesis and the clinical manifestations of SARS-CoV-2, HIV, HCV and IVs in mankind; 2) the onset and spreading of pandemics caused by respiratory viruses according to a perspective historical point of view; 3) the possible development of a persistent SARS-CoV-2 reservoir worldwide; 4) the possibility of SARS-CoV-2 reinfection/reactivation; 5) the possible involvement and impact of climatic factors in increasing the risk of SARS-CoV-2 spreading.

Background: Risk tratification based on pre-test probability may improve the diagnostic accuracy of temporal artery high-resolution compression sonography (hrTCS) in the diagnostic workup of cranial giant cell arteriitis (cGCA). Methods: A logistic regression model with candidate items was derived from a cohort of patients with suspected cGCA (n = 87). The diagnostic accuracy of the model was tested in the derivation cohort and in an independent validation cohort (n = 114) by receiver operator characteristics (ROC)-analysis. The clinical items were composed to a clinical prediction rule, integrated into a stepwise diagnostic algorithm together with CRP-values and hrTCS-values. Results: The model consisted of 4 clinical variables (age &gt; 70, headache, jaw claudication, anterior ischemic optic neuropathy). The diagnostic accuracy of the model for discrimination of patients with and without a final clinical diagnosis of cGCA was excellent in both cohorts (AUC 0.96 and AUC 0.92, respectively). The diagnostic algorithm improved the positive predictive value of hrCTS substantially. Within the algorithm, 32.8% of patients (derivation cohort) and 49.1% (validation cohort) would not have been tested by hrtCS. None of these patients had a final diagnosis of cGCA. Conclusion: A diagnostic algorithm based on a clinical prediction rule improves the diagnostic accuracy of hrTCS.

The replication of species A rotaviruses (RVAs) and other RNA viruses involves recruitment of and inter-action with the cellular organelles lipid droplets (LDs), both physically and functionally. Inhibition of en-zymes involved in the cellular fatty acid biosynthesis pathway or of cellular lipases that degrade LDs re-duces the functions of ‘viral factories’ (viroplasms for rotaviruses or replication compartments of other RNA viruses) and decreases the production of infectious progeny virus. Similarly, disturbance of the cellular lipid homeostasis in various ways blocks the replication of flaviviruses (hepatitis C viruses, Zikavirus, others), HIV-1, SARS-CoV-2, picornaviruses, noroviruses, influenza viruses and other negative-strand RNA viruses.

Despite innovative advances in anti-infective therapies and vaccine development technologies, community-acquired pneumonia (CAP) remains the most persistent cause of infection-related mortality globally. Confronting the ongoing threat posed by Streptococcus pneumoniae (the pneumococcus), the most common bacterial cause of CAP, particularly to the non-immune elderly, remains challenging due to the propensity of the elderly to develop invasive pneumococcal disease (IPD), together with the predilection of the pathogen for the heart. The resultant development of often fatal cardiovascular events (CVEs), particularly during the first seven days of acute infection, is now recognized as a relatively common complication of IPD. The current review represents an update on the prevalence and types of CVEs associated with acute bacterial CAP, particularly IPD. In addition, it is focused on recent insights into the involvement of the pneumococcal pore-forming toxin, pneumolysin (Ply), in subverting host immune defenses, particularly the protective functions of the alveolar macrophage during early-stage disease. This, in turn, enables extra-pulmonary dissemination of the pathogen, leading to cardiac invasion, cardiotoxicity and myocardial dysfunction. The review concludes with an overview of the current status of macrolide antibiotics in the treatment of bacterial CAP in general, as well as severe pneumococcal CAP, including a consideration of the mechanisms by which these agents inhibit the production of Ply by macrolide-resistant strains of the pathogen.

Behavior of supported alloyed and de-alloyed platinum-copper catalysts, which contained 14% - 27% wt. of Pt, was studied in the reactions of methanol electrooxidation (MOR) and oxygen electroreduction (ORR) in 0.1 M HClO4 solutions. Alloyed PtCux/C catalysts were prepared by a multistage sequential deposition of copper and platinum onto a Vulcan XC72 dispersed carbon support. De-alloyed PtCux-y/C catalysts were prepared by PtCux/C materials pretreatment in acid solutions. The effects of the catalysts initial composition and the acid treatment condition on their composition, structure, and catalytic activity in MOR and ORR were studied. Functional characteristics of platinum-copper catalysts were compared with those of commercial Pt/C catalysts when tested, both in an electrochemical cell and in H2/Air membrane-electrode assembly (MEA). It was shown that the acid pretreatment of platinum-copper catalysts practically does not have negative effect on their catalytic activity, but it reduces the amount of copper passing into the solution during the subsequent electrochemical study. The activity of platinum-copper catalysts in the MOR and the current-voltage characteristics of the H2/Air PEMFC MEAs measured in the process of their life tests were much higher than those of the Pt/C catalysts.

C-reactive protein (CRP) and leukocytes are blood biomarkers involved in "Inflamm-Aging", which is a risk factor for the onset and progression of age-related diseases. Studies show that higher serum concentrations of these biomarkers are associated with functional disability, increased risk of low muscle strength, decreased muscle mass and mortality in the elderly. The objective was to estimate the predictive power and discriminating criteria of C-reactive protein and leukocyte concentrations for the risk of adverse health factors in the elderly within 30 days after hospital discharge (HD). Prospective cohort study using exploratory methods and blood biomarkers with 135 older adults admitted to medical and surgical clinics at a government hospital. The elderly were monitored at home after 30 days of HD for adverse health factors (rehospitalization, falls, amount of medication consumed, disability in basic and instrumental activities of daily living and mortality). CRP> 2.4; ≥ 0.7 and> 24.7 mg / dL and leukocytes ≥ 6.410; ≥ 8.690 and> 8.310 mm³ were discriminant for rehospitalization, falls and mortality within 30 days after HD, respectively. The cut-off points described may be used as a reference in the screening of hospitalized elderly vulnerable to adverse health events after hospital discharge.

The present study was aimed to evaluate the levels of oxidative stress markers in breast diseases by measuring the 8-hydoxy-2-deoxyguanosine (8-OHdG), vitamin A, vitamin C, vitamin E and total antioxidant status (TAS) alterations in relation to cell proliferation activity and disease progression. Significant increases in the level of oxidative damage marker 8-OHdG and cell proliferation activity were observed in breast carcinoma patients in comparison to benign and normal controls, which were accompanied by significant decrease in non enzymatic antioxidants and TAS concentrations. 8-OHdG and cell proliferation level were negatively correlated with non enzymatic antioxidants viz., Vitamin A, Vitamin C, vitamin E level and total antioxidant activity. Altered levels of biomarkers of oxidative stress and cell proliferation activity amongst the malignant, benign and controls suggest a correlation of increased oxidative stress and cell proliferation activity in the progression of disease in breast carcinoma patients. Among the oxidative stress markers and cell proliferation index, decreased level of vitamin A, vitamin C, vitamin E, TAS and increased level of 8-OHdG, cell proliferation index emerged as best predicted biomarkers for subjects with malignancy and benign breast disease.

Since the discovery of transposable elements (TEs) in Maize in the 1940s by Barbara McClintock [1] transposable elements have been described as junk, as selfish elements with no benefit to the host, and more recently as major determinants of genome structure and genome evolution. TEs are DNA sequences that are capable of moving to new sites in the genome and make additional copies while doing so. To limit the propagation of TEs, host silencing mechanisms are directed at transposon-encoded genes that are required for mobilization. The mutagenic properties of TEs, the potential of TEs to form new genes and affect gene expression, together with the host silencing mechanisms shape eukaryotic genomes and drive genome evolution. While TEs constitute more than half of the genome in many higher eukaryotes, transposable elements in the nematode C. ele-gans form a relatively small proportion of genome, about 15% [2]. Genetic studies of transposon silencing and the discovery of RNAi in C. elegans, propelled C. elegans to the forefront of studies of RNA-based mechanisms that silence TEs. Here, I will review the transposable elements that are present and active in the C. elegans genome, and the host defense mechanisms that silence these elements.

Vasculitis diseases include Kawasaki Disease (KD), Kawasaki Disease Shock Syndrome (KDSS), Multisystem Inflammatory Syndromes (MIS), Henoch-Schönlein purpura (HS) or IgA Vasculitis, and additional vasculitis diseases. These diseases are often preceded by infections or immunizations. Disease incidence rates are higher in children than adults. These diseases have been extensively studied, but understanding of the disease etiology remains to be established. Many studies have failed to demonstrate an association between these vasculitis diseases and vaccination. Here, the Vaccine Adverse Event Reporting System (VAERS) is used to demonstrate that, in certain rare cases, the number of cases of KD, MIS, and HS is higher than background following vaccination. These rare cases are predicted to occur in individuals with genetic risk factors who produce antibody titer levels above primary immune response level. Herein, the model of humoral immune response antibodies bound to antigens (pathogen or vaccine) creating immune complexes is proposed. These immune complexes are proposed to bind Fc receptors on immune cells and platelets resulting in cell activation and release of inflammatory molecules including histamine and serotonin. Immune complexes and inflammatory molecules including serotonin and histamine likely trigger vasculitis. Elevated serotonin and likely histamine drive initial vasoconstrictions disrupting blood flow. Increased blood flow pressure from cardiac capillary vasoconstrictions is predicted to trigger coronary artery aneurysms in some patients. For KDSS and MIS patients, these cardiac capillary vasoconstrictions are predicted to result in ischemia followed by ventricular dysfunction. Ongoing ischemia can result in long-term cardiac damage. Cases associated with pathogens are likely to have persistent infections triggering disease onset.

The demand for dietary supplements containing collagen has been growing for years. The speciality and uniqueness of the dietary supplement (DS) examined in our study is the presence of L-arginine and hyaluronic acid alongside collagen and vitamin C. The individual mechanisms of action and physiological role of these compounds are understood, but they have not yet been tested in the combination and amounts of the dietary supplement used in this study. In this study, we investigated the effectiveness of the DS in elderly patients with musculoskeletal complaints. Somatometric, body composition, physiotherapy and laboratory tests were performed at the beginning and at the end of the study. The two-month study involved 30 people, randomly divided into two groups: a control group (CG) and an experimental group (EG). All subjects consumed 25 ml DS per day and EG members also participated in physiotherapy 3 times a week. Alongside the DS, blood lipid levels changed: LDL decreased, HDL increased, LDL/HDL ratio significantly decreased in both groups. For EG, the results improved more markedly. In 3 items of the body composition test, there was a significant improvement in both groups, which was attributed to the use of the dietary supplement. For the EG, there were significant changes in 5 additional test items, which we attribute to the addition of regular physical activity. Knee and hip joint range of motion (ROM) showed significant improvements in the study group, while in the CG the DS can cause significant improvements in joint range of motion in a passive condition as well.

We study C*-algebraic versions of following conjectures/theorems: (1) Bieberbach conjecture (de Branges theorem) (2) Robertson conjecture (3) Lebedev-Milin conjecture (4) Zalcman conjecture (5) Krzyz conjecture (6) Corona conjecture (Carleson theorem). We prove that the C*-algebraic Bieberbach Conjecture for invertible coefficients is true for second degree C*-algebraic polynomials.

Excessive intracellular glucose in insulin independent tissues including nerve, nephron, lens and retina invites mishandling of metabolism of glucose resulting in a background of increased oxidative stress, advanced glycation end products (AGE) formation, lipid peroxidation and failure of antioxidant defense systems in type 2 diabetes mellitus (T2DM). All these detrimental biochemical anomalies ultimately attack biological membranes and especially capillary beds of retina and glomerulus of kidney, resulting in break-down of inner blood-retinal i.e. initiation of diabetic retinopathy (DR). If these disarrays are corrected to a large extent, development of DR can be avoided or delayed. In this prospective clinical trial, 185 patients with T2DM who received B-vitamins, vitamin-C, and E along with anti-diabetic medication for five years, demonstrated a slower rate of the development of DR and reduced abnormal biochemical mediators like reactive oxygen species (ROS), malondialdehyde (MDA), AGE, and vascular endothelial growth factor (VEGF) compared to 175 T2DM individuals who were treated with only anti-hyperglycemic drugs.

L-17 is a thiadiazine derivative with putative anti-inflammatory, neuroprotective, and antidepressant-like properties. In this study, we applied combined in silico, ex vivo, and in vivo electrophysiology techniques to reveal the potential mechanism of action of L-17. PASS 10.4 Professional Extended software suggested that L-17 might have pro-cognitive, antidepressant, and antipsychotic effects. Docking energy assessment with AutoDockVina predicted that the binding affinities of L-17 to the serotonin transporter (SERT) and serotonin receptors 3 and 1A (5-HT3 and 5-HT1A) receptors are compatible to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and selective antagonists of 5-HT3 and 5-HT1A receptors, granisetron and WAY100135, respectively. Acute pre-treatment with L-17 robustly increased c-Fos immunoreactivity in the amygdala (central nucleus), suggesting increased neuronal excitability in this brain area after L-17 administration. Acute L-17 also dose-dependently inhibited of 5-HT neurons of the dorsal raphe nucleus (DRN). This inhibition was partially reversed by subsequent administration of WAY100135, suggesting the involvement of extracellular 5-HT. Based on in silico predictions, c-Fos immunohistochemistry, and in vivo electrophysiology, we suggest that L-17 is a potent 5-HT reuptake inhibitor and/or partial 5-HT1A receptor antagonist. Thus, L-17 might be a representative of a new class of antidepressant drugs. Since L-17 also possesses neuro- and cardio-protective properties, it can be useful in post-stroke and post-myocardial infarction (MI) depression. In general, combined in silico predictions and ex vivo neurochemical and in vivo electrophysiological assessment might be a useful strategy for early preclinical assessment of the affectivity and neural mechanism in action of the novel CNS drugs.

Background: The mortality and severity in COVID-19 is increased in patients with comorbidities. The aim of this study was to evaluate the unknown risk of severity and mortality in COVID-19 patients with underlying kidney and liver diseases. Method: We retrieved data on the clinical features and primary composite end point of COVID-19 patients released from inception till 16^th of April 2020 from Medline and Embase. The data on two comorbidities, liver diseases and chronic kidney disease, present in COVID-19 were pooled and statistically analysed to explain the associated severity and mortality rate. Results: 142 abstracts were screened, and 41 full articles were then read. In total, 22 studies including 5595 COVID-19 patients were included in this study with case fatality rate of 16%. The prevalence of liver diseases and CKD were 3% (95%CI; 2%-3%) and 1% (95%CI; 1%-2%) respectively. In patients with COVID-19 and underlying liver diseases, 57.33% (43/75) cases were severe with 17.65% mortality. While in CKD patients with COVID-19, 83.93% (47/56) severity and 53.33% (8/15) mortality were reported. Conclusion: This study found an increased risk of severity and mortality in COVID-19 patients with liver diseases and CKD. This will allow for better clinical management and inform more stringent preventative measures for this group of patients.

In this study, we introduce a novel framework for the estimation of residual renal function (RRF), based on the population compartmental kinetic behavior of Beta 2 Microglobulin (B2M) and its dialytic removal. Using this model, we simulated a large cohort of patients with various levels of RRF receiving either conventional high-flux hemodialysis or on-line hemodiafiltration. These simulations were used to estimate a novel population kinetic (PK) equation for RRF (PK-RRF) that was validated in an external public dataset of real patients. We assessed the performance of the resulting equation(s) against their ability to estimate urea clearance using cross-validation. Our equations derived entirely from computer simulations and advanced statistical modeling, and had extremely high discrimination (AUC 0.808 – 0.909) when applied to a human dataset of measurements of RRF. A clearance-based equation that utilized pre and post dialysis B2M measurements, patient weight, treatment duration and ultrafiltration had higher discrimination than an equation previously derived in humans. Furthermore, the derived equations appeared to have higher clinical usefulness as assessed by Decision Curve Analysis, potentially supporting decisions that for individualizing dialysis frequency in patients with preserved RRF.

The purpose of this study is nutrient resources recovery by achieving the optimal chemical oxygen demand (COD) and carbon to nitrogen ratio (C/N) in co-composting wastewater treatment plant sludge with Municipal Solid Wastes (MSW). In this effort, the co-composting has been conducted in form of a case study in the northern region of Iran. In this research, 192 tests were carried out on four series of samples examined in terms of waste to sludge ratio, different aeration period, the percent of porous materials and the moisture content. This study was carried out at a temperature of 50 °C for a 15 day period by application of the in-vessel system and shows that the best ratio for waste to sludge is 2:1, while the 8 hour period is the best aeration period. The porous material which can be added to the composting process is limited to 15% in weight. In other words, any more or less amount of this material will adversely impact the process. Moreover, this research suggests that the sludge dewatering is not required in such processes. In Addition, the efficiency of both COD and C/N reductions equals to about 40%.

Formation of Fe- and Mg-rich smectite and zeolite under alkaline conditions is concerned as secondary minerals after alkaline alteration of bentonite in a repository of radioactive wastes. It might be crucial for safety assessment whether smectite will be formed or not as secondary minerals after alkaline alteration of bentonite. In present paper, Fe- and Mg-rich smectite which are currently interacting with hyperalkaline groundwater was found at Narra in Palawan, Philippines. Mineralogical and geochemical investigation was conducted to understand formation process of smectite and factors determined secondary mineral species. Our study revealed a certain amount of smectite may have been produced under hyperalkaline conditions, altered from amorphous or poorly crystalline material such as M-S-H and F-S-H. Key factor which decides smectite or zeolite as secondary minerals after alkaline alteration of bentonite might be whether nuclei of M-S-H and/or F-S-H will be formed or not. This might be decided by the presence of dissolved Mg2+ and Fe2+ in the system. Our suggested formation process of smectite under alkaline conditions is analogue with generally-accepted model of smectite formation that might have been occurred on early Mars.

Transient receptor potential melastatin-8 (TRPM8) is a cation channel that is activated by cold and “cooling agents” such as menthol and icilin, which induce a cold sensation. Stimulation of TRPM8 activates an intracellular signaling cascade that ultimately leads to a change in the gene expression pattern of the cells. Here, we investigated the TRPM8-induced signaling pathway that links TRPM8 channel activation to gene transcription. Using a pharmacological approach, we show that inhibition of phosphatidylinositol 4-phosphate 5 kinase alpha (PIP5K), an enzyme essential for the biosynthesis of phosphatidylinositol 4,5-bisphosphate, attenuated TRPM8-induced gene transcription. Analyzing the link between TRPM8 and Gq proteins, we show that pharmacological inhibition of the beta gamma subunits impairs TRPM8 signaling. In addition, genetic studies showed that TRPM8 requires an activated Galpha subunit for signaling. In the nucleus, the TRPM8-induced signaling cascade triggers an activation of the transcription factor AP-1, a complex consisting of a dimer of basic region leucine zipper (bZIP) transcription factors. Here, we identified the bZIP protein c-Jun as an essential component of AP-1 within the TRPM8-induced signling cscade. In summary, with PIP5K, Gq subunits and c-Jun we have identified key molecules in the TRPM8-induced signaling from the plasma membrane to the nucleus.

Fluorinated compounds and co-enzymes are being widely researched and employed throughout research community because of their versatile physical, chemical and biological properties. In this work, we synthesized NiS-NiO/S-g-C3N4, a highly effective photocatalyst for C(sp3)-F bond activation and the regeneration of coenzyme (1,4-NADH) employing a new and ecologically acceptable route. The obtained photocatalyst exhibited important photocatalytic properties, such as good solar light harvesting ability, suitability of the optical band-gap, and facilitating efficient charge migrations. As a result, the newly designed NiS-NiO/S-g-C3N4 photocatalyst shows the excellent yield for regenerations of 1,4-NADH (51%). Further, a method of combining C(sp3)-F bond activation with photocatalysis has been demonstrated that represents a very powerful and sustainable approach, that can be a major breakthrough for the field of pharmaceutical.

Historically, viral hepatitis is a considerable public health problem in Central Asian countries, which may have worsened after dissolution of the Soviet Union. However, up-to-date seroepidemiological studies are lacking. The aim of the present study was, therefore, to provide current estimates of seroprevalence of viral hepatitis in Kyrgyzstan, one of the economically least developed countries in the region. We conducted a population-based cross-sectional study in 2018 in the capital of Kyrgyzstan, Bishkek (n=1075). Participants, children and adults, were recruited from an outpatient clinic. Data were collected during face-to-face interviews. A blood sample (6 ml) was collected from each participant and tested with ELISA for the presence of serological markers for five viral hepatitides (A, B, C, D and E). Poststratification weighting was performed to obtain nationally representative findings. The overwhelming majority of the study participants were positive for anti-HAV (estimated seroprevalence, 75.3%; 95% confidence interval: 72.5–77.9%). The weighted seroprevalence estimates of HBsAg, anti-HCV and anti-HDV were 2.2% (1.5–3.3%), 3.8% (2.8–5.1%), and 0.40% (0.15–1.01%), respectively. Anti-HEV seropositivity was 3.3% (2.4–4.5%). Of the 33 HBsAg positive participants, five (15%) were anti-HDV positive. Our study confirms that Kyrgyzstan remains a high endemic country for hepatitis virus A and C infections. However, seroprevalences of HBV and HDV were lower than previously reported, and based on these data, the country could potentially be reclassified from high to (lower) intermediate endemicity. The observed anti-HEV seroprevalence resembles the low endemicity pattern characteristic of high-income countries.

Fanconi anemia (FA) develops due to a mutation in one of the FANC genes that are involved in repair of interstrand crosslinks (ICLs). FANCG, a member of the FA core complex, is essential for ICL repair. Previous FANCG-deficient mouse models were generated with drug-based selection cassettes in mixed mice backgrounds, leading to a disparity in interpretation of genotype-related phenotype. To exclude these confounders, we created a Fancg-KO (KO) mouse model using CRISPR/Cas9. The entire Fancg locus was targeted and maintained on the immunological well-characterized C57BL/6J background. Intercrossing of heterozygous mice resulted in sub-Mendelian numbers of homozygous mice, suggesting loss of FANCG can be embryonic lethal. KO mice displayed infertility, hypogonadism but no other developmental problems. Bone marrow analysis revealed a defect in various hematopoietic stem and progenitor subsets with a bias towards myelopoiesis. Cell lines derived from Fancg-KO mice were hypersensitive to crosslinking agents-cisplatin and Mitomycin C, and Fancg-KO mouse embryonic fibroblasts (MEFs) displayed increased γ-H2AX upon cisplatin treatment. Reconstitution of these MEFs with Fancg cDNA corrected for the ICL hypersensitivity. Collectively, this project provides a new, genetically and immunologically well-defined Fancg-KO mouse model for further in vivo and in vitro studies on FANCG and ICL repair.

Vaginal ecosystem is a unique environment where, in physiological conditions, lactobacilli dominate. However, also pathogenic microbial species, responsible of vaginitis and vaginosis, can harbor vaginal microbiota. To extend the data published by De Seta and Larsen in Pathogens (2021), here we analyzed both the anti-Candida and anti-inflammatory properties of the vaginal gel formulation, Respecta® Balance Gel (RBG), commercialized as an adjuvant to treat vaginitis and vaginosis. We evaluated its activity by an in vitro model where a monolayer of A-431 vaginal epithelial cells was infected by Candida albicans in the presence of RBG or the placebo formulation (pRBG). Specifically, we tested the RBG capacity to counteract C. albicans virulence factors as well as their anti-inflammatory properties. Our results show that, unlike the placebo, RBG reduces ,reduces, C. albicans adhesion, its capacity to form hyphae and C. albicans-induced vaginal cell damage. Interestingly, both RBG and pRBG reduce LPS-induced IL-8 secretion (being RBG the most effective) demonstrating that also the placebo retains anti-inflammatory properties. By our experimental approach we highlight the possible role of farnesol on such effects, but we would like to point out that lactic acid, polydextrose and glycogen too must be relevant in the actual application. Taken together, our results show that RBG impairs C. albicans virulence and is able to reduce the inflammation in the vaginal environment, ultimately allowing the establishment of a balanced vaginal ecosystem.

This survey reports on the DNA identification and occurrence of Culex torrentium and Cx. pipiens s.s. in Belgium. These native disease vector mosquito species are morphologically difficult to separate and the biotypes of Cx. pipiens s.s. are morphologically indistinguishable. Culex torrentium and Cx. pipiens s.s. were identified using the COI and ACE2 loci. We recorded 1,248 Cx. pipiens s.s. and 401 Cx. torrentium specimens from 24 locations in Belgium (collected between 2017 and 2019). Culex pipiens biotypes pipiens and molestus, and their hybrids, were differentiated by fragment size analysis of the CQ11 locus (956 pipiens and 227 molestus biotype specimens, 29 hybrids). Hybrids were observed at 13 out of 16 sympatric sites. These results confirm that both species are widespread in Belgium, but while Cx. torrentium revealed many COI haplotypes, Cx. pipiens s.s. showed only one abundant haplotype. This latter observation may either reflect a recent population-wide demographic or range expansion, or a recent bottleneck, possibly linked to a Wolbachia infection. Finally, new evidence is provided for the asymmetric but limited introgression of the molestus biotype into the pipiens biotype.

Objectives: 1) to demonstrate the anti-inflammatory and anabolic effect of Ozone by determining in serum samples the biochemical levels of IL-6 and IGF-1 in knee osteoarthritis (OA) patients in a real world in Rehabilitation Setting; 2) to evaluate clinical effectiveness by Visual Analog Scale (VAS) and WOMAC scale, and biochemical effect by C-reactive protein (CRP), uric acid and erythrocyte sedimentation rate (ESR). Material and methods: 65 patients with knee OA Kellgren Lawrence (KL) grade 2 or more were analyzed in a retrospective observational study. The study run from January 2018 to September 2021. Inclusion criteria: a) patients 18 years or older; b) with knee OA KL 2º or more; c) biochemical analysis before-and-after treatment; d) pain more than 3 on VAS. Exclusion Criteria: a) previous knee surgery; b) favism; c) pregnancy; d) any other disease that originates lack of collaboration for infiltration. Primary Outcome variables: a) IL-6; b) IGF-1 in diabetes mellitus (DM)/obese and non-DM/non-obese patients; both before-and-after Ozone treatment. Secondary Outcome variables: a) CRP, b) ESR, c) uric acid, d) VAS pain, e) WOMAC pain, function and stiffness. Ozone protocol consisted of 4 sessions (once a week) of an intra-articular infiltration of 20 mL (20µg/mL concentration) of a gas mixture of Oxygen-Ozone 95-5% (produced by Ozone generator Ozonosan-α Plus ®). For biochemical evaluation, SNIBE MAGLUMI ™ IL-6 (CLIA) and SNIBE MAGLUMI ™ IGF-1 (CLIA) kits were used. CRP and uric acid were analyzed by Abbott Alinity c kit; and ESR was evaluated by DIESSE VES MATIC CUBE 30. Results: There is a linear correlation between age and OA severity. IL-6 decreased both in DM and non-DM patients and in all OA KL grades (from 2.7 to 1.59 pg/mL). IGF-1 decreased in total group (OA + DM + obesity) from 112.09 to 107.19 ng/mL. When only knee OA patients were analyzed, Ozone improved IGF-1 levels (from 100.17 to 102.03 ng/mL). Ozone decreased CRP, ESR, uric acid, and improved VAS pain, WOMAC pain, function and stiffness (p<0.05). Conclusions: Ozone is a valid option for the management of knee osteoarthritis in real world Rehabilitation Setting, because of its anti-inflammatory, metabolic and anabolic properties. Ozone downregulates pro-inflammatory IL-6 cytokine. Ozone has a metabolic/hypoglycemic effect on obese/diabetic knee osteoarthritis patients by reducing IGF-1. Ozone has an anabolic effect on non-diabetic/non-obese patients by improving IGF-1. Ozone reduces other biomarkers of inflammation (CRP, ESR and uric acid) and improves, pain, function and quality of life.

Background: Strong indicators of inflammation, such as C-reactive protein (CRP), hypersensitive CRP (hs-CRP), and a series of hematological indices, including platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), hematocrit (HCT) and red blood cell distribution width (RDW), are regarded related with the incidence of contrast induced nephropathy (CIN) closely. Whereas, it remains unclear whether they can function as predictors of CIN onset. The objective of this meta-analysis was to determine the relationship between above indicators and CIN incidence among patients receiving coronary intervention. Methods: Clinical studies were retrieved from the electronic databases of PubMed, EMBASE, Google Scholar, Clinical Trials, and science direct from their inception to June 3rd, 2020. Meta-analysis was performed on pool eligible studies. Two reviewers screened all titles and abstracts and independently assessed all articles. Results: A total of 26 studies involving 29,454 patients were included in the meta-analysis. Pooled analysis results revealed that patients with higher CRP (odds ratio [OR]=1.06, 95% confidence interval [CI]: 1.01–1.12, P=0.02), hs-CRP (OR=1.03, 95% CI: 1.01–1.06, P=0.004), NLR (OR=1.11, 95% CI: 1.01–1.20, P=0.02), RDW (OR=1.35, 95% CI: 1.19–1.53, P<0.00001), and lower HCT (OR=0.94, 95% CI: 0.92–0.97, P=0.0003) all exhibited significantly higher CIN rates, but there was no significant association between PLR and CIN risk (OR=1.12, 95% CI: 0.99–1.26, P=0.07). Conclusion: The meta-analysis reported here demonstrates that pre-angiography CRP/hs-CRP and some hematological indices are associated with CIN.

I propose a new strategy to suppress human cancer completely with two entirely new drug compounds exploiting cancer's Warburg effect characterized by a defective mitochondrial aerobic respiration, substituted for by cytosolic aerobic fermentation/glycolysis of D-(+)-glucose into L-(+)-lactic acid. The two essentially new drugs compound 1 [P(op)T(est)162] and compound 3 (PT167) represent new highly symmetric, four-bladed propeller-shaped polyammonium cations. The in vitro antineoplastic highly efficacious drug compound 3 represents a covalent combination of compound 1 and compound 2 (PT166). The intermediate drug compound 2 is an entirely new colchic(in)oid derivative synthesized from colchicine. Compound 2's structure was determined by X-ray crystallography. Compound 1 and compound 3 were active in vitro versus 60 human cancer cell lines of the National Cancer Institute (NCI) Developmental Therapeutics Program (DTP) 60-cancer cell testing. Compound 1 and compound 3 both not only stop the growth of cancer cells to ±0% (cancerostatic effect), but completely kill nearly all 60 cancer cells to a level of almost −100% (tumoricidal effect). Compound 1 and compound 3 induce mitochondrial apoptosis (under cytochrome c release) in all cancer cells tested by (re)activating (in most cancers impaired) p53 function which results in a decrease of cancer's dysregulated cyclin D1 and an induction of the cell cycle-halting cyclin-dependent kinase inhibitor p21^Waf1/p21^Cip1.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one third of global population and became the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) also remain significant challenges to liver health even in the 21st century. The coexistence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. Thorough understanding of the pathobiological interlink and interactions between MAFLD and these two chronic viral hepatitis infections are crucial for appropriate management of patients. We update these interlinks in this comprehensive clinical review.

Background: Macrophage inflammatory protein-1 alpha (MIP-1α) and C-reactive protein (CRP) are pro-inflammatory biomarkers that quantify clinical and subclinical inflammation in cardiac ischemia in cardiac inflammation and disease. Adiponectin is an anti-inflammatory marker associated with good health. The susceptibility of periodontitis patients to cardiovascular events needs to be evaluated. Objective: This study aims to assess the levels of biomarkers in periodontitis patients with and without acute myocardial infarction (AMI) compared to controls. Material and methods: Pro-inflammatory and anti-inflammatory analytes were examined by collecting unstimulated saliva from three groups (n = 20/each): healthy individuals, individuals with stage III periodontitis, and post-myocardial infarction patients with stage III periodontitis. The samples were collected within 48 hours of AMI. Results: Adiponectin levels were significantly lower in patients with periodontitis with and without AMI compared to controls, while CRP and MIP-1α were significantly higher in patients with periodontitis with and without AMI compared to controls. The highest titers for MIP-1α and CRP were detected among patients with periodontitis with and AMI. Conclusion: Our study provides evidence of the association between periodontitis and salivary analytes that occur in tandem with cardiovascular disease. The lower levels of Adiponectin and higher levels of CRP and MIP-1α in patients with periodontitis indicate that this condition is a potential risk factor for cardiovascular disease. The findings emphasize the importance of early detection and intervention for periodontitis patients to prevent cardiovascular events.

The toxin-antitoxin (TA) systems have been attracting attention due to their role in regulating prokaryotic cell responses to stress and their biotechnological potential. Much recognition has been given to type II TA system of mesophiles, but so far, limited attention has been given to thermophiles. Here, we are presenting the putative type II TA families encoded on the genomes of four Geobacillus strains. We employed the TA finder tool to mine for TA-coding genes and manually curated the results using various tools. We identified 28 putative TA pairs, distributed over 8 TA families. Among the identified TAs, 15 represent putative novel toxins and antitoxins that have been overlooked or annotated as hypothetical proteins in their genome records. We also identified a potentially new TA composite, AbrB-ParE. Furthermore, we are suggesting the Geobacillus acetyltransferase toxin-antitoxin (GacTA) family which potentially represents one of the unique TA families that has a reverse gene order. Moreover, we are proposing a hypothesis on the regulation of the xre-cog2856 gene expression, which seems to involve c-di-AMP. This study aims for highlighting the significance of studying TAs in Geobacillus, since they have special features. It also aims for facilitating future experimental research.

The quinoline derivative, N-(7-chloro-4-morpholinoquinolin-2-yl)benzamide, was synthesized in a conventional three-step procedure from 4,7-dichloroquinoline using N-oxidation reaction/C2-amidation reaction/C4 SNAr reaction sequence. The structure of the compound was fully characterized by FT-IR, 1H‐, 13C-NMR, DEPT-135°, and ESI-MS techniques. Its physicochemical parameters (Lipinski’s descriptors) were also calculated using the online SwissADME database. Such derivatives are relevant therapeutic agents exhibiting potent anticancer, antibacterial, antifungal, and antiparasitic properties.

A whole-exome capture and next-generation sequencing applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, severe cognitive deficit, without any identifiable Syndromic pattern, and to her parents, disclosed a de novo heterozygous pathogenic mutation, c.697_699del p.Phe233del (rs786204835)(ACMG classification PS2, PM1, PM2, PP5), harbored in the PURA gene (MIM*600473) (5q31.3), associated to Autosomal Dominant Mental Retardation 31 (MIM # 616158). We used the significant improvement in the accuracy of protein structure prediction recently implemented in AlphaFold that incorporates novel neural network architectures and training procedures based on the evolutionary, physical, and geometric constraints of protein structures. The wild-type (WT) sequence and the mutated one, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURA WT and the PURA-Phe233del showed that the occurrence of the Phe233del affects between 220-320 amino acids. The distortion in the PURA structural confor-mation in the ~5Å surrounding area after the p.Phe233del produces a conspicuous disruption of the repeat III, where the DNA and RNA helix unwinding capability occurs. PURA Protein-DNA Docking corroborated these results in silico Analysis that showed a loss of the contact of the PURA-Phe233del III repeat domain model with the DNA. Together, i) the energetic and stereochemical, ii) the hydropathic indices and polarity surfaces, and iii) the hybrid Quantum Mechanics-Molecular Mechanics (QM-MM) analyses of the PURA molecular models demarcate at the atomic resolution the specific surrounding region affected by these mutations and paves the way for future cell-based functional analysis. To the best of our knowledge, this is the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects in protein structure using artificial intelligence algorithms and molecular and atomic resolution stereochemical analyses.

The world is in the grips of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increase concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D [25(OH)D] concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome, and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D₃ for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/ml (100–150 nmol/l). For treatment of people who become infected with COVID-19, higher vitamin D₃ doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.

The carbonized elastomer-based composites (CECs) possess a number of attractive features in terms of thermomechanical and electromechanical performance, durability in aggressive media and facile net-shape formability, but their relatively low ductility and strength limit their suitability for structural engineering applications. Prospective applications such as structural elements of MEMS can be envisaged, since smaller principal dimensions reduce the susceptibility of components to residual stress accumulation during carbonization, and to brittle fracture in general. We report the results of operando in-SEM study of micro-deformation and fracture behavior of CECs based on NBR elastomeric matrices filled with carbon and silicon carbide. Nanostructured carbon composite materials were manufactured via compounding of elastomeric substance with carbon and SiC fillers using mixing rolling mill, vulcanization, and low-temperature carbonization. Double Edge Notched Tensile (DENT) specimens of vulcanized and carbonized elastomeric composites were subjected to in situ tensile testing in the chamber of the scanning electron microscope (SEM) Tescan Vega 3 using Deben Microtest 1 kN Tensile Stage. The series of acquired SEM images were analyzed by means of Digital Image Correlation (DIC) using Ncorr open source software to map the spatial distribution of strain. These maps were correlated with Finite Element Modelling (FEM) simulations to refine the values of elastic moduli. Besides, the elastic moduli were derived from unloading curve nanoindentation hardness measurements carried out using NanoScan-4D tester and interpreted using the Oliver-Pharr method. Carbonization causes significant increase of elastic moduli from 0.86 ± 0.07 to 14.12 ± 1.20 GPa for the composite with graphite and carbon black fillers. Nanoindentation measurements yield somewhat lower values, namely, 0.25 ± 0.02 GPa and 9.83 ± 1.10 GPa before and after carbonization respectively. The analysis of fractography images suggests that crack initiation, growth and propagation may occur both at the notch stress concentrator and relatively far from the notch. Possible causes of such response are discussed, namely, (1) residual stresses introduced by processing; (2) shape and size of fillers; and (3) the emanation and accumulation of gases in composites during carbonization.