Tree mortality is a key process shaping forest dynamics. Thus, there is a growing need for indicators of the likelihood of tree death. During the last decades, an increasing number of tree-ring based ...studies have aimed to derive growth–mortality functions, mostly using logistic models. The results of these studies, however, are difficult to compare and synthesize due to the diversity of approaches used for the sampling strategy (number and characteristics of alive and death observations), the type of explanatory growth variables included (level, trend, etc.), and the length of the time window (number of years preceding the alive/death observation) that maximized the discrimination ability of each growth variable. We assess the implications of key methodological decisions when developing tree-ring based growth–mortality relationships using logistic mixed-effects regression models. As examples, we use published tree-ring datasets from Abies alba (13 different sites), Nothofagus dombeyi (one site), and Quercus petraea (one site). Our approach is based on a constant sampling size and aims at (1) assessing the dependency of growth–mortality relationships on the statistical sampling scheme used, (2) determining the type of explanatory growth variables that should be considered, and (3) identifying the best length of the time window used to calculate them. The performance of tree-ring-based mortality models was reasonably high for all three species (area under the receiving operator characteristics curve, AUC > 0.7). Growth level variables were the most important predictors of mortality probability for two species (A. alba, N. dombeyi), while growth-trend variables need to be considered for Q. petraea. In addition, the length of the time window used to calculate each growth variable was highly uncertain and depended on the sampling scheme, as some growth–mortality relationships varied with tree age. The present study accounts for the main sampling-related biases to determine reliable species-specific growth–mortality relationships. Our results highlight the importance of using a sampling strategy that is consistent with the research question. Moving towards a common methodology for developing reliable growth–mortality relationships is an important step towards improving our understanding of tree mortality across species and its representation in dynamic vegetation models.
Renal ischemia-reperfusion injury (IRI) leads to endoplasmic reticulum (ER) stress, thereby initiating the unfolded protein response (UPR). When sustained, this response may trigger the inflammation ...and tubular cell death that acts to aggravate the damage. Here, we show that knockdown of the BET epigenetic reader BRD4 reduces the expression of ATF4 and XBP1 transcription factors under ER stress activation. BRD4 is recruited to the promoter of these highly acetylated genes, initiating gene transcription. Administration of the BET protein inhibitor, JQ1, one hour after renal damage induced by bilateral IRI, reveals reduced expression of
and
genes, low KIM-1 and NGAL levels and recovery of the serum creatinine and blood urea nitrogen levels. To determine the molecular pathways regulated by ATF4 and XBP1, we performed stable knockout of both transcription factors using CRISPR-Cas9 and RNA sequencing. The pathways triggered under ER stress were mainly XBP1-dependent, associated with an adaptive UPR, and partially regulated by JQ1. Meanwhile, treatment with JQ1 downmodulated most of the pathways regulated by ATF4 and related to the pathological processes during exacerbated UPR activation. Thus, BRD4 inhibition could be useful for curbing the maladaptive UPR activation mechanisms, thereby ameliorating the progression of renal disease.
Loss of protein homeostasis (proteostasis) in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR), restoring correct protein folding. Sustained ER stress exacerbates ...activation of the major UPR branches (IRE1α/XBP1, PERK/ATF4, ATF6), inducing expression of numerous genes involved in inflammation, cell death, autophagy, and oxidative stress. We investigated whether epigenetic dynamics mediated by histone H3K9 and H3K27 methylation might help to reduce or inhibit the exacerbated and maladaptive UPR triggered in tubular epithelial cells. Epigenetic treatments, specific silencing, and chromatin immunoprecipitation assays were performed in human proximal tubular cells subjected to ER stress. Pharmacological blockage of KDM4C and JMJD3 histone demethylases with SD-70 and GSKJ4, respectively, enhanced trimethylation of H3K9 and H3K27 in the ATF4 and XBP1 genes, inhibiting their expression and that of downstream genes. Conversely, specific G9a and EZH2 knockdown revealed increases in ATF4 and XBP1 expression. This is a consequence of the reduced recruitment of G9a and EZH2 histone methylases, diminished H3K9me3 and H3K27me3 levels, and enhanced histone acetylation at the ATF4 and XBP1 promoter region. G9a and EZH2 cooperate to maintain the repressive chromatin structure in both UPR-induced genes, ATF4 and XBP1. Therefore, preserving histone H3K9 and H3K27 methylation could ameliorate the ER stress, and consequently the oxidative stress and the triggered pathological processes that aggravate renal damage.
Chagas disease or American trypanosomiasis is a worldwide public health problem. In this work, we evaluated 26 new propyl and isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives as ...potential trypanocidal agents. Additionally, molecular docking and enzymatic assays on trypanothione reductase (TR) were performed to provide a basis for their potential mechanism of action. Seven compounds showed better trypanocidal activity on epimastigotes than the reference drugs, and only four displayed activity on trypomastigotes; T-085 was the lead compound with an IC50 = 59.9 and 73.02 µM on NINOA and INC-5 strain, respectively. An in silico analysis proposed compound T-085 as a potential TR inhibitor with better affinity than the natural substrate. Enzymatic analysis revealed that T-085 inhibits parasite TR non-competitively. Compound T-085 carries a carbonyl, a CF3, and an isopropyl carboxylate group at 2-, 3- and 7-position, respectively. These results suggest the chemical structure of this compound as a good starting point for the design and synthesis of novel trypanocidal derivatives with higher TR inhibitory potency and lower toxicity.
Advances in genetic and epigenetic studies modified some concepts of health and disease that had been kept intact for decades. In this respect, in the last few years, microorganisms that have evolved ...with superior life forms for millions of years have taken an increased prominence. The genes of organisms and their microbiota constitute a microbiome that intervenes in health maintenance. The oral cavity is inhabited by a variety of microorganisms, their control aids in stabilising oral and systemic disease. The objective of this article is to update some concepts related to oral microbiome and its correlation with general and oral health.
To design and analyze the efficacy of an Ecohealth competency-based course on the prevention and control of vector-borne-diseases for specific stakeholders.
Multiple stakeholders and sectors of the ...region were consulted to identify Ecohealth group-specific competencies using an adjusted analysis matrix. Eight courses based on the competencies were implemented to train EA tutors. The effectiveness of the course was evaluated through the use of paired- t-tests by intervention group.
Strategic, tactical, academia and community stakeholder groups and their competencies were identified. An overall gain of 43 percentage points (p<0.001) was observed in terms of competencies score in trained tutors, which further trained 1 033 people.
The identification of the stakeholders and their competencies proved to be useful to guide training courses to significantly improve the initial competencies and create a critical mass to further advance the EA in the region.
The visible light-induced perfluoroalkyl (RF) radical reactions on peracetylglycals derived from hexoses and pentoses (galactal, glucal, arabinal, and xylal derivatives) were investigated. Various ...photocatalysts and perfluoroalkyl iodides (RF–I) were employed as sources of RF radicals with LEDs as the irradiation source. Particularly noteworthy was the use of an Iridium photocatalyst, IrdF(CF3)ppy2(dtbpy))PF6, which yielded two distinct product types when applied to glucal. On the one hand, the 2-RF-substituted glucal was formed, a trend observed even when utilizing organic dyes as photocatalysts. On the other hand, the unexpected addition product, namely the 1-RF-2-iodo-α-manno-configured C-glycosyl derivative, was also obtained, as a result of a highly regioselective addition reaction of the RF moiety into the anomeric carbon, followed by attachment of the iodine atom on C-2 in axial disposition. This result contrasted with other radical reactions carried out on 2-unsubstituted glycals, where the incipient radical adds to C-2, generating a stabilized 1-glycosyl radical. The photocatalyzed radical perfluoroalkylations of peracetyl glycals derived from galactose, arabinose, and xylose all afforded the 2-RF-substituted glycals in good yields as a result of the expected vinylic substitution reaction. Mechanistic studies revealed that the 1-RF-2-iodo-α-manno-configured C-glycosyl derivatives arise from a radical chain reaction, whereas the 2-RF-substituted glycals proceed from inefficient chain processes.
•The effect of electric pulses on cisplatin transport across the plasma membrane is described.•The coupled multi-physics model is based on partial differential equations.•Finite elements are used ...with an explicit membrane discretization.•Pore aperture is favored at the cell poles by the electric field and the mechanical stress.
The use of electrochemotherapy (ECT) is a well-established technique to increase the cellular uptake of cytotoxic agents within certain cancer treatment strategies. The study of the mechanisms that take part in this complex process is of high interest to gain a deeper knowledge of it, enabling the improvement of these strategies. In this work, we present a coupled multi-physics electroporation model based on a related previous one, to describe the effect of a set of electric pulses on cisplatin transport across the plasma membrane. The model applies a system of partial differential equations that includes Poisson’s equation for the electric field, Nernst-Planck’s equation for species transport, Maxwell’s tensor and mechanical equilibrium equation for membrane deformation and Smoluchowski’s equation for pore creation dynamics. Our numerical results were compared with previous numerical and experimental published data with good qualitative and quantitative agreement. These results indicate that pore aperture is favored at the cell poles by the electric field and mechanical stress forces, giving support to the dominant hypothesis of hydrophilic pore creation as the main mechanism of drug entry during an ECT treatment.
Campylobacter spp. and Arcobacter butzleri are foodborne pathogens associated with the consumption of contaminated raw chicken meat. At the industry level, the combination of new and common ...antimicrobials could be used as a strategy to control the presence of pathogens in chicken carcasses. The objective of this study was to determine the bacteriostatic and bactericidal effects of a mixture of chlorine (Cl) and sodium gallate (SG) on a mixture of two Campylobacter species (Campylobacter jejuni and Campylobacter coli) and A. butzleri. Using a central composite experimental design, it was established that the optimum inhibitory SG-Cl concentration for Campylobacter spp. was 44 to 45 ppm. After 15 h of incubation, Campylobacter species growth was reduced by 37.5% and the effect of Cl was potentiated by SG at concentrations above 45 ppm. In the case of A. butzleri, optimum levels of 28 and 41 ppm were observed for SG and Cl, respectively; no synergism was reported, as this bacterium was more sensitive to lower Cl concentrations than Campylobacter. After a 20-min pretreatment with peracetic acid (50 ppm), the optimum condition to achieve a >1.0-Log CFU/mL reduction of Campylobacter spp. was exposure to 177 ppm of Cl and 44 ppm of SG for 56 min. As A. butzleri showed lower resistance to the bacteriostatic effect of the Cl-SG combination, it was assumed that optimum bactericidal conditions for Campylobacter spp. were effective to control the former; this was confirmed with subsequent validation of the model. The SG-Cl combination has bactericidal properties against Campylobacter and A. butzleri, and it may be a useful strategy to improve sanitary practices applied in the poultry industry.
The aging process is associated with the accumulation of epigenetic alterations in immune cells, although the origin of these changes is not clear. Understanding this epigenetic drift in the immune ...system can provide essential information about the progression of the aging process and the immune history of each individual.
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