Comparative effects of trichothecene mycotoxins on bovine platelet function: Acetyl T-2 toxin,a more potent inhibitor than T-2 toxin

The effects of the trichothecene mycotoxins (acetyl T-2 toxin, T-2 toxin, HT-2 toxin, palmityl T-2 toxin, diacetoxyscirpenol (DAS), deoxynivalenol (DON), and T-2 tetraol) on bovine platelet function were examined in homologous plasma stimulated with platelet activating factor (PAF). The mycotoxins inhibited platelet function with the following order of potency: acetyl T-2 toxin > palmityl T-2 toxin = DAS > HT-2 toxin = T-2 toxin. While T-2 tetraol was completely ineffective as an inhibitor, DON exhibited minimal inhibitory activity at concentrations above 10×10^?4M. The stability of the platelet aggregates formed was significantly reduced in all mycotoxin treated platelets compared to that of the untreated PAF controls. It is suggested that the increased sensitivity of PAF stimulated bovine platelets to the more lipophilic mycotoxins may be related to their more efficient partitioning into the platelet membrane compared to the more hydrophilic compounds.     

An extensive review on antifungal approaches in the treatment of mucormycosis

During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B ( 1 ) and isavuconazole ( 2 ) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole ( 3 ) and deferasirox ( 4 ) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 ( 5 ) and APX001A ( 6 ), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.     

Monoclonal antibodies to rabbit liver cytochrome P-448

Cytochrome P-448 (mol wt 55,000 Daltons) from rabbit liver was purified to a specific content of 16.6 nmol/mg. Mice were immunised with this preparation, their spleens removed and dissociated lymphocytes hybridised with myeloma cells. Four monoclonal antibodies against cytochrome P-448 were raised and partially characterised. All four antibodies interacted with cytochrome P-448 in intact microsomal fractions and selectively immunoadsorbed cytochrome P-448 from solubilised microsomal preparations. One of the antibodies inhibited benzo[a] pyrene hydroxylase activity in a reconstituted system, one had no effect on activity and two increased activity. The possible applications of such antibodies are discussed.     

Saikosaponin-d,a novel SERCA inhibitor,induces autophagic cell death in apoptosis-defective cells

Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase pump, leading to autophagy induction through the activation of the Ca²⁺/calmodulin-dependent kinase kinase–AMP-activated protein kinase–mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells.     

Interdependency of stress relaxation and afferent nerve discharge in rat small intestine

Background and aimsTo be able to characterize intestinal mechano-electrical transduction, i.e. the mechanoreceptor behaviour, quantitative nerve studies with controlled and quantified stimulus are needed. This study aimed to determine the relationship between mechanical stress relaxation and afferent discharge adaptation evoked by fast isovolumetric bag distensions in the rat jejunum.MethodsMultiunit afferent activity was recorded in vivo from jejunum afferents from five male Wistar rats. The jejunum was distended via a bag at a distension speed of 0.5 ml/s to volumes of 0.2, 0.25, 0.3 and 0.4 ml, respectively. The distension was stopped and the volume was kept constant for 2 min to induce stress relaxation. The pressure in the bag, the afferent discharge (spike rate) and the diameter of the segment during the relaxation time were recorded simultaneously.ResultsThe afferent discharge responses to distension showed a pattern with a peak during the sudden loading followed by decreasing activity with time. At distension volumes of 0.2, 0.25, 0.3 and 0.4 ml, the afferent discharge declined faster and to a greater extent (94%, 91%,96% and 87%) than the stress decreased (55%, 45%, 59% and 56%) during stress relaxation (p<0.001). Both the stress and the afferent discharge during the constant volume distension were independent of the distension volumes (p>0.5). The stress and the afferent discharge during the distension can be described mathematically on the basis of the quasi-linear theory of viscoelasticity. The association between the stress and the afferent discharge during the constant volume distension is linear with the same slope under various distension volumes.ConclusionsIntestinal mechanoreceptors were sensitive to the stress stimulus and a linear association between the stress relaxation and afferent discharge adaptation was found. The quasi-linear theory of visco-elasticity can be transferred to analysis of mechanical stimulus evoked afferent discharge.     

Stress‐associated H3K4 methylation accumulates during postnatal development and aging of rhesus macaque brain

Epigenetic modifications are critical determinants of cellular and developmental states. Epigenetic changes, such as decreased H3K27me3 histone methylation on insulin/IGF1 genes, have been previously shown to modulate lifespan through gene expression regulation. However, global epigenetic changes during aging and their biological functions, if any, remain elusive. Here, we examined the histone modification H3K4 dimethylation (H3K4me2) in the prefrontal cortex of individual rhesus macaques at different ages by chromatin immunoprecipitation, followed by deep sequencing (ChIP‐seq) at the whole genome level. Through integrative analysis of the ChIP‐seq profiles with gene expression data, we found that H3K4me2 increased at promoters and enhancers globally during postnatal development and aging, and those that correspond to gene expression changes in cis are enriched for stress responses, such as the DNA damage response. This suggests that metabolic and environmental stresses experienced by an organism are associated with the progressive opening of chromatin. In support of this, we also observed increased expression of two H3K4 methyltransferases, SETD7 and DPY30, in aged macaque brain.     

Comparative morphology of populations of Monstera Adans. (Araceae) from natural forest fragments in Northeast Brazil using elliptic Fourier Analysis of leaf outlines

Summary  A comparative study of the leaf outline morphometrics of Monstera adansonii var. klotzschiana, M. adansonii var. laniata and M. praetermissa was carried out. The study focused on populations in isolated montane humid (brejo) forests of Ceará state in Northeast Brazil and compared them with populations from Amazonia and the Brazilian Atlantic Forest. Digitised outlines were prepared from a total of 1,695 field-collected leaf images from 20 populations, and elliptic Fourier analysis was used to generate matrices of coefficients, from which six shape variables (principal components) were extracted using Principal Components Analysis. Intra-population variability and inter-population differences were analysed with multivariate distance methods. Separate analyses were carried out for each of three leaf size classes (juvenile, submature, mature) because of the strong heteroblasty typical of this genus. Juvenile leaves were the least variable size class within populations of M. adansonii var. klotzschiana. The shape variables expressed very similar types of variation in all three size classes. The Ceará brejo populations of M. adansonii var. klotzschiana showed significant differences between mature leaf outlines in all pairwise comparisons; the Pacatuba population was the most distinct. The Ceará populations did not cluster together exclusively. In all three size classes, populations clustered together into their taxonomic groups, most clearly so in mature leaves. No correlation between morphological and geographic distance matrices was found, nor between morphological and molecular distance. The study showed that leaf outline shape is a practicable and useful quantitative trait for studying morphological variability at species, varietal and population levels. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Plant collecting spread and densities: their potential impact on biogeographical studies in Thailand

Aims To produce representative aggregate maps of plant collection locations in Thailand and discuss their impact on biogeographical studies in Thailand and the surrounding region. Location Thailand. Methods A representative data set comprising 6593 plant specimen records for Thailand has been assembled. The data set contains ± all known collections for fifteen representative plant families and further records for another 104. All records are localized to Changwat (province), 6441 to at least quarter degree square. Results Analysis shows that the spread of collecting activity in Thailand is markedly uneven; 20% of collections come from a single Changwat (Chiang Mai) and 53% of Changwat have fifty or fewer collections. The distribution of collections by Changwat and by quarter degree square is erratic with most squares and Changwat having few collections, both in proportionate and absolute terms. Some of the most densely forested Changwats and squares appear undercollected. Distribution maps for common, easily recognized tree species in the genus Syzygium show distributional gaps. Conclusions Thailand is defined as an undercollected country. Even within the few well‐collected quarter degree squares the spread of collecting is still poor; almost all collections being localized to one of three mountain ranges or their foothills. There are many gaps in collecting activity which make impossible a straightforward interpretation of biogeographical pattern. It is argued that targeted collecting activity is needed, that assembly of this type of data set is therefore essential and that our data set and its interpretation is a model for all countries in the region.     

The β3‐integrin endothelial adhesome regulates microtubule‐dependent cell migration

Integrin β3 is seen as a key anti‐angiogenic target for cancer treatment due to its expression on neovasculature, but the role it plays in the process is complex; whether it is pro‐ or anti‐angiogenic depends on the context in which it is expressed. To understand precisely β3's role in regulating integrin adhesion complexes in endothelial cells, we characterised, by mass spectrometry, the β3‐dependent adhesome. We show that depletion of β3‐integrin in this cell type leads to changes in microtubule behaviour that control cell migration. β3‐integrin regulates microtubule stability in endothelial cells through Rcc2/Anxa2‐driven control of active Rac1 localisation. Our findings reveal that angiogenic processes, both in vitro and in vivo, are more sensitive to microtubule targeting agents when β3‐integrin levels are reduced.