Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy

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Impacts of thermal mismatches on chytrid fungus Batrachochytrium dendrobatidis prevalence are moderated by life stage,body size,elevation and latitude

Global climate change is increasing the frequency of unpredictable weather conditions; however, it remains unclear how species‐level and geographic factors, including body size and latitude, moderate impacts of unusually warm or cool temperatures on disease. Because larger and lower‐latitude hosts generally have slower acclimation times than smaller and higher‐latitude hosts, we hypothesised that their disease susceptibility increases under ‘thermal mismatches’ or differences between baseline climate and the temperature during surveying for disease. Here, we examined how thermal mismatches interact with body size, life stage, habitat, latitude, elevation, phylogeny and International Union for Conservation of Nature (IUCN) conservation status to predict infection prevalence of the chytrid fungus Batrachochytrium dendrobatidis (Bd) in a global analysis of 32 291 amphibian hosts. As hypothesised, we found that the susceptibility of larger hosts and hosts from lower latitudes to Bd was influenced by thermal mismatches. Furthermore, hosts of conservation concern were more susceptible than others following thermal mismatches, suggesting that thermal mismatches might have contributed to recent amphibian declines.     

Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors

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Tranexamic acid suppresses the release of mitochondrial DNA,protects the endothelial monolayer and enhances oxidative phosphorylation

Damage-associated molecular patterns, including mitochondrial DNA (mtDNA) are released during hemorrhage resulting in the development of endotheliopathy. Tranexamic acid (TXA), an antifibrinolytic drug used in hemorrhaging patients, enhances their survival despite the lack of a comprehensive understanding of its cellular mechanisms of action. The present study is aimed to elucidate these mechanisms, with a focus on mitochondria. We found that TXA inhibits the release of endogenous mtDNA from granulocytes and endothelial cells. Furthermore, TXA attenuates the loss of the endothelial monolayer integrity induced by exogenous mtDNA. Using the Seahorse XF technology, it was demonstrated that TXA strongly stimulates mitochondrial respiration. Studies using Mitotracker dye, cells derived from mito-QC mice, and the ActivSignal IPAD assay, indicate that TXA stimulates biogenesis of mitochondria and inhibits mitophagy. These findings open the potential for improvement of the strategies of TXA applications in trauma patients and the development of more efficient TXA derivatives.     

Growth response of African catfish,Clarias gariepinus (B.), larvae and fingerlings fed protease‐incorporated diets

African catfish, Clarias gariepinus (B.), is one of the promising freshwater fish species in African aquaculture but the expansion of its farming needs more production of its larvae. The use of live food organisms at first feeding for larvae is still obligatory. That increases the cost of larvae production. Hence, the incorporating of exogenous enzymes especially protease in artificial microdiets may provide affordable alternatives for enhancing the larvae performance. The present study was carried out to evaluate the growth and survival of larvae or fingerlings of African catfish fed artificial diets incorporated with different protease levels. Four artificial diets were formulated and enriched with protease enzyme at levels of 0.0, 750, 1,000, and 1,250 unit/kg diet; after that diets were made into crumbles (100–200 µm diameter). After absorption of the yolk sac, diets were offered to fish larvae (3.6 ± 0.2 mg) in triplicates as a starter feed up to apparent satiation every two hours for 30 days. In another treatment, fish larvae were fed on newly hatched Artemia nauplii (2,500 Artemia/L) as a starter food. In another experiment, African catfish fingerlings (10.1 ± 1.6 g) were fed on the same diets up to satiation twice a day for 2 months. It was noticed that the dietary protease improved larval growth and survival but not as Artemia nauplii did where fish larvae fed on Artemia nauplii showed highest growth and survival followed by those fed a diet enriched with 1,250 unit/kg diet of protease. The mortality of larvae fed protease‐enriched diets as well as the control diet was occurred mostly at the first week reaching its maximum at the third week. The poor growth was observed with fish larvae fed the control diet. Meanwhile, catfish fingerlings fed protease‐enriched diets showed higher growth over those fed the control diet. The larvae survival (11.0%–41.7%) was enhanced by increasing protease levels and it was lower than that of fingerlings (95.6%–100.0%). Furthermore, protein retention and digestibility were significantly improved with protease supplementation over the control diet especially at a level of 1,000 unit/kg diet. As compared with the previous studies, live food should be used in larvae rearing for the first week after that a starter diet enriched with protease at levels of 1,250 unit/kg diet should be used. In case of fish fingerlings, the dry diets should be enriched with 1,100 unit/kg diet to improve diet digestibility and subsequently enhance their growth.     

Targeting human CALR‐mutated MPN progenitors with a neoepitope‐directed monoclonal antibody

Calreticulin (CALR) is recurrently mutated in myelofibrosis via a frameshift that removes an endoplasmic reticulum retention signal, creating a neoepitope potentially targetable by immunotherapeutic approaches. We developed a specific rat monoclonal IgG2α antibody, 4D7, directed against the common sequence encoded by both insertion and deletion mutations. 4D7 selectively bound to cells co‐expressing mutant CALR and thrombopoietin receptor (TpoR) and blocked JAK‐STAT signalling, TPO‐independent proliferation and megakaryocyte differentiation of mutant CALR myelofibrosis progenitors by disrupting the binding of CALR dimers to TpoR. Importantly, 4D7 inhibited proliferation of patient samples with both insertion and deletion CALR mutations but not JAK2 V617F and prolonged survival in xenografted bone marrow models of mutant CALR‐dependent myeloproliferation. Together, our data demonstrate a novel therapeutic approach to target a problematic disease driven by a recurrent somatic mutation that would normally be considered undruggable.     

Endoparasites of western lowland gorillas (Gorilla gorilla gorilla) at Bai Hokou, Central African Republic

A coprologic study of free-ranging western lowland gorillas (Gorilla gorilla gorilla) at Bai Hokou, Dzangha-Ndoki National Park, Central African Republic (2 degrees 51'34'N, 16 degrees 28'03'E) was conducted from October 1999 to November 2000. All 75 fecal samples examined were positive for endoparasites, and each contained at least two species. Parasites present included two genera of amoebae, entodiniomorph ciliates, including Prototapirella gorillae, Troglodytella spp., and Gorillophilus thoracatus, a Balantidium-like organism, strongyle/trichostrongyle eggs (including a presumptive Mammomonogamus sp. and several other genera), Strongyloides sp., Probstmayria sp., a spirurid, a trichuroid, and several unidentified trematodes. Flagellates and cestodes were not found. Despite the presence of a variety of parasite genera, in general, levels of parasitism were low. These data provide baseline parasitologic data for this population as part of a comprehensive health-monitoring program. With the advent of ecotourism in this study area, continued monitoring is indicated for insuring the health of both gorillas and humans in the Bai Hokou study area.     

Comprehensive analysis of class I and class II HLA antigens and chronic hepatitis B virus infection

Following an acute hepatitis B virus (HBV) infection, clearance or persistence is determined in part by the vigor and breadth of the host immune response. Since the human leukocyte antigen system (HLA) is an integral component of the immune response, we hypothesized that the highly polymorphic HLA genes are key determinants of viral clearance. HLA class I and II genes were molecularly typed in 194 Caucasian individuals with viral persistence and 342 matched controls who had cleared the virus. A single class I allele, A*0301 (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.30 to 0.72; P = 0.0005) was associated with viral clearance. The class II allele DRB1*1302 was also associated with clearance (OR, 0.42; 95% CI, 0.19 to 0.93; P = 0.03), but its significance decreased in a multivariate model that included other alleles associated with disease outcome as covariates. B*08 was associated with viral persistence both independently (OR, 1.59; 95% CI, 1.04 to 2.43; P = 0.03) and as part of the conserved Caucasian haplotype A*01-B*08-DRB1*03. The B*44-Cw*1601 (OR, 2.23; 95% CI, 1.13 to 4.42; P = 0.02) and B*44-Cw*0501 (OR, 1.99; 95% CI, 1.22 to 3.24; P = 0.006) haplotypes were also associated with viral persistence. Interestingly, both the B*08 haplotype and DR7, which forms a haplotype with B*44-Cw*1601, have been associated with nonresponse to the HBV vaccine. The associations with class I alleles are consistent with a previously implicated role for CD8-mediated cytolytic-T-cell response in determining the outcome of an acute HBV infection.     

Mapping the microtubule binding regions of calponin

The smooth muscle basic calponin interacts with F-actin and inhibits the actomyosin ATPase in a calmodulin or phosphorylation modulated manner. It also binds in vitro to microtubules and its acidic isoform, present in nonmuscle cells, and co-localizes with microfilaments and microtubules in cultured neurons. To assess the physiological significance and the molecular basis of the calponin-microtubule interaction, we have first studied the solution binding of recombinant acidic calponin to microtubules using quantitative cosedimentation analyses. We have also characterized, for the first time, the ability of both calponin isoforms to induce the inhibition of the microtubule-stimulated ATPase activity of the cytoskeletal, kinesin-related nonclaret dysjunctional motor protein (ncd) and the abolition of this effect by calcium calmodulin. This property makes calponin a potent inhibitor of all filament-activated motor ATPases and, therefore, a potential regulatory factor of many motor-based biological events. By combining the enzymatic measurements of the ncd-microtubules system with various in vitro binding assays employing proteolytic, recombinant and synthetic fragments of basic calponin, we further unambiguously identified the interaction of microtubules at two distinct calponin sites. One is inhibitory and resides in the segment 145-182, which also binds F-actin and calmodulin. The other one is noninhibitory, specific for microtubules, and is located on the COOH-terminal repeat-containing region 183-292. Finally, quantitative fluorescence studies of the binding of basic calponin to the skeletal pyrenyl F-actin in the presence of microtubules did not reveal a noticeable competition between the two sets of filaments for calponin. This result implies that calponin undergoes a concomitant binding to both F-actin and microtubules by interaction at the former site with actin and at the second site with microtubules. Thus, in the living cells, calponin could potentially behave as a cross-linking protein between the two major cytoskeletal filaments.