Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of ...111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767-BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767-BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro, but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors.
The CO2 concentration in the atmosphere is increasing and threatening the earth's climate. Selective CO2 capture at large point sources will help to reduce the CO2 emissions to the atmosphere. ...Biochar with microporous structure could be a potential material to capture CO2. The impact of feedstock type, pyrolysis temperature and steam activation of biochars were evaluated for CO2 adsorption capacity. Pine sawdust biochars were produced at 550 °C, and steam activated for 45 min at the same temperature after completing the pyrolysis (PS550 and PSS550). Paper mill sludge biochars were produced at 300 and 600 °C (PMS300 and PMS600). The CO2 adsorption capacity of biochars was tested at 25 °C using a volumetric sorption analyzer. Pine sawdust biochars showed significantly higher CO2 adsorption capacity than paper mill sludge biochars due to high surface area and microporosity. Pine sawdust biochars were then evaluated for dynamic adsorption under representative post-combustion flue gas concentration conditions (15% CO2, 85% N2) using a breakthrough rig. Both materials showed selective CO2 uptake over N2 which is the major component along with CO2 in flue gas. PSS550 had slightly higher CO2 adsorption capacity (0.73 mmol g^-1 vs 0.67 mmol g^-1) and CO2 over N2 selectivity (26 vs 18) than PS550 possibly due to increase of microporosity, surface area, and oxygen containing basic functional groups through steam activation. Pine sawdust biochar is an environmentally friendly and low-cost material to capture CO2.
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•Pine sawdust biochars showed higher CO2 adsorption than paper mill sludge biochars.•Surface area and micro porosity play a vital role in CO2 adsorption.•Aromaticity and basic functional groups also facilitate CO2 adsorption.•Steam activation enhances CO2 over N2 selectivity compared to pristine biochar.
Ammonia-oxidizing archaea (AOA), that is, members of the Thaumarchaeota phylum, occur ubiquitously in the environment and are of major significance for global nitrogen cycling. However, controls on ...cell growth and organic carbon assimilation by AOA are poorly understood. We isolated an ammonia-oxidizing archaeon (designated strain DDS1) from seawater and used this organism to study the physiology of ammonia oxidation. These findings were confirmed using four additional Thaumarchaeota strains from both marine and terrestrial habitats. Ammonia oxidation by strain DDS1 was enhanced in coculture with other bacteria, as well as in artificial seawater media supplemented with α-keto acids (e.g., pyruvate, oxaloacetate). α-Keto acid-enhanced activity of AOA has previously been interpreted as evidence of mixotrophy. However, assays for heterotrophic growth indicated that incorporation of pyruvate into archaeal membrane lipids was negligible. Lipid carbon atoms were, instead, derived from dissolved inorganic carbon, indicating strict autotrophic growth. α-Keto acids spontaneously detoxify H₂O₂ via a nonenzymatic decarboxylation reaction, suggesting a role of α-keto acids as H₂O₂ scavengers. Indeed, agents that also scavenge H₂O₂, such as dimethylthiourea and catalase, replaced the α-keto acid requirement, enhancing growth of strain DDS1. In fact, in the absence of α-keto acids, strain DDS1 and other AOA isolates were shown to endogenously produce H₂O₂ (up to ∼4.5 μM), which was inhibitory to growth. Genomic analyses indicated catalase genes are largely absent in the AOA. Our results indicate that AOA broadly feature strict autotrophic nutrition and implicate H₂O₂ as an important factor determining the activity, evolution, and community ecology of AOA ecotypes.
Summary
Background
Skin colonization or infection with Staphylococcus aureus is known to trigger aggravation of atopic dermatitis (AD). However, the exact mechanisms by which S. aureus can worsen AD ...are unknown.
Objective
We investigated whether and how S. aureus‐derived membrane vesicles (MVs) contribute to worsening of AD.
Methods
Immunohistochemical and immunoelectron microscopic analyses were performed to detect staphylococcal protein A (SPA) in the epidermis of AD lesions. HaCaT cells were treated with S. aureus MVs and were analysed for the expression of cytokine genes. Immunopathology and cytokine gene profiles were analysed after topical application of S. aureus MVs to AD‐like skin lesions in a mouse model.
Results
The MV component SPA was detected in the keratinocytes as well as in the intercellular space of the epidermis of AD lesions colonized with S. aureus. Intact MVs from S. aureus delivered their components to keratinocytes and stimulated pro‐inflammatory cytokine gene expression in vitro. A knock‐down of Toll‐like receptor 2 or nucleotide‐binding oligomerization domain 2 using small interfering RNAs suppressed interleukin‐8 gene expression. Topical application of intact S. aureus MVs to AD‐like skin lesions in the mouse model induced massive infiltration of inflammatory cells and the resulting eczematous dermatitis. This inflammatory reaction was associated with a mixed Th1/Th2 immune response and enhanced expression of chemokine genes in AD‐like skin lesions.
Conclusions and Clinical Relevance
This study showed the importance of S. aureus MVs as a potent mediator for worsening of AD among many exogenous worsening factors of AD. Thus, S. aureus MVs may be regarded as one of the therapeutic targets for the management of AD aggravation.
Postreperfusion syndrome (PRS), an acute decrease in blood pressure after reperfusion of the liver graft, occurs frequently during liver transplantation surgery. We supposed that the activation of ...the kallikrein–kinin system leading to extensive systemic vasodilatation was a possible cause. The effect of pretreatment with nafamostat mesilate (NM), a broad spectrum serine protease inhibitor, on the occurrence of PRS was evaluated. Sixty‐two adult liver recipients were randomized to receive an intravenous bolus of either 0.02 mg/kg of NM (NM group, n = 31) or an equal volume of normal saline (control group, n = 31) just before reperfusion of the liver graft. Occurrence of PRS and intraoperative use of vasoactive drugs were compared between the two groups. Postoperative recovery was also compared. PRS was significantly less frequent (48% vs. 81%, p = 0.016) requiring less vasopressors in the NM group compared to the control group. The NM group also showed faster recovery of the mean arterial pressure. Perioperative laboratory values were similar between the two groups. Pretreatment with 0.02 mg/kg of NM immediately before reperfusion decreases the frequency of PRS and vasopressor requirements during the reperfusion period in liver transplantation.
Nafamostat mesilate administration before reperfusion of the liver graft attenuates the occurrence of postreperfusion syndrome and vasopressor requirements during orthotopic liver transplantation.
We present the analysis of OGLE-2016-BLG-0613, for which the lensing light curve appears to be that of a typical binary-lens event with two caustic spikes but with a discontinuous feature on the ...trough between the spikes. We find that the discontinuous feature was produced by a planetary companion to the binary lens. We find four degenerate triple-lens solution classes, each composed of a pair of solutions according to the well-known wide/close planetary degeneracy. One of these solution classes is excluded due to its relatively poor fit. For the remaining three pairs of solutions, the most-likely primary mass is about , while the planet is a super Jupiter. In all cases, the system lies in the Galactic disk, about halfway toward the Galactic bulge. However, in one of these three solution classes, the secondary of the binary system is a low-mass brown dwarf, with relative mass ratios (1:0.03:0.003), while in the two others the masses of the binary components are comparable. These two possibilities can be distinguished in about 2024 when the measured lens-source relative proper motion will permit separate resolution of the lens and source.
•Male rats exhibited a decrease in body weight when subjected to a high salt diet.•Male rats fed a high salt diet had an increased preference for sucrose solution.•When fed a high salt diet, male ...rats displayed a more active stress-coping behavior.•Male and female rats showed elevated water intake when subjected to a high salt diet.•Female rats were less susceptible to the effects of the high salt diet.
Eating diets high in salt has been associated with alterations in the immune system and the potential development of neuropsychiatric disorders. This area of research shows promise, but there is currently a limited amount of research on this topic. The present study investigated whether a high salt diet (HSD) affects anhedonia and stress-coping response behaviors in young male and female Wistar rats. In this study, male and female Wistar rats were fed an HSD (8 % NaCl w/w) from weaning to post-natal day (PND) 64. From PND 60 to 64, the rats underwent a spontaneous locomotor activity test (SLA), sucrose splash test (SST), sucrose preference test (SPT), and forced swim test (FST), followed by euthanasia at PND 65. Male and female rats consuming the HSD exhibited an increase in water intake compared to the corresponding control diet (CD) groups. Male rats had lower body weight despite having similar food intakes compared to the CD group. Male rats displayed an active stress-coping behavior in the FST, characterized by increased mobility. Additionally, HSD-fed males exhibited a greater preference for sucrose solution in the SPT. However, no effect of diet and sex were detected in the SST and the SLA, and hypothalamic levels of leptin and ghrelin receptors. On the other hand, female rats were less susceptible to the experimental conditions applied in this protocol than males.
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Summary
The chloroplast NAD(P)H dehydrogenase‐like (NDH) complex consists of about 30 subunits from both the nuclear and chloroplast genomes and is ubiquitous across most land plants. In some ...orchids, such as Phalaenopsis equestris, Dendrobium officinale and Dendrobium catenatum, most of the 11 chloroplast genome‐encoded ndh genes (cp‐ndh) have been lost. Here we investigated whether functional cp‐ndh genes have been completely lost in these orchids or whether they have been transferred and retained in the nuclear genome. Further, we assessed whether both cp‐ndh genes and nucleus‐encoded NDH‐related genes can be lost, resulting in the absence of the NDH complex. Comparative analyses of the genome of Apostasia odorata, an orchid species with a complete complement of cp‐ndh genes which represents the sister lineage to all other orchids, and three published orchid genome sequences for P. equestris, D. officinale and D. catenatum, which are all missing cp‐ndh genes, indicated that copies of cp‐ndh genes are not present in any of these four nuclear genomes. This observation suggests that the NDH complex is not necessary for some plants. Comparative genomic/transcriptomic analyses of currently available plastid genome sequences and nuclear transcriptome data showed that 47 out of 660 photoautotrophic plants and all the heterotrophic plants are missing plastid‐encoded cp‐ndh genes and exhibit no evidence for maintenance of a functional NDH complex. Our data indicate that the NDH complex can be lost in photoautotrophic plant species. Further, the loss of the NDH complex may increase the probability of transition from a photoautotrophic to a heterotrophic life history.
Significance statement
The NDH complex is composed of multiple genes encoded by the chloroplast and nuclear genomes. Some photoautotrophs have been shown to lack all the chloroplast genome‐encoded ndh genes but the genes in the nucleus have never been assessed. Through sequencing the ndh‐complete orchid genome, Apostasia odorata, we showed that the missing ndh genes in ndh‐free orchids are not transferred to the nucleus, and the nuclear NDH‐related genes were also lost resulting in no NDH complex.
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