Abstract Laser plasma electron acceleration from the interaction of an intense femtosecond laser pulse with an isolated microparticle surrounded by a low-density gas is studied here. Experiments ...presented here show that optimized plasma tailoring by introducing a pre-pulse boosts parametric instabilities to produce MeV electron energies and generates electron temperatures as large as 200 keV with the total charge being as high as 350 fC/shot/sr, even at a laser intensity of a few times 10 16 Wcm −2 . Corroborated by particle-in-cell simulations, these measurements reveal that two plasmon decay in the vicinity of the microparticle is the main contributor to hot electron generation.
Comparative studies of the divergence of quantitative traits and neutral molecular markers, known as Q(ST)-F(ST) comparisons, provide a means for researchers to distinguish between natural selection ...and genetic drift as causes of population differentiation in complex polygenic traits. The use of Q(ST)-F(ST) comparisons has increased rapidly in the last few years, highlighting the utility of this approach for addressing a wide range of questions that are relevant to evolutionary and ecological genetics. These studies have also provided lessons for the design of future Q(ST)-F(ST) comparisons. Methods based on the Q(ST)-F(ST) approach could also be used to analyse various types of 'omics' data in new and revealing ways.
Crossovers (COs) are formed during meiosis by the repair of programmed DNA double-strand breaks (DSBs) and are required for the proper segregation of chromosomes. More DSBs are made than COs, and the ...remaining DSBs are repaired as noncrossovers (NCOs). The distribution of recombination events along a chromosome occurs in a stereotyped pattern that is shaped by CO-promoting and CO-suppressing forces, collectively referred to as crossover patterning mechanisms. Chromosome inversions are structural aberrations that, when heterozygous, disrupt the recombination landscape by suppressing crossing over. In Drosophila species, the local suppression of COs by heterozygous inversions triggers an increase in crossing over on freely recombining chromosomes termed the interchromosomal (IC) effect 1, 2. The molecular mechanism(s) by which heterozygous inversions suppress COs, whether noncrossover gene conversions (NCOGCs) are similarly affected, and what mediates the increase in COs in the rest of the genome remain open questions. By sequencing whole genomes of individual offspring from mothers containing heterozygous inversions, we show that, although COs are suppressed by inversions, NCOGCs occur throughout inversions at higher than wild-type frequencies. We confirm that CO frequency increases on the freely recombining chromosomes, yet CO interference remains intact. Intriguingly, NCOGCs do not increase in frequency on the freely recombining chromosomes and the total number of DSBs is approximately the same per genome. Together, our data show that heterozygous inversions change the recombination landscape by altering the relative proportions of COs and NCOGCs and suggest that DSB fate may be plastic until a CO assurance checkpoint has been satisfied.
•Heterozygous inversions shift the crossover landscape (the interchromosomal effect)•Crossovers on freely recombining chromosomes increase and noncrossovers decrease•Unlike crossovers, noncrossovers are not suppressed by inversion breakpoints•The interchromosomal effect does not increase the number of double-strand breaks
Heterozygous inversions suppress crossing over during meiosis while increasing crossover frequency elsewhere in the genome. Crown et al. show that noncrossover frequency decreases on chromosomes able to undergo exchange, inversion breakpoints do not suppress noncrossovers, and inversions alter genome-wide double-strand break repair outcomes.
trans -acting small interfering RNAs (tasiRNAs) are plant-specific endogenous siRNAs produced via a unique pathway whose first step is the microRNA (miRNA)-programmed RNA-induced silencing complex ...(RISC)–mediated cleavage of tasiRNA gene (TAS) transcripts. One of the products is subsequently transformed into tasiRNAs by a pathway that requires several factors including SUPPRESSOR OF GENE SILENCING3 (SGS3) and RNA-DEPENDENT RNA POLYMERASE6. Here, using in vitro assembled ARGONAUTE (AGO)1–RISCs, we show that SGS3 is recruited onto RISCs only when they bind target RNA. Following cleavage by miRNA173 (miR173)-programmed RISC, SGS3 was found in complexes containing cleaved TAS2 RNA and RISC. The 3′ cleavage fragment (the source of tasiRNAs) was protected from degradation in this complex. Depletion of SGS3 did not affect TAS2 RNA cleavage by miR173-programmed RISC, but did affect the stability of the 3′ cleavage fragment. When the 3′ nucleotide of 22-nt miR173 was deleted or the corresponding nucleotide in TAS2 RNA was mutated, the complex was not observed and the 3′ cleavage fragment was degraded. Importantly, these changes in miR173 or TAS2 RNA are known to lead to a loss of tasiRNA production in vivo. These results suggest that (i) SGS3 associates with AGO1–RISC via the double-stranded RNA formed by the 3′-terminal nucleotides of 22-nt miR173 and corresponding target RNA, which probably protrudes from the AGO1–RISC molecular surface, (ii) SGS3 protects the 3′ cleavage fragment of TAS2 RNA from degradation, and (iii) the observed SGS3-dependent stabilization of the 3′ fragment of TAS2 RNA is key to tasiRNA production.
Satellite and tower-based metrics of forest-scale photosynthesis generally increase with dry season progression across central Amazônia, but the underlying mechanisms lack consensus.
We conducted ...demographic surveys of leaf age composition, and measured the age dependence of leaf physiology in broadleaf canopy trees of abundant species at a central eastern Amazon site. Using a novel leaf-to-branch scaling approach, we used these data to independently test the much-debated hypothesis – arising from satellite and tower-based observations – that leaf phenology could explain the forest-scale pattern of dry season photosynthesis.
Stomatal conductance and biochemical parameters of photosynthesis were higher for recently mature leaves than for old leaves. Most branches had multiple leaf age categories simultaneously present, and the number of recently mature leaves increased as the dry season progressed because old leaves were exchanged for new leaves.
These findings provide the first direct field evidence that branch-scale photosynthetic capacity increases during the dry season, with a magnitude consistent with increases in ecosystem-scale photosynthetic capacity derived from flux towers. Interactions between leaf age-dependent physiology and shifting leaf age-demographic composition are sufficient to explain the dry season photosynthetic capacity pattern at this site, and should be considered in vegetation models of tropical evergreen forests.
Glioblastoma multiforme (GBM) is an invariably fatal central nervous system tumor despite treatment with surgery, radiation, and chemotherapy. Further insights into the molecular and cellular ...mechanisms that drive GBM formation are required to improve patient outcome. MicroRNAs are emerging as important regulators of cellular differentiation and proliferation, and have been implicated in the etiology of a variety of cancers, yet the role of microRNAs in GBM remains poorly understood. In this study, we investigated the role of microRNAs in regulating the differentiation and proliferation of neural stem cells and glioblastoma-multiforme tumor cells.
We used quantitative RT-PCR to assess microRNA expression in high-grade astrocytomas and adult mouse neural stem cells. To assess the function of candidate microRNAs in high-grade astrocytomas, we transfected miR mimics to cultured-mouse neural stem cells, -mouse oligodendroglioma-derived stem cells, -human glioblastoma multiforme-derived stem cells and -glioblastoma multiforme cell lines. Cellular differentiation was assessed by immunostaining, and cellular proliferation was determined using fluorescence-activated cell sorting.
Our studies revealed that expression levels of microRNA-124 and microRNA-137 were significantly decreased in anaplastic astrocytomas (World Health Organization grade III) and glioblastoma multiforme (World Health Organization grade IV) relative to non-neoplastic brain tissue (P < 0.01), and were increased 8- to 20-fold during differentiation of cultured mouse neural stem cells following growth factor withdrawal. Expression of microRNA-137 was increased 3- to 12-fold in glioblastoma multiforme cell lines U87 and U251 following inhibition of DNA methylation with 5-aza-2'-deoxycytidine (5-aza-dC). Transfection of microRNA-124 or microRNA-137 induced morphological changes and marker expressions consistent with neuronal differentiation in mouse neural stem cells, mouse oligodendroglioma-derived stem cells derived from S100 beta-v-erbB tumors and cluster of differentiation 133+ human glioblastoma multiforme-derived stem cells (SF6969). Transfection of microRNA-124 or microRNA-137 also induced G1 cell cycle arrest in U251 and SF6969 glioblastoma multiforme cells, which was associated with decreased expression of cyclin-dependent kinase 6 and phosphorylated retinoblastoma (pSer 807/811) proteins.
microRNA-124 and microRNA-137 induce differentiation of adult mouse neural stem cells, mouse oligodendroglioma-derived stem cells and human glioblastoma multiforme-derived stem cells and induce glioblastoma multiforme cell cycle arrest. These results suggest that targeted delivery of microRNA-124 and/or microRNA-137 to glioblastoma multiforme tumor cells may be therapeutically efficacious for the treatment of this disease.
Interactions among global change stressors and their effects at large scales are often proposed, but seldom evaluated. This situation is primarily due to lack of comprehensive, sufficiently ...long‐term, and spatially extensive datasets. Seagrasses, which provide nursery habitat, improve water quality, and constitute a globally important carbon sink, are among the most vulnerable habitats on the planet. Here, we unite 31 years of high‐resolution aerial monitoring and water quality data to elucidate the patterns and drivers of eelgrass (Zostera marina) abundance in Chesapeake Bay, USA, one of the largest and most valuable estuaries in the world, with an unparalleled history of regulatory efforts. We show that eelgrass area has declined 29% in total since 1991, with wide‐ranging and severe ecological and economic consequences. We go on to identify an interaction between decreasing water clarity and warming temperatures as the primary drivers of this trend. Declining clarity has gradually reduced eelgrass cover the past two decades, primarily in deeper beds where light is already limiting. In shallow beds, however, reduced visibility exacerbates the physiological stress of acute warming, leading to recent instances of decline approaching 80%. While degraded water quality has long been known to influence underwater grasses worldwide, we demonstrate a clear and rapidly emerging interaction with climate change. We highlight the urgent need to integrate a broader perspective into local water quality management, in the Chesapeake Bay and in the many other coastal systems facing similar stressors.
We used 31 years of aerial imaging and water quality data to document the decline of eelgrass in Chesapeake Bay, USA. Losses are being driven by an interaction between increasing summertime temperatures, and reduced light availability due to declining water clarity (Secchi). As a key foundational habitat, the loss of eelgrass in this region will have severe ecological and economic consequences for citizens of the Bay.
Lodgepole pine needle leachates from trees killed by the mountain pine beetle epidemic in Colorado were evaluated for dissolved organic matter (DOM) character, biodegradation, treatability by ...coagulation and disinfection byproduct (DBP) formation. An average of 8.0 (±0.62) mg-DOC/g-dry weight of litter was leached from three sets of needle samples representing different levels of forest floor degradation. Fluorescence analysis included collection of excitation and emission matrices, examination of peak intensities and development of a 4-component parallel factor (PARAFAC) analysis model. Peak intensity and PARAFAC analyses provided complementary results showing that fresh leachates were initially dominated by polyphenolic/protein-like components (60-70%) and humic-like fluorescence increased (40-70%) after biodegradation. Humic-like components were removed by coagulation (20-64%), while polyphenolic/protein-like components were not, which may create challenges for utilities required to meet OM removal regulations. DBP formation yields after 24 h chlorination were 20.5-26.4 μg/mg-DOC for trihalomethanes and 9.0-14.5 μg/mg-DOC for haloacetic acids for fresh leachates; increased after biodegradation to 19.2-64.2 and 7.1-30.9 μg/mg-DOC, respectively; and decreased after coagulation (fresh: 11.3-17.7;5.7-7.6 μg/mg-DOC, respectively; biodegraded: 12.0-27.3 and 2.9-7.2 μg/mg-DOC, respectively), reflective of changes in concentration of humic material. Humic-like PARAFAC components and peak intensities were positively correlated (R(2) ≥ 0.45) to DBP concentrations, while polyphenolic/protein-like components were not (R(2) ≤ 0.17).
Impaired endothelium-dependent vasodilation is a hallmark of obesity-induced hypertension. The recognition that Ca
signaling in endothelial cells promotes vasodilation has led to the hypothesis that ...endothelial Ca
signaling is compromised during obesity, but the underlying abnormality is unknown. In this regard, transient receptor potential vanilloid 4 (TRPV4) ion channels are a major Ca
influx pathway in endothelial cells, and regulatory protein AKAP150 (A-kinase anchoring protein 150) enhances the activity of TRPV4 channels.
We used endothelium-specific knockout mice and high-fat diet-fed mice to assess the role of endothelial AKAP150-TRPV4 signaling in blood pressure regulation under normal and obese conditions. We further determined the role of peroxynitrite, an oxidant molecule generated from the reaction between nitric oxide and superoxide radicals, in impairing endothelial AKAP150-TRPV4 signaling in obesity and assessed the effectiveness of peroxynitrite inhibition in rescuing endothelial AKAP150-TRPV4 signaling in obesity. The clinical relevance of our findings was evaluated in arteries from nonobese and obese individuals.
We show that Ca
influx through TRPV4 channels at myoendothelial projections to smooth muscle cells decreases resting blood pressure in nonobese mice, a response that is diminished in obese mice. Counterintuitively, release of the vasodilator molecule nitric oxide attenuated endothelial TRPV4 channel activity and vasodilation in obese animals. Increased activities of inducible nitric oxide synthase and NADPH oxidase 1 enzymes at myoendothelial projections in obese mice generated higher levels of nitric oxide and superoxide radicals, resulting in increased local peroxynitrite formation and subsequent oxidation of the regulatory protein AKAP150 at cysteine 36, to impair AKAP150-TRPV4 channel signaling at myoendothelial projections. Strategies that lowered peroxynitrite levels prevented cysteine 36 oxidation of AKAP150 and rescued endothelial AKAP150-TRPV4 signaling, vasodilation, and blood pressure in obesity. Peroxynitrite-dependent impairment of endothelial TRPV4 channel activity and vasodilation was also observed in the arteries from obese patients.
These data suggest that a spatially restricted impairment of endothelial TRPV4 channels contributes to obesity-induced hypertension and imply that inhibiting peroxynitrite might represent a strategy for normalizing endothelial TRPV4 channel activity, vasodilation, and blood pressure in obesity.
In this review we highlight the most recent studies furthering the clinical development of selinexor, a novel exportin-1 inhibitor, for the treatment of multiple myeloma and non-Hodgkin lymphomas.
...Three pivotal trials, the SADAL trial for diffuse large B-cell lymphoma, and the BOSTON and selinexor treatment of refractory myeloma trials for multiple myeloma, have recently led to the regulatory approval of selinexor monotherapy or combination regimens. They are complemented by several earlier phase clinical trials with iterative combinations, adding selinexor to novel therapies and cytotoxic chemotherapy regimens at various stages in the disease courses. In some, selinexor appears synergistic, occasionally overcoming treatment refractoriness, whereas in other situations appears additive. Consistent issues with tolerability are seen across trials, although consensus guidelines on their preemption and management have recently been adopted which may improve treatment success. While comparative data are lacking, the efficacy of selinexor-based regimens does not approach that of contemporaneous cellular and immunotherapies.
Selinexor is a novel and potentially synergistic therapy for lymphoid malignancies, although requires refined supportive measures and strategies to improve its efficacy. Likely, for continued success, it will need to identify niches that complement recent advances, such as bridging to cellular therapies or maintenance thereafter.
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