Carbon emissions to the atmosphere from inland waters are globally significant and mainly occur at tropical latitudes. However, processes controlling the intensity of CO2 and CH4 emissions from ...tropical inland waters remain poorly understood. Here, we report a data-set of concurrent measurements of the partial pressure of CO2 (pCO2) and dissolved CH4 concentrations in the Amazon (n = 136) and the Congo (n = 280) Rivers. The pCO2 values in the Amazon mainstem were significantly higher than in the Congo, contrasting with CH4 concentrations that were higher in the Congo than in the Amazon. Large-scale patterns in pCO2 across different lowland tropical basins can be apprehended with a relatively simple statistical model related to the extent of wetlands within the basin, showing that, in addition to non-flooded vegetation, wetlands also contribute to CO2 in river channels. On the other hand, dynamics of dissolved CH4 in river channels are less straightforward to predict, and are related to the way hydrology modulates the connectivity between wetlands and river channels.
Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.
CheckMate 331 is a ...randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).
Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.
Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.
•The primary endpoint of OS with nivolumab versus chemotherapy as second-line treatment of SCLC was not met.•Crossing of the survival curves indicates higher long-term survival with nivolumab in a subset of patients.•Post hoc analyses suggest patients with baseline LDH ≤ ULN and those without liver metastases may benefit from nivolumab.•The safety profile of nivolumab was consistent with prior studies and more favorable than that of chemotherapy.
The turnover of brain proteins is critical for organism survival, and its perturbations are linked to pathology. Nevertheless, protein lifetimes have been difficult to obtain in vivo. They are ...readily measured in vitro by feeding cells with isotopically labeled amino acids, followed by mass spectrometry analyses. In vivo proteins are generated from at least two sources: labeled amino acids from the diet, and non-labeled amino acids from the degradation of pre-existing proteins. This renders measurements difficult. Here we solved this problem rigorously with a workflow that combines mouse in vivo isotopic labeling, mass spectrometry, and mathematical modeling. We also established several independent approaches to test and validate the results. This enabled us to measure the accurate lifetimes of ~3500 brain proteins. The high precision of our data provided a large set of biologically significant observations, including pathway-, organelle-, organ-, or cell-specific effects, along with a comprehensive catalog of extremely long-lived proteins (ELLPs).
Summary
Copy number variation (CNV) might be one of the main contributors to phenotypic diversity and evolutionary adaptation in animals and plants, employing a wide variety of mechanisms, such as ...gene dosage and transcript structure alterations, to modulate organismal plasticity. In the past 4 years, considerable advances have been made in the characterization of the genomic architecture of CNV in domestic species. First, low‐resolution CNV maps were produced for cattle, goat, sheep, pig, dog, chicken, duck and turkey, showing that these structural polymorphisms comprise a significant part of these genomes. Furthermore, CNVs have been associated with several pigmentation (white coat in horse, pig and sheep) and morphological (late feathering and pea comb in chicken) traits, as well as with susceptibility to a wide array of diseases and developmental disorders, for example osteopetrosis, anhidrotic ectodermal dysplasia, copper toxicosis, intersexuality, cone degeneration, periodic fever and dermoid sinus, among others. In the future, development of high‐resolution tools for CNV detection and typing combined with the implementation of databases integrating CNV, QTL and gene expression data will be essential to identify and measure the impact of this source of structural variation on the many phenotypes that are relevant to animal breeders and veterinary practitioners.
The ability to form memories is a prerequisite for an organism's behavioral adaptation to environmental changes. At the molecular level, the acquisition and maintenance of memory requires changes in ...chromatin modifications. In an effort to unravel the epigenetic network underlying both short- and long-term memory, we examined chromatin modification changes in two distinct mouse brain regions, two cell types and three time points before and after contextual learning. We found that histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression. Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning. Finally, our data provide evidence for a molecular framework of memory acquisition and maintenance, wherein DNA methylation could alter the expression and splicing of genes involved in functional plasticity and synaptic wiring.
Advanced age is not only a major risk factor for a range of disorders within an aging individual but may also enhance susceptibility for disease in the next generation. In humans, advanced paternal ...age has been associated with increased risk for a number of diseases. Experiments in rodent models have provided initial evidence that paternal age can influence behavioral traits in offspring animals, but the overall scope and extent of paternal age effects on health and disease across the life span remain underexplored. Here, we report that old father offspring mice showed a reduced life span and an exacerbated development of aging traits compared with young father offspring mice. Genome-wide epigenetic analyses of sperm from aging males and old father offspring tissue identified differentially methylated promoters, enriched for genes involved in the regulation of evolutionarily conserved longevity pathways. Gene expression analyses, biochemical experiments, and functional studies revealed evidence for an overactive mTORC1 signaling pathway in old father offspring mice. Pharmacological mTOR inhibition during the course of normal aging ameliorated many of the aging traits that were exacerbated in old father offspring mice. These findings raise the possibility that inherited alterations in longevity pathways contribute to intergenerational effects of aging in old father offspring mice.
The field of morphometrics is developing quickly. Recent advances have enabled geometric techniques to be applied to many zoological problems, particularly those involving epidemiologically-relevant ...mosquitoes. Herein, we briefly introduce geometric morphometric (GM) techniques and then review selected groups of mosquitoes (Culicidae) to which those techniques have been applied. In most of the reviewed cases, GM was capable of satisfactorily discriminating among the tested groups primarily when the studies considered differences within and among species, sexual dimorphism, treatments and the separation of laboratory strains. Although GM approaches have developed quite rapidly, some caution must be taken during data processing for a reliable biometrical approach, such as allometry and asymmetry analyses, scale removal and wing clarification staining for landmark digitization. We also critically forecast directions in this field and discuss how the creation of image databases should enhance species identification in culicids.
•Despite its mathematical sophistication, geometric morphometric techniques are easy to adopt.•In entomology this technique has been used to solve a series of biological problems.•This technique can discriminate groups, especially when applied to sexual dimorphism, treatments, and separation of strains.•Some caution must be taken during data processing, such as allometry and asymmetry analyses.•Researchers are seeking a method to automatically identify species of mosquitoes based on wing vein patterns.
Several lines of evidence indicate that medical schools have been failing to adequately nurture empathy and the ethical dimension in their graduates, the lack of which may play a central role in the ...genesis of medical errors, itself a major source of avoidable deaths, incapacity and wasted resources. It has been widely proposed that medical schools should adopt evaluation strategies as a means to promote a culture of respectful relationships. However, it is not clear if evaluation strategies in medical schools have addressed key domains related to that aim, such as ethics, through the perspective of their students. Hence, we conducted a national survey of instruments used by Brazilian medical schools to assess clerkship rotations from the perspective of students, with a main focus on the ethical domain.
The authors invited 121 randomly selected institutions to participate in the study. Key informants answered a questionnaire about clerkship rotations and sent copies of any instrument used to assess the quality of clerkship rotations according to the students' perspectives.
Twenty-six (53%) of 49 participating schools used an instrument to assess the quality of clerkship rotations according to the perspective of students. Just 13 (27%) schools had instruments containing at least one question encompassing the ethical domain. Only 2 (4%) schools asked students specifically about the occurrence of any negative experience concerning the ethical domain during rotations. Merely 1 (2%) school asked students about having witnessed patient mistreatment and none asked about mistreatment against students themselves.
There are several missed opportunities in the way medical schools assess the quality of clerkship rotations regarding the ethical domain. Closing the gap between usual institutional discourses regarding ethics and how that dimension is assessed within clerkship rotations might represent an important step towards the improvement of medical education and healthcare systems.
Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy ...and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA‐Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than fivefold. The data provide strong evidence for the existence of large and multi‐cluster MXEs in higher vertebrates and offer new insights into MXE evolution. More than 82% of the MXE clusters are conserved in mammals, and five clusters have homologous clusters in Drosophila. Finally, MXEs are significantly enriched in pathogenic mutations and their spatio‐temporal expression might predict human disease pathology.
Synopsis
Predicted human mutually exclusive splicing events are validated using 515 published RNA‐seq datasets, and their extent, mechanism, and functional roles in health and disease are investigated.
855 mutually exclusive exons (MXEs) were validated, 42% of which are novel exons.
Many large and multi‐cluster MXEs exist in mammals.
Over 82% of the detected MXEs are evolutionary conserved.
Exon‐level MXE expression patterns might predict human pathology.
Predicted human mutually exclusive splicing events are validated using 515 published RNA‐seq datasets, and their extent, mechanism, and functional roles in health and disease are investigated.
The multiple high‐pressure (HP), low‐temperature (LT) metamorphic units of Western and Central Anatolia offer a great opportunity to investigate the subduction‐ and continental accretion‐related ...evolution of the eastern limb of the long‐lived Aegean subduction system. Recent reports of the HP–LT index mineral Fe‐Mg‐carpholite in three metasedimentary units of the Gondwana‐derived Anatolide–Tauride continental block (namely the Afyon Zone, the Ören Unit and the southern Menderes Massif) suggest a more complicated scenario than the single‐continental accretion model generally put forward in previous studies. This study presents the first isotopic dates (white mica 40Ar–39Ar geochronology), and where possible are combined with P–T estimates (chlorite thermometry, phengite barometry, multi‐equilibrium thermobarometry), on carpholite‐bearing rocks from these three HP–LT metasedimentary units. It is shown that, in the Afyon Zone, carpholite‐bearing assemblages were retrogressed through greenschist‐facies conditions at c. 67–62 Ma. Early retrograde stages in the Ören Unit are dated to 63–59 Ma. In the Kurudere–Nebiler Unit (HP Mesozoic cover of the southern Menderes Massif), HP retrograde stages are dated to c. 45 Ma, and post‐collisional cooling to c. 26 Ma. These new results support that the Ören Unit represents the westernmost continuation of the Afyon Zone, whereas the Kurudere–Nebiler Unit correlates with the Cycladic Blueschist Unit of the Aegean Domain. In Western Anatolia, three successive HP–LT metamorphic belts thus formed: the northernmost Tavşanlı Zone (c. 88–82 Ma), the Ören–Afyon Zone (between 70 and 65 Ma), and the Kurudere–Nebiler Unit (c. 52–45 Ma). The southward younging trend of the HP–LT metamorphism from the upper and internal to the deeper and more external structural units, as in the Aegean Domain, points to the persistence of subduction in Western Anatolia between 93–90 and c. 35 Ma. After the accretion of the Menderes–Tauride terrane, in Eocene times, subduction stopped, leading to continental collision and associated Barrovian‐type metamorphism. Because, by contrast, the Aegean subduction did remain active due to slab roll‐back and trench migration, the eastern limb (below Southwestern Anatolia) of the Hellenic slab was dramatically curved and consequently teared. It therefore is suggested that the possibility for subduction to continue after the accretion of buoyant (e.g. continental) terranes probably depends much on palaeogeography.
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