Microbial contamination is an obstacle to widespread production of advanced biofuels and chemicals. Current practices such as process sterilization or antibiotic dosage carry excess costs or ...encourage the development of antibiotic resistance. We engineered Escherichia coli to assimilate melamine, a xenobiotic compound containing nitrogen. After adaptive laboratory evolution to improve pathway efficiency, the engineered strain rapidly outcompeted a control strain when melamine was supplied as the nitrogen source. We additionally engineered the yeasts Saccharomyces cerevisiae and Yarrowia lipolytica to assimilate nitrogen from cyanamide and phosphorus from potassium phosphite, and they outcompeted contaminating strains in several low-cost feedstocks. Supplying essential growth nutrients through xenobiotic or ecologically rare chemicals provides microbial competitive advantage with minimal external risks, given that engineered biocatalysts only have improved fitness within the customized fermentation environment.
Analysis of emission lines in gaseous nebulae yields direct measures of physical conditions and chemical abundances and is the cornerstone of nebular astrophysics. Although the physical problem is ...conceptually simple, its practical complexity can be overwhelming since the amount of data to be analyzed steadily increases; furthermore, results depend crucially on the input atomic data, whose determination also improves each year. To address these challenges we created PyNeb, an innovative code for analyzing emission lines. PyNeb computes physical conditions and ionic and elemental abundances and produces both theoretical and observational diagnostic plots. It is designed to be portable, modular, and largely customizable in aspects such as the atomic data used, the format of the observational data to be analyzed, and the graphical output. It gives full access to the intermediate quantities of the calculation, making it possible to write scripts tailored to the specific type of analysis one wants to carry out. In the case of collisionally excited lines, PyNeb works by solving the equilibrium equations for an n-level atom; in the case of recombination lines, it works by interpolation in emissivity tables. The code offers a choice of extinction laws and ionization correction factors, which can be complemented by user-provided recipes. It is entirely written in the python programming language and uses standard python libraries. It is fully vectorized, making it apt for analyzing huge amounts of data. The code is stable and has been benchmarked against IRAF/NEBULAR. It is public, fully documented, and has already been satisfactorily used in a number of published papers.
The life cycle of Northern Hemisphere downward wave coupling between the stratosphere and troposphere via wave reflection is analyzed. Downward wave coupling events are defined by extreme negative ...values of a wave coupling index based on the leading principal component of the daily wave-1 heat flux at 30 hPa. The life cycle occurs over a 28-day period. In the stratosphere there is a transition from positive to negative total wave-1 heat flux and westward to eastward phase tilt with height of the wave-1 geopotential height field. In addition, the zonal-mean zonal wind in the upper stratosphere weakens leading to negative vertical shear.
Following the evolution in the stratosphere there is a shift toward the positive phase of the North Atlantic Oscillation (NAO) in the troposphere. The pattern develops from a large westward-propagating wave-1 anomaly in the high-latitude North Atlantic sector. The subsequent equatorward propagation leads to a positive anomaly in midlatitudes. The near-surface temperature and circulation anomalies are consistent with a positive NAO phase. The results suggest that wave reflection events can directly influence tropospheric weather.
Finally, winter seasons dominated by extreme wave coupling and stratospheric vortex events are compared. The largest impacts in the troposphere occur during the extreme negative seasons for both indices, namely seasons with multiple wave reflection events leading to a positive NAO phase or seasons with major sudden stratospheric warmings (weak vortex) leading to a negative NAO phase. The results reveal that the dynamical coupling between the stratosphere and NAO involves distinct dynamical mechanisms that can only be characterized by separate wave coupling and vortex indices.
Gaps in our understanding of genetic susceptibility to malignant hyperthermia (MH) limit the application and interpretation of genetic diagnosis of the condition. Our aim was to define the prevalence ...and role of variants in the three genes implicated in MH susceptibility in the largest comprehensively phenotyped MH cohort worldwide.
We initially included one individual from each positive family tested in the UK MH Unit since 1971 to detect variants in RYR1, CACNA1S, or STAC3. Screening for genetic variants has been ongoing since 1991 and has involved a range of techniques, most recently next generation sequencing. We assessed the pathogenicity of variants using standard guidelines, including family segregation studies. The prevalence of recurrent variants of unknown significance was compared with the prevalence reported in a large database of sequence variants in low-risk populations.
We have confirmed MH susceptibility in 795 independent families, for 722 of which we have a DNA sample. Potentially pathogenic variants were found in 555 families, with 25 RYR1 and one CACNA1S variants previously unclassified recurrent variants significantly over-represented (P<1×10−7) in our cohort compared with the Exome Aggregation Consortium database. There was genotype–phenotype discordance in 86 of 328 families suitable for segregation analysis. We estimate non-RYR1/CACNA1S/STAC3 susceptibility occurs in 14–23% of MH families.
Our data provide current estimates of the role of variants in RYR1, CACNA1S, and STAC3 in susceptibility to MH in a predominantly white European population.
The effects of thyroid dysfunction in patients with preexisting heart failure have not been adequately studied. We examined the prevalence of thyroid dysfunction and associations with cardiovascular ...outcomes in a large, prospective cohort of outpatients with preexisting heart failure.
We examined associations between thyroid dysfunction and New York Heart Association class, atrial fibrillation, and a composite end point of ventricular assist device placement, heart transplantation, or death in 1365 participants with heart failure enrolled in the Penn Heart Failure Study. Mean age was 57 years, 35% were women, and the majority had New York Heart Association class II (45%) or III (32%) symptoms. More severe heart failure was associated with higher thyroid-stimulating hormone (TSH), higher free thyroxine (FT4), and lower total triiodothyronine (TT3) concentrations ( P<0.001 all models). Atrial fibrillation was positively associated with higher levels of FT4 alone ( P≤0.01 all models). There were 462 composite end points over a median 4.2 years of follow-up. In adjusted models, compared with euthyroidism, subclinical hypothyroidism (TSH 4.51-19.99 mIU/L with normal FT4) was associated with an increased risk of the composite end point overall (hazard ratio, 1.82; 95% CI, 1.27-2.61; P=0.001) and in the subgroup with TSH ≥7.00 mIU/L (hazard ratio, 3.25; 95% CI, 1.96-5.39; P<0.001), but not in the subgroup with TSH 4.51-6.99 mIU/L (hazard ratio, 1.26; 95% CI, 0.78-2.06; P=0.34). Isolated low T3 was also associated with the composite end point (hazard ratio, 2.12; 95% CI, 1.65-2.72; P<0.001).
In patients with preexisting heart failure, subclinical hypothyroidism with TSH ≥7 mIU/L and isolated low T3 levels are associated with poor prognosis. Clinical trials are needed to explore therapeutic effects of T4 and T3 administration in heart failure.
Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes.
We conducted a retrospective analysis of data from a series of 7374 ...consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology.
A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77×10
).
In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).
Premise of the study: Using sequence data generated via target enrichment for phylogenetics requires reassembly of high-throughput sequence reads into loci, presenting a number of bioinformatics ...challenges. We developed HybPiper as a user-friendly platform for assembly of gene regions, extraction of exon and intron sequences, and identification of paralogous gene copies. We test HybPiper using baits designed to target 333 phylogenetic markers and 125 genes of functional significance in Artocarpus (Moraceae). Methods and Results: HybPiper implements parallel execution of sequence assembly in three phases: read mapping, contig assembly, and target sequence extraction. The pipeline was able to recover nearly complete gene sequences for all genes in 22 species of Artocarpus. HybPiper also recovered more than 500 bp of nontargeted intron sequence in over half of the phylogenetic markers and identified paralogous gene copies in Artocarpus. Conclusions: HybPiper was designed for Linux and Mac OS X and is freely available at https://github.com/mossmatters/HybPiper.
Observations show Arctic sea ice has declined and midlatitude storminess has weakened during Northern Hemisphere (NH) summertime. It is currently unclear whether Arctic sea ice loss impacts ...summertime storminess because most previous work focuses on other seasons. Here we quantify the impact of Arctic sea ice loss on NH summertime storminess using equilibrium and transient climate model simulations. The equilibrium simulations show mid‐to‐late 21st century Arctic sea ice loss weakens summertime storminess, but only in the presence of ocean coupling. With ocean coupling, the equator‐to‐pole temperature and atmospheric energy gradients significantly weaken due to increased surface turbulent flux in the polar region following Arctic sea ice loss. The transient simulations show Arctic sea ice loss does not significantly weaken summertime storminess until the late 21st century. Furthermore, Arctic Amplification, which is dominated by Arctic sea ice loss in the present day, does not significantly impact the present‐day weakening of summertime storminess.
Plain Language Summary
Present‐day summertime climate change in the NH is characterized by rapid Arctic sea ice loss and weakening of weather systems. While these trends are projected to continue throughout the 21st century, their connection is not well understood. Using climate model simulations, we show mid‐to‐late 21st century Arctic sea ice loss weakens the summertime weather system by decreasing the equator‐to‐pole energy (and temperature) difference. In addition, we demonstrate transient Arctic sea ice loss does not significantly contribute to weakening summertime weather system until the late 21st century. The results suggest that present‐day Arctic sea ice loss and Arctic Amplification have not contributed significantly to the observed weakening of weather systems.
Key Points
Equilibrium and transient climate model simulations are used to quantify the summertime storminess response to Arctic sea ice loss
The equilibrium response to mid‐to‐late 21st century Arctic sea ice loss involves weaker summertime storminess due to ocean coupling
The transient weakening of present‐day summertime storminess is not significantly affected by Arctic sea ice loss and Arctic Amplification
Most cancer-related deaths are a result of metastasis, and thus the importance of this process as a target of therapy cannot be understated. By asking 'how can we effectively treat cancer?', we do ...not capture the complexity of a disease encompassing >200 different cancer types - many consisting of multiple subtypes - with considerable intratumoural heterogeneity, which can result in variable responses to a specific therapy. Moreover, we have much less information on the pathophysiological characteristics of metastases than is available for the primary tumour. Most disseminated tumour cells that arrive in distant tissues, surrounded by unfamiliar cells and a foreign microenvironment, are likely to die; however, those that survive can generate metastatic tumours with a markedly different biology from that of the primary tumour. To treat metastasis effectively, we must inhibit fundamental metastatic processes and develop specific preclinical and clinical strategies that do not rely on primary tumour responses. To address this crucial issue, Cancer Research UK and Cancer Therapeutics CRC Australia formed a Metastasis Working Group with representatives from not-for-profit, academic, government, industry and regulatory bodies in order to develop recommendations on how to tackle the challenges associated with treating (micro)metastatic disease. Herein, we describe the challenges identified as well as the proposed approaches for discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer.
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