Significance With the recent discoveries of large reserves of natural gas, the efficient utilization of one-carbon compounds for chemical synthesis would reduce the raw material cost for the ...petroleum-based chemical industry. Methanol is produced industrially from methane and is a feedstock chemical for the synthesis of higher carbon compounds. However, current chemical synthesis of higher carbon compounds from methanol requires high temperature and pressure. Natural biological pathways for methanol utilization are carbon and ATP inefficient. Here we constructed a synthetic biocatalytic pathway that allows the efficient conversion of methanol to higher-chain alcohols or other higher carbon compounds without carbon loss or ATP expenditure. The high carbon efficiency and favorable operating conditions are attractive for industrial applications.
Methanol is an important intermediate in the utilization of natural gas for synthesizing other feedstock chemicals. Typically, chemical approaches for building C–C bonds from methanol require high temperature and pressure. Biological conversion of methanol to longer carbon chain compounds is feasible; however, the natural biological pathways for methanol utilization involve carbon dioxide loss or ATP expenditure. Here we demonstrated a biocatalytic pathway, termed the methanol condensation cycle (MCC), by combining the nonoxidative glycolysis with the ribulose monophosphate pathway to convert methanol to higher-chain alcohols or other acetyl-CoA derivatives using enzymatic reactions in a carbon-conserved and ATP-independent system. We investigated the robustness of MCC and identified operational regions. We confirmed that the pathway forms a catalytic cycle through ¹³C-carbon labeling. With a cell-free system, we demonstrated the conversion of methanol to ethanol or n -butanol. The high carbon efficiency and low operating temperature are attractive for transforming natural gas-derived methanol to longer-chain liquid fuels and other chemical derivatives.
Mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Existing mouse intestinal tumor models display mainly small intestinal lesions and carcinomas are rare. ...We defined human CDX2 sequences conferring colon epithelium-preferential transgene expression in the adult mouse. Mice carrying a CDX2P-NLS Cre recombinase transgene and a loxP-targeted Apc allele developed mainly colorectal tumors, with carcinomas seen in 6 of 36 (17%) of mice followed for 300 days. Like human colorectal lesions, the mouse tumors showed biallelic Apc inactivation, beta-catenin dysregulation, global DNA hypomethylation, and aneuploidy. The predominantly distal colon and rectal distribution of tumors seen in mice where one Apc allele was inactivated in epithelial cells from distal ileum to rectum suggests that regional differences in the intestinal tract in the frequency and nature of secondary genetic and epigenetic events associated with adenoma outgrowth have a contributing role in determining where adenomas develop. The presence of large numbers of small intestine tumors seemed to inhibit colorectal tumor development in the mouse, and gender-specific effects on tumor multiplicity in the distal mouse colon and rectum mimic the situation in humans where males have a larger number of advanced adenomas and carcinomas in the distal colon and rectum than females. The mouse model of colon-preferential gene targeting described here should facilitate efforts to define novel factors and mechanisms contributing to human colon tumor pathogenesis, as well as work on tumor-promoting environmental factors and agents and strategies for cancer prevention and treatment.
Stability in a metabolic system may not be obtained if incorrect amounts of enzymes are used. Without stability, some metabolites may accumulate or deplete leading to the irreversible loss of the ...desired operating point. Even if initial enzyme amounts achieve a stable steady state, changes in enzyme amount due to stochastic variations or environmental changes may move the system to the unstable region and lose the steady-state or quasi-steady-state flux. This situation is distinct from the phenomenon characterized by typical sensitivity analysis, which focuses on the smooth change before loss of stability. Here we show that metabolic networks differ significantly in their intrinsic ability to attain stability due to the network structure and kinetic forms, and that after achieving stability, some enzymes are prone to cause instability upon changes in enzyme amounts. We use Ensemble Modelling for Robustness Analysis (EMRA) to analyze stability in four cell-free enzymatic systems when enzyme amounts are changed. Loss of stability in continuous systems can lead to lower production even when the system is tested experimentally in batch experiments. The predictions of instability by EMRA are supported by the lower productivity in batch experimental tests. The EMRA method incorporates properties of network structure, including stoichiometry and kinetic form, but does not require specific parameter values of the enzymes.
The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been ...encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response.
For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis.
Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8
edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007).
The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.
Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be ...developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.
This study presents radar-based precipitation estimates collected during the 2-month U.S. Department of Energy Atmospheric Radiation Measurement Program (ARM)–NASA Midlatitude Continental Convective ...Clouds Experiment (MC3E). Emphasis is on the usefulness of radar observations from the C-band and X-band scanning ARM precipitation radars (CSAPR and XSAPR, respectively) for rainfall estimation products to distances within 100 km of the Lamont, Oklahoma, ARM facility. The study utilizes a dense collection of collocated ARM, NASA Global Precipitation Measurement, and nearby surface Oklahoma Mesonet gauge records to evaluate radar-based hourly rainfall products and campaign-optimized methods over individual gauges and for areal rainfall characterizations. Rainfall products are also evaluated against the performance of a regional NWS Weather Surveillance Radar-1988 Doppler (WSR-88D) S-band dual-polarization radar product. Results indicate that the CSAPR system may achieve similar point– and areal–gauge bias and root-mean-square (RMS) error performance to a WSR-88D reference for the variety of MC3E deep convective events sampled. The best campaign rainfall performance was achieved when using radar relations capitalizing on estimates of the specific attenuation from the CSAPR system. The XSAPRs demonstrate limited capabilities, having modest success in comparison with the WSR-88D reference for hourly rainfall accumulations that are under 10 mm. All rainfall estimation methods exhibit a reduction by a factor of 1.5–2.5 in RMS errors for areal accumulations over a 15-km² NASA dense gauge network, with the smallest errors typically associated with dual-polarization radar methods.
Highlights • Recent developments of mathematical modeling have facilitated strain design. • Robustness for stability has emerged as an important criterion for strain design. • Data acquisition and ...managing techniques are in need in modern systems biology.
Why sex is so common remains unclear; what is certain is that the predominance of sex despite its profound costs means that it must confer major advantages. Here, we use elemental and nucleic acid ...assays to evaluate a key element of a novel, integrative hypothesis considering whether sex might be favoured because of differences in body composition between sexuals and asexuals. We found that asexual Potamopyrgus antipodarum, a New Zealand snail, have markedly higher bodily phosphorus and nucleic acid content per unit mass than sexual counterparts. These differences coincide with and are almost certainly linked to the higher ploidy of the asexuals. Our results are the first documented body composition differences between sexual and asexual organisms, and the first detected phenotypic difference between sexual and asexual P. antipodarum, an important natural model system for the study of the maintenance of sex. These findings also verify a central component of our hypothesis that competition between diploid sexuals and polyploid asexuals could be influenced by phosphorus availability.
Abstract One of the most intense air mass transformations on Earth happens when cold air flows from frozen surfaces to much warmer open water in cold-air outbreaks (CAOs), a process captured ...beautifully in satellite imagery. Despite the ubiquity of the CAO cloud regime over high-latitude oceans, we have a rather poor understanding of its properties, its role in energy and water cycles, and its treatment in weather and climate models. The Cold-Air Outbreaks in the Marine Boundary Layer Experiment (COMBLE) was conducted to better understand this regime and its representation in models. COMBLE aimed to examine the relations between surface fluxes, boundary layer structure, aerosol, cloud, and precipitation properties, and mesoscale circulations in marine CAOs. Processes affecting these properties largely fall in a range of scales where boundary layer processes, convection, and precipitation are tightly coupled, which makes accurate representation of the CAO cloud regime in numerical weather prediction and global climate models most challenging. COMBLE deployed an Atmospheric Radiation Measurement Mobile Facility at a coastal site in northern Scandinavia (69°N), with additional instruments on Bear Island (75°N), from December 2019 to May 2020. CAO conditions were experienced 19% (21%) of the time at the main site (on Bear Island). A comprehensive suite of continuous in situ and remote sensing observations of atmospheric conditions, clouds, precipitation, and aerosol were collected. Because of the clouds’ well-defined origin, their shallow depth, and the broad range of observed temperature and aerosol concentrations, the COMBLE dataset provides a powerful modeling testbed for improving the representation of mixed-phase cloud processes in large-eddy simulations and large-scale models.
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