To date little is known about the genetic background that drives the production and diversification of secondary metabolites in the Hypoxylaceae. With the recent availability of high-quality genome ...sequences for 13 representative species and one relative (Xylaria hypoxylon) we attempted to survey the diversity of biosynthetic pathways in these organisms to investigate their true potential as secondary metabolite producers. Manual search strategies based on the accumulated knowledge on biosynthesis in fungi enabled us to identify 783 biosynthetic pathways across 14 studied species, the majority of which were arranged in biosynthetic gene clusters (BGC). The similarity of BGCs was analysed with the BiG-SCAPE engine which organised the BGCs into 375 gene cluster families (GCF). Only ten GCFs were conserved across all of these fungi indicating that speciation is accompanied by changes in secondary metabolism. From the known compounds produced by the family members some can be directly correlated with identified BGCs which is highlighted herein by the azaphilone, dihydroxynaphthalene, tropolone, cytochalasan, terrequinone, terphenyl and brasilane pathways giving insights into the evolution and diversification of those compound classes. Vice versa, products of various BGCs can be predicted through homology analysis with known pathways from other fungi as shown for the identified ergot alkaloid, trigazaphilone, curvupallide, viridicatumtoxin and swainsonine BGCs. However, the majority of BGCs had no obvious links to known products from the Hypoxylaceae or other well-studied biosynthetic pathways from fungi. These findings highlight that the number of known compounds strongly underrepresents the biosynthetic potential in these fungi and that a tremendous number of unidentified secondary metabolites is still hidden. Moreover, with increasing numbers of genomes for further Hypoxylaceae species becoming available, the likelihood of revealing new biosynthetic pathways that encode new, potentially useful compounds will significantly improve. Reaching a better understanding of the biology of these producers, and further development of genetic methods for their manipulation, will be crucial to access their treasures.
The amount and extent of coastal flooding caused by hurricanes can be sensitive to the timing or speed of the storm. For storms moving parallel to the coast, the hazards can be stretched over a ...larger area. Hurricane Matthew was a powerful storm that impacted the southeastern U.S. during October 2016, moving mostly parallel to the coastline from Florida through North Carolina. In this study, three sources for atmospheric forcing are considered for a simulation of Matthew's water levels, which are validated against extensive observations, and then the storm's effects are explored on this long coastline. It is hypothesized that the spatial variability of Matthew's effects on total water levels is partly due to the surge interacting nonlinearly with tides. By changing the time of occurrence of the storm, differences in storm surge are observed in different regions due to the storm coinciding with other periods in the tidal cycles. These differences are found to be as large as 1 m and comparable to the tidal amplitude. A change in forward speed of the storm also should alter its associated flooding due to differences in the duration over which the storm impacts the coastal waters. With respect to the forward speed, the present study contributes to established results by considering the scenario of a shore-parallel hurricane. A faster storm caused an increase in peak water levels along the coast but a decrease in the overall volume of inundation. On the other hand, a slower storm pushed more water into the estuaries and bays and flooded a larger section of the coast. Implications for short-term forecasting and long-term design studies for storms moving parallel to long coastlines are discussed herein.
•OWI winds represent Hurricane Matthew's effects more accurately than WF and GAHM.•Nonlinear interaction between surge and tide can alter storm tide significantly.•A shore-parallel storm can interact with various stages in the tidal cycle.•A faster storm would have caused higher surges on the open coast.•A slower storm would have pushed more water into the estuaries and bays.
Regulatory protein phosphorylation controls normal and pathophysiological signaling in eukaryotic cells. Despite great advances in mass-spectrometry-based proteomics, the extent, localization, and ...site-specific stoichiometry of this posttranslational modification (PTM) are unknown. Here, we develop a stringent experimental and computational workflow, capable of mapping more than 50,000 distinct phosphorylated peptides in a single human cancer cell line. We detected more than three-quarters of cellular proteins as phosphoproteins and determined very high stoichiometries in mitosis or growth factor signaling by label-free quantitation. The proportion of phospho-Tyr drastically decreases as coverage of the phosphoproteome increases, whereas Ser/Thr sites saturate only for technical reasons. Tyrosine phosphorylation is maintained at especially low stoichiometric levels in the absence of specific signaling events. Unexpectedly, it is enriched on higher-abundance proteins, and this correlates with the substrate KM values of tyrosine kinases. Our data suggest that P-Tyr should be considered a functionally separate PTM of eukaryotic proteomes.
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•Deepest phosphoproteome with more than 50,000 distinct phosphopeptides•Stringent computational pipeline for high-quality phosphoproteomics analysis•Large-scale phosphosite occupancies extracted from label-free data•At least 75% of the proteome phosphorylated following an 80/20 rule
Here, Sharma et al. use mass spectrometry to map the phosphoproteome to a depth of about 50,000 distinct phosphopeptides. They show that at least 75% of the proteome is phosphorylated following an 80/20 rule and that specific signaling states are characterized by high fractional site occupancies. They uncover fundamental differences between Ser/Thr and Tyr phosphorylation. Notably, they find that pTyr is much more tightly controlled and tends to occur on higher-abundance proteins and that the pTyr proteome appears to be “finite.”
Abstract
Hurricane Gustav (2008) made landfall in southern Louisiana on 1 September 2008 with its eye never closer than 75 km to New Orleans, but its waves and storm surge threatened to flood the ...city. Easterly tropical-storm-strength winds impacted the region east of the Mississippi River for 12–15 h, allowing for early surge to develop up to 3.5 m there and enter the river and the city’s navigation canals. During landfall, winds shifted from easterly to southerly, resulting in late surge development and propagation over more than 70 km of marshes on the river’s west bank, over more than 40 km of Caernarvon marsh on the east bank, and into Lake Pontchartrain to the north. Wind waves with estimated significant heights of 15 m developed in the deep Gulf of Mexico but were reduced in size once they reached the continental shelf. The barrier islands further dissipated the waves, and locally generated seas existed behind these effective breaking zones.
The hardening and innovative deployment of gauges since Hurricane Katrina (2005) resulted in a wealth of measured data for Gustav. A total of 39 wind wave time histories, 362 water level time histories, and 82 high water marks were available to describe the event. Computational models—including a structured-mesh deepwater wave model (WAM) and a nearshore steady-state wave (STWAVE) model, as well as an unstructured-mesh “simulating waves nearshore” (SWAN) wave model and an advanced circulation (ADCIRC) model—resolve the region with unprecedented levels of detail, with an unstructured mesh spacing of 100–200 m in the wave-breaking zones and 20–50 m in the small-scale channels. Data-assimilated winds were applied using NOAA’s Hurricane Research Division Wind Analysis System (H*Wind) and Interactive Objective Kinematic Analysis (IOKA) procedures. Wave and surge computations from these models are validated comprehensively at the measurement locations ranging from the deep Gulf of Mexico and along the coast to the rivers and floodplains of southern Louisiana and are described and quantified within the context of the evolution of the storm.
Abstract
Proton radioactivity was discovered exactly 50 years ago. First, this nuclear decay mode sets the limit of existence on the nuclear landscape on the neutron-deficient side. Second, it ...comprises fundamental aspects of both quantum tunnelling as well as the coupling of (quasi)bound quantum states with the continuum in mesoscopic systems such as the atomic nucleus. Theoretical approaches can start either from bound-state nuclear shell-model theory or from resonance scattering. Thus, proton-radioactivity guides merging these types of theoretical approaches, which is of broader relevance for any few-body quantum system. Here, we report experimental measurements of proton-emission branches from an isomeric state in
54m
Ni, which were visualized in four dimensions in a newly developed detector. We show that these decays, which carry an unusually high angular momentum, ℓ = 5 and ℓ = 7, respectively, can be approximated theoretically with a potential model for the proton barrier penetration and a shell-model calculation for the overlap of the initial and final wave functions.
Senescent cells show an altered secretome profile termed the senescence-associated secretory phenotype (SASP). There is an increasing body of evidence that suggests that the accumulation of ...SASP-positive senescent cells in humans is partially causal in the observed shift to a low-level pro-inflammatory state in aged individuals. This in turn suggests the SASP as a possible therapeutic target to ameliorate inflammatory conditions in the elderly, and thus a better understanding of the signalling pathways underlying the SASP are required. Prior studies using the early generation p38 MAPK inhibitor SB203580 indicated that p38 signalling was required for the SASP. In this study, we extend these observations using two next-generation p38 inhibitors (UR-13756 and BIRB 796) that have markedly improved selectivity and specificity compared to SB203580, to strengthen the evidence that the SASP is p38-dependent in human fibroblasts. BIRB 796 has an efficacy and toxicity profile that has allowed it to reach Phase III clinical trials, suggesting its possible use to suppress the SASP in vivo. We also demonstrate for the first time a requirement for signalling through the p38 downstream MK2 kinase in the regulation of the SASP using two MK2 inhibitors. Finally, we demonstrate that a commercially-available multiplex cytokine assay technology can be used to detect SASP components in the conditioned medium of cultured fibroblasts from both young and elderly donors. This assay is a high-throughput, multiplex microtitre-based assay system that is highly sensitive, with very low sample requirements, allowing it to be used for low-volume human biological fluids. Our initial studies using existing multiplex plates form the basis for a “SASP signature” assay that could be used as a high-throughput system in a clinical study setting. Our findings therefore provide important steps towards the study of, and intervention in, the SASP in human ageing and age-related disease.
Abstract
We present the results of a survey of CO(1−0) emission in 14 infrared luminous dusty star-forming galaxies (DSFGs) at 2 <
z
< 4 with the NSF’s Karl G. Jansky Very Large Array. All sources ...are detected in
12
CO(1−0), with an angular resolution of ∼1″. Seven sources show extended and complex structure. We measure CO luminosities of
(
μ
)
L
CO
(
1
−
0
)
′
=
0.4
–
2.9
×
10
11
K km s
−1
pc
2
, and molecular gas masses of
(
μ
)
M
H
2
=
1.3
–
8.6
×
10
11
M
⊙
, where (
μ
) is the magnification factor. The derived molecular gas depletion times of
t
dep
= 40–460 Myr, cover the expected range of both normal star-forming galaxies and starbursts. Compared to the higher −
J
CO transitions previously observed for the same sources, we find CO temperature brightness ratios of
r
32/10
= 0.4–1.4,
r
43/10
= 0.4–1.7, and
r
54/10
= 0.3–1.3. We find a wide range of CO spectral line energy distributions (SLEDs), in agreement with other high-
z
DSFGs, with the exception of three sources that are most comparable to Cloverleaf and APM08279+5255. Based on radiative transfer modeling of the CO SLEDs we determine densities of
n
H
2
=
0.3
−
8.5
×
10
3
cm
−3
and temperatures of
T
K
= 100–200 K. Lastly, four sources are detected in the continuum, three have radio emission consistent with their infrared-derived star formation rates, while HerBS-70E requires an additional synchrotron radiation component from an active galactic nucleus. Overall, we find that even though the sample is similarly luminous in the infrared, by tracing the CO(1−0) emission a diversity of galaxy and excitation properties are revealed, demonstrating the importance of CO(1−0) observations in combination to higher-
J
transitions.
Predicting 30-day procedure-related mortality risk and 30-day unplanned readmission in patients undergoing lower extremity endovascular interventions for peripheral artery disease (PAD) may assist in ...improving patient outcomes. Risk prediction of 30-day mortality can help clinicians identify treatment plans to reduce the risk of death, and prediction of 30-day unplanned readmission may improve outcomes by identifying patients who may benefit from readmission prevention strategies. The goal of this study is to develop machine learning models to stratify risk of 30-day procedure-related mortality and 30-day unplanned readmission in patients undergoing lower extremity infra-inguinal endovascular interventions. We used a cohort of 14,444 cases from the American College of Surgeons National Surgical Quality Improvement Program database. For each outcome, we developed and evaluated multiple machine learning models, including Support Vector Machines, Multilayer Perceptrons, and Gradient Boosting Machines, and selected a random forest as the best-performing model for both outcomes. Our 30-day procedure-related mortality model achieved an AUC of 0.75 (95% CI: 0.71-0.79) and our 30-day unplanned readmission model achieved an AUC of 0.68 (95% CI: 0.67-0.71). Stratification of the test set by race (white and non-white), sex (male and female), and age (≥65 years and <65 years) and subsequent evaluation of demographic parity by AUC shows that both models perform equally well across race, sex, and age groups. We interpret the model globally and locally using Gini impurity and SHapley Additive exPlanations (SHAP). Using the top five predictors for death and mortality, we demonstrate differences in survival for subgroups stratified by these predictors, which underscores the utility of our model.
We have conducted a Galactic plane survey of methanol masers at 6668 MHz using a seven-beam receiver on the Parkes telescope. Here we present results from the first part, which provides sensitive ...unbiased coverage of a large region around the Galactic Centre. Details are given for 183 methanol maser sites in the longitude range 345° through the Galactic Centre to 6°. Within 6° of the Galactic Centre, we found 88 maser sites, of which more than half (48) are new discoveries. The masers are confined to a narrow Galactic latitude range, indicative of many sources at the Galactic Centre distance and beyond, and confined to a thin disc population; there is no high-latitude population that might be ascribed to the Galactic bulge. Within 2° of the Galactic Centre the maser velocities all lie between −60 and +77 km s−1, a range much smaller than the 540 km s−1 range observed in CO. Elsewhere, the maser with highest positive velocity (+107 km s−1) occurs, surprisingly, near longitude 355° and is probably attributable to the Galactic bar. The maser with the most negative velocity (−127 km s−1) is near longitude 346°, within the longitude–velocity locus of the near side of the ‘3-kpc arm’. It has the most extreme velocity of a clear population of masers associated with the near and far sides of the 3-kpc arm. Closer to the Galactic Centre the maser space density is generally low, except within 0.25 kpc of the Galactic Centre itself, the ‘Galactic Centre zone’, where it is 50 times higher, which is hinted at by the longitude distribution, and confirmed by the unusual velocities.
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