Designing catalysts that achieve the rates and selectivities of natural enzymes is a long-standing goal in protein chemistry. Here, we show that an ultrahigh-throughput droplet-based microfluidic ...screening platform can be used to improve a previously optimized artificial aldolase by an additional factor of 30 to give a >10
rate enhancement that rivals the efficiency of class I aldolases. The resulting enzyme catalyses a reversible aldol reaction with high stereoselectivity and tolerates a broad range of substrates. Biochemical and structural studies show that catalysis depends on a Lys-Tyr-Asn-Tyr tetrad that emerged adjacent to a computationally designed hydrophobic pocket during directed evolution. This constellation of residues is poised to activate the substrate by Schiff base formation, promote mechanistically important proton transfers and stabilize multiple transition states along a complex reaction coordinate. The emergence of such a sophisticated catalytic centre shows that there is nothing magical about the catalytic activities or mechanisms of naturally occurring enzymes, or the evolutionary process that gave rise to them.
Summary
Background
Photonumeric scales have consistently shown superiority over descriptive equivalents. They have the advantage of providing a consistent visual frame of reference by minimizing ...variability in perception and subjectivity. A photonumeric scale to assess hypertrophic facial photodamage already exists. However, there is currently no objective measure for atrophic facial photodamage. To address this, we have devised a nine‐point photonumeric standardized scale.
Objectives
To design, test and validate a photonumeric scale for the assessment of atrophic facial photodamage against a descriptive scale for the same indication.
Methods
A pool of 393 facial photographs (en face and 45° oblique) from 131 individuals with atrophic facial photodamage was created. Five photographic standards were selected and assigned grades zero through to eight, where zero is no photodamage and eight is severe atrophic photodamage, thus making a nine‐point scale. Twenty photographs spanning the entire range of values were selected to test the scale. Testing was performed alongside a descriptive equivalent. A panel of 10 dermatologists, 10 nondermatology clinicians and 14 dermatology scientists marked the two scales; marking was repeated 1 week later.
Results
There was a significantly greater agreement between the graders using the photonumeric scale than the descriptive scale (kappa values 0·71 and 0·37 with standardized errors of 0·57 and 0·17, respectively) with no significant difference in repeatability between the two methods (P < 0·05).
Conclusions
The study describes a new photonumeric scale for atrophic photodamage. This would be a useful adjunct in both the clinical and research settings.
What's already known about this topic?
Photonumeric scales demonstrate consistent superiority when compared with descriptive equivalents.
Hypertrophic facial photodamage has been assessed successfully in terms of both severity and treatment response using a well‐established photonumeric scale.
What does this study add?
A new photonumeric scale created and validated for the assessment of a newly recognized clinical phenotype of facial photodamage – atrophic photodamage.
Linked Comment: Li et al. Br J Dermatol 2018; 178:1008–1009.
Plain language summary available online
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Climate change is altering the rate and distribution of primary production in the world's oceans. Primary production is critical to maintaining biodiversity and supporting fishery catches, but ...predicting the response of populations to primary production change is complicated by predation and competition interactions. We simulated the effects of change in primary production on diverse marine ecosystems across a wide latitudinal range in Australia using the marine food web model Ecosim. We link models of primary production of lower trophic levels (phytoplankton and benthic producers) under climate change with Ecosim to predict changes in fishery catch, fishery value, biomass of animals of conservation interest, and indicators of community composition. Under a plausible climate change scenario, primary production will increase around Australia and generally this benefits fisheries catch and value and leads to increased biomass of threatened marine animals such as turtles and sharks. However, community composition is not strongly affected. Sensitivity analyses indicate overall positive linear responses of functional groups to primary production change. Responses are robust to the ecosystem type and the complexity of the model used. However, model formulations with more complex predation and competition interactions can reverse the expected responses for some species, resulting in catch declines for some fished species and localized declines of turtle and marine mammal populations under primary productivity increases. We conclude that climate-driven primary production change needs to be considered by marine ecosystem managers and more specifically, that production increases can simultaneously benefit fisheries and conservation. Greater focus on incorporating predation and competition interactions into models will significantly improve the ability to identify species and industries most at risk from climate change.
Background
Photoageing describes complex cutaneous changes which occur following chronic exposure to solar ultraviolet radiation (UVR). Amongst White Northern Europeans, facial photoageing appears as ...distinct clinical phenotypes: ‘hypertrophic’ photoageing (HP) and ‘atrophic’ photoageing (AP). Deep, coarse wrinkles predominate in individuals with HP, whereas those with AP have relatively smooth, unwrinkled skin with pronounced telangiectasia. AP individuals have an increased propensity for developing keratinocyte cancers.
Objectives
To investigate whether histological differences underlie these distinct phenotypes of facial photoageing.
Methods
Facial skin biopsies were obtained from participants with AP (10 M, 10 F; mean age: 78.7 years) or HP (10 M, 10 F; mean age: 74.5 years) and were assessed histologically and by immunohistochemistry.
Results
Demographic characterization revealed 95% of AP subjects, as compared to 35% with HP, were Fitzpatrick skin type I/II; of these, 50% had a history of one or more keratinocyte cancers. There was no history of keratinocyte cancers in the HP cohort. Analysis of UVR‐induced mitochondrial DNA damage confirmed that all volunteers had received similar lifetime cumulative doses of sun exposure. Histologically, male AP had a significantly thicker epidermis than did AP females or those of either sex with HP. HP facial skin exhibited severe solar elastosis, whereas in AP facial skin, solar elastosis was apparent only in females. Loss of papillary dermal fibrillin‐rich microfibrils occurred in all HP and AP female subjects, but not in AP males. Furthermore, male AP had a significant reduction in collagen VII at the dermal–epidermal junction than did AP females or those of either sex with HP.
Conclusions
This study provides further evidence that AP and HP represent distinct clinical and histological entities. Knowledge of these two phenotypes is clinically relevant due to the increased prevalence of keratinocyte cancers in those – particularly males – with the AP phenotype.
Summary
Background
Skin health declines with age and this is partially attributed to immunosenescence. Mast cells (MCs) are innate immune cells that coordinate tissue immune responses integral to ...skin homeostasis and disease.
Objectives
To understand how MCs contribute to human skin ageing, we investigated how intrinsic ageing impacts MC phenotype and MC relationships with other immune cells and skin structures.
Methods
In photoprotected skin biopsies from young (≤ 30 years) and aged (≥ 75 years) individuals, immunostaining and spatial morphometry were performed to identify changes in MC phenotype, number, distribution and interaction with the vasculature and nerve fibres. Quantitative polymerase chain reaction was used to measure changes in gene expression related to immune cell activity and neuropeptide signalling.
Results
Skin MCs, macrophages and CD8+ T cells increased in number in intrinsically aged vs. young skin by 40%, 44% and 90%, respectively (P < 0·05), while CD4+ T cells and neutrophils were unchanged. In aged skin, MCs were more numerous in the papillary dermis and showed a reduced incidence of degranulation (50% lower than in young, P < 0·01), a conserved tryptase–chymase phenotype and coexpression of granzyme B. In aged skin, MCs increased their association with macrophages (~ 48% vs. ~27%, P < 0·05) and nerve fibres (~29% vs. 16%, P < 0·001), while reducing their interactions with blood vessels (~34% vs. 45%, P < 0·001). Additionally, we observed modulation of gene expression of vasoactive intestinal peptide (VIP; increased) and substance P (decreased) with age; this was associated with an increased frequency of VIP+ nerve fibres (around three times higher in aged skin, P < 0·05), which were strongly associated with MCs (~19% in aged vs. 8% in young, P < 0·05).
Conclusions
In photoprotected skin we observed an accumulation of MCs with increasing age. These MCs have both altered functionality and distribution within the skin, which supports a role for these cells in altered tissue homeostasis during ageing.
What's already known about this topic?
In aged skin, immunity becomes dysregulated leading to greater baseline inflammation and dampened adaptive immunity.
Mast cells (MCs) are regarded as multifunctional regulators of tissue homeostasis and immunity and are known to increase in number in the skin with age.
What does this study add?
This study shows that the increase in MCs in aged skin is localized to the papillary dermis, where these cells are in closer proximity to macrophages but have reduced interaction with the microvasculature and other immune populations.
We show that in aged skin, MCs also exhibit lower amounts of degranulation and form closer interactions with macrophages and vasoactive intestinal peptide‐positive nerve fibres while lessening their association with the dermal vasculature.
What is the translational message?
Alterations in MC frequency, functionality and distribution may contribute to the immunosenescent skin phenotype associated with intrinsic ageing.
The changes in MC behaviour may also play a role in neurogenic inflammation and could provide a therapeutic target for age‐associated pruritus.
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ABSTRACT We present the catalog of optical and infrared counterparts of the Chandra COSMOS-Legacy Survey, a 4.6 Ms Chandra program on the 2.2 deg2 of the COSMOS field, combination of 56 new ...overlapping observations obtained in Cycle 14 with the previous C-COSMOS survey. In this Paper we report the i, K, and 3.6 m identifications of the 2273 X-ray point sources detected in the new Cycle 14 observations. We use the likelihood ratio technique to derive the association of optical/infrared (IR) counterparts for 97% of the X-ray sources. We also update the information for the 1743 sources detected in C-COSMOS, using new K and 3.6 m information not available when the C-COSMOS analysis was performed. The final catalog contains 4016 X-ray sources, 97% of which have an optical/IR counterpart and a photometric redshift, while 54% of the sources have a spectroscopic redshift. The full catalog, including spectroscopic and photometric redshifts and optical and X-ray properties described here in detail, is available online. We study several X-ray to optical (X/O) properties: with our large statistics we put better constraints on the X/O flux ratio locus, finding a shift toward faint optical magnitudes in both soft and hard X-ray band. We confirm the existence of a correlation between X/O and the the 2-10 keV luminosity for Type 2 sources. We extend to low luminosities the analysis of the correlation between the fraction of obscured AGNs and the hard band luminosity, finding a different behavior between the optically and X-ray classified obscured fraction.
Background
Fixed combination calcipotriol 50 μg/g (Cal) plus betamethasone 0.5 mg/g (BD) foam has been developed as a new treatment option for patients with psoriasis.
Methods
The randomized, ...parallel‐group, investigator‐blinded Phase III, 12‐week PSO‐ABLE study compared the efficacy and safety of Cal/BD foam with Cal/BD gel. Patients aged ≥18 years with mild‐to‐severe psoriasis were randomized 4:4:1:1 to once‐daily Cal/BD foam, Cal/BD gel, foam vehicle or gel vehicle (NCT02132936). The primary efficacy endpoint was the proportion of patients who were clear/almost clear with a ≥ 2 grade improvement according to the physician's global assessment of disease severity (i.e. treatment success) at week 4 for Cal/BD foam vs. week 8 for Cal/BD gel. Secondary efficacy endpoints included: proportion of patients achieving at least a 75% reduction in modified psoriasis area and severity index (mPASI75), and time to treatment success (TTTS). Safety was monitored throughout.
Results
A total of 463 patients were randomized: Cal/BD foam (n = 185), Cal/BD gel (n = 188), foam vehicle (n = 47), gel vehicle (n = 43); overall completion rate was 90%. Cal/BD foam achieved higher treatment success rates (38% vs. 22%; P < 0.001) and mPASI75 (52% vs. 35%; P < 0.001) by week 4 than Cal/BD gel by week 8. Median TTTS with Cal/BD foam was 6 weeks; this could not be determined for Cal/BD gel as 50% treatment success was not achieved (P < 0.001). Adverse drug reactions were reported in 14 (7.6%) Cal/BD aerosol foam patients and 7 (3.7%) Cal/BD gel patients; all were single events except for itch with Cal/BD aerosol foam (n = 5; 2.7%) and worsening psoriasis with Cal/BD gel (n = 3; 1.6%).
Conclusion
Cal/BD aerosol foam showed significantly greater efficacy after 4 weeks, than 8 weeks of treatment with Cal/BD gel, with similar tolerability.
The atmospheric methane burden is increasing rapidly, contrary to pathways compatible with the goals of the 2015 United Nations Framework Convention on Climate Change Paris Agreement. Urgent action ...is required to bring methane back to a pathway more in line with the Paris goals. Emission reduction from “tractable” (easier to mitigate) anthropogenic sources such as the fossil fuel industries and landfills is being much facilitated by technical advances in the past decade, which have radically improved our ability to locate, identify, quantify, and reduce emissions. Measures to reduce emissions from “intractable” (harder to mitigate) anthropogenic sources such as agriculture and biomass burning have received less attention and are also becoming more feasible, including removal from elevated‐methane ambient air near to sources. The wider effort to use microbiological and dietary intervention to reduce emissions from cattle (and humans) is not addressed in detail in this essentially geophysical review. Though they cannot replace the need to reach “net‐zero” emissions of CO2, significant reductions in the methane burden will ease the timescales needed to reach required CO2 reduction targets for any particular future temperature limit. There is no single magic bullet, but implementation of a wide array of mitigation and emission reduction strategies could substantially cut the global methane burden, at a cost that is relatively low compared to the parallel and necessary measures to reduce CO2, and thereby reduce the atmospheric methane burden back toward pathways consistent with the goals of the Paris Agreement.
Plain Language Summary
Methane is a powerful climate warmer, and the amount of methane in the air is growing rapidly. Reducing human‐caused methane emissions is urgent if the 2015 United Nations Paris Agreement to limit climate warming is to succeed. There is hope, though the problem of methane mitigation is very wide and complex. Much of the task is in finding, identifying, and quantifying emissions. Rapid technical advances are making it much easier to locate and thus cut emissions from fossil fuel industries (gas, coal, and oil). Assessing emissions from landfill and sewage facilities is also becoming easier. In particular, poorly regulated landfills in fast‐growing tropical megacities need attention. Agricultural emissions are less tractable but may also be reduced to some extent, especially by improving manure management. Many methane mitigation options offer cost‐effective approaches to cut global warming and bring the amount of methane in the air back to a pathway that is consistent with the aims of the Paris Agreement.
Key Points
The atmospheric methane burden is rising fast; this growth is an increasing threat to the Paris Agreement of the UN Framework Convention on Climate Change (UNFCCC)
New gas measurement technologies, on the ground and in the air, have greatly improved our ability to locate and quantify emissions and to identify mitigation targets
Emissions can be cut by ending fossil fuel emissions, cutting biomass burning, improving landfills, especially in the tropics, and changing cattle farming practice
ABSTRACT The COSMOS-Legacy survey is a 4.6 Ms Chandra program that has imaged 2.2 deg2 of the COSMOS field with an effective exposure of ks over the central 1.5 deg2 and of ks in the remaining area. ...The survey is the combination of 56 new observations obtained as an X-ray Visionary Project with the previous C-COSMOS survey. We describe the reduction and analysis of the new observations and the properties of 2273 point sources detected above a spurious probability of 2 × 10−5. We also present the updated properties of the C-COSMOS sources detected in the new data. The whole survey includes 4016 point sources (3814, 2920 and 2440 in the full, soft, and hard band). The limiting depths are 2.2 × 10−16, 1.5 × 10−15, and 8.9 × 10−16 in the 0.5-2, 2-10, and 0.5-10 keV bands, respectively. The observed fraction of obscured active galactic nuclei with a column density >1022 cm−2 from the hardness ratio (HR) is ∼50 %. Given the large sample we compute source number counts in the hard and soft bands, significantly reducing the uncertainties of 5%-10%. For the first time we compute number counts for obscured (HR > −0.2) and unobscured (HR < −0.2) sources and find significant differences between the two populations in the soft band. Due to the unprecedent large exposure, COSMOS-Legacy area is three times larger than surveys at similar depths and its depth is three times fainter than surveys covering similar areas. The area-flux region occupied by COSMOS-Legacy is likely to remain unsurpassed for years to come.
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