Protein-modified biomaterials can be used to modulate cellular function in three dimensions. However, as the dynamic heterogeneous control over complex cell physiology continues to be sought, ...strategies that permit a reversible and user-defined tethering of fragile proteins to materials remain in great need. Here we introduce a modular and robust semisynthetic approach to reversibly pattern cell-laden hydrogels with site-specifically modified proteins. Exploiting a versatile sortase-mediated transpeptidation, we generate a diverse library of homogeneous, singly functionalized proteins with bioorthogonal reactive handles for biomaterial modification. We demonstrate the photoreversible immobilization of fluorescent proteins, enzymes and growth factors to gels with excellent spatiotemporal resolution while retaining native protein bioactivity. Localized epidermal growth factor presentation enables dynamic regulation over proliferation, intracellular mitogen-activated protein kinase signalling and subcellularly resolved receptor endocytosis. Our method broadly permits the modification and patterning of a wide range of proteins, which provides newfound avenues to probe and direct advanced cellular fates in four dimensions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In light of the existing preliminary evidence of a link between Covid-19 and poor air quality, which is largely based upon correlations, we estimate the relationship between long term air pollution ...exposure and Covid-19 in 355 municipalities in the Netherlands. Using detailed data we find compelling evidence of a positive relationship between air pollution, and particularly
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concentrations, and Covid-19 cases, hospital admissions and deaths. This relationship persists even after controlling for a wide range of explanatory variables. Our results indicate that, other things being equal, a municipality with 1 μg/m
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concentrations will have 9.4 more Covid-19 cases, 3.0 more hospital admissions, and 2.3 more deaths. This relationship between Covid-19 and air pollution withstands a number of sensitivity and robustness exercises including instrumenting pollution to mitigate potential endogeneity in the measurement of pollution and modelling spatial spillovers using spatial econometric techniques.
Light is a uniquely powerful tool for controlling molecular events in biology. No other external input (e.g., heat, ultrasound, magnetic field) can be so tightly focused or so highly regulated as a ...clinical laser. Drug delivery vehicles that can be photonically activated have been developed across many platforms, from the simplest “caging” of therapeutics in a prodrug form, to more complex micelles and circulating liposomes that improve drug uptake and efficacy, to large-scale hydrogel platforms that can be used to protect and deliver macromolecular agents including full-length proteins. In this Review, we discuss recent innovations in photosensitive drug delivery and highlight future opportunities to engineer and exploit such light-responsive technologies in the clinical setting.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although biochemically patterned hydrogels are capable of recapitulating many critical aspects of the heterogeneous cellular niche, exercising spatial and temporal control of the presentation and ...removal of biomolecular signalling cues in such systems has proved difficult. Here, we demonstrate a synthetic strategy that exploits two bioorthogonal photochemistries to achieve reversible immobilization of bioactive full-length proteins with good spatial and temporal control within synthetic, cell-laden biomimetic scaffolds. A photodeprotection-oxime-ligation sequence permits user-defined quantities of proteins to be anchored within distinct subvolumes of a three-dimensional matrix, and an ortho-nitrobenzyl ester photoscission reaction facilitates subsequent protein removal. By using this approach to pattern the presentation of the extracellular matrix protein vitronectin, we accomplished reversible differentiation of human mesenchymal stem cells to osteoblasts in a spatially defined manner. Our protein-patterning approach should provide further avenues to probe and direct changes in cell physiology in response to dynamic biochemical signalling.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Studies have shown that the remnants of destroyed planets and debris-disk planetesimals can survive the volatile evolution of their host stars into white dwarfs, but few intact planetary bodies ...around white dwarfs have been detected. Simulations predict that planets in Jupiter-like orbits around stars of ≲8 Mꙩ (solar mass) avoid being destroyed by the strong tidal forces of their stellar host, but as yet, there has been no observational confirmation of such a survivor. Here we report the non-detection of a main-sequence lens star in the microlensing event MOA-2010-BLG-477Lb using near-infrared observations from the Keck Observatory. We determine that this system contains a 0.53 ± 0.11 Mꙩ white-dwarf host orbited by a 1.4 ± 0.3 Jupiter-mass planet with a separation on the plane of the sky of 2.8 ± 0.5 astronomical units, which implies a semi-major axis larger than this. This system is evidence that planets around white dwarfs can survive the giant and asymptotic giant phases of their host’s evolution, and supports the prediction that more than half of white dwarfs have Jovian planetary companions. Located at approximately 2.0 kiloparsecs towards the center of our Galaxy, it is likely to represent an analogue to the end stages of the Sun and Jupiter in our own Solar System.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Biological signalling is regulated through a complex and tightly choreographed interplay between cells and their extracellular matrix. The spatiotemporal control of these interactions is essential ...for tissue function, and disruptions to this dialogue often result in aberrant cell fate and disease. When disturbances are well understood, correct biological function can be restored through the precise introduction of therapeutics. Moreover, model systems with modifiable physiochemical properties are needed to probe the effects of therapeutic molecules and to investigate cell–matrix interactions. Photoresponsive biomaterials benefit from spatiotemporal tunability, which allows for site-specific therapeutic delivery in vivo and 4D modulation of synthetic cell culture platforms to mimic the dynamic heterogeneity of the human body in vitro. In this Review, we discuss how light can be exploited to modify different biomaterials in the context of photomediated drug delivery and phototunable cell culture platforms. We survey various photochemistries for their applicability in vitro and in vivo and for the biochemical and biophysical modification of materials. Finally, we highlight emerging tools and provide an outlook for the field of photoresponsive biomaterials.Light can initiate chemistries with high spatial and temporal control. In this Review, photoresponsive biomaterials developed for controlled drug delivery and complex tissue engineering are investigated with a focus on photochemistries that provide dynamic precision.
This paper examines the extent to which the EKC inverted U relationship can be explained by trade and specifically the migration or displacement of ‘dirty’ industries from the developed regions to ...the developing regions (the pollution haven hypothesis (PHH)). Using detailed data on North–South trade flows for pollution intensive products the evidence for the PHH is assessed. Emissions of 10 air and water pollutants are then estimated, controlling for trade openness, structural change and ‘dirty’ North–South trade flows. Evidence of pollution haven effects is found, although such effects do not appear to be widespread and appear to be relatively small compared to the roles played other explanatory variables.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Despite clear evidence that manifest variable path analysis requires highly reliable measures, path analyses with fallible measures are commonplace even in premier journals. Using fallible measures ...in path analysis can cause several serious problems: (a) As measurement error pervades a given data set, many path coefficients may be either over- or underestimated. (b) Extensive measurement error diminishes power and can prevent invalid models from being rejected. (c) Even a little measurement error can cause valid models to appear invalid. (d) Differential measurement error in various parts of a model can change the substantive conclusions that derive from path analysis. (e) All of these problems become increasingly serious and intractable as models become more complex. Methods to prevent and correct these problems are reviewed. The conclusion is that researchers should use more reliable measures (or correct for measurement error in the measures they do use), obtain multiple measures for use in latent variable modeling, and test simpler models containing fewer variables.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
Hydrogel biomaterials derived from natural biopolymers (e.g., fibrin, collagen, decellularized extracellular matrix) are regularly utilized in three-dimensional (3D) cell culture and tissue ...engineering. In contrast to those based on synthetic polymers, natural materials permit enhanced cytocompatibility, matrix remodeling, and biological integration. Despite these advantages, natural protein-based gels have lagged behind synthetic alternatives in their tunability; methods to selectively modulate the biochemical properties of these networks in a user-defined and heterogeneous fashion that can drive encapsulated cell function have not yet been established. Here, we report a generalizable strategy utilizing a photomediated oxime ligation to covalently decorate naturally derived hydrogels with bioactive proteins including growth factors. This bioorthogonal photofunctionalization is readily amenable to mask-based and laser-scanning lithographic patterning, enabling full four-dimensional (4D) control over protein immobilization within virtually any natural protein-based biomaterial. Such versatility affords exciting opportunities to probe and direct advanced cell fates inaccessible using purely synthetic approaches in response to anisotropic environmental signaling.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Platelet rich plasma (PRP) was tested as a potential therapy for androgenetic alopecia (AGA) through two different clinical protocols in which one population (18 participants) received half-head ...treatment with autologous non-activated PRP (A-PRP) produced by CPunT Preparation System (Biomed Device, Modena, Italy) and the other half-head with placebo, and a second separated population in which all participants (n = 6, 3 participants per group) received treatment with calcium-activated PRP (AA-PRP) produced from one of two different PRP collection devices (Regen Blood Cell Therapy or Arthrex Angel System). For the A-PRP study, three treatments were administered over 30-day intervals. Trichoscan analysis of patients, three months post-treatment, showed a clinical improvement in the number of hairs in the target area (36 ± 3 hairs) and in total hair density (65± 5 hair cm2), whereas negligible improvements in hair count (1.1± 1.4 hairs) and density (1.9 ± 10.2 hair cm2) were seen in the region of the scalp that received placebo. Microscopic evaluation conducted two weeks after treatment showed also an increase in epidermal thickness, Ki67+ keratinocytes, and in the number of follicles. The AA-PRP treatment groups received a singular set of injections, and six months after the treatments were administered, notable differences in clinical outcomes were obtained from the two PRP collection devices (+90 ± 6 hair cm2 versus -73 ± 30 hair cm2 hair densities, Regen versus Arthrex). Growth factor concentrations in AA-PRP prepared from the two collection devices did not differ significantly upon calcium activation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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