Photodegradation of Hair Proteins: Mechanistic Insights and the Role of Transition Metals

The main aim of this project was to study the effects of redox active transition metals present in hair fibres upon the photodegradation of hair proteins. Tyrosine based keratin model systems were developed to enable this photochemically critical amino acid to be studied in isolation from other photo-active hair components. The photochemical activity of tyrosine was found to be strongly dependent on molecular environment. In free solution, tyrosyl radicals were very short-lived, whereas radicals in solid systems persisted for many hours. PEG-Tyr block copolymers provide accurate models of tyrosine in a protein polypeptide, in the form of micelles and stable hydrogels. Tyrosine molecular environment in micelles is comparable to α-helical structures of proteins, as analysed by nitroxide spin labelling experiments. Despite significantly different bulk properties, the molecular environment and reactivity of tyrosine in micelles and gels is remarkably similar, although diffusion of reactive oxygen species (ROS) and Fe(III) becomes a limiting factor in gels. Spin labelling provided a method to monitor the gelation process in real-time. Both Fe(III) and Cu(II) influenced tyrosine photodegradation in PEG-Tyr systems: 100 ppm Fe(III) increased degradation by around 2.2 times, whereas Cu(II) slowed photodegradation due to Cu-Tyr complexation. The effect of Fe(III) was attributed to increased ROS production leading to autoxidation, direct redox chemistry between metal and tyrosine, and sensitisation of tyrosine by metal complexes. Partitioning of Fe(III) within micelles resulted in a significant enhancement in activity, indicating that Fe(III) can catalytically influence tyrosine photooxidation at concentrations relevant to hair fibres. In a separate study, the effect of humidity upon the formation and decay of protein-based radicals in UV exposed human hair samples was investigated. Increased water content increases radical reactivity, explaining greater protein degradation at higher humidity. Antioxidant studies suggest autoxidation is less significant within hair proteins compared to model systems

Molecular environment and reactivity in gels and colloidal solutions under identical conditions

A PEG-Tyr block copolymer forms a kinetically stable colloidal solution in water at room temperature which undergoes an irreversible conversion to a gel phase upon heating. A micellar solution and a gel can therefore be studied under identical experimental conditions. This made it possible to compare physical properties and chemical reactivity of micelles and gels in identical chemical environments and under identical conditions. EPR spectra of the spin-labelled copolymer showed that tyrosine mobility in gels was slightly reduced compared to micelles. Chemical reactivity was studied using photochemical degradation of tyrosine and tyrosine dimerization, in the absence and in the presence of an Fe(iii) salt. The reactivity trends were explained by reduced tyrosine mobility in the gel environment. The largest reactivity difference in gels and micelles was observed for bimolecular dityrosine formation which was also attributed to the reduction in molecular mobility

Integrin Expression by Human Epidermal Keratinocytes Can Be Modulated by Interferon-γ, Transforming Growth Factor-β, Tumor Necrosis Factor-α, and Culture on a Dermal Equivalent

Receptors of the integrin family are largely confined to the basal layer of keratinocytes, both in human epidermis and in stratified cultures of human keratinocytes. However, suprabasal integrin expression is observed during epidermal wound healing and in psoriatic lesions. We have investigated potential stimuli of suprabasal expression. Addition of transforming growth factor-β (TGF-β), interferon-γ (IFN-γ or tumor necrosis factor-α (TNF-α) to keratinocytes cultured with a 3T3 feeder layer did not induce suprabasal expression. The cytokines caused small changes in the levels of α2β1 or α3β1 on the surface of basal keratinocytes but had no significant effect on the proportion of cells adhering to fibronectin, type IV collagen, and laminin, and did not cause changes in the mobility of integrin subunits on polyacrylamide gels. Injection of TNF-α or IFN-γ intradermally into healthy human volunteers induced an inflammatory response but did not induce suprabasal integrin expression. However, we did observe transient suprabasal Integrin expression when keratinocytes were grown on a dermal equivalent consisting of fibroblasts in a collagen gel. One week after raising the cultures to the air-liquid interface, β1 integrins were found in all the viable cell layers, with suprabasal cells co-expressing integrins and involucrin; 1 week later integrins were confined to the basal layer. Addition of TGF-β, IFN-γ, or TNF-α to the dermal equivalents neither induced nor inhibited suprabasal integrin expression. We conclude that suprabasal integrin expression is not induced by the inflammatory cytokines tested, and instead may reflect the proliferation/differentiation status of the epidermis

Reversible Photoreduction as a Trigger for Photoresponsive Gels

We present here a new type of photoresponsive, reversible low molecular weight gel. All previous examples rely on a photoisomerisation, ring-closing or dimerization. We show that photoreduction of a perylene bisimide gelator results in the formation of a stable radical anion. The formation of the radical anion results in a change in the packing of the perylene bisimides in the self-assembled aggregates, leading to a change in fibrous network and an increase in the rheological properties of the gels. An increase in the rheological properties is extremely rare for a photoresponsive gel; normally, irradiation results in a gel-to-sol transition, and the gel falling apart. As the radical anion decays, which takes several hours in air, the original gel properties are restored. This photoreduction can be cycled many times. Finally, we show that the mechanical properties are different between irradiated and nonirradiated sections in a patterned gel

The informatics challenges facing biobanks:a perspective from a United Kingdom biobanking network

The challenges facing biobanks are changing from simple collections of materials to quality-assured fit-for-purpose clinically annotated samples. As a result, informatics awareness and capabilities of a biobank are now intrinsically related to quality. A biobank may be considered a data repository, in the form of raw data (the unprocessed samples), data surrounding the samples (processing and storage conditions), supplementary data (such as clinical annotations), and an increasing ethical requirement for biobanks to have a mechanism for researchers to return their data. The informatics capabilities of a biobank are no longer simply knowing sample locations; instead the capabilities will become a distinguishing factor in the ability of a biobank to provide appropriate samples. There is an increasing requirement for biobanking systems (whether in-house or com-mercially sourced) to ensure the informatics systems stay apace with the changes being experienced by the biobanking community. In turn, there is a requirement for the biobanks to have a clear informatics policy and directive that is embedded into the wider decision making process. As an example, the Breast Cancer Campaign Tissue Bank in the UK was a collaboration between four individual and diverse biobanks in the UK, and an informatics platform has been developed to address the challenges of running a distributed network. From developing such a system there are key observations about what can or cannot be achieved by informatics in isolation. This article will highlight some of the lessons learned during this development process

Potential higher risk of tethered spinal cord in children after prenatal surgery for myelomeningocele:A systematic review and meta-analysis

Introduction We performed a systematic review and meta-analysis on the incidence of secondary tethered spinal cord (TSC) between prenatal and postnatal closure in patients with MMC. The objectives was to understand the incidence of secondary TSC after prenatal surgery for MMC compared to postnatal surgery for MMC. Material and methods On May 4, 2023, a systematic search was conducted in Medline, Embase, and the Cochrane Library to gather relevant data. Primary studies focusing on repair type, lesion level, and TSC were included, while non-English or non-Dutch reports, case reports, conference abstracts, editorials, letters, comments, and animal studies were excluded. Two reviewers assessed the included studies for bias risk, following PRISMA guidelines. TSC frequency in MMC closure types was determined, and the relationship between TSC occurrence and closure technique was analyzed using relative risk and Fisher's exact test. Subgroup analysis revealed relative risk differences based on study designs and follow-up periods. A total of ten studies, involving 2,724 patients, were assessed. Among them, 2,293 patients underwent postnatal closure, while 431 received prenatal closure for the MMC defect. In the prenatal closure group, TSC occurred in 21.6% (n = 93), compared to 18.8% (n = 432) in the postnatal closure group. The relative risk (RR) of TSC in patients with prenatal MMC closure versus postnatal MMC closure was 1.145 (95%CI 0.939 to 1.398). Fisher's exact test indicated a statistically non-significant association (p = 0.106) between TSC and closure technique. When considering only RCT and controlled cohort studies, the overall RR for TSC was 1.308 (95%CI 1.007 to 1.698) with a non-significant association (p = .053). For studies focusing on children up until early puberty (maximum 12 years follow-up), the RR for tethering was 1.104 (95%CI 0.876 to 1.391), with a non-significant association (p = 0.409). Conclusion and discussion This review found no significant increase in relative risk of TSC between prenatal and postnatal closure in MMC patients, but a trend of increased TSC in the prenatal group. More longterm data on TSC after fetal closure is needed for better counseling and outcomes in MMC.</p

Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration

Acknowledgements We are indebted to Jim Humphries, JennyCorrigan, LizDarley, Elizabeth Joynson, Natalie Walters, Sara Wells and the whole necropsy, histology, genotyping and MLC ward 6 teams at MRC Harwell for excellent technical assistance. We thank the staff of the WTSI Illumina Bespoke Team for the RNA-seq data, the Sanger Mouse Genetics Project for the initial mouse characterization and Dr David Adams for critical reading of the manuscript. We also thank KOMP for the mouse embryonic stem cells carrying the knockout first promoter-less allele (tm1a(KOMP)Wtsi) within Zfp016. Conflict of Interest statement. None declared. Funding This work was funded by the UK Medical Research Council (MRC) to A.A.-A. and a Motor Neurone Disease Association (MNDA) project grant to A.A.-A. and EMCF. D.L.H.B. is a Wellcome Trust Senior Clinical Scientist Fellow and P.F. is a MRC/MNDA Lady Edith Wolfson Clinician Scientist Fellow. Funding to pay the Open Access publication charges for this article was provided by the MRC grant number: MC_UP_A390_1106.Peer reviewedPublisher PD

The emission by dust and stars of nearby galaxies in the Herschel KINGFISH survey

Using new far-infrared imaging from the Herschel Space Observatory with ancillary data from ultraviolet (UV) to submillimeter wavelengths, we estimate the total emission from dust and stars of 62 nearby galaxies in the KINGFISH survey in a way that is as empirical and model independent as possible. We collect and exploit these data in order to measure from the spectral energy distributions (SEDs) precisely how much stellar radiation is intercepted and re-radiated by dust, and how this quantity varies with galaxy properties. By including SPIRE data, we are more sensitive to emission from cold dust grains than previous analyses at shorter wavelengths, allowing for more accurate estimates of dust temperatures and masses. The dust/stellar flux ratio, which we measure by integrating the SEDs, has a range of nearly three decades (from 10(-2.2) to 10(0.5)). The inclusion of SPIRE data shows that estimates based on data not reaching these far-IR wavelengths are biased low by 17% on average. We find that the dust/stellar flux ratio varies with morphology and total infrared (IR) luminosity, with dwarf galaxies having faint luminosities, spirals having relatively high dust/stellar ratios and IR luminosities, and some early types having low dust/stellar ratios. We also find that dust/stellar flux ratios are related to gas-phase metallicity ((log(f(dust)/f(*)) over bar) = -0.66 +/- 0.08 and -0.22 +/- 0.12 for metal-poor and intermediate-metallicity galaxies, respectively), while the dust/stellar mass ratios are less so (differing by approximate to 0.2 dex); the more metal-rich galaxies span a much wider range of the flux ratios. In addition, the substantial scatter between dust/stellar flux and dust/stellar mass indicates that the former is a poor proxy of the latter. Comparing the dust/stellar flux ratios and dust temperatures, we also show that early types tend to have slightly warmer temperatures (by up to 5 K) than spiral galaxies, which may be due to more intense interstellar radiation fields, or possibly to different dust grain compositions. Finally, we show that early types and early-type spirals have a strong correlation between the dust/stellar flux ratio and specific star formation rate, which suggests that the relatively bright far-IR emission of some of these galaxies is due to ongoing (if limited) star formation as well as to the radiation field from older stars, which is heating the dust grains

Recovering Stellar Population Properties and Redshifts from Broad-Band Photometry of Simulated Galaxies: Lessons for SED Modeling

We present a detailed analysis of our ability to determine stellar masses, ages, reddening and extinction values, and star formation rates of high-redshift galaxies by modeling broad-band SEDs with stellar population synthesis. In order to do so, we computed synthetic optical-to-NIR SEDs for model galaxies taken from hydrodynamical merger simulations placed at redshifts 1.5 < z < 3. Viewed under different angles and during different evolutionary phases, the simulations represent a wide variety of galaxy types (disks, mergers, spheroids). We show that simulated galaxies span a wide range in SEDs and color, comparable to these of observed galaxies. In all star-forming phases, dust attenuation has a large effect on colors, SEDs, and fluxes. The broad-band SEDs were then fed to a standard SED modeling procedure and resulting stellar population parameters were compared to their true values. Disk galaxies generally show a decent median correspondence between the true and estimated mass and age, but suffer from large uncertainties. During the merger itself, we find larger offsets (e.g., log M_recovered - log M_true = -0.13^{+0.10}_{-0.14}). E(B-V) values are generally recovered well, but the estimated total visual absorption Av is consistently too low, increasingly so for larger optical depths. Since the largest optical depths occur during the phases of most intense star formation, it is for the highest SFRs that we find the largest underestimates. The masses, ages, E(B-V), Av, and SFR of merger remnants (spheroids) are very well reproduced. We discuss possible biases in SED modeling results caused by mismatch between the true and template star formation history, dust distribution, metallicity variations and AGN contribution.Comment: Accepted for publication in the Astrophysical Journal, 24 pages, 19 figure

On Sizes, Kinematics, M/L Gradients, and Light Profiles of Massive Compact Galaxies at z~2

We present a detailed analysis of the structure and resolved stellar populations of simulated merger remnants, and compare them to observations of compact quiescent galaxies at z ~ 2. We find that major merging is a viable mechanism to produce systems of ~ 10^11 Msun and ~ 1 kpc size, provided the gas fraction at the time of final coalescence is high (~ 40%), and provided that the progenitors are compact star-forming galaxies, as expected at high redshift. Their integrated spectral energy distributions and velocity dispersions are in good agreement with the observations, and their position in the (v_{maj}/sigma, ellipticity) diagram traces the upper envelope of the distribution of lower redshift early-type galaxies. The simulated merger remnants show time- and sightline-dependent M/L ratio gradients that result from a superposition of radially dependent stellar age, stellar metallicity, and extinction. The median ratio of effective radius in rest-frame V-band light to that in mass surface density is ~ 2 during the quiescent remnant phase. This is typically expressed by a negative color gradient (i.e., red core), which we expect to correlate with the integrated color of the system. Finally, the simulations differ from the observations in their surface brightness profile shape. The simulated remnants are typically best fit by high (n >> 4) Sersic indices, whereas observed quiescent galaxies at z ~ 2 tend to be less cuspy (median n ~ 2.3). Limiting early star formation in the progenitors may be required to prevent the simulated merger remnants from having extended wings.Comment: Accepted for publication in The Astrophysical Journal, 21 pages, 17 figure