ArcTiCA: Arctic tidal constituents atlas.

Tides in the Arctic Ocean affect ocean circulation and mixing, and sea ice dynamics and thermodynamics. However, there is a limited network of available in situ tidal coefficient data for understanding tidal variability in the Arctic Ocean; e.g., the global TICON-3 database contains only 111 sites above 60°N and 21 above 70°N. At the same time, the presence of sea ice and latitude limits of satellite altimetry complicate altimetry-based retrievals of Arctic tidal coefficients. This leads to a reliance on ocean tide models whose accuracy depend on having sufficient in situ data for validation and assimilation. Here, we present a comprehensive new dataset of tidal constituents in the Arctic region, combining analyses of in situ measurements from tide gauges, ocean bottom pressure sensors and GNSS interferometric reflectometry. The new dataset contains 914 measurement sites above 60°N and 399 above 70°N, with each site being quality-assessed and expert guidance provided to help maximise the usage of the dataset. We also compare the dataset to recent tide models.

Topical niacinamide does not stimulate hair growth based on the existing body of evidence.

Niacinamide has been suggested to impact hair biology via stimulation of VEGF synthesis. Testing in an in vitro VEGF synthesis assay, it was found that niacinamide cannot stimulate VEGF synthesis across a broad dose-response range.

The walking dead: sequential nuclear and organelle destruction during hair development.

BACKGROUND: Transition of hair shaft keratinocytes from actively respiring, nucleated cells to structural cells devoid of nucleus and cytoplasm is key to hair production. This form of cell 'death', or cornification, requires cellular organelle removal to allow the cytoplasm to become packed with keratin filament bundles that further require cross-linking to create a strong hair fibre. Although these processes are well described in epidermal keratinocytes, there is a lack of understanding of such mechanisms, specifically in the hair follicle. OBJECTIVES: To gain insights into cornification mechanisms within the hair follicle and thus improve our understanding of normal hair physiology. METHODS: Scalp biopsies and hair-pluck samples were obtained from healthy human donors and analysed microscopically after immunohistochemical staining. RESULTS: A focal point of respiratory activity was evident in keratogenous zone cells within the hair shaft, which also exhibited nuclear damage. Nuclear degradation occurred via both caspase-dependent and caspase-independent pathways. Conversely, mitophagy was driven by Bnip3L and restricted to the boundary of the keratogenous zone at Adamson's Fringe. CONCLUSIONS: We propose a model of stepwise living-dead transition within the first 1 mm of hair formation, whereby fully functional, nucleated cells first consolidate required functions by degrading nuclear DNA, yet continue to respire and provide the source of reactive oxygen species required for keratin cross-linking. Finally, as the cells become packed with keratin bundles, Bnip3L expression triggers mitophagy to rid the cells of the last remaining 'living' characteristic, thus completing the march from 'living' to 'dead' within the hair follicle.

Preserving fibre health: reducing oxidative stress throughout the life of the hair fibre.

Hair health is an important attribute to women globally--specifically attributes such as shine, healthy tips, frizz-free and strength. However, many women will claim to have at least moderate hair damage caused by habits and practices such as washing, combing and brushing, use of heated implements and regular use of chemical treatments. The objective of this work was to investigate two mechanisms of damage--hair colouring and UV exposure--where oxidative processes are involved. The role of copper in these oxidative processes was then investigated: its presence in hair and its consequent impact on hair damage via free radical formation. Finally, the role of chelants N,N'-ethylene diamine disuccinic acid (EDDS) and histidine in preventing free radical formation was investigated and shown to improve hair health.

Advanced hair damage model from ultra-violet radiation in the presence of copper.

OBJECTIVE: Damage to hair from UV exposure has been well reported in the literature and is known to be a highly complex process involving initiation via absorption of UV light followed by formation and propagation of reactive oxygen species (ROS). The objective of this work was to understand these mechanisms, explain the role of copper in accelerating the formation of ROS and identify strategies to reduce the hair damage caused by these reactive species. METHODS: The location of copper in hair was measured by Transmission electron microscopy-(TEM) X-ray energy dispersive spectroscopy (XEDS) and levels measured by ICP-OES. Protein changes were measured as total protein loss via the Lowry assay, and MALDI ToF was used to identify the biomarker protein fragments. TBARS assay was used to measure lipid peroxide formation. Sensory methods and dry combing friction were used to measure hair damage due to copper and UV exposure and to demonstrate the efficacy of N,N' ethylenediamine disuccinic acid (EDDS) and histidine chelants to reduce this damage. RESULTS: In this work, a biomarker protein fragment formed during UV exposure is identified using mass spectrometry. This fragment originates from the calcium-binding protein S100A3. Also shown is the accelerated formation of this peptide fragment in hair containing low levels of copper absorbed from hair during washing with tap water containing copper ions. Transmission electron microscopy (TEM) X-ray energy dispersive spectroscopy (XEDS) studies indicate copper is located in the sulphur-poor endo-cuticle region, a region where the S100A3 protein is concentrated. A mechanism for formation of this peptide fragment is proposed in addition to the possible role of lipids in UV oxidation. A shampoo and conditioner containing chelants (EDDS in shampoo and histidine in conditioner) is shown to reduce copper uptake from tap water and reduce protein loss and formation of S100A3 protein fragment. In addition, the long-term consequences of UV oxidation and additional damage induced by copper are illustrated in a four-month wear study where hair was treated with a consumer relevant protocol of hair colouring treatments, UV exposure and regular shampoo and conditioning. CONCLUSIONS: The role of copper in accelerating UV damage to hair has been demonstrated as well as the ability of chelants such as EDDS and histidine in shampoo and conditioner products to reduce this damage.

Role of copper in photochemical damage to hair.

OBJECTIVE: The objective of this work was to identify whether low levels of redox metals such as copper will accelerate damage to hair on exposure to UV irradiation and whether this damage can be prevented. METHODS: The methods used were proteomics to measure the protein damage via protein loss after different periods of exposure and mass spectroscopy methods to identify specific marker peptides that are specifically created by this type of damage. RESULTS: In this work, we have developed new insights into the mechanism of UV damage using these proteomic methods. A marker fragment in the hair protein loss extract was identified (m/z = 1279) that is unique to UV exposure and increases with time of UV exposure. We have also identified for the first time in hair the role of exogenous copper in increasing UV damage both in terms of total protein degradation and also increased formation of the marker fragment and proposed a mechanism of action. It has been demonstrated that shampoo treatment containing a chelant such as N,N'-ethylenediamine disuccinic acid (EDDS) reduced copper accumulation in hair. CONCLUSION: This work provides evidence for the role of copper in UV-induced damage to hair and strategies to reduce copper levels in hair using a chelant such as EDDS.

The role of chelants in controlling Cu(II)-induced radical chemistry in oxidative hair colouring products.

The catalytic formation of hydroxyl radicals in oxidative hair colourant systems in the presence of added copper ions was measured and quantified using a colorimetric probe N,N'-(5-nitro-1,3-phenylene)bisglutaramide. Also monitored in the same experiments was the decomposition of hydrogen peroxide. The first set of experiments was performed using aqueous model solutions containing the key oxidant actives in a hair colourant, ammonium hydroxide and hydrogen peroxide at pH 10, with added copper and calcium ions. The second set of experiments was performed in the presence of hair containing different levels of copper in conditions very close to those found during hair colouring. Both sets of experiments demonstrate the ability of copper ions to trigger the formation of hydroxyl radicals and catalyse the decomposition of hydrogen peroxide. The ability of chelants ethylenediamine tetraacetic acid (EDTA) and N,N'-ethylenediamine disuccinic acid (EDDS) to moderate the flux of hydroxyl radicals formed in solution systems was demonstrated in the presence of copper ions alone. However, only EDDS was successful in the presence of both calcium and copper ions. This was confirmed in the hair experiments where again only EDDS was successful at preventing hydroxyl radical formation where hair is added as the source of copper and calcium ions. These results are explained using metal speciation modelling and demonstrate the importance of the chelant to be able to specifically bind and prevent the one-electron redox chemistry of copper in the presence of high levels of calcium ions as found in hair. The formation of hydroxyl radicals during the colouring process was shown to lead to hair structure damage as measured by protein loss. EDDS was demonstrated to significantly reduce cuticle damage by suppressing the formation of the hydroxyl radicals in systems with realistic concentrations of calcium and copper.

The proteomic profile of hair damage.

BACKGROUND: Monilethrix is a congenital hair shaft disorder with associated fragility. Many of the changes seen in monilethrix hair on light microscopy and scanning electron microscopy are also seen in hair weathering and cosmetic damage to hair. OBJECTIVES: We used monilethrix as a model to investigate the relationship between hair protein structure and hair strength and resistance to cosmetic insult. METHODS: We applied proteomic techniques to identify novel peptide damage markers for chemical oxidative damage to hair. RESULTS: The findings suggest that specific sites in the protein structure of hair are targeted during oxidative damage from bleaching, a unique insight into how chemical damage compromises the structural integrity of the hair shaft at the molecular level. CONCLUSIONS: Applying proteomics to the study of congenital and acquired hair shaft disorders can deliver new insights into hair damage and novel strategies to strengthen hair.

A novel cosmetic approach to treat thinning hair.

BACKGROUND: Many of today's treatments associated with 'thinning hair', such as female pattern hair loss and telogen effluvium, are focused on two of the key aspects of the condition. Over-the-counter or prescription medications are often focused on improving scalp hair density while high-quality cosmetic products work to prevent further hair damage and minimize mid-fibre breakage. Fibre diameter is another key contributor to thinning hair, but it is less often the focus of medical or cosmetic treatments. OBJECTIVES: To examine the ability of a novel leave-on technology combination [caffeine, niacinamide, panthenol, dimethicone and an acrylate polymer (CNPDA)] to affect the diameter and behaviour of individual terminal scalp hair fibres as a new approach to counteract decreasing fibre diameters. METHODS: Testing methodology included fibre diameter measures via laser scan micrometer, assessment of fibre mechanical and behavioural properties via tensile break stress and torsion pendulum testing, and mechanistic studies including cryoscanning electron microscopy and autoradiographic analysis. RESULTS: CNPDA significantly increased the diameter of individual, existing terminal scalp hair fibres by 2-5 µm, which yields an increase in the cross-sectional area of approximately 10%. Beyond the diameter increase, the CNPDA-thickened fibres demonstrated the altered mechanical properties characteristic of thicker fibres: increased suppleness/pliability (decreased shear modulus) and better ability to withstand force without breaking (increased break stress). CONCLUSIONS: Although cosmetic treatments will not reverse the condition, this new approach may help to mitigate the effects of thinning hair.

Synthesis and evaluation of a series of 2'-deoxy analogues of the antiviral agent 5,6-dichloro-2-isopropylamino-1-(beta-L-ribofuranosyl)-1H-benzimidazole (1263W94).

A series of 2'-deoxy analogues of the antiviral agent 5,6-dichloro-2-isopropylamino-1-(beta-L-ribofuranosyl)-1H-benzimidazole (1263W94) were synthesized and evaluated for activity against human cytomegalovirus (HCMV) and for cytotoxicity. The 2-substituents in the benzimidazole moiety correspond to those that were used in the 1263W94 series. In general, as was found in the 1263W94 series, cyclic and branched alkylamino groups were needed for potent activity against HCMV. Three analogues 3a, 3b and 3d were as potent as 1263W94. Further evaluation of two analogues, 3a and 3b, suggested that these 2'-deoxy analogues may act via a novel mechanism of action similar to that of 1263W94. These 2'-deoxy analogues generally lacked cytotoxicity in vitro. Pharmacokinetic parameters in mice and protein binding properties of 3a were quite similar to 1263W94. However, the oral bioavailability of 3a was only half of that observed for 1263W94.

Involvement of Gialpha2 in sodium butyrate-induced erythroblastic differentiation of K562 cells.

The chronic myelogenous leukaemia cell line K562 can be triggered in culture to differentiate along the erythrocytic pathway in response to a variety of stimulatory agents. In the presence of sodium butyrate, these cells differentiate to erythroblasts and acquire the capability to synthesize haemoglobin. We used this cell system to study alterations in the levels of several G-protein subunits during the cell differentiation programme and to assess the involvement of G(i)alpha2 in this process. Western immunoblot analysis revealed the presence of G(s)alpha1, G(s)alpha2, G(i)alpha2, G(q)alpha, Galpha(12), Gbeta1 and Gbeta2 in K562 cells. G(o)alpha, G(z)alpha, Galpha(13) and Galpha(16) were not detected. Although the levels of several G-protein subunits were altered after treatment with sodium butyrate, the most striking change was the robust increase in the levels of G(i)alpha2, which was accompanied by an increase in the mRNA for G(i)alpha2. Inactivation of G(i)alpha2 by adding Bordetella pertussis toxin to the cultures inhibited erythroblastic differentiation by as much as 62%, as measured by haemoglobin accumulation. Furthermore, the addition of an oligonucleotide anti-sense to G(i)alpha2 inhibited the sodium butyrate-induced robust increase in G(i)alpha2 levels, decreasing it to the basal levels seen in control cells; this treatment decreased the erythroblastic differentiation of the cells (as measured by haemoglobin expression) by 50%. Taken together, these findings imply that increased levels of G(i)alpha2 contribute to the sodium butyrate-induced erythroblastic differentiation of K562 cells.

Inhibition of Epstein-Barr virus replication by a benzimidazole L-riboside: novel antiviral mechanism of 5, 6-dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole.

Although a number of antiviral drugs inhibit replication of Epstein-Barr virus (EBV) in cell culture, and acyclovir (ACV) suppresses replication in vivo, currently available drugs have not proven effective for treatment of EBV-associated diseases other than oral hairy leukoplakia. Benzimidazole riboside compounds represent a new class of antiviral compounds that are potent inhibitors of human cytomegalovirus (HCMV) replication but not of other herpesviruses. Here we characterize the effects of two compounds in this class against lytic replication of EBV induced in a Burkitt lymphoma cell line latently infected with EBV. We analyzed linear forms of EBV genomes, indicative of lytic replication, and episomal forms present in latently infected cells by terminal probe analysis followed by Southern blot hybridization as well as the high-molecular-weight unprocessed viral DNA by pulsed-field gel electrophoresis. D-Ribofuranosyl benzimidazole compounds that act as inhibitors of HCMV DNA maturation, including BDCRB (5, 6-dichloro-2-bromo-1-beta-D-ribofuranosyl-1H-benzimidazole), did not affect the accumulation of high-molecular-weight or monomeric forms of EBV DNA in the induced cells. In contrast, the generation of linear EBV DNA as well as precursor viral DNA was sensitive to the L-riboside 1263W94 [5, 6-dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole]. The 50% inhibitory concentration range for 1263W94 was 0.15 to 1. 1 microM, compared with 10 microM for ACV. Thus, 1263W94 is a potent inhibitor of EBV. In addition, 1263W94 inhibited the phosphorylation and the accumulation of the essential EBV replicative cofactor, early antigen D.

Acyclovir is phosphorylated by the human cytomegalovirus UL97 protein.

Acyclovir (ACV) has shown efficacy in the prophylactic suppression of human cytomegalovirus (HCMV) reactivation in immunocompromised renal transplant patients without the toxicity associated with ganciclovir (GCV). The HCMV UL97 gene product, a protein kinase, is responsible for the phosphorylation of GCV in HCMV-infected cells. This report provides evidence for the phosphorylation of ACV by UL97. Anabolism studies with the HCMV wild-type strain AD169 and with recombinant mutants derived from marker transfer experiments performed by using mutant UL97 DNA from both clinical isolates and a laboratory-derived strain resistant to GCV showed that mutations in the UL97 gene cripple the ability of recombinant virus-infected cells to anabolize both GCV and ACV. These mutant UL97 recombinant viruses were less susceptible to both GCV and ACV than was the wild-type strain. A recombinant herpes simplex virus type 1 strain, in which the thymidine kinase gene is deleted and the UL13 gene is replaced with the HCMV UL97 gene, was able to induce the phosphorylation of ACV in infected cells. Finally, purified UL97 phosphorylated both GCV and ACV to their monophosphates. Our results indicate that UL97 promotes the selective activity of ACV against HCMV.

Induction of lytic Epstein-Barr virus (EBV) infection in EBV-associated malignancies using adenovirus vectors in vitro and in vivo.

The consistent presence of EBV genomes in certain tumor types (in particular, AIDS-related central nervous system lymphomas and nasopharyngeal carcinomas) may allow novel, EBV-based targeting strategies. Tumors contain the latent (transforming) form of EBV infection. However, expression of either of the EBV immediate-early proteins, BZLF1 and BRLF1, is sufficient to induce lytic EBV infection, resulting in death of the host cell. We have constructed replication-deficient adenovirus vectors expressing the BZLF1 or BRLF1 immediate-early genes and examined their utility for killing latently infected lymphoma cells in vitro and in vivo. We show that both the BZLF1 and BRLF1 vectors efficiently induce lytic EBV infection in Jijoye cells (an EBV-positive Burkitt lymphoma cell line). Furthermore, lytic EBV infection converts the antiviral drug, ganciclovir (GCV), into a toxic (phosphorylated) form, which inhibits cellular as well as viral DNA polymerase. When Jijoye cells are infected with the BZLF1 or BRLF1 adenovirus vectors in the presence of GCV, viral reactivation is induced, but virus replication is inhibited (thus preventing the release of infectious EBV particles); yet cells are still efficiently killed. Finally, we demonstrate that the BZLF1 and BRLF1 adenovirus vectors induce lytic EBV infection when they are directly inoculated into Jijoye cell tumors grown in severe combined immunodeficiency mice. These results suggest that induction of lytic EBV infection in tumors, in combination with GCV, may be an effective strategy for treating EBV-associated malignancies.

Three-dimensional laser imaging system for measuring wound geometry.

BACKGROUND AND OBJECTIVE: A low cost laser imager was designed and fabricated for measurement of wound geometry. METHODS: The accuracy of the imager was validated using reference depressions of known dimensions. Perimeter, area, and volume were compared to planimetric and packing techniques on simulated wound models. RESULTS: Wound tracing and alginate measurement methods required approximately 20 times longer for the reference standards, and 11 times longer for the simulated wounds than with the laser scanning method (LSM). LSM consistently overestimated the reference perimeter by 0.73+/-0.20 cm and the area by 0.98+/-0.62 cm2. Volume estimates were not statistically different. The tracing method underestimated the perimeter by 0.34+/-0.27 cm and the area by 1.07+/-1.09 cm2. Volume measurements by the alginate method were not statistically different. The perimeters of the simulated wounds averaged 1.29+/-0.27 cm greater using the LSM than obtained by the tracing method, and areas greater by 2.02+/-1.30 cm2. Volume scans averaged 1.04+/-0.61 cm3 greater than by the alginate method.

Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure.

Receptor-mediated Gq signaling promotes hypertrophic growth of cultured neonatal rat cardiac myocytes and is postulated to transduce in vivo cardiac pressure overload hypertrophy. Although initially compensatory, hypertrophy can proceed by unknown mechanisms to cardiac failure. We used adenoviral infection and transgenic overexpression of the alpha subunit of Gq to autonomously activate Gq signaling in cardiomyocytes. In cultured cardiac myocytes, overexpression of wild-type Galphaq resulted in hypertrophic growth. Strikingly, expression of a constitutively activated mutant of Galphaq, which further increased Gq signaling, produced initial hypertrophy, which rapidly progressed to apoptotic cardiomyocyte death. This paradigm was recapitulated during pregnancy in Galphaq overexpressing mice and in transgenic mice expressing high levels of wild-type Galphaq. The consequence of cardiomyocyte apoptosis was a transition from compensated hypertrophy to a rapidly progressive and lethal cardiomyopathy. Progression from hypertrophy to apoptosis in vitro and in vivo was coincident with activation of p38 and Jun kinases. These data suggest a mechanism in which moderate levels of Gq signaling stimulate cardiac hypertrophy whereas high level Gq activation results in cardiomyocyte apoptosis. The identification of a single biochemical stimulus regulating cardiomyocyte growth and death suggests a plausible mechanism for the progression of compensated hypertrophy to decompensated heart failure.

In vivo antiviral activity and pharmacokinetics of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine in woodchuck hepatitis virus-infected woodchucks.

The (-) enantiomer of cis-5-fluoro-1l-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine [(-)-FTC)], a substituted oxathiolane compound with anti-hepatitis B virus activity in vitro, was assessed for its efficacy in woodchucks with naturally acquired woodchuck hepatitis virus (WHV) infection. Pharmacokinetics and in vitro anabolism were also determined. (-)-FTC was anabolized to the 5'-triphosphate in a dose-related fashion, reaching a maximum concentration at about 24 h in cultured woodchuck hepatocytes. Following administration of a dose of 10 mg/kg of body weight intraperitoneally (i.p.), the clearance of (-)-FTC from plasma was monoexponential, the terminal half-life was 3.76 +/- 1.4 h, and the systemic clearance was 0.12 +/- 0.06 liters/h/kg. The antiviral efficacy of (-)-FTC in the woodchuck model was assessed by quantitation of serum WHV DNA levels and by WHV particle-associated DNA polymerase activity at two dosages, 30 and 20 mg/kg given i.p. twice daily (b.i.d.), respectively. The level of WHV DNA in serum was reduced 20- to 150-fold (average, 56-fold) in the 30-mg/kg-b.i.d. treatment group and 6- to 49-fold (average, 27-fold) in the 20-mg/kg-b.i.d. treatment group. Viral DNA polymerase levels diminished accordingly. One week after treatment was discontinued, WHV levels returned to pretreatment levels in both studies. These animals were biopsied before and following treatment with 30 mg of (-)-FTC per kg. Their livers were characterized by a mild increase in cytoplasmic lipid levels, but this change was not associated with altered liver enzyme levels. Serum chemistry and hematology results were within the normal ranges for all treated animals. We conclude that (-)-FTC is a potent antihepadnaviral agent and that it has no detectable toxic effects in woodchucks when given for up to 25 days. Further development of (-)-FTC as an anti-hepatitis B virus therapy for patients is warranted.

Structural determinants for agonist binding affinity to thromboxane/prostaglandin endoperoxide (TP) receptors. Analysis of chimeric rat/human TP receptors.

The two most extensively characterized thromboxane/prostaglandin endoperoxide (TP) receptors, from human platelets and rat vascular smooth muscle, exhibit thromboxane agonist [15-(1alpha,2beta(5Z), 3alpha-(1E,3S), 4alpha)]-7-[3-hydroxy-4-(p-iodophenoxy)-1-butenyl-7-oxabi cyclohepteno ic acid (I-BOP) binding affinities that differ by an order of magnitude, rat TP having the higher affinity. We utilized this difference in I-BOP affinity to identify structural determinants of TP receptor heterogeneity. No significant difference was found in the rank order of affinities for a series of thromboxane receptor ligands to bind to cloned human TPalpha versus rat TP, indicating that these represent species homologs, not distinct TP subtypes. Structural determinants for observed differences in I-BOP binding Kd were localized by creating chimeric human/rat TP followed by mutational substitution of specific critical amino acids. Initially, seven chimeric receptors with splice sites in transmembranes 1, 2, 4, or 7 were constructed and expressed in HEK293 cells for analysis of ligand binding properties. Substitution of any part except the carboxyl tail of the human TP into the rat TP resulted in a receptor with I-BOP binding affinity intermediate between the two. Analysis of chimeras in which only the extracellular amino terminus and a portion of transmembrane 1 were switched localized the determinant of high affinity binding to the region between amino acids 3 and 40. Using this chimera, amino acids in the human portion (extracellular amino terminus and part of transmembrane 1) were replaced with analogous amino acids from rat TP to regain high affinity I-BOP binding. Only when amino acid Val37 and either Val36 or Ala40 were reverted to their respective rat TP counterparts (Ala36, Leu37, and Gly40, respectively) was high affinity I-BOP binding recovered. The mechanism for the increased I-BOP affinity may be the lengthening of the amino acid side chain at position 37, thus extending this group further into the putative I-BOP binding pocket, with compensatory shortening of side chains in spatially adjacent amino acids.