SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation.

SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations cause oculocutaneous albinism type 4 (OCA4) and polymorphisms are associated with pigmentation variation, but the localization, function, and regulation of SLC45A2 and its variants remain unknown. We show that SLC45A2 localizes to a cohort of mature melanosomes that only partially overlaps with the cohort expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that in melanocytes SLC45A2 expression, like OCA2 expression, results in the deacidification of maturing melanosomes to support melanin synthesis. Interestingly, OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 likely functions later during melanosome maturation than OCA2. Moreover, the light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes due to rapid proteasome-dependent degradation resulting in lower protein expression levels in melanosomes than the dark skin-associated allelic L374 variant. Our data suggest that SLC45A2 maintains melanosome neutralization that is initially orchestrated by transient OCA2 activity to support melanization at late stages of melanosome maturation, and that a common allelic variant imparts reduced activity due to protein instability

A novel SARS-CoV-2 (T Cell) vaccine candidate designed using the iVAX platform

EpiVax, Inc., a Rhode Island-based Biotechnology company, develops vaccines that exploit T cell immunity using the innovative iVAX vaccine antigen design platform. The premise of our strategy is the crucial role T cells play in development of protective antibody and cell-mediated immunity in natural infection. Because vaccines aim to recapitulate protective immune responses in infection, a vaccine should effectively harness T cell immunity to be protective. The significance of T cell immunity is underscored by COVID-19. Efficacy trial and real-world COVID-19 vaccine data for different vaccine modalities show a single vaccine dose is as much as 90% effective starting 14 days post-administration, when 100% of vaccinees have functional CD4 and CD8 T cells but no detectable neutralizing antibodies. As T cells support the SARS-CoV-2 antibody response, clear virus-infected cells, and may be required to block transmission, we set out to develop a vaccine designed by iVAX to enhance T cell immunity and provide long lasting protection. Please click Download on the upper right corner to see the full abstract

A novel germline variant in the DOT1L gene co-segregating in a Dutch family with a history of melanoma

A proportion of patients diagnosed with melanoma has a positive family history. Despite increasing knowledge on the genes responsible for familial clustering, the genetic basis in the majority of the families with an inherited predisposition to melanoma remains to be clarified. To identify novel melanoma-susceptibility genes, we applied whole-exome sequencing on DNA from two members of a family with four melanoma cases, not explained by established high penetrance melanoma-susceptibility genes. Whole-exome sequencing identified 10 rare, co-segregating, predicted deleterious missense gene variants. Subsequent co-segregation analysis revealed that only variants in the DOT1L (R409H) and the SLCO4C1 (P597A) genes were present in the other two affected members of this family. DOT1L is a methyltransferase that methylates histone H3 lysine 79 (H3K79). It is involved in maintenance of genomic stability, since mutations in the DOT1L gene have been previously reported to compromise the removal of ultraviolet photoproducts in ultraviolet-irradiated melanocytes, thereby enhancing malignant transformation. We hypothesized that the presence of DOT1L R409H variant might be associated with an increased risk of melanoma, since we found co-segregation of the DOT1L mutation in all four melanoma-affected family members. However, this missense variant did neither lead to detectable loss-of-heterozygosity nor reduction of histone methyltransferase activity in melanoma samples from mutation carriers nor altered ultraviolet-survival of mouse embryonic stem cells containing an engineered homozygous DOT1L R409H mutation. Although functional analysis of this rare co-segregating variant did not reveal compromised histone methyltransferase activity and ultraviolet exposure sensitivity, the role of DOT1L as melanoma susceptibility gene deserves further study.Dermatology-oncolog

Photobiomodulation devices for hair regrowth and wound healing: a therapy full of promise but a literature full of confusion.

yesPhotobiomodulation is reported to positively influence hair regrowth, wound healing, skin rejuvenation, and psoriasis. Despite rapid translation of this science to commercial therapeutic solutions, significant gaps in our understanding of the underlying processes remain. The aim of this review was to seek greater clarity and rationality specifically for the selection of optical parameters for studies on hair regrowth and wound healing. Our investigation of 90 reports published between 1985-2015 revealed major inconsistencies in optical parameters selected for clinical applications. Moreover, poorly understood photoreceptors expressed in skin such as cytochrome c oxidase, cryptochromes, opsins, may trigger different molecular mechanisms. All this could explain the plethora of reported physiological effects of light. To derive parameters for optimal clinical efficacy of photobiomodulation, we recommend a more rational approach, underpinning clinical studies with research of molecular targets and pathways using well-defined biological model systems enabling easy translation of optical parameters from in vitro to in vivo. Furthermore, special attention needs to be paid when conducting studies for hair regrowth, aiming for double-blind, placebo-controlled randomized clinical trials as the gold standard for quantifying hair growth.European Marie-Curie Actions Programme, Grant agreement no.: 60788

A new path in defining light parameters for hair growth: discovery and modulation of photoreceptors in human hair follicle

YesBackground and Objective: Though devices for hair growth based on low levels of light have shown encouraging results, further improvements of their efficacy is impeded by a lack of knowledge on the exact molecular targets that mediate physiological response in skin and hair follicle. The aim of this study was to investigate the expression of selected light-sensitive receptors in the human hair follicle and to study the impact of UV-free blue light on hair growth ex vivo. Material and Methods: The expression of Opsin receptors in human skin and hair follicles has been characterised using RT-qPCR and immunofluorescence approaches. The functional significance of Opsin 3 was assessed by silencing its expression in the hair follicle cells followed by a transcriptomic profiling. Proprietary LED-based devices emitting two discrete visible wavelengths were used to access the effects of selected optical parameters on hair growth ex vivo and outer root sheath cells in vitro. Results: The expression of OPN2 (Rhodopsin) and OPN3 (Panopsin, Encephalopsin) was detected in the distinct compartments of skin and anagen hair follicle. Treatment with 3.2 J/cm2 of blue light with 453 nm central wavelength significantly prolonged anagen phase in hair follicles ex vivo that was correlated with sustained proliferation in the light-treated samples. In contrast, hair follicle treatment with 3.2 J/cm2 of 689 nm light (red light) did not significantly affect hair growth ex vivo. Silencing of OPN3 in the hair follicle outer root sheath cells resulted in the altered expression of genes involved in the control of proliferation and apoptosis, and abrogated stimulatory effects of blue light (3.2 J/cm2; 453 nm) on proliferation in the outer root sheath cells. Conclusions: We provide the first evidence that 1) OPN2 and OPN3 are expressed in human hair follicle, and 2) 453 nm blue light at low radiant exposure exerts a positive effect on hair growth ex vivo, potentially via interaction with OPN3.This study was supported by the European Marie-Curie Actions Programme, Grant agreement no.: 60788

Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu

Data set for the genome-wide transcriptome analysis of human epidermal melanocytes

The data in this article contains data related to the research articled entitle Genome-wide transcriptome analysis of human epidermal melanocytes. This data article contains a complete list of gene and transcript isoform expression in human epidermal melanocytes. Transcript isoforms that are differentially expressed in lightly versus darkly pigmented melanocytes are identified. We also provide data showing the gene expression profiles of cell signaling gene families (receptors, ion channels, and transcription factors) in melanocytes. The raw sequencing data used to perform this transcriptome analysis is located in the NCBI Sequence Read Archive under Accession No. SRP039354 http://dx.doi.org/10.7301/Z0MW2F2N