Summary
Circulating nucleic acids have been shown to have potential as non‐invasive diagnostic markers in cancer. We therefore investigated whether microRNAs also have diagnostic utility by comparing ...levels of tumour‐associated MIRN155 (miR‐155), MIRN210 (miR‐210) and MIRN21 (miR‐21) in serum from diffuse large B‐cell lymphoma (DLBCL) patients (n = 60) with healthy controls (n = 43). Levels were higher in patient than control sera (P = 0·009, 0·02 and 0·04 respectively). Moreover, high MIRN21 expression was associated with relapse‐free survival (P = 0·05). This is the first description of circulating microRNAs and suggests that microRNAs have potential as non‐invasive diagnostic markers for DLBCL and possibly other cancers.
The skin typically tolerates exposure to various microbes and chemicals in the environment. Here, we investigated how the epidermis maintains this innate immune tolerance to stimuli that are ...recognized by Toll-like receptors (TLRs). Loss of tolerance to TLR ligands occurred after silencing of the histone deacetylases (HDACs) HDAC8 and HDAC9 in keratinocytes. Transcriptional analysis identified MAP2K3 as suppressed by HDAC8/9 activity and a potential key intermediary for establishing this tolerance. HDAC8/9 influenced acetylation at H3K9 and H3K27 marks in the MAP2K3 promoter. Proteomic analysis further identified SSRP1 and SUPT16H as associated with HDAC8/9 and responsible for transcriptional elongation of MAP2K3. Silencing of MAP2K3 blocked the capacity of HDAC8/9 to influence cytokine responses. Relevance in vivo was supported by observations of increased MAP2K3 in human inflammatory skin conditions and the capacity of keratinocyte HDAC8/9 to influence dendritic cell maturation and T cell proliferation. Keratinocyte-specific deletion of HDAC8/9 also increased inflammation in mice after exposure to ultraviolet radiation, imiquimod, or
These findings define a mechanism for the epidermis to regulate inflammation in the presence of ubiquitous TLR ligands.
A subset of dermal fibroblasts undergo rapid differentiation into adipocytes in response to infection and acutely produce the cathelicidin antimicrobial peptide gene
Vitamin A and other retinoids ...inhibit adipogenesis yet can show benefit to skin disorders, such as cystic acne, that are exacerbated by bacteria. We observed that retinoids potently increase and sustain the expression of
in preadipocytes undergoing adipogenesis despite inhibition of markers of adipogenesis, such as
, and
Retinoids increase cathelicidin in both mouse and human preadipocytes, but this enhancement of antimicrobial peptide expression did not occur in keratinocytes or a sebocyte cell line. Preadipocytes undergoing adipogenesis more effectively inhibited growth of
when exposed to retinoic acid. Whole transcriptome analysis identified hypoxia-inducible factor 1-α (HIF-1α) as a mechanism through which retinoids mediate this response. These observations uncouple the lipid accumulation element of adipogenesis from the innate immune response and uncover a mechanism, to our knowledge previously unsuspected, that may explain therapeutic benefits of retinoids in some skin disorders.
PIKfyve, VAC14, and FIG4 form a complex that catalyzes the production of PI(3,5)P2, a signaling lipid implicated in process ranging from lysosome maturation to neurodegeneration. While previous ...studies have identified VAC14 and FIG4 mutations that lead to both neurodegeneration and coat color defects, how PIKfyve regulates melanogenesis is unknown. In this study, we sought to better understand the role of PIKfyve in melanosome biogenesis. Melanocyte-specific PIKfyve knockout mice exhibit greying of the mouse coat and the accumulation of single membrane vesicle structures in melanocytes resembling multivesicular endosomes. PIKfyve inhibition blocks melanosome maturation, the processing of the melanosome protein PMEL, and the trafficking of the melanosome protein TYRP1. Taken together, these studies identify a novel role for PIKfyve in controlling the delivery of proteins from the endosomal compartment to the melanosome, a role that is distinct from the role of PIKfyve in the reformation of lysosomes from endolysosomes.
Innate immune defense against deep tissue infection by
is orchestrated by fibroblasts that become antimicrobial when triggered to differentiate into adipocytes. However, the role of this process in ...noninfectious human diseases is unknown. To investigate the potential role of adipogenesis by dermal fibroblasts in acne, a disorder triggered by
, single-cell RNA sequencing was performed on human acne lesions and mouse skin challenged by
. A transcriptome consistent with adipogenesis was observed within specific fibroblast subsets from human acne and mouse skin lesions infected with
. Perifollicular dermal preadipocytes in human acne and mouse skin lesions showed colocalization of PREF1, an early marker of adipogenesis, and cathelicidin (
), an antimicrobial peptide. This capacity of
to specifically trigger production of cathelicidin in preadipocytes was dependent on TLR2. Treatment of wild-type mice with retinoic acid (RA) suppressed the capacity of
to form acne-like lesions, inhibited adipogenesis, and enhanced cathelicidin expression in preadipocytes, but lesions were unresponsive in
mice, despite the anti-adipogenic action of RA. Analysis of inflamed skin of acne patients after retinoid treatment also showed enhanced induction of cathelicidin, a previously unknown beneficial effect of retinoids in difficult-to-treat acne. Overall, these data provide evidence that adipogenic fibroblasts are a critical component of the pathogenesis of acne and represent a potential target for therapy.
Inflammatory disorders of the skin are frequently associated with inflammatory bowel diseases (IBDs). To explore mechanisms by which these organs communicate, we performed single-cell RNA-Seq ...analysis on fibroblasts from humans and mice with IBD. This analysis revealed that intestinal inflammation promoted differentiation of a subset of intestinal stromal fibroblasts into preadipocytes with innate antimicrobial host defense activity. Furthermore, this process of reactive adipogenesis was exacerbated if mouse skin was inflamed as a result of skin wounding or infection. Since hyaluronan (HA) catabolism is activated during skin injury and fibroblast-to-adipocyte differentiation is dependent on HA, we tested the hypothesis that HA fragments could alter colon fibroblast function by targeted expression of human hyaluronidase-1 in basal keratinocytes from mouse skin. Hyaluronidase expression in the skin activated intestinal stromal fibroblasts, altered the fecal microbiome, and promoted excessive reactive adipogenesis and increased inflammation in the colon after challenge with dextran sodium sulfate. The response to digested HA was dependent on expression of TLR4 by preadipocytes. Collectively, these results suggest that the association between skin inflammation and IBD may be due to recognition by mesenchymal fibroblasts in the colon of HA released during inflammation of the skin.
Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly ...used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.
Spiny lobsters have an extended larval development in offshore waters that ends with the non-feeding post-larvae swimming across the continental shelf and settling in shallow coastal waters. We ...tested the hypothesis that recent declines in the recruitment of a number of spiny lobster populations in different parts of the world are the result of increasing coastal water temperatures that deplete the metabolic reserves of recently settled post-larvae. We examined the resilience of recently settled juvenile lobsters to the depletion of their reserves in 2 species of spiny lobster from temperate waters. Juveniles of Jasus edwardsii survived on average (±SE) for 34.44 ± 3.44 d without feeding at 19–21°C, while Sagmariasus verreauxi survived for 39.96 ± 1.40 d, with no differences in survival among 3 temperature regimes (17, 20 and 23°C). The point of no return for recently-settled juveniles of S. verreauxi was estimated to be 30.40 ± 13.50 d, which was close to their average survival under starvation conditions. Starved juvenile lobsters close to the point of no return with extremely low remaining protein and lipid (6.52% lipid and 27.18% protein of dry body mass) were capable of surviving once food was supplied. These results indicate that newly settled juveniles of spiny lobsters from temperate waters can endure adverse nutritional conditions over a wide range of thermal conditions for prolonged periods, making them resilient to future increases in water temperatures as a result of climate change.
The chromosomal location of two genetic loci involved in the transport of cyanocobalamin (B
12
) in
Escherichia coli
K-12 was determined. One gene,
btuA
, is believed to code for the transport ...protein in the cytoplasmic membrane, because a mutant with an alteration in this gene has lost the ability to accumulate B
12
within the cell although normal levels of the surface receptors for B
12
are present. The other locus,
btuB
, apparently codes for the surface receptor on the outer membrane. These mutants have lost the ability to bind B
12
and have greatly reduced transport activity, although growth experiments have shown that they can utilize B
12
for growth, but with decreased efficiency. This surface receptor for B
12
also appears to function as the receptor for the E colicins, because
btuB
mutants are resistant to the E colicins, and mutants selected for resistance to colicin E1 are defective in B
12
binding and transport. The gene order was determined by transduction analysis to be
cyc-argH-btuA-btuB-rif-purD
. In addition, mutations in
metH
, the gene for the B
12
-dependent homocysteine methylating enzyme, were obtained in this study. This gene was localized between
metA
and
malB
.
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