Perturbations in the transcriptional programs specifying epidermal differentiation cause diverse skin pathologies ranging from impaired barrier function to inflammatory skin disease. However, the ...global scope and organization of this complex cellular program remain undefined. Here we report single-cell RNA sequencing profiles of 92,889 human epidermal cells from 9 normal and 3 inflamed skin samples. Transcriptomics-derived keratinocyte subpopulations reflect classic epidermal strata but also sharply compartmentalize epithelial functions such as cell-cell communication, inflammation, and WNT pathway modulation. In keratinocytes, ∼12% of assessed transcript expression varies in coordinate patterns, revealing undescribed gene expression programs governing epidermal homeostasis. We also identify molecular fingerprints of inflammatory skin states, including S100 activation in the interfollicular epidermis of normal scalp, enrichment of a CD1C+CD301A+ myeloid dendritic cell population in psoriatic epidermis, and IL1βhiCCL3hiCD14+ monocyte-derived macrophages enriched in foreskin. This compendium of RNA profiles provides a critical step toward elucidating epidermal diseases of development, differentiation, and inflammation.
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•Stereotyped keratinocyte subpopulations modularly comprise human epidermis•Scalp keratinocytes exhibit an inherent inflammatory transcriptional program•Myeloid dendritic cells predominate APCs in psoriatic epidermis•Macrophages represent major APCs in foreskin epidermis
Cheng et al. report single-cell RNA sequencing of normal and inflamed human epidermis, revealing a discrete set of specialized keratinocytes that exhibit a distinct composition at different anatomic sites. Myeloid dendritic cells and macrophages also vary sharply with epidermal anatomic site and inflammation, indicating dynamic programming of antigen-presenting cells.
Background
PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemical (IHC) staining is used to aid melanoma diagnosis. PRAME expression in nevus‐associated melanoma (NAM) has not been ...evaluated.
Methods
PRAME IHC was applied to cases of NAM; staining for each population of melanocytes (benign and malignant) was graded based on the percentage of labeled cells. No labeling was graded 0, 1% to 25% labeling was 1+, 26% to 50% was 2+, 51% to 75% was 3+, and >76% was 4+.
Results
Thirty‐six cases were reviewed. Sixty‐seven percent (24/36) of melanomas were PRAME positive (4+) while no (0/36) nevi showed 4+ positivity. Eighty‐one percent (29/36) of nevi were completely PRAME negative compared to 17% (6/36) of melanomas. In 67% of cases (24/36) PRAME differentiated between benign and malignant melanocyte populations.
Conclusions
We identified a high rate (67%) of differential PRAME staining in adjacent benign and malignant melanocyte populations in NAM. In PRAME positive (4+) melanomas, PRAME differentiates 100% (24/24) of benign and malignant melanocyte populations. When 4+ staining is used as the threshold for positivity, PRAME staining has a sensitivity of 67% (24/36) and a specificity of 100% (36/36). These results support PRAME IHC can assist in distinguishing melanocyte populations in melanoma arising within nevi.
To systematically review evidence on depression screening in coronary heart disease (CHD) by assessing the (1) accuracy of screening tools; (2) effectiveness of treatment; and (3) effect of screening ...on depression outcomes.
A 2008 American Heart Association (AHA) Science Advisory recommended routine depression screening in CHD.
CINAHL, Cochrane, EMBASE, ISI, MEDLINE, PsycINFO and SCOPUS databases searched through December 2, 2011; manual journal searches; reference lists; citation tracking; trial registries. Included articles (1) compared a depression screening instrument to a depression diagnosis; (2) compared depression treatment to placebo or usual care in a randomized controlled trial (RCT); or (3) assessed the effect of screening on depression outcomes in a RCT.
There were few examples of screening tools with good sensitivity and specificity using a priori-defined cutoffs in more than one patient sample among 15 screening accuracy studies. Depression treatment with antidepressants or psychotherapy generated modest symptom reductions among post-myocardial infarction (post-MI) and stable CHD patients (N = 6; effect size = 0.20-0.38), but antidepressants did not improve symptoms more than placebo in 2 heart failure (HF) trials. Depression treatment did not improve cardiac outcomes. No RCTs investigated the effects of screening on depression outcomes.
There is evidence that treatment of depression results in modest improvement in depressive symptoms in post-MI and stable CHD patients, although not in HF patients. There is still no evidence that routine screening for depression improves depression or cardiac outcomes. The AHA Science Advisory on depression screening should be revised to reflect this lack of evidence.
Neovascular AMD (nAMD) leads to vision loss and is a leading cause of visual impairment in the industrialised world. Current treatments that target blood vessel growth have not been able to treat ...subretinal fibrosis and nAMD patients continue to lose vision. The molecular mechanisms involved in the development of fibrotic lesions in nAMD are not well understood. The aim of this study was to further understand subretinal fibrosis in the laser photocoagulation model of choroidal neovascularization (CNV) by studying the whole transcriptome of the RPE/choroid following CNV and the application of an anti-fibrotic following CNV. Seven days after laser induced CNV, RPE and choroid tissue was separated and underwent RNAseq. Differential expression analysis and pathway analysis revealed an over representation of immune signalling and fibrotic associated pathways in CNV compared to control RPE/choroid tissue. Comparisons between the mouse CNV model to human CNV revealed an overlap in upregulated expression for immune genes (Ccl2, Ccl8 and Cxcl9) and extracellular matrix remodeling genes (Comp, Lrcc15, Fndc1 and Thbs2). Comparisons between the CNV model and other fibrosis models showed an overlap of over 60% of genes upregulated in either lung or kidney mouse models of fibrosis. Treatment of CNV using a novel cinnamoyl anthranilate anti-fibrotic (OCX063) in the laser induced CNV model was selected as this class of drugs have previously been shown to target fibrosis. CNV lesion leakage and fibrosis was found to be reduced using OCX063 and gene expression of genes within the TGF-beta signalling pathway. Our findings show the presence of fibrosis gene expression pathways present in the laser induced CNV mouse model and that anti-fibrotic treatments offer the potential to reduce subretinal fibrosis in AMD.
Current proteomic studies clarified canonical synaptic proteins that are common to many types of synapses. However, proteins of diversified functions in a subset of synapses are largely hidden ...because of their low abundance or structural similarities to abundant proteins. To overcome this limitation, we have developed an “ultra-definition” (UD) subcellular proteomic workflow. Using purified synaptic vesicle (SV) fraction from rat brain, we identified 1,466 proteins, three times more than reported previously. This refined proteome includes all canonical SV proteins, as well as numerous proteins of low abundance, many of which were hitherto undetected. Comparison of UD quantifications between SV and synaptosomal fractions has enabled us to distinguish SV-resident proteins from potential SV-visitor proteins. We found 134 SV residents, of which 86 are present in an average copy number per SV of less than one, including vesicular transporters of nonubiquitous neurotransmitters in the brain. We provide a fully annotated resource of all categorized SV-resident and potential SV-visitor proteins, which can be utilized to drive novel functional studies, as we characterized here Aak1 as a regulator of synaptic transmission. Moreover, proteins in the SV fraction are associated with more than 200 distinct brain diseases. Remarkably, a majority of these proteins was found in the low-abundance proteome range, highlighting its pathological significance. Our deep SV proteome will provide a fundamental resource for a variety of future investigations on the function of synapses in health and disease.
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•Oxide/Sb2S3 heterostructure is fabricated by one-step thermolysis in air ambient.•Oxygen stoichiometry in oxides influence photoelectrochemical performance.•Air-annealed TiO2/Sb2S3 ...shows the better current density of 1.79 mA/cm2.•Hydrogen annealed ZnO/Sb2S3 shows superior PEC performance (J ~ 3.9 mA/cm2)•Hydrogen annealing is beneficial for ZnO, whereas air-annealing is favored for TiO2.
Semiconductor heterostructures such as TiO2/Sb2S3 and ZnO/Sb2S3 are promising for photoelectrochemical applications. In this work, we demonstrate the photoelectrochemical performance with enhanced current densities of Sb2S3 sensitized nanorods of TiO2 (TNR) and ZnO (ZNR) photoanodes. ZNR and TNR are synthesized by the hydrothermal method and annealed in the air (AA) and hydrogen (HA) ambient. Stoichiometric Sb2S3 are coated on ZNR and TNR by a facile one-step method using thermolysis of Sb-MPA precursor in air ambient. Structural, optical and microstructural studies are carried out to confirm the formation of phase pure Sb2S3 on ZnO and TiO2 oxide nanorods in the TiO2/Sb2S3 and ZnO/Sb2S3 heterojunction photoanodes. Photoelectrochemical studies show enhanced performance from the Sb2S3 sensitized photoanodes in comparison to the bare TNR or ZNR photoanodes. TNR-AA/Sb2S3(MPA) and TNR-HA/Sb2S3(MPA) heterostructures exhibit current densities of 1.79 mA/cm2 and 1.58 mA/cm2, respectively, which is six times higher than the uncoated photoanodes (0.38 mA/cm2 for TNR-AA and 0.20 mA/cm2 for TNR-HA). In the case of ZNR, we see a 10 to 15 fold increase in current density (~3.3 to 4 mA/cm2) upon sensitizing with Sb2S3 on photoanodes. Further hydrogen annealed ZNR sensitized with Sb2S3 (ZNR-HA/Sb2S3(MPA)) shows a slightly higher current density (3.9 mA/cm2) than the air annealed ZNR-AA/Sb2S3(MPA) (3.32 mA/cm2). Hydrogen annealing is beneficial for ZNR, whereas air-annealing is favored for TNR. Also, stability studies and photocurrent measurements are discussed for these photoanodes.
Doxorubicin (Dox) was conjugated to a zinc(II) phthalocyanine (ZnPc) through an acid‐cleavable hydrazone linker. This azido‐containing conjugate was then anchored to the nanochannels of an ...alkyne‐modified mesoporous silica nanoparticle (MSN) system via copper(I)‐catalyzed azide–alkyne cycloaddition. An analogous nanosystem was also prepared by immobilization of a hydrazine‐substituted ZnPc to the MSN followed by coupling with Dox. The release of Dox under acidic conditions was studied in phosphate‐buffered saline. After internalization into human hepatocellular carcinoma HepG2 cells, these nanoparticles showed fluorescence not only for ZnPc, but also for Dox, suggesting that release of Dox was triggered by the acidic intracellular environment. The chemocytotoxic Dox together with singlet oxygen generated upon irradiation on the encapsulated ZnPc in these MSNs could kill the cells effectively. A synergistic cytotoxicity was suggested by a less‐than‐unity combination index. These nanoparticles function as both nanophotosensitizers for photodynamic therapy and as nanoplatforms for pH‐controlled drug release.
Photodynamic duo: Doxorubicin (Dox) was conjugated to a zinc(II) phthalocyanine (ZnPc) and then anchored to mesoporous silica. The chemocytotoxic Dox released under acidic conditions together with singlet oxygen generated upon irradiation on the encapsulated ZnPc could kill cancer cells effectively. The nanoparticles function as both nanophotosensitizers for photodynamic therapy and as nanoplatforms for pH‐controlled drug release.
Personomics: A Progress Report Hellmann, David B.; Ziegelstein, Roy C.
The American journal of medicine,
August 2023, 2023-08-00, 20230801, Letnik:
136, Številka:
8
Journal Article
PDF
