Fibrotic skin disease represents a major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix. Fibroblasts are found to be ...heterogeneous in multiple fibrotic diseases, but fibroblast heterogeneity in fibrotic skin diseases is not well characterized. In this study, we explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases, by using single-cell RNA-seq. Our results indicate that keloid fibroblasts can be divided into 4 subpopulations: secretory-papillary, secretory-reticular, mesenchymal and pro-inflammatory. Interestingly, the percentage of mesenchymal fibroblast subpopulation is significantly increased in keloid compared to normal scar. Functional studies indicate that mesenchymal fibroblasts are crucial for collagen overexpression in keloid. Increased mesenchymal fibroblast subpopulation is also found in another fibrotic skin disease, scleroderma, suggesting this is a broad mechanism for skin fibrosis. These findings will help us better understand skin fibrotic pathogenesis, and provide potential targets for fibrotic disease therapies.
Bone metabolism can be influenced by a range of factors. We selected children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and lifestyles similar to those of healthy children to ...control for the confounding factors that may influence bone metabolism. We aimed to identify the specific effects of epilepsy and/or anti-seizure medications (ASMs) on bone metabolism.
Patients with SeLECTS were divided into an untreated group and a monotherapy group, and the third group was a healthy control group. We determined the levels of various biochemical markers of bone metabolism, including procollagen type I nitrogenous propeptide (PINP), alkaline phosphatase (ALP), osteocalcin (OC), collagen type I cross-linked C-telopeptide (CTX), calcium, magnesium, phosphorus, parathyroid hormone (PTH), and vitamin D
(VD
).
A total of 1487 patients (from 19 centers) were diagnosed with SeLECTS; 1032 were analyzed, including 117 patients who did not receive any ASMs (untreated group), 643 patients who received only one ASM (monotherapy group), and 272 children in the healthy control group. Except for VD
, other bone metabolism of the three groups were different (p < .001). Bone metabolism was significantly lower in the untreated group than the healthy control group (p < .05). There were significant differences between the monotherapy and healthy control group in the level of many markers. However, when comparing the monotherapy and untreated groups, the results were different; oxcarbazepine, levetiracetam, and topiramate had no significant effect on bone metabolism. Phosphorus and magnesium were significantly lower in the valproic acid group than the untreated group (adjusted p < .05, Cliff's delta .282-.768). CTX was significantly higher in the lamotrigine group than in the untreated group (adjusted p = .012, Cliff's delta = .316).
Epilepsy can affect many aspects of bone metabolism. After controlling epilepsy and other confounders that affect bone metabolism, we found that the effects of ASMs on bone metabolism differed. Oxcarbazepine, levetiracetam, and topiramate did not affect bone metabolism, and lamotrigine corrected some of the abnormal markers of bone metabolism in patients with epilepsy.
Petrological evidence is provided for partial melting of ultrahigh-pressure (UHP) metamorphic granitic gneiss in the Sulu orogen. Petrographic observations show the occurrence of elongated, highly ...cuspate feldspars in grain boundaries, interstitial cuspate feldspars in triple junctions, felsic veinlets mainly consisting of K-feldspar+quartz, and feldspar crystal faces against quartz. These features indicate that the feldspar and quartz would have grown from anatectic melts in the granitic gneiss. Zircon domains grown from these melts were identified based on CL images, mineral inclusions and REE patterns. Some large zircon grains (>100μm) contain small relict domains of magmatic origin, suggesting nearly complete dissolution of the protolith zircon during the anatexis. All newly grown zircon domains are categorized into two groups based on the presence or absence of coesite inclusions. One group of domains contain no coesite inclusion and exhibit high U contents but low Th/U ratios (<0.1), steep REE patterns with strong negative Eu anomalies, and UPb ages of 217±2 to 224±2Ma. The other group of domains contain coesite inclusions and exhibit low U contents and very low Th/U ratios (<0.01), steep REE patterns with strong negative Eu anomalies, and UPb ages of 221±5 to 226±3Ma. The two groups of zircon domains are thus interpreted as growing from the anatectic melts at different pressures because they exhibit marked negative Eu anomalies that are absent for metamorphic zircons grown from aqueous fluids. The zircon UPb ages of 217±2 to 226±3Ma are close to, but slightly younger than, known ages for major UHP metamorphism in the Sulu orogen. Therefore, the UHP gneiss experienced incipient melting during the initial exhumation subsequent to the peak UHP metamorphism and extensive anatexis later at lower pressures. Muscovite relicts coexist with cuspate feldspars, suggesting that the anatectic melts originate from dehydration melting due to decompression breakdown of phengitic muscovite in the UHP granitic gneiss. As the degree of partial melting increases with temperature, significant fractions of the anatectic melts would be produced in the regional gneiss provided that the UHP rocks experienced “hot” exhumation. Such melts can be gathered together, being eventually emplaced as synexhumation granitic intrusions.
► We provide petrological evidence for anatexis of UHP granitic gneiss during continental collision. ► Anatectic zircon was identified by the distinctive trace elements. ► Zircons record incipient melting after peak metamorphism and extensive anatexis during further exhumation. ► The dehydration-driven anatexis may be caused by phengite breakdown in the UHP rocks. ► Partial melting occurred more widely in the Sulu UHP terrane than previously thought.
Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent ...Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.
(
) has long been known to cause opportunistic infections and has recently been implicated in colorectal cancer (CRC), which has attracted broad attention. However, the mechanism by which it is ...involved in CRC development is not fully understood.
To explore its potential causative role in CRC development, we evaluated the colon pathology, mucosa barrier, colon microbiota and host transcriptome profile after
infection in an azoxymethane/dextran sulfate sodium salt (AOM/DSS) mouse model.
Three groups of mice were compared to reveal the differences,
, the control, AOM/DSS-induced CRC and AOM/DSS-FUSO infection groups.
Both the AOM/DSS and AOM/DSS-FUSO groups exhibited a significantly reduced body weight and increased tumor numbers than the control group, and AOM/DSS mice with
infection showed the highest tumor formation ratio among the three groups. Moreover, the colon pathology was the most serious in the AOM/DSS-FUSO group. We found that the structure of the colon microbiota changed considerably after
infection; striking differences in mucosal microbial population patterns were observed between the AOM/DSS-FUSO and AOM/DSS groups, and inflammation-inducing bacteria were enriched in the mucosal microbiota in the AOM/DSS-FUSO group. By comparing intestinal transcriptomics data from AOM
AOM/DSS-FUSO mice, we showed that transcriptional activity was strongly affected by dysbiosis of the gut microbiota. The most microbiota-sensitive genes were oncogenes in the intestine, and the cyclic adenosine monophosphate signaling pathway, neuroactive ligand-receptor interaction, PPAR signaling pathway, retinol metabolism, mineral absorption and drug metabolism were highly enriched in the AOM/DSS-FUSO group. Additionally, we showed that microbial dysbiosis driven by
infection enriched eight taxa belonging to Proteobacteria
which correlates with increased expression of oncogenic genes.
Our study demonstrated that
infection altered the colon mucosal microbiota by enriching pathogens related to the development of CRC, providing new insights into the role of
in the oncogenic microbial environment of the colon.
Zircon is a key accessary mineral for metamorphic geochronology and geochemical tracing, but it has been a challenge to interpret its complex chemical zoning and age record acquired during multiple ...episodes of anatectic metamorphism in collisional orogens. This is illustrated by a combined study of petrography, phase equilibrium modeling and metamorphic
P-T-t
determination for granulites from the Bohemian Massif in the Variscan Orogen. These rocks record multiple episodes of zircon growth during anatectic metamorphism. They started from the compressional heating for prograde metamorphism to high-pressure (HP) to ultrahigh-pressure (UHP) eclogite facies with low degrees of partial melting. Afterwards, they underwent a decompressional stage from UHP eclogite facies to HP granulite facies for dehydration melting. These were followed by a further decompressional stage either to kyanite granulite facies or to sillimanite granulite facies at ultrahigh-temperature (UHT) conditions. Episodes of zircon growth are linked to specific metamorphic conditions for peritectic reactions on the basis of zoning patterns, trace element signatures, index mineral inclusions in dated domains and textural relationships to coexisting minerals. The results indicate that relict zircon domains are preserved even at UHT granulite facies conditions. A few zircon domains in the kyanite granulite grew during the prograde to peak UHP metamorphism, possibly corresponding to consumption of biotite and plagioclase but growth of garnet. During the decompressional exhumation to the HP granulite-facies, relict or prograde zircon domains were mostly dissolved into anatectic melts produced by muscovite breakdown. Most zircon grains grew during this transition to the HP granulite-facies in the kyanite granulite and are chemically related to continuous growth of garnet, whereas abundant zircon grains grew subsequently at the UHT granulite facies in the sillimanite granulite and are chemically related to garnet breakdown reactions. Another peak of zircon growth occurred at the final crystallization of anatectic melts in the sillimanite granulite rather than in the kyanite granulite, and these zircon grains mostly show oscillatory zoning, low HREE + Y contents and significantly negative Eu anomalies. In terms of the inference for protolith nature, it appears that zircon in metasedimentary rocks can grow at a short timescale in different stages of anatectic metamorphism, and its dissolution and growth are mainly dictated by anatectic conditions and extent, the property of peritectic reactions, and the stability of Ti-rich minerals.
The pollution of organic dyes has become a serious environmental problem. It is still urgent to prepare a highly efficient and environment-friendly photocatalyst for pollutants removal. Herein, a ...micro-/nanostructured ZnFe
2
O
4
hollow sphere/GO (ZnFe
2
O
4
/GO) composite photocatalyst was prepared through a one-step hydrothermal method with high performance and recycling property. The obtained micro-/nanostructured composite was assembled by ZnFe
2
O
4
hollow spheres and GO nanosheets. The special self-assembled hollow nanosphere structure enlarged visible light harvesting. In addition, luminescence property demonstrates that the introduction of graphene oxide (GO) inhibits the recombination of electron–hole pairs, leading to enhancement of photocatalytic activity of ZnFe
2
O
4
. Under visible light irradiation, the ZnFe
2
O
4
/GO composite exhibited excellent photocatalytic activity for Congo red (93%), higher than that of the pure ZnFe
2
O
4
hollow spheres (only 60%) and commercial ZnFe
2
O
4
nanoparticles (40%). Moreover, the micro-/nanostructured ZnFe
2
O
4
/GO composite photocatalyst can be regenerated with high efficiency and remains over 80% activity after seven regenerations. This work not only supplies a new strategy for one-step preparation of such ZnFe
2
O
4
/GO micro-/nanostructures for structurally enhanced photocatalysis, but also provides a highly efficient photocatalyst for wastewater treatment.
Graphical abstract
The recycling of continental crust via trench sediment subduction and subduction erosion is well established in modern oceanic subduction zones, and this is fundamental to subduction zone magmatism ...and mantle heterogeneity. Although a similar process likely took place in ancient oceanic subduction zones, its evaluation is difficult because most geological records were erased by subsequent continental collision and post-collisional reworking processes. To address this issue, a comprehensive geochemical study was conducted for Mesozoic basaltic to andesitic plutonic rocks and surviving contemporaneous paleo-trench sediments from the Himalayan orogen in southern Tibet. These plutonic rocks show variably enriched Sr-Nd-Pb-Hf isotope compositions with εNd(t) values varying from −5.6 to +4.7, which are neither positively nor negatively correlated with Mg# values. This indicates that they were not affected by crustal contamination but rather inherited from heterogeneous magma sources. There are consistently continuous variations in the Sr-Nd-Pb-Hf isotope space among the paleo-trench sediments, the arc plutonic rocks, and basaltic rocks from the Yarlung Tsangpo ophiolite suites, indicating that the binary mixing between the paleo-trench sediment-derived melts and the ambient mantle dictated the radiogenic isotope compositions of the arc igneous rocks. These qualitative interpretations are further verified by quantitative geochemical examination of the compositional links in Nd and Hf isotopes between the paleo-trench sediments and arc rocks. As a consequence, the present study has for the first time identified and systematically demonstrated the key role of paleo-trench sediments in constraining the continental crust recycling as well as the origin and compositional heterogeneity of arc igneous rocks above ancient oceanic subduction zones.
•Paleo-trench sediments can constrain crustal recycling in ancient subduction zones.•Geochemical features of the Gangdese arc plutonic rocks vary greatly along strike.•The covariations between element and isotope ratios are the feature of primary magmas.•Source composition and melting degree have dictated the composition of the arc rocks.•Mantle sources of the arc magmas would containtrench sediment-derived melts.
Galectin-9, a tandem-repeat galectin, plays an important role in the regulation of innate immune response against various microbial infections. Here, galectin-9 from mudskipper (Boleophthalmus ...pectinirostris) was identified and named as BpGal-9. Putative BpGal-9 contains two conserved carbohydrate recognition domains (CRDs), one CRD within N-terminal (N-CRD) and the other one within C-terminal (C-CRD). Multi-alignment analysis indicated that BpGal-9 shared the highest amino acid sequence identity of 64.3 % with that of Southern platyfish (Xiphophorus maculatus). Phylogenetic analysis showed that BpGal-9 grouped tightly with other teleosts galectin-9 and was most closely related to that of Southern platyfish. BpGal-9 transcripts were more abundant in the intestine, and its expression upregulated significantly in the intestine, kidney, spleen, gills, and skin after Edwardsiella tarda infection. Meanwhile, BpGal-9 expression significantly increased in hemocytes and serum of mudskipper infected by E. tarda. The recombinant BpGal-9 (rBpGal-9) and rBpGal-9C-CRD could agglutinate all tested bacteria, whereas rBpGal-9N-CRD could only agglutinate three kinds of bacteria. When targeting the same bacteria, rBpGal-9 showed stronger agglutinating activities than rBpGal-9C-CRD or rBpGal-9N-CRD. In addition, the induction effect of three recombinant proteins on the mRNA expression of anti-inflammatory cytokines (BpIL-10 and BpTGF-β) was better than that on the pro-inflammatory cytokines (BpIL-1β and BpTNF-α). Our result suggested that the N-CRD and C-CRD of galectin-9 contribute differently to its multiple functions in innate immunity in teleosts.
Continental ultrahigh-pressure (UHP) metamorphic belts were tectonically developed from oceanic subduction to continental subduction. Petrological records of the tectonic transition can be preserved ...if the subducted oceanic crust is exhumed together with dominant crustal rocks of continental origin in collisional orogens. This is illustrated by the coexistence of continental-type and oceanic-type UHP eclogites in the North Qaidam orogen, northern Tibet. An integrated study of whole-rock major-trace elements, Sr-Nd isotopes and mineral O isotopes for eclogites, as well as zircon U-Pb ages and trace elements was carried out for UHP eclogites and gneisses from the North Qaidam orogen. The results allow discriminating between the two types of eclogites in their protolith origin. The continental-type eclogites are dominant there and characterized by Neoproterozoic protolith ages of ca. 850Ma, versatile trace element compositions, mostly positive εNd(t) values, and normal mantle-like δ18O values. Their protoliths are continental mafic igneous rocks that are originated from multiple mantle sources with different compositions. In comparison, the oceanic-type eclogites are minor there and have protolith ages of ca. 500Ma, positive εNd(t) values, and lower δ18O values than normal mantle δ18O values. Their protoliths are a kind of oceanic mafic igneous rocks that experienced high-T seafloor hydrothermal alteration. Both IAB-like and MORB- to OIB-like trace element compositions occur in the oceanic-type eclogites, suggesting their origination from a backarc basin close to the continental margin. Zircon U-Pb dating of the oceanic-type eclogites, continental-type eclogites and gneisses yields similar eclogite-facies metamorphic ages of 427–439Ma, with coesite inclusions in metamorphic zircons from one gneiss. The identical metamorphic ages for the two types of eclogites indicate that the exposed eclogites of oceanic origin were primarily residing in the continental margin and they were entrained by the UHP metamorphic rocks of continental origin for exhumation along the same subduction channel toward the surface. Therefore, identifying the occurrence of oceanic-type eclogites in the continental-type eclogite-gneiss associations is a valid means to decipher the tectonic development from oceanic subduction to continental collision.
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•Continental- and oceanic-type UHP eclogites are distinguished by geochemistry.•The two types of eclogites have the identical peak metamorphic ages.•They record the tectonic evolution from oceanic subduction to continental collision.
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