Up-regulation of BTN3A1 on CD14+ cells promotes Vγ9Vδ2 T cell activation in psoriasis.

Vγ9Vδ2 T cells play an important role in the development and progression of psoriasis vulgaris (PV), but how they promote skin inflammation and the molecular mechanisms underlying Vγ9Vδ2 T cell dysfunction are poorly understood. Here, we show that circulating Vγ9Vδ2 T cells are decreased and exhibit enhanced proliferation and increased production of IFN-γ and TNF-α in PV patients. Monocytes from PV patients express higher levels of the phosphoantigen sensor butyrophilin 3A1 (BTN3A1) than monocytes from healthy controls. Blockade of BTN3A1 suppresses Vγ9Vδ2 T cell activation and abolishes the difference in Vγ9Vδ2 T cell activation between PV patients and healthy controls. The CD14+ cells in PV skin lesions highly express BTN3A1 and juxtapose to Vδ2 T cells. In addition, IFN-γ induces the up-regulation of BTN3A1 on monocytes. Collectively, our results demonstrate a crucial role of BTN3A1 on monocytes in regulating Vγ9Vδ2 T cell activation and highlight BTN3A1 as a potential therapeutic target for psoriasis.

Establishment of a Mouse Model for Porokeratosis Due to Mevalonate Diphosphate Decarboxylase Deficiency.

INTRODUCTION: Porokeratosis (PK) is an autoinflammatory keratinization disease (AIKD) characterized by circular or annular skin lesions with a hyperkeratotic rim, pathologically shown as the cornoid lamella. Four genes that cause PK are associated with the mevalonate (MV) pathway. In Chinese PK patients, mevalonate diphosphate decarboxylase (MVD) is the most common causative gene. The lack of an animal model has greatly limited research on PK pathogenesis. MATERIALS AND METHODS: In this research, we constructed K14-CreERT2-Mvdfl/fl mice using the Cre-LoxP system to create a mouse model for in-depth studies of PK. The Epidermal Mvd gene was knocked out by intraperitoneal injection of Tamoxifen (TAM). Pathology, immunohistochemistry, RNA-seq, and Western Blot analysis were performed. RESULTS: Skin lesions appeared following Mvd deficiency, and pathological examination revealed the characteristic cornoid lamella, as well as cutaneous inflammation. Furthermore, we observed elevated levels of IL-17A and IL-1ß, and a decreased Loricrin level in epidermal Mvd-deficient mice. Compared with the wild-type (WT) group, Mvd deficiency activated the expression of lipid metabolism-related proteins. CONCLUSION: We developed the first mouse model for PK research, enabling further studies on disease development and treatment approaches.

The draft genome of the Tibetan partridge (Perdix hodgsoniae) provides insights into its phylogenetic position and high-altitude adaptation.

The Tibetan partridge (Perdix hodgsoniae) is a widely distributed endemic species in high-altitude areas across the Tibetan Plateau where the hypoxia, lower temperature and high ultraviolet radiation are pivotal factors influencing survival. However, the underlying genetic adaptation of the Tibetan partridge to extreme environments remains uncertain due to limited genomic resources. Similarly, the phylogenetic position of Perdix within Phasianidae remains controversial due to lacking information. Consequently, we de novo assembled and annotated the whole genome of the Tibetan partridge. The genome size was 1.15 Gb with contig N50 of 3.70 Mb. A total of 202.30 Mb (17.61%) repetitive elements and 445,876 perfect microsatellites were identified. A total of 16,845 functionally annotated protein-coding genes were identified in the Tibetan partridge. Genomic phylogenetic analysis across 30 Galliformes species indicated a close relationship between Perdix and typical pheasants composed of Chrysolophus, Symaticus, Phasianus, Crossopilon, and Lophura. However, the phylogenetic relationship of (Perdix + (Chrysolophus + (Syrmaticus + other pheasants))) was different from those of (Perdix + (Syrmaticus + (Chrysolophus + other pheasants))) in previous studies. Comparative genomic results identified NFKB1 and CREBBP positively selected genes related to hypoxia with 3 and 2 Tibetan partridge-specific missense mutations, respectively. Expanded gene families were mainly associated with energy metabolism and steroid hydroxylase activity, meanwhile, contracted gene families were mainly related to immunity and olfactory perception. Our genomic data considerably contribute to the phylogeny of Perdix and the underlying adaptation strategies of the Tibetan partridge to a high-altitude environment.

The complete mitochondrial genome of Morishitium polonicum (Trematoda, Cyclocoelidae) and its phylogenetic implications.

Trematodes can adversely impact the health and survival of wild animals. The trematode family Cyclocoelidae, which includes large digenean bird parasites, lacks molecular analysis, and reclassifications have not been supported. This study produced the first fully assembled and annotated mitochondrial genome sequence for the trematode Morishitium polonicum. The whole length of the M. polonicum (GenBank accession number: OP930879) mitogenome is 14083 bp, containing 22 transfer ribonucleic acids (tRNAs), 2 ribosomal RNAs (rRNAs, rrnL and rrnS), and a noncoding control section (D-loop) 13777 to 13854 bp in length. The 12 PCG areas have 3269 codons and a total length of 10053 bp, which makes up 71.38% of the mitochondrial genome's overall sequence. Most (10/12) of the PCGs that code for proteins begin with ATG, while the nad4L and nad1 genes have a GTG start codon. Phylogenetic analysis using the concatenated nucleotide sequences of 12 PCGs, and the ML tree analysis results showed that M. polonicum is more closely related to with Echinostomatidae and Fasciolidae, which indicates that the family Cyclocoelidae is more closely associated with Echinochasmidae. This study provides mtDNA information, and analysis of mitogenomic structure and evolution. Moreover, we aimed to understand the phylogenetic relationships of this fluke.

E-TBNet: Light Deep Neural Network for Automatic Detection of Tuberculosis with X-ray DR Imaging.

Currently, the tuberculosis (TB) detection model based on chest X-ray images has the problem of excessive reliance on hardware computing resources, high equipment performance requirements, and being harder to deploy in low-cost personal computer and embedded devices. An efficient tuberculosis detection model is proposed to achieve accurate, efficient, and stable tuberculosis screening on devices with lower hardware levels. Due to the particularity of the chest X-ray images of TB patients, there are fewer labeled data, and the deep neural network model is difficult to fully train. We first analyzed the data distribution characteristics of two public TB datasets, and found that the two-stage tuberculosis identification (first divide, then classify) is insufficient. Secondly, according to the particularity of the detection image(s), the basic residual module was optimized and improved, and this is regarded as a crucial component of this article's network. Finally, an efficient attention mechanism was introduced, which was used to fuse the channel features. The network architecture was optimally designed and adjusted according to the correct and sufficient experimental content. In order to evaluate the performance of the network, it was compared with other lightweight networks under personal computer and Jetson Xavier embedded devices. The experimental results show that the recall rate and accuracy of the E-TBNet proposed in this paper are better than those of classic lightweight networks such as SqueezeNet and ShuffleNet, and it also has a shorter reasoning time. E-TBNet will be more advantageous to deploy on equipment with low levels of hardware.

Soluble (pro)renin receptor regulation of ENaC involved in aldosterone signaling in cultured collecting duct cells.

We have previously shown that activation of (pro)renin receptor (PRR) induces epithelial Na+ channel (ENaC) activity in cultured collecting duct cells. Here, we examined the role of soluble PRR (sPRR), the cleavage product of PRR in ENaC regulation, and further tested its relevance to aldosterone signaling. In cultured mpkCCD cells, administration of recombinant histidine-tagged sPRR (sPRR-His) at 10 nM within minutes induced a significant and transient increase in the amiloride-sensitive short-circuit current as assessed using the Ussing chamber technique. The acute ENaC activation was blocked by the NADPH oxidase 1/4 inhibitor GKT137892 and siRNA against Nox4 but not the ß-catenin inhibitor ICG-001. In primary rat inner medullary collecting duct cells, administration of sPRR-His at 10 nM for 24 h induced protein expression of the α-subunit but not ß- or γ-subunits of ENaC, in parallel with upregulation of mRNA expression as well as promoter activity of the α-subunit. The transcriptional activation of α-ENaC was dependent on ß-catenin signaling. Consistent results obtained by epithelial volt ohmmeter measurement of equivalent current and Ussing chamber determination of short-circuit current showed that aldosterone-induced transepithelial Na+ transport was inhibited by the PRR decoy inhibitor PRO20 and PF-429242, an inhibitor of sPRR-generating enzyme site-1 protease, and the response was restored by the addition of sPRR-His. Medium sPRR was elevated by aldosterone and inhibited by PF-429242. Taken together, these results demonstrate that sPRR induces two phases of ENaC activation via distinct mechanisms and functions as a mediator of the natriferic action of aldosterone.

Soluble (pro)renin receptor via ß-catenin enhances urine concentration capability as a target of liver X receptor.

The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent ß-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.

Collecting duct (pro)renin receptor targets ENaC to mediate angiotensin II-induced hypertension.

The (pro)renin receptor (PRR) is abundantly expressed in the collecting duct (CD) and the expression is further induced by angiotensin II (ANG II). The present study was conducted to investigate the role of CD PRR during ANG II-induced hypertension and to further explore the underlying mechanism. Radiotelemetry demonstrated that a 1-wk ANG II infusion gradually and significantly induced hypertensive response in floxed mice and this response was significantly attenuated in mice lacking PRR in the CD (termed CD PRR KO). ANG II infusion in floxed mice increased urinary renin activity and selectively induced renal medullary α-epithelial sodium channel (α-ENaC) mRNA and protein expression, all of which were blunted in the null mice. In cultured mpkCCD cells grown in Transwells, transepithelial Na+ transport as measured by using a volt-ohmmeter was transiently stimulated by acute ANG II treatment, which was abolished by a PRR antagonist, PRO20. In a chronic setting, ANG II treatment induced α-ENaC mRNA expression in mpkCCD cells, which was similarly blocked by PRO20. Chronic intramedullary infusion of an ENaC inhibitor amiloride in rats significantly attenuated ANG II-induced hypertension. Overall, the present study suggests that CD PRR contributes to ANG II-induced hypertension at least partially via activation of renal medullary ENaC.

Antidiuretic Action of Collecting Duct (Pro)Renin Receptor Downstream of Vasopressin and PGE2 Receptor EP4.

Within the kidney, the (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), particularly in intercalated cells, and it is regulated by the PGE2 receptor EP4 Notably, EP4 also controls urinary concentration through regulation of aquaporin 2 (AQP2). Here, we tested the hypothesis that sequential activation of EP4 and PRR determines AQP2 expression in the CD, thus mediating the antidiuretic action of vasopressin (AVP). Water deprivation (WD) elevated renal PRR expression and urinary soluble PRR excretion in rats. Intrarenal infusion of a PRR decoy peptide, PRO20, or an EP4 antagonist partially prevented the decrease in urine volume and the increase in urine osmolality and AQP2 expression induced by 48-hour WD. In primary cultures of rat inner medullary CD cells, AQP2 expression induced by AVP treatment for 24 hours depended on sequential activation of the EP4 receptor and PRR. Additionally, mice lacking PRR in the CD exhibited increased urine volume and decreased urine osmolality under basal conditions and impaired urine concentrating capability accompanied by severe volume loss and a dangerous level of plasma hyperosmolality after WD. Together, these results suggest a previously undescribed linear AVP/PGE2/EP4/PRR pathway in the CD for regulation of AQP2 expression and urine concentrating capability.

Serum response factor induces endothelial-mesenchymal transition in glomerular endothelial cells to aggravate proteinuria in diabetic nephropathy.

We investigated the expression and function of serum response factor (SRF) in endothelial-mesenchymal transition (EndMT) in glomerular endothelial cells (GEnCs) of diabetic nephropathy (DN). The expression of SRF, endothelial markers (VE-cadherin, CD31), and mesenchymal markers (α-SMA, FSP-1, fibronectin) was examined in GEnCs following high glucose or in renal cortex tissues of DN rats. SRF was upregulated by SRF plasmids and downregulated by CCG-1423 (a small molecule inhibitor of SRF) to investigate how SRF influenced EndMT in GEnCs of DN. Streptozocin (STZ) was used to generate diabetes mellitus DM in rats. In GEnCs after high glucose treatment and in renal cortex tissues of diabetic rats, SRF, α-SMA, FSP-1, and fibronectin increased, while VE-cadherin and CD31 declined. SRF overexpression in GEnCs induced expression of Snail, an important transcription factor mediating EndMT. Blockade of SRF reduced Snail induction, protected GEnCs from EndMT, and ameliorated proteinuria. Together, increased SRF activity provokes EndMT and barrier dysfunction of GEnCs in DN. Targeting SRF by small molecule inhibitor may be an attractive therapeutic strategy for DN.

COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla.

(Pro)renin receptor (PRR) is predominantly expressed in the distal nephron where it is activated by angiotensin II (ANG II), resulting in increased renin activity in the renal medulla thereby amplifying the de novo generation and action of local ANG II. The goal of the present study was to test the role of cycloxygenase-2 (COX-2) in meditating ANG II-induced PRR expression in the renal medulla in vitro and in vivo. Exposure of primary rat inner medullary collecting duct cells to ANG II induced sequential increases in COX-2 and PRR protein expression. When the cells were pretreated with a COX-2 inhibitor NS-398, ANG II-induced upregulation of PRR protein expression was almost completely abolished, in parallel with the changes in medium active renin content. The inhibitory effect of NS-398 on the PRR expression was reversed by adding exogenous PGE2. A 14-day ANG II infusion elevated renal medullary PRR expression and active and total renin content in parallel with increased urinary renin, all of which were remarkably suppressed by the COX-2 inhibitor celecoxib. In contrast, plasma and renal cortical active and total renin content were suppressed by ANG II treatment, an effect that was unaffected by COX-2 inhibition. Systolic blood pressure was elevated with ANG II infusion, which was attenuated by the COX-2 inhibition. Overall, the results obtained from in vitro and in vivo studies established a crucial role of COX-2 in mediating upregulation of renal medullary PRR expression and renin content during ANG II hypertension.

Chromosome-level genome assembly of the kiang (Equus kiang) illuminates genomic basis for its high-altitude adaptation.

The kiang (Equus kiang) can only be observed in the Qinghai-Tibet Plateau (QTP). The kiang displayed excellent athletic performance in the high-altitude environment, which attracted wide interest in the investigation of the potential adaptive mechanisms to the extreme environment. Here, we assembled a chromosome-level genome of the kiang based on Hi-C sequencing technology. A total of 324.14 Gb clean data were generated, and the chromosome-level genome with 26 chromosomes (25 + X) and scaffold N50 of 101.77 Mb was obtained for the kiang. The genomic synteny analysis revealed large-scale chromosomal rearrangement during the evolution process of Equus species. Phylogenetic and divergence analyses revealed that the kiang was the sister branch to the ass and diverged from a common ancestor at approximately 13.5 Mya. The expanded gene families were mainly related to the hypoxia response, metabolism, and immunity. The kiang suffered a significant loss of olfaction-related genes, which might indicate decreased olfactory sensibility. Positively selected genes (PSGs) detected in the kiang were mainly associated with hypoxia response. Especially, there were two species-specific missense amino acid mutations in the PSG STAT3 annotated in the hypoxia-inducible factor 1 signal pathway, which may play an important role in the high-altitude adaptation of the kiang. Moreover, structure variations in the kiang genome were also identified, which possibly contributed to the high-altitude adaptation of the kiang. Comparative analysis revealed a lot of species-specific insertions and deletions in the kiang genome, such as PIK3CB and AKT with 3258 and 189 bp insertions in the intron region, respectively, possibly affecting the expression and regulation of hypoxia-related downstream pathways. This study provided valuable genomic resources, and our findings help a better understanding of the underlying adaptive strategies to the high-altitude environment in the kiang.

Association of screen-based activities and risk of self-harm and suicidal behaviors among young people: A systematic review and meta-analysis of longitudinal studies.

Emerging evidence suggests that screen-based activities are associated with self-harm and suicidal behaviors. This study aimed to examine these associations among young people through a meta-analysis. We systematically searched EBSCO pshyARTICLES, MEDLINE (via PubMed), EMBASE, and Web of Science from their inception to April 1, 2022, and updated on May 1, 2024. Longitudinal studies reporting the association between various screen-based activities and subsequent self-harm and suicidal behaviors in young people aged 10 to 24 were included. Nineteen longitudinal studies were included in the qualitative synthesis, and 13 studies comprising 43,489 young people were included in the meta-analysis, revealing that total screen use is significantly associated with the risks of self-harm and suicidal behaviors. Cyberbullying victimization was also related to these adverse outcomes. Subgroup analyses indicated that social media use and problematic screen use are significant risk factors for self-harm and suicidal behaviors. Study quality was appraised using the Newcastle-Ottawa Scale, and potential publication bias was deemed unlikely to affect the results significantly. These findings suggest that screen-based activities should be considered in the management and intervention strategies for self-harm and suicidal behaviors in young people.

Climate factors and food availability shape the altitudinal migration of birds in the Xiling Snow Mountains, China.

Many bird species in montane regions display altitudinal migration, but so far, the underlying ecological driving mechanisms are not clear. We studied the altitudinal migration behavior patterns and factors influencing altitudinal migration in the Xiling Snow Mountains, which are part of the Hengduan mountain range in southwest China. We recorded the local bird diversity, the seasonal change of: the average temperature (AT), the average humidity (AH), the average invertebrate biomass (AIB), and the amount of plant food sources (PFS) at two study sites (∼1300 and ∼2100 m a.s.l.) during two migration seasons from September 2022 to May 2023. During our surveys, we recorded 96 bird species in total. Among these, 15 altitudinal migrants were identified. The most common family among altitudinal migrants was Leiothrichidae. AT, AIB, and PFS had a significant positive correlation with the monthly number of individuals (MNI) several bird species, implying that increasing temperatures and an increasing abundance of invertebrates and PFS possibly induced upward migration of altitudinal migrants and vice versa. AH possibly only played a minor role in influencing altitudinal migration, since it exhibited no significant correlation with the MNI. Furthermore, we found that the upward migration temperature range of altitudinal migrants ranged between 9.8°C and 13.9°C during spring and the downward migration temperature range ranged between 12.2°C and 7.9°C during autumn. In conclusion, our study and several other studies revealed that the same environmental factors influenced the altitudinal migration patterns of birds in the Hengduan Mountains.

The diet-intestinal microbiota dynamics and adaptation in an elevational migration bird, the Himalayan bluetail (Tarsiger rufilatus).

Migratory birds experience changes in their environment and diet during seasonal migrations, thus requiring interactions between diet and gut microbes. Understanding the co-evolution of the host and gut microbiota is critical for elucidating the rapid adaptations of avian gut microbiota. However, dynamics of gut microbial adaptations concerning elevational migratory behavior, which is prevalent but understudied in montane birds remain poorly understood. We focused on the Himalayan bluetail (Tarsiger rufilatus) in the montane forests of Mt. Gongga to understand the diet-gut microbial adaptations of elevational migratory birds. Our findings indicate that elevational migratory movements can rapidly alter gut microbial composition and function within a month. There was a significant interaction between an animal-based diet and gut microbiota across migration stages, underscoring the importance of diet in shaping microbial communities. Furthermore, the gut microbial composition of T. rufilatus may be potentially altered by high-altitude acclimatization. An increase in fatty acid and amino acid metabolism was observed in response to low temperatures and limited resources, resulting in enhanced energy extraction and nutrient utilization. Moreover, microbial communities in distinct gut segments varied in relative abundance and responses to environmental changes. While the bird jejunum exhibited greater susceptibility to food and environmental fluctuations, there was no significant difference in metabolic capacity among gut segments. This study provides initial evidence of rapid diet-gut microbial changes in distinct gut segments of elevational migratory birds and highlights the importance of seasonal sample collection. Our findings provide a deeper understanding of the unique high-altitude adaptation patterns of the gut microbiota for montane elevational migratory birds.

Functional adhesive hydrogels for biological interfaces.

Hydrogel adhesives are extensively employed in biological interfaces such as epidermal flexible electronics, tissue engineering, and implanted device. The development of functional hydrogel adhesives is a critical, yet challenging task since combining two or more attributes that seem incompatible into one adhesive hydrogel without sacrificing the hydrogel's pristine capabilities. In this Review, we highlight current developments in the fabrication of functional adhesive hydrogels, which are suitable for a variety of application scenarios, particularly those that occur underwater or on tissue/organ surface conditions. The design strategies for a multifunctional adhesive hydrogel with desirable properties including underwater adhesion, self-healing, good biocompatibility, electrical conductivity, and anti-swelling are discussed comprehensively. We then discuss the challenges faced by adhesive hydrogels, as well as their potential applications in biological interfaces. Adhesive hydrogels are the star building blocks of bio-interface materials for individualized healthcare and other bioengineering areas.

Comparative Analyses Reveal the Genetic Mechanism of Ambergris Production in the Sperm Whale Based on the Chromosome-Level Genome.

Sperm whales are a marine mammal famous for the aromatic substance, the ambergris, produced from its colon. Little is known about the biological processes of ambergris production, and this study aims to investigate the genetic mechanism of ambergris production in the sperm whale based on its chromosome-level genome. Comparative genomics analyses found 1207 expanded gene families and 321 positive selected genes (PSGs) in the sperm whale, and functional enrichment analyses suggested revelatory pathways and terms related to the metabolism of steroids, terpenoids, and aldosterone, as well as microbiota interaction and immune network in the intestine. Furthermore, two sperm-whale-specific missense mutations (Tyr393His and Leu567Val) were detected in the PSG LIPE, which has been reported to play vital roles in lipid and cholesterol metabolism. In total, 46 CYP genes and 22 HSD genes were annotated, and then mapped to sperm whale chromosomes. Furthermore, phylogenetic analysis of CYP genes in six mammals found that CYP2E1, CYP51A and CYP8 subfamilies exhibited relative expansion in the sperm whale. Our results could help understand the genetic mechanism of ambergris production, and further reveal the convergent evolution pattern among animals that produce similar odorants.

HIF-1α promotes kidney organoid vascularization and applications in disease modeling.

BACKGROUND: Kidney organoids derived from human pluripotent stem cells (HiPSCs) hold huge applications for drug screening, disease modeling, and cell transplanting therapy. However, these applications are limited since kidney organoid cannot maintain complete morphology and function like human kidney. Kidney organoids are not well differentiated since the core of the organoid lacked oxygen, nutrition, and vasculature, which creates essential niches. Hypoxia-inducible factor-1 α (HIF-1α) serves as a critical regulator in vascularization and cell survival under hypoxia environment. Less is known about the role of HIF-1α in kidney organoids in this regard. This study tried to investigate the effect of HIF-1α in kidney organoid vascularization and related disease modeling. METHODS: For the vascularization study, kidney organoids were generated from human induced pluripotent stem cells. We overexpressed HIF-1α via plasmid transfection or treated DMOG (Dimethyloxallyl Glycine, an agent for HIF-1α stabilization and accumulation) in kidney progenitor cells to detect the endothelium. For the disease modeling study, we treated kidney organoid with cisplatin under hypoxia environment, with additional HIF-1α transfection. RESULT: HIF-1α overexpression elicited kidney organoid vascularization. The endothelial cells and angiotool analysis parameters were increased in HIF-1α plasmid-transfected and DMOG-treated organoids. These angiogenesis processes were partially blocked by VEGFR inhibitors, semaxanib or axitinib. Cisplatin-induced kidney injury (Cleaved caspase 3) was protected by HIF-1α through the upregulation of CD31 and SOD2. CONCLUSION: We demonstrated that HIF-1α elicited the process of kidney organoid vascularization and protected against cisplatin-induced kidney organoid injury in hypoxia environment.

Decreased Imiquimod-Induced Psoriasis-Like Skin Inflammation in a Novel MvdF250S/+ Knock-In Mouse Model.

The mevalonate-diphosphate decarboxylase (MVD) gene, a member of the mevalonate pathway, plays a critical role in regulating the biosynthesis of cholesterol, steroid hormones, and non-steroid isoprenoids. Previous studies have suggested that the MVD c.746 T > C mutation is a major pathogenic gene of porokeratosis (PK), an autoinflammatory keratinization disease (AIKD) with unclear pathogenesis, few effective treatments, and no suitable animal model. To investigate the function of MvdF250S/+ mutation, we developed a novel MvdF250S/+ mouse model carrying an equivalent point mutation to the most common genetic variation among Chinese PK patients (MVDF249S/+) using CRISPR/Cas9 technology, which exhibited reduced cutaneous expression of Mvd protein. In the absence of external stimulation, MvdF250S/+ mice did not display specific phenotypes. However, upon induction with imiquimod (IMQ), MvdF250S/+ mice exhibited decreased susceptibility to skin acute inflammation compared to wild-type (WT) mice, as evidenced by reduced cutaneous proliferation and lower protein levels of IL-17a and IL-1ß. Additionally, after IMQ induction, the MvdF250S/+mice exhibited downregulated collagen generation and upregulated expression of Fabp3 compared to WT mice, whereas no significant changes in the key genes related to cholesterol regulation were found. Furthermore, the MvdF250S/+ mutation activated autophagy. Our findings provided insights into the biological function of MVD in the skin.