Seeded Growth of Size-Tunable Au@Ag Core-Shell Nano-Octahedra and Their Yolk-Shell Derivatives for Near Infrared Photothermal Conversion.

Gold-based nanostructures with well-defined morphologies and hollow interiors have significant potential as a versatile platform for various plasmonic applications including biomedical diagnostics and sensing. In this study, we report the synthesis of Au@Ag core-shell nanocrystals with perfect octahedral shapes and tunable edge lengths via seeded growth. These nanocrystals were then oxidatively carved into yolk-shell nanocages with a retained octahedral morphology. The increase in octahedral edge length and volume of the interior hollow cavity synergistically leads to a red-shift of the LSPR peak. As a result, the optimized Au@AuAg yolk-shell octahedral nanocages showed a remarkable temperature increase of 23 °C upon 15 min irradiation of an 808 nm laser at a power density of 1 W cm-2. This study provides a feasible strategy for creating octahedral AuAg nanostructures with tunable sizes and hollow interiors and validates their promising use in NIR photothermal conversion.

Blue light protection factor: a method to assess the protective efficacy of cosmetics against blue light-induced skin damage in the Chinese population.

BACKGROUND: Previous studies have shown that visible light (VL), especially blue light (BL), could cause significant skin damage. With the emergence of VL protection products, a harmonization of light protection methods has been proposed, but it has not been widely applied in the Chinese population. OBJECTIVE: Based on this framework, we propose an accurate and simplified method to evaluate the efficacy of BL photoprotection for the Chinese population. METHODS: All subjects (n = 30) were irradiated daily using a blue LED light for four consecutive days. Each irradiation dose was 3/4 MPPD (minimum persistent pigmentation darkening). The skin pigmentation parameters, including L*, M, and ITA°, were recorded. We proposed the blue light protection factor (BPF) metric based on the skin pigmentation parameters to evaluate the anti-blue light efficacies of different products. RESULTS: We found that the level of pigmentation rose progressively and linearly as blue light exposure increased. We proposed a metric, BPF, to reflect the anti-blue light efficacy of products based on the linear changes in skin pigment characteristics following daily BL exposure. Moreover, we discovered that the BPF metric could clearly distinguish the anti-blue light efficacies between two products and the control group, suggesting that BPF is an efficient and simple-to-use metric for anti-blue light evaluation. CONCLUSION: Our study proposed an accurate and simplified method with an easy-to-use metric, BPF, to accurately characterize the anti-blue light efficacies of cosmetic products, providing support for further development of anti-blue light cosmetics.

TET1 inhibits liver fibrosis by blocking hepatic stellate cell activation.

Hepatic stellate cells (HSCs) are critical regulator contributing to the onset and progression of liver fibrosis. Chronic liver injury triggers HSCs to undergo vast changes and trans-differentiation into a myofibroblast HSCs, the mechanism remains to be elucidated. This study investigated that the involvement of hydroxymethylase TET1 (ten-eleven translocation 1) in HSC activation and liver fibrosis. It is revealed that TET1 levels were downregulated in the livers in mouse models of liver fibrosis and patients with cirrhosis, as well as activated HSCs in comparison to quiescent HSCs. In vitro data showed that the inhibition of TET1 promoted the activation HSC, whereas TET1 overexpression inhibited HSC activation. Moreover, TET1 could regulate KLF2 (Kruppel-like transcription factors) transcription by promoting hydroxymethylation of its promoter, which in turn suppressed the activation of HSCs. In vivo, it is confirmed that liver fibrosis was aggravated in Tet1 knockout mice after CCl4 injection, accompanied by excessive activation of primary stellate cells, in contrast to wild-type mice. In conclusion, we suggested that TET1 plays a significant role in HSC activation and liver fibrosis, which provides a promising target for anti-fibrotic therapies.

WDFY4 polymorphisms in Chinese patients with anti-MDA5 dermatomyositis is associated with rapid progressive interstitial lung disease.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+DM), is susceptible to development of rapidly progressive interstitial lung disease (RPILD), which has been predominantly reported in East Asia. A Japanese genome-wide study has identified a WDFY4 variant rs7919656 linkage. We sought to evaluate this genetic marker and exploit its possible clinical relevance in Chinese MDA5+DM. METHODS: We genotyped and compared the minor allele A frequency of WDFY4 rs7919656 in patients with MDA5+DM (n = 254) including 190 clinically amyopathic dermatomyositis (CADM), MDA5-DM (n = 53), anti-synthetases syndrome (ASyS, n = 72) and healthy controls (n = 192). Association of the WDFY4 variant with clinical phenotype was evaluated using logistic regression. RESULTS: Although the minor allele A frequencies of WDFY4 rs7919656 in MDA5+DM and CADM were comparable to that in healthy controls, we observed a significant correlation between the WDFY4 variant (GA+AA genotype) and the incidence of RPILD in MDA5+DM (OR: 2.11; 95% CI: 1.21, 3.69; P = 0.007). Moreover, this variant was an independent risk factor for RPILD in multivariate analysis (OR: 4.98; 95% CI: 1.59, 17.19; P = 0.008), along with other well-recognized risk factors, i.e. forced vital capacity % predicted, diffusing capacity for carbon monoxide % predicted, serum ferritin and prednisolone exposure. In addition, this variant was associated with higher expression of WDFY4 in PBMCs of MDA5+DM, especially those with RPILD. WDFY4 overexpression was also observed in lung biopsy of MDA5+DM-RPILD bearing the variant genotype. CONCLUSION: We found that the WDFY4 variant was associated with an increased risk of RPILD, not with disease susceptibility in Chinese MDA5+DM.

TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis.

OBJECTIVES: Innate immunity significantly contributes to systemic sclerosis (SSc) pathogenesis. TLR8 is an important innate immune mediator that is implicated in autoimmunity and fibrosis. However, the expression, mechanism of action, and pathogenic role of TLR8 in SSc remain unclear. The aim of this study was to explore the roles and underlying mechanisms of TLR8 in SSc. METHODS: The expression of TLR8 was analyzed based on a public dataset and then verified in skin tissues and skin fibroblasts of SSc patients. The role of TLR8 in inflammation and fibrosis was investigated using a TLR8-overexpression vector, activator (VTX-2337), inhibitor (cu-cpt-8m), and TLR8 siRNA in skin fibroblasts. The pathogenic role of TLR8 in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse skin inflammation and fibrosis model. RESULTS: TLR8 levels were significantly elevated in SSc skin tissues and myofibroblasts, along with significant activation of the TLR8 pathway. In vitro studies showed that overexpression or activation of TLR8 by a recombinant plasmid or VTX-2337 upregulated IL-6, IL-1ß, COL I, COL III, and α-SMA in skin fibroblasts. Consistently, both TLR8-siRNA and cu-cpt-8m reversed the phenotypes observed in TLR8-activating fibroblasts. Mechanistically, TLR8 induces skin fibrosis and inflammation in a manner dependent on the MAPK, NF-κB, and SMAD2/3 pathways. Subcutaneous injection of cu-cpt-8m significantly alleviated BLM-induced skin inflammation and fibrosis in vivo. CONCLUSION: TLR8 might be a promising therapeutic target to improve the treatment strategy for SSc skin inflammation and fibrosis.

An optimal method for quantifying the facial sebum level and characterizing facial sebum features.

BACKGROUND: Evidence suggests that sebum content is important in skin disorders such as acne. However, sebum levels change depending on the external environment, and quantifying skin sebum levels is challenging. Here, we propose an optimal method for quantifying the facial sebum level. MATERIALS AND METHODS: Four hundred and sixty participants (160 males and 300 females) aged 20-40 were enrolled in this study. A Sebumeter SM 810 was used to measure the sebum level at five facial locations: the forehead, the chin, the left cheek, the right cheek, and the nose. The participants were divided into two groups; one group underwent a one-time measurement (n = 390, male: female = 120: 270), and the other underwent three consecutive measurements (n = 70, male: female = 40: 30). The casual sebum level (CSL) was measured in all patients after a 30-min acclimatization; subsequently, the sebum removal process was conducted, followed by a resting period of 1 h to determine the sebum excretion rate (SER). Spearman's correlation analysis and the Wilcoxon signed-rank test were used to compare the sebum level consistency and differences between the groups. RESULTS: Although three consecutive measurements better reflected the sebum content, the one-time measurement also represented the relative sebum level. One hour after sebum removal, the sebum level recovered to 70%-90%; thus, this method was applicable for use in SER quantification. Of the five testing points, the sebum content was highest in the nose and lowest in the cheeks (both left and right). In addition, the cheeks were the most stable sites in terms of testing points, testing times, and CSL/SER values. A one-time measurement of the CSL could represent the SER 1 h after the sebum removal. In our cohort, the sebum level of males with oily skin was decreased at age 32-35, and that of males with non-oily skin increased at 28-35. The opposite trend was observed in female participants. CONCLUSION: Sebum measurement methods were assessed, including testing times, indices (interval of time) and sites in a conditioned external environment. A one-time measurement of the CSL 1 h after sebum removal was sufficient to determine the sebum level and SER, and the cheeks are recommended as the testing site. Sex and skin type differences were observed in sebum level changes with age.

Boosting Electrocatalytic Oxidation of Formic Acid on Ir(IV)-Doped PdAg Alloy Nanodendrites with Sub-5 nm Branches.

The formic acid oxidation reaction (FAOR) represents an important class of small organic molecule oxidation and is central to the practical application of fuel cells. In this study, we report the fabrication of Ir(IV)-doped PdAg alloy nanodendrites with sub-5 nm branches via stepwise synthesis in which the precursors of Pd and Ag were co-reduced, followed by the addition of IrCl3 to conduct an in situ galvanic replacement reaction. When serving as the electrocatalyst for the FAOR in an acidic medium, Ir(IV) doping unambiguously enhanced the activity of PdAg alloy nanodendrites and improved the reaction kinetics and long-term stability. In particular, the carbon-supported PdAgIr nanodendrites exhibited a prominent mass activity with a value of 1.09 A mgPd-1, which is almost 2.0 times and 2.7 times that of their PdAg and Pd counterparts, and far superior to that of commercial Pt/C. As confirmed by the means of the DFT simulations, this improved electrocatalytic performance stems from the reduced overall barrier in the oxidation of formic acid into CO2 during the FAOR and successful d-band tuning, together with the stabilization of Pd atoms. The current study opens a new avenue for engineering Pd-based trimetallic nanocrystals with versatile control over the morphology and composition, shedding light on the design of advanced fuel cell electrocatalysts.

Seeded Growth of Gold-Copper Janus Nanostructures as a Tandem Catalyst for Efficient Electroreduction of CO2 to C2+ Products.

Gold-copper (Au-Cu) Janus nanostructures (Au-Cu Janus NSs) are successfully prepared using N-oleyl-1,3-propanediamine as capping agent and Cu(acac)2 as the precursor in a typical seeded growth strategy. By preferably depositing Cu atoms on one side of concave cubic Au seeds, the Cu part gradually grows larger as more Cu precursors are added, making the size tuning feasible in the range of 74-156 nm. When employed as an electrocatalyst for electrochemical CO2 reduction (CO2 RR), the Au-Cu Janus NSs display superior performance to Au@Cu core-shell NSs and Cu NPs in terms of C2+ products selectivity (67%) and C2+ partial current density (-0.29 A cm-2 ). Combined experimental verification and theoretical simulations reveal that CO spillover from Au sites to the nearby Cu counterparts would enhance CO coverage and thus promote C-C coupling, highlighting the unique structural advantages of the Au-Cu Janus NSs toward deep reduction of CO2 . The current work provides a facile strategy to fabricate tandem catalyst with a Janus structure and validates its structural advantages toward CO2 RR, which are of critical importance for the rational design of efficient CO2 RR catalyst.

Insights into male androgenetic alopecia using comparative transcriptome profiling: hypoxia-inducible factor-1 and Wnt/ß-catenin signalling pathways.

BACKGROUND: The key pathophysiological changes in androgenetic alopecia (AGA) are limited to hair follicles (HFs) in frontal and vertex regions, sparing the occipital region. OBJECTIVES: To identify biological differences among HF subpopulations. METHODS: Paired vertex and occipital HFs from 10 male donors with AGA were collected for RNA sequencing assay. Furthermore, HF and cell experiments were conducted on the identified key genes to reveal their roles in AGA. RESULTS: Transcriptome profiles revealed that 506 mRNAs, 55 microRNAs and 127 long noncoding RNAs were differentially expressed in the AGA vertex HFs. Pathway analysis of mRNAs and microRNAs revealed involvement of the hypoxia-inducible factor (HIF)-1, Wnt/ß-catenin, and focal adhesion pathways. Differential expression of HIF-1 prolyl hydroxylase enzymes (EGLN1, EGLN3) and Wnt/ß-catenin pathway inhibitors (SERPINF1, SFRP2) was experimentally validated. In vitro studies revealed that reduction of EGLN1, EGLN3, SERPINF1 and SFRP2 stimulated proliferation of dermal papilla cells. Ex vivo HF studies showed that downregulation of EGLN1, EGLN3 and SERPINF1 promoted HF growth, postponed HF catagen transition, and prolonged the anagen stage, suggesting that these genes may be potentially utilized as therapeutic targets for AGA. CONCLUSIONS: We characterized key transcriptome changes in male AGA HFs, and found that HIF-1 pathway-related genes (EGLN1, EGLN3) and Wnt pathway inhibitors (SERPINF1, SFRP2) may play important roles in AGA. What is already known about this topic? Multiple differentially expressed genes and signalling pathways have been found between hair follicles (HFs) in the balding area (frontal and vertex regions) and nonbalding area (occipital region) of individuals with androgenetic alopecia (AGA). A whole-transcriptome atlas of the vertex and occipital region is lacking. What does this study add? We identified a number of differentially expressed genes and pathways between balding vertex and nonbalding occipital AGA HFs by using whole-transcriptome analyses. We identified pathways not previously reported in AGA, such as the hypoxia-inducible factor (HIF)-1 signalling pathway. We verified that HIF-1 pathway-related genes (EGLN1, EGLN3) and Wnt pathway inhibitors (PEDF, SFRP2) played important roles in dermal papilla cell activity, hair growth and the hair cycle. What is the translational message? The EGLN1, EGLN3, SERPINF1 and SFRP2 genes may be potentially utilized as therapeutic targets for AGA.

Fabrication of Gold-Based "Sphere-on-Plate" Hybrid Nanostructures with Dual Plasmonic Absorptions Covering Visible and Near-Infrared II Windows via the Volmer-Weber Growth Mode.

We report a synthetic strategy to create gold(Au)-based "sphere-on-plate" hybrid nanostructures (SPHNSs). The surface doping of plate-like Au seeds with Pt/Ag atoms is found to be crucial to increase the lattice spacing, inducing island-like deposition of Au atoms via the Volmer-Weber growth mode. The resulting products are featured with the morphology that quasi-spherical nanoparticles are scattered over the nanoplates. Due to the presence of two distinctly dimensioned particles in one entity, the current Au-based SPHNSs exhibit unique dual plasmonic absorptions, where the visible absorbance centered at 546 nm is related to the size of the anchored particles. Arising from such a plasmonic advantage, the Au-based SPHNSs exhibit enhancement in photothermal conversion under laser irradiations at the wavelengths of both 808 and 1064 nm. The current work offers a feasible route to fabricate noble metal hybrid nanostructures involving zero-dimensional (0D) and two-dimensional (2D) structures, which could work as promising materials for photothermal conversion.

In Situ Crumpling of Gold Nanosheets into Spherical Three-Dimensional Architecture: Probing the Aggregation-Induced Enhancement in Photothermal Properties.

Assembling two-dimensional noble metal nanocrystals into a three-dimensional mesoporous structure is of great value to solve the re-stacking issue for the practical application, which still remains a challenging technique. Herein, we report the one-pot fabrication of gold (Au) nanostructures with a crumpled paper ball-like morphology (Au NCPBs). The success of current work relies on the use of glutathione to crumple the branched Au nanosheets formed during the early stage, into spherical three-dimensional architecture, where the nanosheets are assembled with a mesoporous structure without intimate contact. When working as the agent toward photothermal conversion, the Au NCPBs exhibit enhanced photothermal conversion efficiency (η = 19.9%), as compared to that of flat and wrinkled Au nanosheets. Such an enhancement should be owing to the aggregation-induced effect, where the shortened inter-sheet distance contributes to an increased coupling between the plasmon oscillations/fields of the interacting Au nanosheets. The present study offers a feasible strategy to create spherical architecture of crumpled Au nanosheets and validates their structural advantage in photothermal applications, which could be potentially extended to other metals or alloys.

Direct and Indirect Effects of Blue Light Exposure on Skin: A Review of Published Literature.

BACKGROUND: The growing use of electronic devices and other artificial light sources in recent decades has changed the pattern of exposure to blue light (400-500 nm). Although some progress has been made in the study of the biological effects of blue light on the skin, many questions in this field remain unexplored. The aim of this article was to review the currently available evidence on the deleterious effects of blue light on the skin as well as the methods and strategies designed to protect from the detrimental effects of blue light. The PubMed and ProQuest databases were searched in January 2022. Search results were supplemented by articles considered relevant by the authors. SUMMARY: The results of in vitro, in vivo, and clinical studies show that blue light produces direct and indirect effects on the skin. The most significant direct effects are the excessive generation of reactive oxygen and nitrogen species, and hyperpigmentation. Reactive oxygen and nitrogen species cause DNA damage and modulate the immune response. Indirect effects of blue light include disruption of the central circadian rhythm regulation via melatonin signaling and local circadian rhythm regulation via direct effects on skin cells. Antioxidants and sunscreens containing titanium dioxide, iron oxides, and zinc oxide can be used to protect against the detrimental effects of blue light as part of a strategy that combines daytime protection and night-time repair. KEY MESSAGES: Blue light produces a wide variety of direct and indirect effects on the skin. As exposure to blue light from artificial sources is likely to continue to increase, this area warrants further investigation.

A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron-metabolism gene.

Standard analyses applied to genome-wide association data are well designed to detect additive effects of moderate strength. However, the power for standard genome-wide association study (GWAS) analyses to identify effects from recessive diplotypes is not typically high. We proposed and conducted a gene-based compound heterozygosity test to reveal additional genes underlying complex diseases. With this approach applied to iron overload, a strong association signal was identified between the fibroblast growth factor-encoding gene, FGF6, and hemochromatosis in the central Wisconsin population. Functional validation showed that fibroblast growth factor 6 protein (FGF-6) regulates iron homeostasis and induces transcriptional regulation of hepcidin. Moreover, specific identified FGF6 variants differentially impact iron metabolism. In addition, FGF6 downregulation correlated with iron-metabolism dysfunction in systemic sclerosis and cancer cells. Using the recessive diplotype approach revealed a novel susceptibility hemochromatosis gene and has extended our understanding of the mechanisms involved in iron metabolism.

Crumpled Versus Flat Gold Nanosheets: Temperature-Regulated Synthesis and Their Plasmonic and Catalytic Properties.

We report a high-yield synthesis of gold (Au) nanosheets with tunable size and surface morphology in the aqueous phase. In particular, crumpled and flat Au nanosheets with a thickness of ∼10 nm could be selectively produced in high purity when the reaction was conducted at room temperature and in an ice-water bath, respectively. Unlike Au nanoplates/nanoprisms in the form of well-defined triangles or hexagons documented in previous studies, the current products exhibit random in-plane branches or holes, together with wavy edges. Strong absorbance in the NIR region was observed for all the Au nanosheet products. When serving as electrocatalysts for the ethanol oxidation reaction, the current products exhibited an enhanced activity and operation stability, as compared to quasi-spherical counterparts.

Ultrahigh-charge electron beams from laser-irradiated solid surface.

Compact acceleration of a tightly collimated relativistic electron beam with high charge from a laser-plasma interaction has many unique applications. However, currently the well-known schemes, including laser wakefield acceleration from gases and vacuum laser acceleration from solids, often produce electron beams either with low charge or with large divergence angles. In this work, we report the generation of highly collimated electron beams with a divergence angle of a few degrees, nonthermal spectra peaked at the megaelectronvolt level, and extremely high charge (∼100 nC) via a powerful subpicosecond laser pulse interacting with a solid target in grazing incidence. Particle-in-cell simulations illustrate a direct laser acceleration scenario, in which the self-filamentation is triggered in a large-scale near-critical-density plasma and electron bunches are accelerated periodically and collimated by the ultraintense electromagnetic field. The energy density of such electron beams in high-Z materials reaches to [Formula: see text], making it a promising tool to drive warm or even hot dense matter states.

Light Induced Regulation Pathway of Anthocyanin Biosynthesis in Plants.

Anthocyanins are natural pigments with antioxidant effects that exist in various fruits and vegetables. The accumulation of anthocyanins is induced by environmental signals and regulated by transcription factors in plants. Numerous evidence has indicated that among the environmental factors, light is one of the most signal regulatory factors involved in the anthocyanin biosynthesis pathway. However, the signal transduction of light and molecular regulation of anthocyanin synthesis remains to be explored. Here, we focus on the research progress of signal transduction factors for positive and negative regulation in light-dependent and light-independent anthocyanin biosynthesis. In particular, we will discuss light-induced regulatory pathways and related specific regulators of anthocyanin biosynthesis in plants. In addition, an integrated regulatory network of anthocyanin biosynthesis controlled by transcription factors is discussed based on the significant progress.

Betatron radiation polarization control by using an off-axis ionization injection in a laser wakefield acceleration.

Tunable X-ray sources from a laser-driven wakefield have wide applications. However, due to the difficulty of electron dynamics control, currently the tunability of laser wakefield-based X-ray sources is still difficult. By using three-dimensional particle-in-cell simulations, we propose a scheme to realize controllable electron dynamics and X-ray radiation. In the scheme, a long wavelength drive pulse excites a plasma wake and an off-axis laser pulse with a short wavelength co-propagates with the drive pulse and ionizes the K-shell electrons of the background high-Z gas. The electrons can be injected in the wakefield with controllable transverse positions and residual momenta. These injected electrons experience controllable oscillations in the wake, leading to tunable radiations both in intensity and polarization.

Seed-Morphology-Directed Synthesis of Concave Gold Nanocrystals with Tunable Sizes.

We report the fabrication of concave gold (Au) nanocrystals with a set of morphologies and controlled sizes via seeded growth. Starting with Au seeds with a well-defined morphology and uniform size, cubic and rodlike Au nanocrystals with a noticeable concave feature could be successfully obtained, respectively. We also track the growth process and record the shape evolution process. The effect of several reaction parameters on product morphology, such as capping agent and concentration of Ag+, are systematically investigated. Their optical and electrochemical properties are investigated via UV-vis extinction spectroscopy and cyclic voltammetry, respectively. Compared to spherical counterparts, the current concave Au nanocrystals exhibit a noticeable red shift of the absorbance peak in UV-vis extinction spectra and characterized electrochemical behavior of stepped facets, illustrating the morphological advantage.

Hepatic autophagy fluctuates during the development of non-alcoholic fatty liver disease.

INTRODUCTION AND OBJECTIVES: Autophagy has emerged as a critical regulatory pathway in non-alcoholic fatty liver disease (NAFLD). However, the variability of hepatic autophagy during NAFLD development remains controversial. This study aimed to elucidate the dynamics of hepatic autophagy and its underlying mechanism during NAFLD development both in vivo and in vitro. MATERIALS AND METHODS: Autophagy markers were evaluated in the livers of mice fed a high fat diet or a methionine-choline-deficient diet and in HepG2 cells treated with palmitic acid (PA) by western blotting. Intrahepatic and intracellular triacylglycerol levels were assessed using biochemical quantification and lipid staining. Autophagic flux was monitored using an LC3 turnover assay and tandem mRFP-GFP-LC3 fluorescence analysis. RESULTS: Hepatic autophagy was enhanced in early stages but blocked at later stages of NAFLD development both in vivo and in vitro. Analysis of autophagic flux revealed that both autophagic synthesis and degradation were initially activated and progressively inhibited afterwards. The activation of mammalian target of rapamycin complex 1 (mTORC1), a central regulator of autophagy, was found to be negatively correlated with autophagic synthesis; moreover, pharmacological inhibition of mTORC1 by rapamycin alleviated hepatic steatosis through recovery of autophagic flux in hepatocytes with prolonged PA treatment. CONCLUSIONS: Hepatic autophagy fluctuates during the development of NAFLD in which mTORC1 signalling plays a critical regulatory role, suggesting a therapeutic potential of autophagy modulation by targeting the mTORC1 signalling pathway in NAFLD.

Clinical characteristics and survival of Chinese patients diagnosed with pulmonary arterial hypertension who carry BMPR2 or EIF2KAK4 variants.

BACKGROUND: Variants in the gene encoding bone morphogenetic protein receptor type II (BMPR2) are the most common genetic cause of pulmonary arterial hypertension (PAH), whereas biallelic variants in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH). Racial background may influence the clinical characteristics of patients diagnosed with PAH or PVOD/PCH. Here, we compared the clinical characteristics and survival between patients with BMPR2 variants or EIF2AK4 variants in a Chinese population. METHODS: Heterozygous variants in BMPR2 and homozygous or compound heterozygous biallelic EIF2AK4 variants predicted to be deleterious were identified as potentially causal. Clinical and radiological data were collected and analysed. The primary outcomes were death or lung transplantation. Hazard ratios (HRs) for death or transplantation associated with the presence of BMPR2 or biallelic EIF2AK4 variants were calculated using Cox proportional hazards models to analyse patient survival. RESULTS: Two hundred thirty-two patients with PAH were enrolled for genetic testing, and PAH patients with associated conditions were excluded from the study. Forty-five patients with BMPR2 variants and 11 patients with biallelic EIF2AK4 variants were recruited. PAH patients with BMPR2 or biallelic EIF2AK4 variants presented symptoms at the ages of 25.57 ± 10.17 years and 31.6 ± 9.38 years, respectively. The whole group of patients showed female dominance either with BMPR2 variants or biallelic EIF2AK4 variants. Specific radiological abnormalities are more prominent in EIF2AK4 variant carriers but can also be found in some patients with BMPR2 variants. Biallelic EIF2AK4 variant carriers had worse survival than BMPR2 variant carriers (p < 0.0001). CONCLUSIONS: Clinical pictures of PAH patients with BMPR2 and biallelic EIF2AK4 variants in the Chinese population differ from other populations by a younger age at diagnosis and demonstrate female dominance in the whole patient group. High-resolution chest CT can help assist in differentiating PAH with PVOD/PCH. BMPR2 variants and biallelic EIF2AK4 variants are associated with adverse outcomes, but the survival of patients with biallelic EIF2AK4 variants is dismal.