CRB1-associated retinal degeneration is dependent on bacterial translocation from the gut.

The Crumbs homolog 1 (CRB1) gene is associated with retinal degeneration, most commonly Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Here, we demonstrate that murine retinas bearing the Rd8 mutation of Crb1 are characterized by the presence of intralesional bacteria. While normal CRB1 expression was enriched in the apical junctional complexes of retinal pigment epithelium and colonic enterocytes, Crb1 mutations dampened its expression at both sites. Consequent impairment of the outer blood retinal barrier and colonic intestinal epithelial barrier in Rd8 mice led to the translocation of intestinal bacteria from the lower gastrointestinal (GI) tract to the retina, resulting in secondary retinal degeneration. Either the depletion of bacteria systemically or the reintroduction of normal Crb1 expression colonically rescued Rd8-mutation-associated retinal degeneration without reversing the retinal barrier breach. Our data elucidate the pathogenesis of Crb1-mutation-associated retinal degenerations and suggest that antimicrobial agents have the potential to treat this devastating blinding disease.

Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin.

Histone lysine acylation, including acetylation and crotonylation, plays a pivotal role in gene transcription in health and diseases. However, our understanding of histone lysine acylation has been limited to gene transcriptional activation. Here, we report that histone H3 lysine 27 crotonylation (H3K27cr) directs gene transcriptional repression rather than activation. Specifically, H3K27cr in chromatin is selectively recognized by the YEATS domain of GAS41 in complex with SIN3A-HDAC1 co-repressors. Proto-oncogenic transcription factor MYC recruits GAS41/SIN3A-HDAC1 complex to repress genes in chromatin, including cell-cycle inhibitor p21. GAS41 knockout or H3K27cr-binding depletion results in p21 de-repression, cell-cycle arrest, and tumor growth inhibition in mice, explaining a causal relationship between GAS41 and MYC gene amplification and p21 downregulation in colorectal cancer. Our study suggests that H3K27 crotonylation signifies a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for transcriptional silencing and H3K27 acetylation for transcriptional activation.

BRD4-PRC2 represses transcription of T-helper 2-specific negative regulators during T-cell differentiation.

BRD4 is a well-recognized transcriptional activator, but how it regulates gene transcriptional repression in a cell type-specific manner has remained elusive. In this study, we report that BRD4 works with Polycomb repressive complex 2 (PRC2) to repress transcriptional expression of the T-helper 2 (Th2)-negative regulators Foxp3 and E3-ubiqutin ligase Fbxw7 during lineage-specific differentiation of Th2 cells from mouse primary naïve CD4+ T cells. Brd4 binds to the lysine-acetylated-EED subunit of the PRC2 complex via its second bromodomain (BD2) to facilitate histone H3 lysine 27 trimethylation (H3K27me3) at target gene loci and thereby transcriptional repression. We found that Foxp3 represses transcription of Th2-specific transcription factor Gata3, while Fbxw7 promotes its ubiquitination-directed protein degradation. BRD4-mediated repression of Foxp3 and Fbxw7 in turn promotes BRD4- and Gata3-mediated transcriptional activation of Th2 cytokines including Il4, Il5, and Il13. Chemical inhibition of the BRD4 BD2 induces transcriptional de-repression of Foxp3 and Fbxw7, and thus transcriptional downregulation of Il4, Il5, and Il13, resulting in inhibition of Th2 cell lineage differentiation. Our study presents a previously unappreciated mechanism of BRD4's role in orchestrating a Th2-specific transcriptional program that coordinates gene repression and activation, and safeguards cell lineage differentiation.

Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption.

BACKGROUND: Lymphatic vessels are responsible for tissue drainage, and their malfunction is associated with chronic diseases. Lymph uptake occurs via specialized open cell-cell junctions between capillary lymphatic endothelial cells (LECs), whereas closed junctions in collecting LECs prevent lymph leakage. LEC junctions are known to dynamically remodel in development and disease, but how lymphatic permeability is regulated remains poorly understood. METHODS: We used various genetically engineered mouse models in combination with cellular, biochemical, and molecular biology approaches to elucidate the signaling pathways regulating junction morphology and function in lymphatic capillaries. RESULTS: By studying the permeability of intestinal lacteal capillaries to lipoprotein particles known as chylomicrons, we show that ROCK (Rho-associated kinase)-dependent cytoskeletal contractility is a fundamental mechanism of LEC permeability regulation. We show that chylomicron-derived lipids trigger neonatal lacteal junction opening via ROCK-dependent contraction of junction-anchored stress fibers. LEC-specific ROCK deletion abolished junction opening and plasma lipid uptake. Chylomicrons additionally inhibited VEGF (vascular endothelial growth factor)-A signaling. We show that VEGF-A antagonizes LEC junction opening via VEGFR (VEGF receptor) 2 and VEGFR3-dependent PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) activation of the small GTPase RAC1 (Rac family small GTPase 1), thereby restricting RhoA (Ras homolog family member A)/ROCK-mediated cytoskeleton contraction. CONCLUSIONS: Our results reveal that antagonistic inputs into ROCK-dependent cytoskeleton contractions regulate the interconversion of lymphatic junctions in the intestine and in other tissues, providing a tunable mechanism to control the lymphatic barrier.

Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation.

The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclin T1 and Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity.

Enolase of Streptococcus suis serotype 2 promotes biomolecular condensation of ribosomal protein SA for HBMECs apoptosis.

BACKGROUND: Ribosomal protein SA (RPSA) of human brain microvascular endothelial cells (HBMECs) can transfer from the cytosol to the cell surface and act as a receptor for some pathogens, including Streptococcus suis serotype 2 (SS2), a zoonotic pathogen causing meningitis in pigs and humans. We previously reported that SS2 virulence factor enolase (ENO) binds to RPSA on the cell surface of HBMECs and induces apoptosis. However, the mechanism that activates RPSA translocation to the cell surface and induces ENO-mediated HBMEC apoptosis is unclear. RESULTS: Here, we show that RPSA localization and condensation on the host cell surface depend on its internally disordered region (IDR). ENO binds to the IDR of RPSA and promotes its interaction with RPSA and vimentin (VIM), which is significantly suppressed after 1,6-Hexanediol (1,6-Hex, a widely used tool to disrupt phase separation) treatment, indicating that ENO incorporation and thus the concentration of RPSA/VIM complexes via co-condensation. Furthermore, increasing intracellular calcium ions (Ca2+) in response to SS2 infection further facilitates the liquid-like condensation of RPSA and aggravates ENO-induced HBMEC cell apoptosis. CONCLUSIONS: Together, our study provides a previously underappreciated molecular mechanism illuminating that ENO-induced RPSA condensation activates the migration of RPSA to the bacterial cell surface and stimulates SS2-infected HBMEC death and, potentially, disease progression. This study offers a fresh avenue for investigation into the mechanism by which other harmful bacteria infect hosts via cell surfaces' RPSA.

TMEM41B Is an Interferon-Stimulated Gene That Promotes Pseudorabies Virus Replication.

Pseudorabies virus (PRV) is a double-stranded DNA virus that causes Aujeszky's disease and is responsible for economic loss worldwide. Transmembrane protein 41B (TMEM41B) is a novel endoplasmic reticulum (ER)-localized regulator of autophagosome biogenesis and lipid mobilization; however, the role of TMEM41B in regulating PRV replication remains undocumented. In this study, PRV infection was found to upregulate TMEM41B mRNA and protein levels both in vitro and in vivo. For the first time, we found that TMEM41B could be induced by interferon (IFN), suggesting that TMEM41B is an IFN-stimulated gene (ISG). While TMEM41B knockdown suppressed PRV proliferation, TMEM41B overexpression promoted PRV proliferation. We next studied the specific stages of the virus life cycle and found that TMEM41B knockdown affected PRV entry. Mechanistically, we demonstrated that the knockdown of TMEM41B blocked PRV-stimulated expression of the key enzymes involved in lipid synthesis. Additionally, TMEM41B knockdown played a role in the dynamics of lipid-regulated PRV entry-dependent clathrin-coated pits (CCPs). Lipid replenishment restored the CCP dynamic and PRV entry in TMEM41B knockdown cells. Together, our results indicate that TMEM41B plays a role in PRV infection via regulating lipid homeostasis. IMPORTANCE PRV belongs to the alphaherpesvirus subfamily and can establish and maintain a lifelong latent infection in pigs. As such, an intermittent active cycle presents great challenges to the prevention and control of PRV disease and is responsible for serious economic losses to the pig breeding industry. Studies have shown that lipids play a crucial role in PRV proliferation. Thus, the manipulation of lipid metabolism may represent a new perspective for the prevention and treatment of PRV. In this study, we report that the ER transmembrane protein TMEM41B is a novel ISG involved in PRV infection by regulating lipid synthesis. Therefore, our findings indicate that targeting TMEM41B may be a promising approach for the development of PRV vaccines and therapeutics.

Activation of AIM2 by hepatitis B virus results in antiviral immunity that suppresses hepatitis C virus during coinfection.

IMPORTANCE: Clinical data suggest that Hepatitis C virus (HCV) levels are generally lower in Hepatitis B virus (HBV) co-infected patients, but the mechanism is unknown. Here, we show that HBV, but not HCV, activated absent in melanoma-2. This in turn results in inflammasome-mediated cleavage of pro-IL-18, leading to an innate immune activation cascade that results in increased interferon-γ, suppressing both viruses.

Selective Removal of Hemicellulose by Diluted Sulfuric Acid Assisted by Aluminum Sulfate.

Hemicellulose can be selectively removed by acid pretreatment. In this study, selective removal of hemicellulose was achieved using dilute sulfuric acid assisted by aluminum sulfate pretreatment. The optimal pretreatment conditions were 160 °C, 1.5 wt% aluminum sulfate, 0.7 wt% dilute sulfuric acid, and 40 min. A component analysis showed that the removal rate of hemicellulose and lignin reached 98.05% and 9.01%, respectively, which indicated that hemicellulose was removed with high selectivity by dilute sulfuric acid assisted by aluminum sulfate pretreatment. Structural characterizations (SEM, FTIR, BET, TGA, and XRD) showed that pretreatment changed the roughness, crystallinity, pore size, and functional groups of corn straw, which was beneficial to improve the efficiency of enzymatic hydrolysis. This study provides a new approach for the high-selectivity separation of hemicellulose, thereby offering novel insights for its subsequent high-value utilization.

Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear. METHODS: VEGF-A/VEGFR2 signal activation and VEGFR2 Y949-dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (Vefgr2Y949F) and mice with conditional endothelial deletion of Vegfr2 after chronic hypoxia exposure. RESULTS: We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by Vefgr2Y949F point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of Vegfr2 promotes the development of PH. CONCLUSIONS: Our results support the notion that VEGF-A/VEGFR2 Y949-dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease.

Optimization of mammalian expression vector by cis-regulatory element combinations.

The regulation of gene expression in mammalian cells by combining various cis-regulatory features has rarely been discussed. In this study, we constructed expression vectors containing various combinations of regulatory elements to examine the regulation of gene expression by different combinations of cis-regulatory elements. The effects of four promoters (CMV promoter, PGK promoter, Polr2a promoter, and EF-1α core promoter), two enhancers (CMV enhancer and SV40 enhancer), two introns (EF-1α intron A and hybrid intron), two terminators (CYC1 terminator and TEF terminator), and their different combinations on downstream gene expression were compared in various mammalian cells using fluorescence microscopy to observe fluorescence, quantitative real-time PCR (qRT-PCR), and western blot. The receptor binding domain (RBD) sequence from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein was used to replace the eGFP sequence in the expression vector and the RBD expression was detected by qRT-PCR and western blot. The results showed that protein expression can be regulated by optimizing the combination of cis-acting elements. The vector with the CMV enhancer, EF-1α core promoter, and TEF terminator was found to express approximately threefold higher eGFP than the unmodified vector in different animal cells, as well as 2.63-fold higher recombinant RBD protein than the original vector in HEK-293T cells. Moreover, we suggest that combinations of multiple regulatory elements capable of regulating gene expression do not necessarily exhibit synergistic effects to enhance expression further. Overall, our findings provide insights into biological applications that require the regulation of gene expression and will help to optimize expression vectors for biosynthesis and other fields. Additionally, we provide valuable insights into the production of RBD proteins, which may aid in developing reagents for diagnosis and treatment during the COVID-19 pandemic.

Alphaherpesvirus upregulates NDRG1 expression to facilitate the nuclear import of viral UL31 and UL34 proteins.

Proteins UL31 and UL34 encoded by alphaherpesvirus are critical for viral primary envelopment and nuclear egress. We report here that pseudorabies virus (PRV), a useful model for research on herpesvirus pathogenesis, uses N-myc downstream regulated 1 (NDRG1) to assist the nuclear import of UL31 and UL34. PRV promoted NDRG1 expression through DNA damage-induced P53 activation, which was beneficial to viral proliferation. PRV induced the nuclear translocation of NDRG1, and its deficiency resulted in the cytosolic retention of UL31 and UL34. Therefore, NDRG1 assisted the nuclear import of UL31 and UL34. Furthermore, in the absence of the nuclear localization signal (NLS), UL31 could still translocate to the nucleus, and NDRG1 lacked an NLS, thus suggesting the existence of other mediators for the nuclear import of UL31 and UL34. We demonstrated that heat shock cognate protein 70 (HSC70) was the key factor in this process. UL31 and UL34 interacted with the N-terminal domain of NDRG1 and the C-terminal domain of NDRG1 bound to HSC70. Replenishment of HSC70ΔNLS in HSC70-knockdown cells, or interference in importin α expression, abolished the nuclear translocation of UL31, UL34, and NDRG1. These results indicated that NDRG1 employs HSC70 to facilitate viral proliferation in the nuclear import of PRV UL31 and UL34.

Telecom-wavelength conversion in a high optical depth cold atomic system.

We experimentally investigate the frequency down-conversion through the four-wave mixing (FWM) process in a cold 85Rb atomic ensemble, with a diamond-level configuration. An atomic cloud with a high optical depth (OD) of 190 is prepared to achieve a high efficiency frequency conversion. Here, we convert a signal pulse field (795 nm) attenuated to a single-photon level, into a telecom light at 1529.3 nm within near C-band range and the frequency-conversion efficiency can reach up to 32%. We find that the OD is an essential factor affecting conversion efficiency and the efficiency may exceed 32% with an improvement in the OD. Moreover, we note the signal-to-noise ratio of the detected telecom field is higher than 10 while the mean signal count is larger than 0.2. Our work may be combined with quantum memories based on cold 85Rb ensemble at 795 nm and serve for long-distance quantum networks.

Optical memory for arbitrary perfect Poincaré states in an atomic ensemble.

Inherent spin angular momentum (SAM) and orbital angular momentum (OAM), which manifest as polarization and spatial degrees of freedom (DOFs) of photons, hold a promise of large capability for applications in classical and quantum information processing. To enable these photonic spin and orbital dynamic properties strongly coupled with each other, Poincaré states have been proposed and offer advantages in data multiplexing, information encryption, precision metrology, and quantum memory. However, since the transverse size of Laguerre-Gaussian beams strongly depends on their topological charge numbers | l |, it is difficult to store asymmetric Poincaré states due to the significantly different light-matter interaction for distinct spatial modes. Here, we experimentally realize the storage of perfect Poincaré states with arbitrary OAM quanta using the perfect optical vortex, in which 121 arbitrarily selected perfect Poincaré states have been stored with high fidelity. The reported work has great prospects in optical communication and quantum networks for dramatically increased encoding flexibility of information.

Highly Efficient Storage of 25-Dimensional Photonic Qudit in a Cold-Atom-Based Quantum Memory.

Building an efficient quantum memory in high-dimensional Hilbert spaces is one of the fundamental requirements for establishing high-dimensional quantum repeaters, where it offers many advantages over two-dimensional quantum systems, such as a larger information capacity and enhanced noise resilience. To date, it remains a challenge to develop an efficient high-dimensional quantum memory. Here, we experimentally realize a quantum memory that is operational in Hilbert spaces of up to 25 dimensions with a storage efficiency of close to 60% and a fidelity of 84.2±0.6%. The proposed approach exploits the spatial-mode-independent interaction between atoms and photons which are encoded in transverse-size-invariant vortex modes. In particular, our memory features uniform storage efficiency and low crosstalk disturbance for 25 individual spatial modes of photons, thus allowing the storing of qudit states programmed from 25 eigenstates within the high-dimensional Hilbert spaces. These results have great prospects for the implementation of long-distance high-dimensional quantum networks and quantum information processing.

RhoA suppresses pseudorabies virus replication in vitro.

The porcine pseudorabies virus (PRV) is one of the most devastating pathogens and brings great economic losses to the swine industry worldwide. Viruses are intracellular parasites that have evolved numerous strategies to subvert and utilize different host processes for their life cycle. Among the different systems of the host cell, the cytoskeleton is one of the most important which not only facilitate viral invasion and spread into neighboring cells, but also help viruses to evade the host immune system. RhoA is a key regulator of cytoskeleton system that may participate in virus infection. In this study, we characterized the function of RhoA in the PRV replication by chemical drugs treatment, gene knockdown and gene over-expression strategy. Inhibition of RhoA by specific inhibitor and gene knockdown promoted PRV proliferation. On the contrary, overexpression of RhoA or activation of RhoA by chemical drug inhibited PRV infection. Besides, our data demonstrated that PRV infection induced the disruption of actin stress fiber, which was consistent with previous report. In turn, the actin specific inhibitor cytochalasin D markedly disrupted the normal fibrous structure of intracellular actin cytoskeleton and decreased the PRV replication, suggesting that actin cytoskeleton polymerization contributed to PRV replication in vitro. In summary, our data displayed that RhoA was a host restriction factor that inhibited PRV replication, which may deepen our understanding the pathogenesis of PRV and provide further insight into the prevention of PRV infection and the development of anti-viral drugs.

Successional Changes of Microbial Communities and Host-Microbiota Interactions Contribute to Dietary Adaptation in Allodiploid Hybrid Fish.

Host-microbiota interactions play critical roles in host development, immunity, metabolism, and behavior. However, information regarding host-microbiota interactions is limited in fishes due to their complex living environment. In the present study, an allodiploid hybrid fish derived from herbivorous Megalobrama amblycephala (♀) × carnivorous Culter alburnus (♂) was used to investigate the successional changes of the microbial communities and host-microbiota interactions during herbivorous and carnivorous dietary adaptations. The growth level was not significantly different in any developmental stage between the two diet groups of fish. The diversity and composition of the dominant microbial communities showed similar successional patterns in the early developmental stages, but significantly changed during the two dietary adaptations. A large number of bacterial communities coexisted in all developmental stages, whereas the abundance of some genera associated with metabolism, including Acinetobacter, Gemmobacter, Microbacterium, Vibrio, and Aeromonas, was higher in either diet groups of fish. Moreover, the abundance of phylum Firmicutes, Actinobacteria, and Chloroflexi was positively correlated with the host growth level. In addition, Spearman's correlation analysis revealed that the differentially expressed homologous genes in the intestine associated with cell growth, immunity, and metabolism were related to the dominant gut microbiota. Our results present evidence that host genetics-gut microbiota interactions contribute to dietary adaptation in hybrid fish, which also provides basic data for understanding the diversity of dietary adaptations and evolution in fish.

A single-cell transcriptomic atlas of the human ciliary body.

The ciliary body critically contributes to the ocular physiology with multiple responsibilities in the production of aqueous humor, vision accommodation and intraocular immunity. Comparatively little work, however, has revealed the single-cell molecular taxonomy of the human ciliary body required for studying these functionalities. In this study, we report a comprehensive atlas of the cellular and molecular components of human ciliary body as well as their interactions using single-cell RNA sequencing (scRNAseq). Cluster analysis of the transcriptome of 14,563 individual ciliary cells from the eyes of 3 human donors identified 14 distinct cell types, including the ciliary epithelium, smooth muscle, vascular endothelial cell, immune cell and other stromal cell populations. Cell-type discriminative gene markers were also revealed. Unique gene expression patterns essential for ciliary epithelium-mediated aqueous humor inflow and ciliary smooth muscle contractility were identified. Importantly, we discovered the transitional states that probably contribute to the transition of ciliary macrophage into retina microglia and verified no lymphatics in the ciliary body. Moreover, the utilization of CellPhoneDB allowed us to systemically infer cell-cell interactions among diverse ciliary cells including those that potentially participate in the pathogenesis of glaucoma and uveitis. Altogether, these new findings provide insights into the regulation of intraocular pressure, accommodation reflex and immune homeostasis under physiological and pathological conditions.

The rare complication of vascular malformations of the limb after sclerotherapy: a report of 3 cases and brief literature review.

BACKGROUND: Vascular malformations are common but complicated types of disease in infants, with unclear causes and lack of effective prevention. The symptoms usually do not disappear and tend to progress without medical intervention. It is extremely necessary to choose correct treatment options for different types of vascular malformations. A large number of studies have confirmed that sclerotherapy has a tendency to become the first-line treatment in near future, but it is also associated with mild or severe complications. Furthermore, to our knowledge, the serious adverse event of progressive limb necrosis has not been systematically analyzed and reported in the literature. CASE PRESENTATION: Three cases (two females and one male) were presented who were all diagnosed as vascular malformations and were treated by several sessions of interventional sclerotherapy. Their previous medical records showed the use of several sclerosants in different sessions including Polidocanol and Bleomycin. The sign of limb necrosis did not occur during the first sclerotherapy, but after the second and third sessions. Furthermore, the short-term symptomatic treatment could improve the necrosis syndrome, but could not change the outcome of amputation. CONCLUSION: Sclerotherapy undoubtedly tends to be the first-line treatment in near future, but the adverse reactions still remain major challenges. Awareness of progressive limb necrosis after sclerotherapy and timely management by experts in centers of experience of this complication can avoid amputation.

Burden of female infertility in China from 1990 to 2019: a temporal trend analysis and forecasting, and comparison with the global level.

BACKGROUND: Infertility is a common reproductive disease that affects not only individuals and families, but also the growth of the social population. Hence, understanding the burden of female infertility in China and worldwide is of great significance for the development of infertility prevention and treatment strategies. METHODS: The Global Burden of Disease Study (GBD 2019) Data Resources were used to collect and collate relevant data on female infertility in China and worldwide from 1990 to 2019. The difference in the number, age-standardised prevalence rate (ASPR), disability-adjusted life years and age-standardised disability-adjusted life years rate (ASDR) of women with infertility in different periods and geographical areas were analysed. The autoregressive integrated moving average method was used to predict the ASPR and ASDR of female infertility in China and worldwide in the next 11years. RESULTS: In the past 30years, the number of female infertility cases increased by 7.06million in China and 56.71million worldwide. The corresponding average annual increase of ASPR was 10.10% and 7.28%, respectively, and that of ASDR was 0.08% and 0.79%, respectively. In addition, there are differences in age and time between Chinese and global female infertility. In 1990, the crude prevalence rate of female infertility was the highest in women aged 40-44years and 35-39years in China and worldwide, respectively. In 2019, the crude prevalence rate of female infertility was still the highest in women aged 40-44years in China, whereas that around the world reached the highest in women aged 30-34years, which was significantly earlier. The forecast for the next 11years suggests that the ASPR and ASDR for female infertility in China will first rise and then decline, but the overall magnitude of change is not very significant, whereas the ASPR and ASDR for female infertility globally are still on the rise. The ASPR value of female infertility is expected to be 5025.56 in 100 000 persons in China and 3725.51 in 100 000 persons worldwide by 2030. The ASDR value of female infertility is expected to be 26.16 in 100 000 persons in China and 19.96 in 100 000 persons worldwide by 2030. CONCLUSION: The burden of female infertility is still increasing in China and worldwide. Therefore, it is of great significance to pay more attention to infertile women, and advocate a healthy lifestyle to reduce the burden of disease for infertile women.