Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile men and cynomolgus monkey and tree shrew models.

Primate-specific genes (PSGs) tend to be expressed in the brain and testis. This phenomenon is consistent with brain evolution in primates but is seemingly contradictory to the similarity of spermatogenesis among mammals. Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia. SSX1 is a PSG expressed predominantly in the testis, and the SSX family evolutionarily expanded independently in rodents and primates. As the mouse model could not be used for studying SSX1, we used a non-human primate model and tree shrews, which are phylogenetically similar to primates, to knock down (KD) Ssx1 expression in the testes. Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology. Further, RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during spermatogenesis. Collectively, our experimental observations in humans and cynomolgus monkey and tree shrew models highlight the crucial role of SSX1 in spermatogenesis. Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment achieved a successful pregnancy. This study provides important guidance for genetic counseling and clinical diagnosis and, significantly, describes the approaches for elucidating the functions of testis-enriched PSGs in spermatogenesis.

NOVA1 prevents overactivation of the unfolded protein response and facilitates chromatin access during human white adipogenesis.

The molecular mechanism underlying white adipogenesis in humans has not been fully elucidated beyond the transcriptional level. Here, we found that the RNA-binding protein NOVA1 is required for the adipogenic differentiation of human mesenchymal stem cells. By thoroughly exploring the interactions between NOVA1 and its binding RNA, we proved that NOVA1 deficiency resulted in the aberrant splicing of DNAJC10 with an in-frame premature stop codon, reduced DNAJC10 expression at the protein level and hyperactivation of the unfolded protein response (UPR). Moreover, NOVA1 knockdown abrogated the down-regulation of NCOR2 during adipogenesis and up-regulated the 47b+ splicing isoform, which led to decreased chromatin accessibility at the loci of lipid metabolism genes. Interestingly, these effects on human adipogenesis could not be recapitulated in mice. Further analysis of multispecies genomes and transcriptomes indicated that NOVA1-targeted RNA splicing is evolutionarily regulated. Our findings provide evidence for human-specific roles of NOVA1 in coordinating splicing and cell organelle functions during white adipogenesis.

Convergent alteration of the mesenchymal stem cell heterogeneity in adipose tissue during aging.

Adipose-derived stem cells (ASCs) from distinct age groups possess different characteristics; however, the age-associated changes in ASCs heterogenicity remain largely unknown. In this study, several publicly available single-cell RNA sequencing (RNA-seq) data cohorts of inguinal adipose tissues, including young (2 weeks), adult (8 weeks), and old (18 months) C57BL/6 mice, were analyzed. Transcriptomic clustering of integrated single-cell RNA-seq data from different age groups revealed the existence of five ASCs subtypes. Interestingly, ASCs showed a loss of heterogeneity with aging, and ASCs subtype 4 (ASC-4) was the dominant subpopulation accounting for more than 98% of aged ASCs converging to the terminal differentiation state. The multidirectional differentiation potentials of different ASCs subtypes were largely distinct while the adipogenic ability of ASC-4 increased with age persistently. Regulon analysis of ASC subtypes further identified Cebpb as the ASC-4-specific transcription factor, which was known as one of the major adipogenic regulators. Analysis of ligand-receptor pairs between ASCs and other cell types in adipose tissue identified age-associated upregulation of inflammatory responses-associated factors including CCL2 and CCL7. Treatment with 100 ng/mL CCL2 in vitro could significantly promote the adipogenesis of ASCs through enhanced phosphorylation of AKT and decreased expression of ß-catenin. In addition, supplementation of 100 ng/mL CCL7 could significantly increase the expression of inflammatory genes and ASC-4-specific transcriptional factors in 2-week-old ASCs, potentially acting as a driver of ASCs convergence. Our findings help to delineate the complex biological processes of ASCs aging and shed light on better regenerative and therapeutic applications of ASCs.

Exosomal PD-L1 confers chemoresistance and promotes tumorigenic properties in esophageal cancer cells via upregulating STAT3/miR-21.

Chemotherapy resistance remains a major obstacle in the treatment of esophageal cancer. Previous researches have shown that an increase in exosomal PD-L1 expression was positively associated with a more advanced clinical stage, a poorer prognosis as well as drug resistance in patients with esophageal squamous cell carcinoma (ESCC). To explore the role of exosomal PD-L1 in ESCC, we performed bioinformatics analysis as well as several in vitro/in vivo functional experiments in a parental sensitive cell line EC-9706 and its derivative, a paclitaxel-resistant subline EC-9706R, and found that the exosomal PD-L1 from EC-9706R was higher than that from EC-9706. Moreover, exosomes from EC-9706R significantly increased invasion, migration and chemoresistance of EC-9706. Anti-PD-L1 treatment in combination with chemotherapy also led to reduced tumor burden in vivo. Inhibition of the release of exosomes by GW4869 or inhibition of STAT3 phosphorylation by stattic could effectively reverse the resistance to paclitaxel mediated by exosomal PD-L1. Furthermore, we found that PD-L1, miR-21, and multidrug resistance (MDR1) gene are involved in the process of exosomal transfer. Moreover, PD-L1 could enhance miR-21 expression by increasing the enrichment of STAT3 on miR-21 promoter. Our results suggested that exosomal PD-L1 may contribute to drug resistance to paclitaxel by regulating the STAT3/miR-21/PTEN/Akt axis and promote tumorigenic phenotype. This study provides a novel potential therapeutic approach to reverse chemoresistance and tumor progression through exosomal PD-L1 in ESCC patients.

Porphyromonas gingivalis promotes progression of esophageal squamous cell cancer via TGFß-dependent Smad/YAP/TAZ signaling.

Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P. gingivalis. Intracellular invasion of P. gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-ß (TGFß)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial-mesenchymal transition (EMT) and stemness features. Furthermore, P. gingivalis augmented secretion and bioactivity of TGFß through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFß axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis. P. gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P. gingivalis or its activated effectors may provide novel insights into clinical management of ESCC.

LPA1-mediated PKD2 activation promotes LPA-induced tissue factor expression via the p38α and JNK2 MAPK pathways in smooth muscle cells.

Tissue factor (TF) is the principal initiator of blood coagulation and is necessary for thrombosis. We previously reported that lysophosphatidic acid (LPA), a potent bioactive lipid, highly induces TF expression at the transcriptional level in vascular smooth muscle cells. To date, however, the specific role of the LPA receptor is unknown, and the intracellular signaling pathways that lead to LPA induction of TF have been largely undetermined. In the current study, we found that LPA markedly induced protein kinase D (PKD) activation in mouse aortic smooth muscle cells (MASMCs). Small-interfering RNA-mediated knockdown of PKD2 blocked LPA-induced TF expression and activity, indicating that PKD2 is the key intracellular mediator of LPA signaling leading to the expression and cell surface activity of TF. Furthermore, our data reveal a novel finding that PKD2 mediates LPA-induced TF expression via the p38α and JNK2 MAPK signaling pathways, which are accompanied by the PKD-independent MEK1/2-ERK-JNK pathway. To identify the LPA receptor(s) responsible for LPA-induced TF expression, we isolated MASMCs from LPA receptor-knockout mice. Our results demonstrated that SMCs isolated from LPA receptor 1 (LPA1)-deficient mice completely lost responsiveness to LPA stimulation, which mediates induction of TF expression and activation of PKD and p38/JNK MAPK, indicating that LPA1 is responsible for PKD2-mediated activation of JNK2 and p38α. Taken together, our data reveal a new signaling mechanism in which the LPA1-PKD2 axis mediates LPA-induced TF expression via the p38α and JNK2 pathways. This finding provides new insights into LPA signaling, the PKD2 pathway, and the mechanisms of coagulation/atherothrombosis.

LncRNA RPL34-AS1 suppresses the proliferation, migration and invasion of esophageal squamous cell carcinoma via targeting miR-575/ACAA2 axis.

BACKGROUND: Long noncoding RNAs (lncRNAs) are abnormally expressed in a broad type of cancers and play significant roles that regulate tumor development and metastasis. However, the pathological roles of lncRNAs in esophageal squamous cell carcinoma (ESCC) remain largely unknown. Here we aimed to investigate the role and regulatory mechanism of the novel lncRNA RPL34-AS1 in the development and progression of ESCC. METHODS: The expression level of RPL34-AS1 in ESCC tissues and cell lines was determined by RT-qPCR. Functional experiments in vitro and in vivo were employed to explore the effects of RPL34-AS1 on tumor growth in ESCC cells. Mechanistically, fluorescence in situ hybridization (FISH), bioinformatics analyses, luciferase reporter assay, RNA immunoprecipitation (RIP) assay and western blot assays were used to detect the regulatory relationship between RPL34-AS1, miR-575 and ACAA2. RESULTS: RPL34-AS1 was significantly down-regulated in ESCC tissues and cells, which was negatively correlated with overall survival in ESCC patients. Functionally, upregulation of RPL34-AS1 dramatically suppressed ESCC cell proliferation, colony formation, invasion and migration in vitro, whereas knockdown of RPL34-AS1 elicited the opposite function. Consistently, overexpression of RPL34-AS1 inhibited tumor growth in vivo. Mechanistically, RPL34-AS1 acted as a competing endogenous RNA (ceRNA) of miR-575 to relieve the repressive effect of miR-575 on its target ACAA2, then suppressed the tumorigenesis of ESCC. CONCLUSIONS: Our results reveal a role for RPL34-AS1 in ESCC tumorigenesis and may provide a strategy for using RPL34-AS1 as a potential biomarker and an effect target for patients with ESCC.

Soluble expression of bioactive recombinant porcine-human chimeric uricase mutant employing MBP-SUMO fusion system.

Urate oxidase is a promising biological medicine for hyperuricemia treatment, but immunogenicity obstructs the development of its clinical application. The recombinant porcine-human chimeric uricase mutant named dHU-wPU is a humanized chimeric uricase based on wild porcine uricase (wPU), which can effectively reduce the limitation of potential immunogenicity with a high homology (92.76%) to deduced human uricase (dHU). Unfortunately, the insoluble expression form of dHU-wPU in E. coli increases the difficulty of production. In this study, we described a more convenient method to efficiently obtain recombinant dHU-wPU protein from E. coli. Combination small ubiquitin-related modifier protein (SUMO) and maltose-binding protein (MBP) was employed to achieve the soluble expression of dHU-wPU. MBP-SUMO-dHU-wPU fusion protein was not only overexpressed in a soluble form, but also showed high purification and cleavage efficiency. Subsequently, we optimized the culture conditions of shake flasks and expanded the production of MBP-SUMO-dHU-wPU fusion protein in a 5 L bioreactor. Finally, about 15 mg of recombinant dHU-wPU was obtained from 1 L M9 fermentation culture by using two-step affinity chromatography, with a SDS-PAGE purity over 90%. In vitro activity analysis showed that dHU-wPU had better ability to catalyze uric acid than wPU.

KIF23 promotes autophagy-induced imatinib resistance in chronic myeloid leukaemia through activating Wnt/ß-catenin pathway.

Imatinib, an inhibitor of tyrosine kinase, shows remarkable efficacy in chronic myeloid leukaemia (CML). Autophagy protects tumour cells against chemotherapeutic stimulation and contributes to imatinib resistance in CML. Kinesin family member 23 (KIF23) is involved in cytokinesis and associated with autophagy. The role of KIF23 in autophagy-induced imatinib resistance in CML was investigated. First, to induce drug resistance, CML cells were exposed to increasing concentrations of imatinib. The concentration of imatinib resistance in CML cells was screened through upregulation of 50% inhibitory concentration (IC50 ) values. KIF23 was elevated in imatinib-resistant tissues and cells of CML. Second, knockdown of KIF23 reduced IC50 values of imatinib-resistant CML cells to imatinib. Moreover, silence of KIF23 also suppressed cell proliferation and promoted apoptosis of imatinib-resistant CML cells. Third, immunofluorescence analysis showed that the number of LC3 bright spots in imatinib-resistant CML cells was reduced by silence of KIF23. Knockdown of KIF23 upregulated p62 expression and downregulated the expression ratio of LC3-II to LC3-I in imatinib-resistant CML cells. Last, silence of KIF23 decreased nuclear ß-catenin and increased cytoplasmic ß-catenin in imatinib-resistant CML cells. Activator of Wnt/ß-catenin attenuated KIF23 silence-induced increase of apoptosis and decrease of autophagy in imatinib-resistant CML cells. In conclusion, loss of KIF23 repressed autophagy-induced imatinib resistance in CML cells through inactivation of Wnt/ß-catenin pathway.

Reactive oxygen species-mediated activation of NLRP3 inflammasome associated with pyroptosis in Het-1A cells induced by the co-exposure of nitrosamines.

Nitrosamines were a class of important environmental carcinogens associated with digestive tract neoplasms. As the early toxic effect of nitrosamines, inflammatory response participated in the malignant transformation of cells and promoted the occurrence and development of tumors. However, the role of NLRP3 inflammasome in the nitrosamines-induced inflammatory response was unclear. In this study, the human esophageal epithelial cells (Het-1A) were used to explore potential mechanisms of the activation of NLRP3 inflammasome under co-exposure to nine nitrosamines commonly found in drinking water at the doses of 0, 4, 20, 100, 500, and 2500 ng/mL. The results showed that nitrosamines stimulated activation of the NLRP3 inflammasome and induced cellular oxidative damage in a dose-dependent manner. Pretreatment of reactive oxygen species scavenger N-acetyl-L-cysteine (NAC), particularly mitochondrial reactive oxygen species (mtROS) scavengers Mito-TEMPO, effectively inhibited the activation of NLRP3 inflammasome, suggesting that nitrosamines could mediate the activation of NLRP3 inflammasome via mtROS. Furthermore, we found that nitrosamines co-exposure also promoted cell pyroptosis through the NLRP3/caspase-1/GSDMD pathway, which was demonstrated by adding the caspase-1 inhibitor Z-YVAD-FMK and constructing NLRP3 downregulated Het-1A cell line. This study revealed the underlying mechanism of the activation of NLRP3 inflammasome initiated by nitrosamines co-exposure and provided new perspectives on the toxic effects of nitrosamines.

Metabolomic transition trajectory and potential mechanisms of N-nitrosomethylbenzylamine induced esophageal squamous cell carcinoma in rats.

Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD+ in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC.

KdPT alleviates imiquimod-induced psoriasis-like skin lesion in mice via inhibiting proliferation and inflammation response.

Psoriasis is a complex chronic skin inflammatory disease characterized by abnormal proliferation, differentiation of keratinocytes and infiltration of lymphocytes and neutrophils. The tripeptide KdPT, structurally derived from the C-terminal amino acid of alpha-melanocyte-stimulating hormone, has shown a significant anti-inflammatory effect on mild-to-moderate active ulcerative colitis in previous reports. In this research, we investigated whether KdPT could consistently ameliorate disease in a mouse model of imiquimod (IMQ)-induced psoriasis by inhibiting proliferation and inflammation response. We demonstrated that KdPT in vitro significantly inhibited the proliferation of human keratinocytes and endothelial cells, and also downgraded the expression of inflammatory factors in LPS-induced RAW264.7, including IL-6, TNF-α and NO. In vivo, KdPT attenuates the severity of IMQ-induced psoriasis-like phenotype in mice. Such an effect was achieved by downregulating the expression of the inflammatory cytokines interleukin (IL)-6, TNF-α, and the proliferation marker Ki67. These results suggested that KdPT might be useful in the treatment for psoriasis.

A retrospective cohort study of obstetric complications and birth outcomes in women with polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women and a high risk factor for adverse pregnancy complications. Therefore, we aimed to analyse the relationship between PCOS and pregnancy complications in a large sample from China. Additionally, since obesity and assisted reproductive technology (ART) are common in women with PCOS, we also aimed to determine whether both of these factors increased the complication incidence for women with PCOS. A retrospective cohort study that included 1357 pregnant women with PCOS and 6940 without PCOS was performed. Our results indicated women with PCOS had higher incidence of gestational diabetes mellitus (GDM), hypertension, postpartum haemorrhage, preterm birth, macrosomia and cervical incompetence. Additionally, obesity was associated with an increased incidence of hypertension and GDM in women with PCOS generally. ART did not result in an increase in the obstetric complication rate in women with PCOS. In conclusion, PCOS appeared to result in an increased risk of adverse pregnancy complications. Obesity may further increase the risks of hypertension and GDM among women with PCOS. However, ART did not increase the risk of pregnancy complications, which suggests that ART is a relatively safe and effective method to address infertility problems in women with PCOS.IMPACT STATEMENTWhat is already known on this subject? There are several studies evaluating the associations of PCOS with the risk of pregnancy complications. However, reports about the risk of pregnancy complications between PCOS women with and without obesity or ART are limited.What do the results of this study add? PCOS appeared to increase the risk of adverse pregnancy complications, including GDM, pregnancy-induced hypertension, postpartum haemorrhage, preterm birth, macrosomia and cervical incompetence. Obesity further increased the risks of hypertension and GDM in women with PCOS, but it did not increase the incidence of macrosomia and postpartum haemorrhage. Additionally, ART did not increase the risk of adverse pregnancy complications among women with PCOS, except for postpartum haemorrhage.What are the implications of these findings for clinical practice and/or further research? This study contributes to the literature because it showed that PCOS independently increased the risk of adverse pregnancy complications in a large sample of patients. Second, obesity is a high risk factor for adverse complications in pregnant women with PCOS. Third, ART is a relatively safe and effective method for addressing infertility problems for women with PCOS.

Dual-Functional Metal-Organic Framework for Luminescent Detection of Carcinoid Biomarkers and High Proton Conduction.

It remains a challenge to exploit dual-functional metal-organic frameworks (MOFs) for applications, including luminescence detection and proton conduction. With the deliberate selection of the bifunctional organic ligand 5-sulfoisophthalic acid monosodium salt (NaH2bts), and the phosphonic acid ligand N,N'-piperazine (bismethylenephosphonic acid; H4L), a robust three-dimensional (3D) noninterpenetrating dual-functional MOF, [Tb(H2L)(H2bts)(H2O)]·H2O (1), has been synthesized hydrothermally. On the basis of the excellent thermal and chemical as well as superior luminescence stabilities in water and solutions with different pHs, 1 can serve as the simple, rapid, and highly selective and sensitive luminescence detection of the carcinoid biomarkers 5-hydroxytryptamine (HT) and its metabolite 5-hydroxyindole-3-acetic acid (HIAA) with detection limits of nanomolar magnitude in water and in simulated blood plasma and urine systems. Due to the change in the signals that could be readily differentiated by the naked eye under a UV lamp, a portable test paper has been developed. The probable quenching mechanisms are discussed in detail. In addition, a great number of hydrogen-bonding networks are formed among the uncoordinated carboxylic oxygen atoms, sulfonate oxygen atoms, protonated nitrogen atoms, and water molecules, which provide potential proton-hopping sites for proton conduction, leading to a maximum proton conductivity of 2.3 × 10-4 S cm-1 at 368 K and 95% relative humidity. The above results suggest that rationally designed dual-functional MOFs can open an avenue for the development of occupational diagnostic tools and alternative energy technology.

Pregnancy outcomes of Chinese women undergoing IVF with embryonic cryopreservation as compared to natural conception.

BACKGROUND: To examine differences in the maternal characteristics and pregnancy outcomes of Chinese women with various causes of infertility who underwent in vitro fertilization (IVF) with embryonic cryopreservation treatment. METHODS: Cases were pregnancies after IVF-ET with embryonic cryopreservation; controls were spontaneously conceived pregnancies. Subgroup analysis was carried out according to etiology of infertility. The IVF treatment group was divided into 5 subgroups according to infertility etiology as follows: ovulation disorder, tubal disease, male infertility, endometriosis, and mixed infertility. Data on demographic characteristics, medical history, laboratory tests, and delivery were reviewed. Logistic regression analysis was performed for pregnancy and perinatal complications and neonatal outcomes. The multivariable model was adjusted for potential confounders. RESULTS: Among singleton pregnancies, compared with spontaneous pregnancies, IVF pregnancies were associated with significant increases in the rates of the following: gestational diabetes mellitus (GDM) (aOR 1.76[95% CI 1.33-2.33]), preeclampsia (2.60[1.61-4.20]), preterm preeclampsia (4.52[2.03-10.06]), postpartum hemorrhage (1.57[1.04-2.36]), intrahepatic cholestasis of pregnancy (3.84[1.06-13.94]), preterm premature rupture of membranes (2.11[1.17-3.81]), preterm birth (1.95[CI 1.26-3.01]), low birthweight (1.90[1.13-3.20]), macrosomia (1.53[1.03-2.27]), and neonatal intensive care unit (NICU) admission (1.69[1.22-2.34]) in the ovulation disorder group; GDM (1.50[1.21-1.86]), placenta previa (2.70[1.59-4.59]), placenta accreta (1.78[1.10-2.89]), postpartum hemorrhage (1.61[1.19-2.18]), macrosomia (1.60[1.21-2.13]) and 5-min Apgar score ≤ 7 (4.09[1.04-16.08]) in the tubal disease group; placenta previa (9.33[4.22-20.62]), small for gestational age (2.29[1.04-5.08]), macrosomia (2.00[1.02-3.95]) and NICU admission (2.35[1.35-4.09]) in the endometriosis group; placenta previa (4.14[2.23-7.68]) and placenta accreta (2.05[1.08-3.87]) in the male infertility group; and GDM (1.85[1.15-2.98]), placenta previa (4.73[1.83-12.21]), placental abruption (3.39[1.20-9.56]), chorioamnionitis (2.93[1.04-8.26]), preterm birth (2.69[1.41-5.15]), and 1-min Apgar score ≤ 7 (4.68[1.62-13.51]) in the mixed infertility group. Among multiple pregnancies, most of the differences that were significant in singleton pregnancies were less extensive or had disappeared. CONCLUSIONS: Infertility etiology within the IVF population was found to affect maternal and neonatal outcomes among all births. During the perinatal period, infertility etiology appears to be an additional risk factor for abnormal pregnancy outcomes besides the use of IVF techniques compared with spontaneous pregnancies. Higher risk was found for ovulation disorders, and lower risk was found for male infertility.

Low lethal doses of Streptococcus iniae caused enteritis in Siberian sturgeon (Acipenser baerii).

In aquaculture, the incidence of enteritis due to Streptococcus iniae infection in Siberian sturgeon (Acipenser baerii) has increased in recent years. The pathogenesis of S. iniae is largely unknown due to the paucity of experimental studies on fish intestinal inflammation. In this study, S. iniae infection of A. baerii juveniles was induced by anal intubation of 0.15 mL at a low lethal dose (2 × 107 CFU/mL). Intestinal pathology and gene expression studies were conducted within 10 days of the experiment. Histopathological examination showed severe intestinal lesions, inflammatory cell infiltration, intestinal submucosa edema, epithelial cell shedding and necrosis. Predominant symptoms of exudative inflammation, metamorphic inflammation and proliferative inflammation on days 1-3, 4-6, and 7-10 post infection were shown, respectively. Ultrastructural observations also revealed fractured microvilli and shedding on days 4-6. Intestinal villi gradually repaired during the subsequent 7-10 days post infection. Expression of the pro-inflammatory cytokines, tumor necrosis factor and interleukin 1ß were up-regulated on days 1-3 followed by a significant decrease on day 5, ultimately reaching control levels on day 10 post infection. A similar pattern was shown in mucus cells, involving mucin secretion and expression of the mucin encoding gene, Mucin-2. These results showed the cellular response to S. iniae infection associated with inflammatory genes expression in the Siberian sturgeon.

Data-Driven H∞ Output Consensus for Heterogeneous Multiagent Systems Under Switching Topology via Reinforcement Learning.

In this article, a novel model-free policy gradient reinforcement learning algorithm is proposed to solve the H∞ tracking problem for discrete-time heterogeneous multiagent systems with external disturbances over switching topology. The dynamics of the followers and the leader are unknown, and the leader's information is missing for each agent due to the switching topology. Therefore, a distributed adaptive observer is introduced to learn the leader's dynamic model and estimate its state for each agent. For the H∞ tracking problem, an exponential discount value function is established and the related discrete-time game algebraic Riccati equation (DTGARE) is derived, which is the key to obtaining the control strategy. Furthermore, a data-based policy gradient algorithm is proposed to approximate the solution of the GAREs online and the utilization of agents' accurate knowledge is avoided. To improve the efficiency of data utilization, an offline dataset and the experience replay scheme are used. In addition, the lower bound of the exponential discount value is explored to ensure the stability of the systems. In the end, a simulation is provided to show the validity of the proposed method.

Adaptive Intermittent Pinning Control for Synchronization of Delayed Nonlinear Memristive Neural Networks With Reaction-Diffusion Items.

In this article, the global exponential synchronization problem is investigated for a class of delayed nonlinear memristive neural networks (MNNs) with reaction-diffusion items. First, using the Green formula, Lyapunov theory, and proposing a new fuzzy adaptive pinning control scheme, some novel algebraic criteria are obtained to ensure the exponential synchronization of the concerned networks. Furthermore, the corresponding control gains can be promptly adjusted based on the current states of partial nodes of the networks. Besides, a fuzzy adaptive aperiodically intermittent pinning control law is also designed to synchronize the fuzzy MNNs (FMNNs). The controller with intermittent mechanism can obtain appropriate rest time and save energy consumption. Finally, some numerical examples are provided to confirm the effectiveness of the results in this article.

Observational study on the potential mechanism of Sanao decoction in the treatment of asthma based on network pharmacology and molecular docking.

Bronchial asthma (BA) is a chronic respiratory disease closely related to immune system dysregulation. Traditional Chinese medicine has long adopted the strategy of Sanao decoction in the treatment of bronchial asthma. However, due to the multi-target and multi-pathway characteristics of Chinese herbal medicine, we are still unclear about the specific mechanism of Sanao decoction in treating bronchial asthma. To investigate the mechanism of action of Sanao decoction in the treatment of BA using a network pharmacology approach and preliminary validation by molecular docking technology. Traditional Chinese medicine systems pharmacology database and analysis platform and UniProt databases were used to search the active ingredients and targets of Sanao decoction, and BA-related targets were screened according to GeneCards and online Mendelian inheritance in man database databases. The intersection targets were imported into the STRING database to construct a protein-protein interaction network, and Cytoscape 3.9.1 software was used to screen out hub genes. This study also constructed a "drug-ingredient-target" visual network diagram. Gene Ontology and Kyoto Encyclopedia of Genomes enrichment analysis was performed on targets in the protein-protein interaction network using the ClusterProfiler package in R, with a P value < .05. Autodock software was used for molecular docking to complete the preliminary verification of core components and targets. A total of 73 active compounds and 308 targets of Sanao decoction, including 1640 BA-related disease targets, were retrieved from mainstream databases. Gene Ontology analysis and Kyoto encyclopedia of genes and genomes enrichment analysis suggested that Sanao decoction plays a role in the treatment of BA through signaling pathways such as PI3K-Akt, MAPK, and IL-17 signaling pathway. The 9 core goals represent the main elements related to Sanao decoction in the treatment of BA. Subsequently, the molecular docking results showed that most of the active compounds of Sanao decoction have strong binding efficiency with the hub gene. Sanao decoction has a key impact on BA through multiple channels. In summary, this intricate network reflects the potential of Sanao decoction in treating BA, a multifactorial disease. In addition, this study laid the foundation for further in vivo and in vitro experimental research and expanded the clinical application of Sanao decoction.

Effects of ultrasonic treatment on the structure and functional characteristics of myofibrillar proteins from black soldier fly.

In the process of utilizing black soldier fly larvae (BSFL) lipids to develop biodiesel, many by-products will be produced, especially the underutilized protein components. These proteins can be recycled through appropriate treatment and technology, such as the preparation of feed, biofertilizers or other kinds of bio-products, so as to achieve the efficient use of resources and reduce the generation of waste. Myofibrillar protein (MP), as the most important component of protein, is highly susceptible to environmental influences, leading to oxidation and deterioration, which ultimately affects the overall performance of the protein and product quality. For it to be high-quality and fully exploited, in this study, black soldier fly myofibrillar protein (BMP) was extracted and primarily subjected to ultrasonic treatment to investigate the impact of varying ultrasonic powers (300, 500, 700, 900 W) on the structure and functional properties of BMP. The results indicated that as ultrasonic power increased, the sulfhydryl content and turbidity of BMP decreased, leading to a notable improvement in the stability of the protein emulsion system. SEM images corroborated the changes in the microstructure of BMP. Moreover, the enhancement of ultrasound power induced modifications in the intrinsic fluorescence spectra and FTIR spectra of BMP. Additionally, ultrasonic treatment resulted in an increase in carbonyl content and emulsifying activity of BMP, with both peaking at 500 W. It was noteworthy that BMP treated with ultrasound exhibited stronger digestibility compared to the untreated. In summary, 500 W was determined as the optimal ultrasound parameter for this study. Overall, ultrasound modification of insect MPs emerges as a dependable technique capable of altering the structure and functionality of BMP.