Genetic modifiers modulate phenotypic expression of tafazzin deficiency in a mouse model of Barth syndrome.

Barth syndrome is an X-linked disorder caused by loss-of-function mutations in Tafazzin (TAZ), an acyltransferase that catalyzes remodeling of cardiolipin, a signature phospholipid of the inner mitochondrial membrane. Patients develop cardiac and skeletal muscle weakness, growth delay and neutropenia, although phenotypic expression varies considerably between patients. Taz knockout mice recapitulate many of the hallmark features of the disease. We used mouse genetics to test the hypothesis that genetic modifiers alter the phenotypic manifestations of Taz inactivation. We crossed TazKO/X females in the C57BL6/J inbred strain to males from eight inbred strains and evaluated the phenotypes of first-generation (F1) TazKO/Y progeny, compared to TazWT/Y littermates. We observed that genetic background strongly impacted phenotypic expression. C57BL6/J and CAST/EiJ[F1] TazKO/Y mice developed severe cardiomyopathy, whereas A/J[F1] TazKO/Y mice had normal heart function. C57BL6/J and WSB/EiJ[F1] TazKO/Y mice had severely reduced treadmill endurance, whereas endurance was normal in A/J[F1] and CAST/EiJ[F1] TazKO/Y mice. In all genetic backgrounds, cardiolipin showed similar abnormalities in knockout mice, and transcriptomic and metabolomic investigations identified signatures of mitochondrial uncoupling and activation of the integrated stress response. TazKO/Y cardiac mitochondria were small, clustered and had reduced cristae density in knockouts in severely affected genetic backgrounds but were relatively preserved in the permissive A/J[F1] strain. Gene expression and mitophagy measurements were consistent with reduced mitophagy in knockout mice in genetic backgrounds intolerant of Taz mutation. Our data demonstrate that genetic modifiers powerfully modulate phenotypic expression of Taz loss-of-function and act downstream of cardiolipin, possibly by altering mitochondrial quality control.

Afucosylated anti-EBOV antibody MIL77-3 engages sGP to elicit NK cytotoxicity.

MIL77-3 is one component of antibody cocktail that is produced in our lab and represents an effective regimen for animals suffering from Zaire Ebolavirus (EBOV) infection. MIL77-3 is engineered to increase its affinity for the FcγRIIIa (CD16a) by deleting the fucose in the framework region. The potential effects of this modification on host immune responses, however, remain largely unknown. Herein, we demonstrated that MIL77-3 recognized secreted glycoproptein (sGP), produced by EBOV, and formed the immunocomplex to potently augment antibody-dependent cytotoxicity of human peripheral blood-derived natural killer cells (pNKs), including CD56dim and CD56bright subpopulations, in contrast to the counterparts (Mab114, rEBOV548, fucosylated MIL77-3). Intriguingly, this effect was not observed when NK92-CD16a cell line was utilized and restored by the addition of beads-coupled or membrane-anchored sGP in combination with MIL77-3. Furthermore, sGP bound to unrecognized receptors on T cells contaminated in pNKs rather than NK92-CD16a cells. Administration of beads-coupled sGP/MIL77-3 complex in mice elicited NK activation. Overall, this work reveals an immune-stimulating function of sGP/MIL77-3 complex by triggering cytotoxic activity of NK cells, highlighting the necessity to evaluate the potential impact of MIL77-3 on host immune reaction in clinical trials. IMPORTANCE: Zaire Ebolavirus (EBOV) is highly lethal and causes sporadic outbreaks. The passive administration of monoclonal antibodies (mAbs) represents a promising treatment regimen against EBOV. Mounting evidence has shown that the efficacy of a subset of therapeutic mAbs in vivo is intimately associated with its capacity to trigger NK activity, supporting glycomodification of Fc region of anti-EBOV mAbs as a putative strategy to enhance Fc-mediated immune effector function as well as protection in vivo. Our work here uncovers the potential harmful influence of this modification on host immune responses, especially for mAbs with cross-reactivity to secreted glycoproptein (sGP) (e.g., MIL77-3), and highlights it is necessary to evaluate the NK-stimulating activity of a fucosylated mAb engaged with sGP when a new candidate is developed.

Distinct mechanisms underlying cross-modal semantic conflict and response conflict processing.

Interference from task-irrelevant stimuli can occur during the semantic and response processing stages. Previous studies have shown both common and distinct mechanisms underlying semantic conflict processing and response conflict processing in the visual domain. However, it remains unclear whether common and/or distinct mechanisms are involved in semantic conflict processing and response conflict processing in the cross-modal domain. Therefore, the present electroencephalography study adopted an audiovisual 2-1 mapping Stroop task to investigate whether common and/or distinct mechanisms underlie semantic conflict and response conflict. Behaviorally, significant cross-modal semantic conflict and significant cross-modal response conflict were observed. Electroencephalography results revealed that the frontal N2 amplitude and theta power increased only in the semantic conflict condition, while the parietal N450 amplitude increased only in the response conflict condition. These findings indicated that distinct neural mechanisms were involved in cross-modal semantic conflict and response conflict processing, supporting the domain-specific cognitive control mechanisms from a cross-modal multistage conflict processing perspective.

Cognitive and neural mechanisms of voluntary versus forced language switching in Chinese-English bilinguals: an fMRI study.

The ecological validity of bilingual code-switching has garnered increasing attention in recent years. Contrary to traditional studies that have focused on forced language switching, emerging theories posit that voluntary switching may not incur such a cost. To test these claims and understand differences between forced and voluntary switching, the present study conducted a systematic comparison through both behavioral and neural perspectives. Utilizing fMRI alongside picture-naming tasks, our findings diverge from prior work. Voluntary language switching not only demonstrated switching costs at the behavioral level but also significantly activated brain regions associated with inhibitory control. Direct comparisons of voluntary and forced language switching revealed no significant behavioral differences in switching costs, and both shared several common brain regions that were activated. On the other hand, a nuanced difference between the two types of language switching was revealed by whole-brain analysis: voluntary switching engaged fewer language control regions than forced switching. These findings offer a comprehensive view of the neural and behavioral dynamics involved in bilingual language switching, challenging prior claims that voluntary switching imposes no behavioral or neural costs, and thus providing behavioral and neuroimaging evidence for the involvement of inhibitory control in voluntary language switching.

Distinct and common mechanisms of cross-model semantic conflict and response conflict in an auditory relevant task.

The mechanisms of semantic conflict and response conflict in the Stroop task have mainly been investigated in the visual modality. However, the understanding of these mechanisms in cross-modal modalities remains limited. In this electroencephalography (EEG) study, an audiovisual 2-1 mapping Stroop task was utilized to investigate whether distinct and/or common neural mechanisms underlie cross-modal semantic conflict and response conflict. The response time data showed significant effects on both cross-modal semantic and response conflicts. Interestingly, the magnitude of semantic conflict was found to be smaller in the fast response time bins than in the slow response time bins, whereas no such difference was observed for response conflict. The EEG data demonstrated that cross-modal semantic conflict specifically increased the N450 amplitude. However, cross-modal response conflict specifically enhanced theta band power and theta phase synchronization between the medial frontal cortex (MFC) and lateral prefrontal electrodes as well as between the MFC and motor electrodes. In addition, both cross-modal semantic conflict and response conflict led to a decrease in P3 amplitude. Taken together, these findings provide cross-modal evidence for domain-specific mechanism in conflict detection and suggest both domain-specific and domain-general mechanisms exist in conflict resolution.

Polycystic Ovary Syndrome Fuels Cardiovascular Inflammation and Aggravates Ischemic Cardiac Injury.

BACKGROUND: Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear. METHODS: Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models. RESULTS: Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C+ monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C+ monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14++CD16- monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional Vcam1 silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI. CONCLUSIONS: Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.

The association between social rewards and anxiety: Links from neurophysiological analysis in virtual reality and social interaction game.

Individuals' affective experience can be intricate, influenced by various factors including monetary rewards and social factors during social interaction. However, within this array of factors, divergent evidence has been considered as potential contributors to social anxiety. To gain a better understanding of the specific factors associated with anxiety during social interaction, we combined a social interaction task with neurophysiological recordings obtained through an anxiety-elicitation task conducted in a Virtual Reality (VR) environment. Employing inter-subject representational similarity analysis (ISRSA), we explored the potential linkage between individuals' anxiety neural patterns and their affective experiences during social interaction. Our findings suggest that, after controlling for other factors, the influence of the partner's emotional cues on individuals' affective experiences is specifically linked to their neural pattern of anxiety. This indicates that the emergence of anxiety during social interaction may be particularly associated with the emotional cues provided by the social partner, rather than individuals' own reward or prediction errors during social interaction. These results provide further support for the cognitive theory of social anxiety and extend the application of VR in future cognitive and affective studies.

A Spatiotemporal Controllable Biomimetic Skin for Accelerating Wound Repair.

Skin injury repair is a dynamic process involving a series of interactions over time and space. Linking human physiological processes with materials' changes poses a significant challenge. To match the wound healing process, a spatiotemporal controllable biomimetic skin is developed, which comprises a three-dimensional (3D) printed membrane as the epidermis, a cell-containing hydrogel as the dermis, and a cytokine-laden hydrogel as the hypodermis. In the initial stage of the biomimetic skin repair wound, the membrane frame aids wound closure through pre-tension, while cells proliferate within the hydrogel. Next, as the frame disintegrates over time, cells released from the hydrogel migrate along the residual membrane. Throughout the process, continuous cytokines release from the hypodermis hydrogel ensures comprehensive nourishment. The findings reveal that in the rat full-thickness skin defect model, the biomimetic skin demonstrated a wound closure rate eight times higher than the blank group, and double the collagen content, particularly in the early repair process. Consequently, it is reasonable to infer that this biomimetic skin holds promising potential to accelerate wound closure and repair. This biomimetic skin with mechanobiological effects and spatiotemporal regulation emerges as a promising option for tissue regeneration engineering.

Functional TET2 gene polymorphisms increase the risk of neuroblastoma in Chinese children.

The 5-methylcytosine (m5C) is the key chemical modification in RNAs. As one of the demethylases in m5C, TET2 has been shown as a tumor suppressor. However, the impact of TET2 gene polymorphisms on neuroblastoma has not been elucidated. 402 neuroblastoma patients and 473 controls were genotyped for TET2 gene polymorphisms using the TaqMan method. The impact of TET2 gene polymorphisms on neuroblastoma susceptibility was determined using multivariate logistic regression analysis. We also adopted genotype-tissue expression database to explore the impact of TET2 gene polymorphisms on the expression of host and nearby genes. We used the R2 platform and Sangerbox tool to analyze the relationship between gene expression and neuroblastoma risk and prognosis through non-parametric testing and Kaplan-Meier analysis, respectively. We found the TET2 gene polymorphisms (rs10007915 G > C and rs7670522 A > C) and the combined 2-5 risk genotypes can significantly increase neuroblastoma risk. Stratification analysis showed that these significant associations were more prominent in certain subgroups. TET2 rs10007915 G > C and rs7670522 A > C are significantly associated with reduced expression of TET2 mRNA. Moreover, lower expression of TET2 gene is associated with high risk, MYCN amplification, and poor prognosis of neuroblastoma. The rs10007915 G > C and rs7670522 A > C are significantly related to the increased expression of inorganic pyrophosphatase 2 mRNA, and higher expression of PPA2 gene is associated with high risk, MYCN amplification, and poor prognosis of neuroblastomas. In summary, TET2 rs10007915 G > C and rs7670522 A > C significantly confer neuroblastoma susceptibility, and further research is needed to investigate the underlying mechanisms.

Correlation Analysis Between Tumor Deposit and Clinicopathologic Characteristics and Prognosis of Gastric Cancer: A Multicenter Retrospective Study.

BACKGROUND: The mechanism underlying the formation of gastric tumor deposits (TDs) is unclear. We aimed to explore the risk factors for the formation and prognostic value of TDs. METHODS: This retrospective analysis included 781 locally advanced gastric cancer (LAGC) patients from four medical institutions in China, from June 2014 to June 2018. The risk factors for TD formation and prognostic value were determined through univariate and multivariate analyses. RESULTS: Univariate analysis revealed that TD positivity was closely related to tumor diameter, Borrmann classification, differentiation degree, pT stage, pN stage, pTNM stage, and nerve and vascular invasion (p < 0.05). Multivariate logistic regression revealed that tumor diameter ≥ 5 cm (odds ratio [OR] 1.836, 95% confidence interval [CI] 1.165-2.894, p = 0.009) and vascular invasion (OR 2.152, 95% CI 1.349-3.433, p = 0.001) were independent risk factors for TD positivity. Multivariate Cox analysis revealed that TD positivity (OR 1.533, 95% CI 1.101-2.134, p = 0.011), tumor diameter ≥ 5 cm (OR 1.831, 95% CI 1.319-2.541, p < 0.001), pT4a stage (OR 1.652, 95% CI 1.144-2.386, p = 0.007), and vascular invasion (OR 1.458, 95% CI 1.059-2.008, p = 0.021) were independent risk factors for GC prognosis. The 5-year overall and disease-free survival of the TD-positive group showed significant effects among patients in the pT4a and pN3b stages (p < 0.05). CONCLUSIONS: TDs are closely related to tumor diameter and vascular invasion in LAGC patients, and TD positivity is an independent prognostic factor for LAGC patients, especially those at pT4a and pN3b stages.

Identification of autophagy-related signatures in doxorubicin-induced cardiotoxicity.

PURPOSE: Doxorubicin is an antibiotic drug used clinically to treat infectious diseases and tumors. Unfortunately, it is cardiotoxic. Autophagy is a cellular self-decomposition process that is essential for maintaining homeostasis in the internal environment. Accordingly, the present study was proposed to characterize the autophagy-related signatures of doxorubicin-induced cardiotoxicity. METHODS: Datasets related to doxorubicin-induced cardiotoxicity were retrieved by searching the GEO database and differentially expressed genes (DEGs) were identified. DEGs were taken to intersect with autophagy-related genes to obtain autophagy-related signatures, and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction (PPI) network were performed on them. Further, construction of miRNA-hub gene networks and identification of target drugs to reveal potential molecular mechanisms and therapeutic strategies. Animal models of doxorubicin-induced cardiotoxicity were constructed to validate differences in gene expression for autophagy-related signatures. RESULTS: PBMC and heart samples from the GSE37260 dataset were selected for analysis. There were 995 and 2357 DEGs in PBMC and heart samples, respectively, and they had 23 intersecting genes with autophagy-related genes. RT-qPCR confirmed the differential expression of 23 intersecting genes in doxorubicin-induced cardiotoxicity animal models in general agreement with the bioinformatics results. An autophagy-related signatures consisting of 23 intersecting genes is involved in mediating processes and pathways such as autophagy, oxidative stress, apoptosis, protein ubiquitination and phosphorylation. Moreover, Akt1, Hif1a and Mapk3 are hub genes in autophagy-associated signatures and their upstream miRNAs are mainly rno-miR-1188-5p, rno-miR-150-3p and rno-miR-326-3p, and their drugs are mainly CHEMBL55802, Carboxyamidotriazole and 3-methyladenine. CONCLUSION: This study identifies for the first-time autophagy-related signatures in doxorubicin's cardiotoxicity, which could provide potential molecular mechanisms and therapeutic strategies for doxorubicin-induced cardiotoxicity.

Safety of embryo cryopreservation: insights from mid-term placental transcriptional changes.

BACKGROUND: In recent years, with benefits from the continuous improvement of clinical technology and the advantage of fertility preservation, the application of embryo cryopreservation has been growing rapidly worldwide. However, amidst this growth, concerns about its safety persist. Numerous studies have highlighted the elevated risk of perinatal complications linked to frozen embryo transfer (FET), such as large for gestational age (LGA) and hypertensive disorders during pregnancy. Thus, it is imperative to explore the potential risk of embryo cryopreservation and its related mechanisms. METHODS: Given the strict ethical constraints on clinical samples, we employed mouse models in this study. Three experimental groups were established: the naturally conceived (NC) group, the fresh embryo transfer (Fresh-ET) group, and the FET group. Blastocyst formation rates and implantation rates were calculated post-embryo cryopreservation. The impact of FET on fetal growth was evaluated upon fetal and placental weight. Placental RNA-seq was conducted, encompassing comprehensive analyses of various comparisons (Fresh-ET vs. NC, FET vs. NC, and FET vs. Fresh-ET). RESULTS: Reduced rates of blastocyst formation and implantation were observed post-embryo cryopreservation. Fresh-ET resulted in a significant decrease in fetal weight compared to NC group, whereas FET reversed this decline. RNA-seq analysis indicated that the majority of the expression changes in FET were inherited from Fresh-ET, and alterations solely attributed to embryo cryopreservation were moderate. Unexpectedly, certain genes that showed alterations in Fresh-ET tended to be restored in FET. Further analysis suggested that this regression may underlie the improvement of fetal growth restriction in FET. The expression of imprinted genes was disrupted in both FET and Fresh-ET groups. CONCLUSION: Based on our experimental data on mouse models, the impact of embryo cryopreservation is less pronounced than other in vitro manipulations in Fresh-ET. However, the impairment of the embryonic developmental potential and the gene alterations in placenta still suggested it to be a risky operation.

Exploring the relationship between gut microbiota and breast cancer risk in European and East Asian populations using Mendelian randomization.

BACKGROUND: Several studies have explored the potential link between gut microbiota and breast cancer; nevertheless, the causal relationship between gut microbiota and breast cancer remains unclear. METHODS: We utilized summary statistics from genome-wide association studies (GWAS) of the gut microbiome from the MiBioGen project with summary data from GWAS on breast cancer from the FinnGen consortium and the IEU database, with the IEU data sourced from the Biobank Japan. Preliminary statistical analyses were conducted using inverse variance weighting (IVW), supplemented by various sensitivity analysis methods, including MR-Egger regression, weighted median, weighted mode, simple median, and simple mode, to ensure the robustness of our findings. Heterogeneity and pleiotropy were assessed to avoid misleading conclusions caused by unconsidered confounders or non-specific effects of genetic variants, ensuring that the results reflect a genuine causal relationship. RESULTS: In European populations, four types of gut microbiota were associated with breast cancer. The genus Erysipelatoclostridium was positively associated with the risk of breast cancer, with an odds ratio (OR) of 1.21 (95% confidence interval [CI] 1.083-1.358), false discovery rate (FDR) = 0.0039. The class Coriobacteriia, order Coriobacteriales, and family Coriobacteriaceae, which belong to the same phylogenetic system, showed a consistent inversely association with breast cancer risk, with an OR of 0.757 (95% CI 0.616-0.930), FDR = 0.0281. In East Asian populations, three types of gut microbiota were related to breast cancer. The Eubacterium ruminantium group was positively associated with breast cancer risk, with an OR of 1.259 (95% CI 1.056-1.499), FDR = 0.0497. The families Porphyromonadaceae and Ruminococcaceae were inversely associated with breast cancer risk, with ORs of 0.304 (95% CI 0.155-0.596), FDR = 0.0005, and 0.674 (95% CI 0.508-0.895), FDR = 0.03173, respectively. However, these two taxa had limited instrumental variables, restricting the statistical power and potentially affecting the interpretation of the results. CONCLUSION: This MR analysis demonstrated a probable causal link between specific gut microbiota and breast cancer. This study, through Mendelian randomization analysis comparing European and East Asian populations, reveals that gut microbiota may influence breast cancer risk differently across populations, providing potential directions for developing targeted prevention and treatment methods.

The outcome of advanced and recurrent cervical cancer patients treated with first-line platinum and paclitaxel with or without indication for immune checkpoint inhibitors: the comparative study.

OBJECTIVE: Immune checkpoint inhibitor (ICI) therapy activates the immune system to recognize and eliminate cancer cells that have escaped surveillance. This study aimed to compare the treatment outcome of advanced and recurrent cervical cancer patients treated with first-line platinum and paclitaxel with or without ICI. METHODS: Data from 69 advanced and recurrent cervical cancer patients treated with first-line ICI plus platinum and paclitaxel (N = 33) or first-line platinum and paclitaxel (N = 36) were reviewed between March 2020 and January 2023 in this retrospective study. Patients chose treatment based on the actual disease condition, patient willingness, and medical advice. Additionally, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were calculated, and adverse events were gained. RESULTS: There was no difference in baseline data between patients receiving the two different treatments (all P > 0.05). Complete response rate (18.2% vs. 8.3%; P = 0.294), ORR (48.5% vs. 30.6%; P = 0.127), and DCR (81.8% vs. 72.2%; P = 0.345) tended to ascend in patients treated with ICI plus platinum and paclitaxel compared to those treated with platinum and paclitaxel, although there was no statistical significance. In patients treated with ICI plus platinum and paclitaxel, the median PFS was 10.3 months and the median OS was not reached. Meanwhile, the median PFS and OS were 7.7 and 16.9 months in patients treated with platinum and paclitaxel. PFS (P = 0.036) and OS (P = 0.033) were increased in patients treated with ICI plus platinum and paclitaxel versus those treated with platinum and paclitaxel, which was verified by multivariate Cox regression analyses (both P < 0.05). No difference was observed in the occurrence of adverse events between patients receiving the two different treatments (all P > 0.05). CONCLUSION: First-line ICI plus platinum and paclitaxel yields better treatment responses, longer survival, and non-differential adverse events versus first-line platinum and paclitaxel in advanced and recurrent cervical cancer patients.

Association of maternal mild hypothyroidism in the first and third trimesters with obstetric and perinatal outcomes: a prospective cohort study.

BACKGROUND: Mild hypothyroidism, including subclinical hypothyroidism and isolated maternal hypothyroxinemia, is fairly common in pregnant women, but its impact on pregnancy outcomes is less clear, especially mild hypothyroidism in late pregnancy. OBJECTIVE: To evaluate the impact of subclinical hypothyroidism and isolated maternal hypothyroxinemia in the first and third trimesters, respectively, on obstetric and perinatal outcomes. STUDY DESIGN: This large prospective study was conducted at the International Peace Maternity and Child Health Hospital in Shanghai; 52,027 pregnant women who underwent the first-trimester antenatal screening at International Peace Maternity and Child Health Hospital were consecutively enrolled from January 2013 to December 2016. To evaluate the impact of maternal subclinical hypothyroidism and isolated maternal hypothyroxinemia in the first trimester on pregnancy outcomes, participants were divided into 3 groups according to thyroid function in the first trimester: first-trimester euthyroidism group (n=33,130), first-trimester subclinical hypothyroidism group (n=884), and first-trimester isolated maternal hypothyroxinemia group (n=846). Then, to evaluate the impact of maternal subclinical hypothyroidism and isolated maternal hypothyroxinemia in the third trimester on pregnancy outcomes, the first-trimester euthyroidism group was subdivided into 3 groups according to thyroid function in the third trimester: third-trimester euthyroidism group (n=30,776), third-trimester subclinical hypothyroidism group (n=562), and third-trimester isolated maternal hypothyroxinemia group (n=578). Obstetric and perinatal outcomes, including preterm birth, preeclampsia, gestational hypertension, gestational diabetes mellitus, large for gestational age, small for gestational age, macrosomia, cesarean delivery, and fetal demise were measured and compared between those in either subclinical hypothyroidism/isolated maternal hypothyroxinemia group and euthyroid group. Binary logistic regression was used to assess the association of subclinical hypothyroidism or isolated maternal hypothyroxinemia with these outcomes. RESULTS: Thirty-four thousand eight hundred sixty pregnant women who had first (weeks 8-14) and third trimester (weeks 30-35) thyrotropin and free thyroxine concentrations available were included in the final analysis. Maternal subclinical hypothyroidism in the first trimester was linked to a lower risk of gestational diabetes mellitus (adjusted odds ratio 0.64, 95% confidence interval 0.50-0.82) compared with the euthyroid group. However, third-trimester subclinical hypothyroidism is associated with heightened rates of preterm birth (adjusted odds ratio 1.56, 95% confidence interval 1.10-2.20), preeclampsia (adjusted odds ratio 2.23, 95% confidence interval 1.44-3.45), and fetal demise (adjusted odds ratio 7.00, 95% confidence interval 2.07-23.66) compared with the euthyroid group. Isolated maternal hypothyroxinemia in the first trimester increased risks of preeclampsia (adjusted odds ratio 2.14, 95% confidence interval 1.53-3.02), gestational diabetes mellitus (adjusted odds ratio 1.45, 95% confidence interval 1.21-1.73), large for gestational age (adjusted odds ratio 1.64, 95% confidence interval 1.41-1.91), macrosomia (adjusted odds ratio 1.85, 95% confidence interval 1.49-2.31), and cesarean delivery (adjusted odds ratio 1.35, 95% confidence interval 1.06-1.74), while isolated maternal hypothyroxinemia in the third trimester increased risks of preeclampsia (adjusted odds ratio 2.85, 95% confidence interval 1.97-4.12), large for gestational age (adjusted odds ratio 1.49, 95% confidence interval 1.23-1.81), and macrosomia (adjusted odds ratio 1.60, 95% confidence interval 1.20-2.13) compared with the euthyroid group. CONCLUSION: This study indicates that while first-trimester subclinical hypothyroidism did not elevate the risk for adverse pregnancy outcomes, third-trimester subclinical hypothyroidism was linked to several adverse pregnancy outcomes. Isolated maternal hypothyroxinemia in the first and third trimesters was associated with adverse pregnancy outcomes, yet the impact varied by trimester. These results suggest the timing of mild hypothyroidism in pregnancy may be pivotal in determining its effects on adverse pregnancy outcomes and underscore the importance of trimester-specific evaluations of thyroid function.

A single-molecule fluorescent probe for visualizing viscosity and hypoxia in lysosomes and zebrafish embryos.

Viscosity and hypoxia, as microenvironment parameters, play important roles in maintaining normal biological processes and homeostasis. Therefore, simultaneous and sensitive detection of these elements with simple and effective methods could offer precise information in biology. Here, we report a two-site lysosome-targeting fluorescent probe, NVP, for monitoring viscosity and nitroreductase with dual emission channels (emission shift is 86 nm). The NVP probe has displayed highly sensitive and selective responses towards viscosity and nitroreductase, respectively. Significantly, the fluctuations of viscosity and NTR have been detected in vitro and in vivo. We expect that the dual-responsive fluorescent NVP probe will become a potential molecular tool for the exploration of deeper functions of viscosity and hypoxia.

Molecular characterization of a novel narnavirus infecting the phytopathogenic fungus Botryosphaeria dothidea.

Here, a novel mycovirus, Botryosphaeria dothidea narnavirus 5 (BdNV5), was discovered in the plant-pathogenic fungus Botryosphaeria dothidea strain ZM210167-1. The BdNV5 genome sequence is 2,397 nucleotides (nt) in length and contains a putative open reading frame (ORF) encoding an RNA-dependent RNA polymerase (RdRp) with a molecular mass of 72.77 kDa. A BLASTp search using the RdRp amino acid (aa) sequence showed that it was most similar to the RdRp of Botryosphaeria dothidea narnavirus 4 (42.35%). In a phylogenetic tree based on RdRp aa sequences, BdNV5 clustered with members of the family Narnaviridae. BdNV5 is thus a novel member of the family Narnaviridae infecting the phytopathogenic fungus B. dothidea.

Integrative Inducer Intervention and Transcriptomic Analyses Reveal the Metabolism of Paralytic Shellfish Toxins in Azumapecten farreri.

Paralytic shellfish toxins (PSTs) are widely distributed neurotoxins, and the PST metabolic detoxification mechanism in bivalves has received increasing attention. To reveal the effect of phase I (cytochrome P450)-II (GST)-III (ABC transport) metabolic systems on the PST metabolism in Azumapecten farreri, this study amplified stress on the target systems using rifampicin, dl-α-tocopherol, and colchicine; measured PST levels; and conducted transcriptomic analyses. The highest toxin content reached 1623.48 µg STX eq/kg in the hepatopancreas and only 8.8% of that in the gills. Inducer intervention significantly decreased hepatopancreatic PST accumulation. The proportional reductions in the rifampicin-, dl-α-tocopherol-, and colchicine-induced groups were 55.3%, 50.4%, and 36.1%, respectively. Transcriptome analysis showed that 11 modules were significantly correlated with PST metabolism (six positive/five negative), with phase I CYP450 and phase II glutathione metabolism significantly enriched in negatively correlated pathways. Twenty-three phase I-II-III core genes were further validated using qRT-PCR and correlated with PST metabolism, revealing that CYP46A1, CYP4F6, GSTM1, and ABCF2 were significantly correlated, while CYP4F11 and ABCB1 were indirectly correlated. In conclusion, phase I-II-III detoxification enzyme systems jointly participate in the metabolic detoxification of PSTs in A. farreri. This study provides key data support to profoundly elucidate the PST metabolic detoxification mechanism in bivalves.

The clinical significance of plasma sCD25 as valuable biomarker for progression and prognosis of tuberculosis.

BACKGROUND: sCD25 is an important immune molecule for T cell regulation. Tracking the detection of plasma sCD25 plays an important role in the evaluation of immune function, progression, and prognosis of tuberculosis (TB) patients. This study analyzed the association of plasma sCD25 levels with clinical, laboratory, CT imaging characteristics, and clinical outcome of TB patients. METHODS: The clinical data of 303 TB patients treated in the Fifth People's Hospital of Suzhou from October 2019 to January 2022 were retrospectively analyzed. The levels of sCD25 in plasma were detected by ELISA. According to the cut-off threshold of plasma sCD25 levels, the patients were divided into a low-value group (Group TB1) and a high-value group (Group TB2). The association of plasma sCD25 levels with clinical, laboratory, and CT imaging characteristics of TB patients, as well as their TB treatment outcome were analyzed. RESULTS: The levels of plasma sCD25 of patients with TB patients were higher than that of the healthy control group (P < 0.01). Among the 303 TB patients, the levels were increased in Group TB2 patients (0.602 ± 0.216 vs. 1.717 ± 0.604 ng/ml, P < 0.001), and there was a progressive reduction after anti-TB treatment. Furthermore, patients in Group TB2 showed higher positive rates in sputum smear (52.0% vs. 34.3%; P = 0.003), sputum culture (69.7% vs. 56.9%; P = 0.032), Xpert MTB/RIF (66.3% vs. 51.2%; P = 0.013) and TB-DNA (51.5% vs. 31.2%; P = 0.001) than those in Group TB1. Patients in Group TB2 had higher incidence in cough (78.8% vs. 62.3%; P = 0.004), expectoration (64.4% vs. 45.1%; P = 0.001), concomitant extrapulmonary TB (14.1% vs. 5.9%; P = 0.016), cavities (47.9% vs. 34.0%; P = 0.022), and unfavorable outcomes after anti-TB treatment. CONCLUSION: The clinical, laboratory and radiological manifestations of TB patients with high plasma sCD25 levels indicate that the disease is more severe. Tracking plasma sCD25 detection of TB patients has evident clinical significance. It is noteworthy that when the plasma sCD25 levels are significantly elevated, patients should be cautious of the TB progression and disease severity.

The role of oxytocin in modulating self-other distinction in human brain: a pharmacological fMRI study.

Self-other distinction is crucial for human interaction. Although with conflicting results, studies have found that oxytocin (OT) sharpens the self-other perceptual boundary. However, little is known about the effect of OT on self-other perception, especially its neural basis. Moreover, it is unclear whether OT influences self-other discrimination when the other is a child or an adult. This double-blind, placebo-controlled study investigated the effect of OT on self-face perception at the behavioral and neural levels. For the stimuli, we morphed participants' faces and child or adult strangers' faces, resulting in 4 conditions. After treatment with either OT or placebo, participants reported whether a stimulus resembled themselves while being scanned using functional magnetic resonance imaging (fMRI). Behavioral results showed that people judged adult-morphed faces better than child-morphed faces. Moreover, fMRI results showed that the OT group exhibited increased activity in visual areas and the inferior frontal gyrus for self-faces. This difference was more pronounced in the adult-face condition. In multivariate fMRI and region of interest analyses, better performance in the OT group indicated that OT increased self-other distinction, especially for adult faces and in the left hemisphere. Our study shows a significant effect of OT on self-referential processes, proving the potential effect of OT on a left hemisphere self-network.