Clinical application of dual-layer spectral CT multi-parameter feature to predict microvascular invasion in hepatocellular carcinoma.

OBJECTIVE: This study aimed to investigate the feasibility of using dual-layer spectral CT multi-parameter feature to predict microvascular invasion of hepatocellular carcinoma. METHODS: This retrospective study enrolled 50 HCC patients who underwent multiphase contrast-enhanced spectral CT studies preoperatively. Combined clinical data, radiological features with spectral CT quantitative parameter were constructed to predict MVI. ROC was applied to identify potential predictors of MVI. The CT values obtained by simulating the conventional CT scans with 70 keV images were compared with those obtained with 40 keV images. RESULTS: 50 hepatocellular carcinomas were detected with 30 lesions (Group A) with microvascular invasion and 20 (Group B) without. There were significant differences in AFP,tumer size, IC, NIC,slope and effective atomic number in AP and ICrr in VP between Group A ((1000(10.875,1000),4.360±0.3105, 1.7750 (1.5350,1.8825) mg/ml, 0.1785 (0.1621,0.2124), 2.0362±0.2108,8.0960±0.1043,0.2830±0.0777) and Group B (4.750(3.325,20.425),3.190±0.2979,1.4700 (1.4500,1.5775) mg/ml, 0.1441 (0.1373,0.1490),1.8601±0.1595, 7.8105±0.7830 and 0.2228±0.0612) (all p < 0.05). Using 0.1586 as the threshold for NIC, one could obtain an area-under-curve (AUC) of 0.875 in ROC to differentiate between tumours with and without microvascular invasion. AUC was 0.625 with CT value at 70 keV and improved to 0.843 at 40 keV. CONCLUSION: Dual-layer spectral CT provides additional quantitative parameters than conventional CT to enhance the differentiation between hepatocellular carcinoma with and without microvascular invasion. Especially, the normalized iodine concentration (NIC) in arterial phase has the greatest potential application value in determining whether microvascular invasion exists, and can offer an important reference for clinical treatment plan and prognosis assessment.

Safety, immunogenicity and protective effect of sequential vaccination with inactivated and recombinant protein COVID-19 vaccine in the elderly: a prospective longitudinal study.

The safety and efficacy of COVID-19 vaccines in the elderly, a high-risk group for severe COVID-19 infection, have not been fully understood. To clarify these issues, this prospective study followed up 157 elderly and 73 young participants for 16 months and compared the safety, immunogenicity, and efficacy of two doses of the inactivated vaccine BBIBP-CorV followed by a booster dose of the recombinant protein vaccine ZF2001. The results showed that this vaccination protocol was safe and tolerable in the elderly. After administering two doses of the BBIBP-CorV, the positivity rates and titers of neutralizing and anti-RBD antibodies in the elderly were significantly lower than those in the young individuals. After the ZF2001 booster dose, the antibody-positive rates in the elderly were comparable to those in the young; however, the antibody titers remained lower. Gender, age, and underlying diseases were independently associated with vaccine immunogenicity in elderly individuals. The pseudovirus neutralization assay showed that, compared with those after receiving two doses of BBIBP-CorV priming, some participants obtained immunological protection against BA.5 and BF.7 after receiving the ZF2001 booster. Breakthrough infection symptoms last longer in the infected elderly and pre-infection antibody titers were negatively associated with the severity of post-infection symptoms. The antibody levels in the elderly increased significantly after breakthrough infection but were still lower than those in the young. Our data suggest that multiple booster vaccinations at short intervals to maintain high antibody levels may be an effective strategy for protecting the elderly against COVID-19.

Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis.

The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis. Identifying circadian therapeutic targets could facilitate the development of new treatments that leverage circadian modulation to ablate tumor-resident CSCs, inhibit tumor metastasis and enhance response to current therapies.

Integrated evidence of transcriptional, metabolic, and intestinal microbiota changes in Ruditapes philippinarum due to perfluorooctanoic acid-induced immunotoxicity.

Perfluorooctanoic acid (PFOA) is a toxic pollutant that bioaccumulates and is a significant public health concern due to its ubiquitous and persistent occurrence in global environments. Few studies have evaluated the adverse effects of PFOA on immune system, and this is particularly true for mollusks. Here, the PFOA-associated effects on immune system were evaluated in Ruditapes philippinarum using integrated analysis of metabolomes, microbiomes, and transcriptomes, providing evidence for possible mechanisms related to immunotoxicity. PFOA exposure caused clear variation in several important metabolites related to immune regulatory function within the haemolyph from R. philippinarum, while also altering key metabolic pathways, including those of lipids, unsaturated fatty acids (UFAs), and bile acids (BAs). After exposure to PFOAs, intestinal bacterial communities also clearly changed, with the predominant microflora becoming Mycoplasma and Bacteroidetes that are related to intestinal inflammation. Molecular analyses provided consistent results, wherein the expression of immune-related genes was significantly altered. Integration of the multi-'omics' analyses suggested that the TLR/MyD88/NF-kB pathway, along with PI3K-Akt-mTOR pathway, PPAR-mediated lipid metabolism and the autophagy signaling pathway, likely play important roles in initiating immunotoxic effects in R. philippinarum after PFOA exposure. These results provide further evidence that PFOA exposure can lead to immunologic dysfunction and also provide new insights into the mechanisms of PFAS alteration of bivalve immune function.

Characteristics of blood immune cell profile and their correlation with disease progression in patients infected with HIV-1.

BACKGROUND: Antiretroviral therapy (ART) can reduce viral load in individuals infected with human immunodeficiency virus (HIV); however, some HIV-infected individuals still cannot achieve optimal immune recovery even after ART. Hence, we described the profile of peripheral immune cells and explored the association with disease progression in patients infected with HIV-1. METHODS: Mass cytometry analysis was used to characterize the circulating immune cells of 20 treatment-naïve (TNs), 20 immunological non-responders (INRs), 20 immunological responders (IRs), and 10 healthy controls (HCs). Correlation analysis was conducted between cell subpopulation percentages and indicators including HIV-1 cell-associated (CA)-RNA, DNA, CD4+ T cell count, and CD4/CD8 ratio. RESULTS: Global activation, immunosenescence, and exhaustion phenotypes were observed in myeloid cells and T cells from individuals with HIV-1 infection. We also found that specific subsets or clusters of myeloid, CD4+ T, and CD8+ T cells were significantly lost or increased in TN individuals, which could be partially restored after receiving ART. The percentages of several subpopulations correlated with HIV-1 CA-RNA, DNA, CD4+ T cell count, and CD4/CD8 ratio, suggesting that changes in immune cell composition were associated with therapeutic efficacy. CONCLUSION: These data provide a complete profile of immune cell subpopulations or clusters that are associated with disease progression during chronic HIV-1 infection, which will improve understanding regarding the mechanism of incomplete immune recovery in INRs.

Effect of SARS-CoV-2 Breakthrough Infection on HIV Reservoirs and T-Cell Immune Recovery in 3-Dose Vaccinated People Living with HIV.

People living with human immunodeficiency virus (PLWH) are a vulnerable population with a higher risk of severe coronavirus disease 2019 (COVID-19); therefore, vaccination is recommended as a priority. Data on viral reservoirs and immunologic outcomes for PLWH breakthrough infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently limited. In this study, we investigated the effects of SARS-CoV-2 breakthrough infection on hematological parameters, human immunodeficiency virus (HIV) reservoir size, and T-cell recovery in PLWH receiving antiretroviral therapy (ART) after SARS-CoV-2 booster vaccination. The results indicated that during breakthrough infection, booster vaccination with homologous and heterologous vaccines was safe in PLWH after receiving two doses of inactivated vaccination. The absolute CD4 counts decreased in the heterologous group, whereas the CD8 counts decreased in the homologous booster group after breakthrough infection in PLWH. Breakthrough infection increased HIV reservoirs and was associated with increased T-cell activation in PLWH who received virally suppressed ART and a 3-dose vaccination. According to our data, the breakthrough infection of SARS-CoV-2 may put PLWH at a greater risk for increased HIV reservoirs, even if these individuals were virally suppressed with ART after 3-dose SARS-CoV-2 vaccination.

Severe intestinal barrier damage in HIV-infected immunological non-responders.

The intestinal epithelial barrier plays an important role during human immunodeficiency virus (HIV) disease progression. However, the extent to which the intestinal epithelial barrier is damaged in immunological non-responders (INRs) and immunological responders (IRs) is largely unknown. In this study, we investigated and compared the levels of intestinal gland damage and related molecules, including the tight junction protein claudin-1, apoptosis marker caspase-3, HIV DNA, CD4+ T cell count, and inflammation marker tumor necrosis factor-α (TNF-α) among the IRs (n = 10), INRs (n = 8), and healthy controls (HCs, n = 7). Intestinal damage was not completely restored in both INRs and IRs and was more serious in INRs than that in IRs. Moreover, intestinal damage was positively correlated with HIV DNA levels and negatively correlated with CD4+ T cell counts. These results provide insight into understanding the characteristics of intestinal epithelial barrier damage between IRs and INRs.

Effects of luxS gene on growth characteristics, biofilm formation, and antimicrobial resistance of multi-antimicrobial-resistant Vibrio parahaemolyticus Vp2015094 isolated from shellfish.

AIMS: Vibrio parahaemolyticus is an important foodborne pathogen worldwide, which can cause gastroenteritis. This study aimed to investigate the effect of quorum sensing system LuxS/AI-2-related gene luxS on the biological characteristics and antimicrobial resistance of V. parahaemolyticus Vp2015094 from shellfish, which carried a multi-antimicrobial-resistant plasmid. METHODS AND RESULTS: The critical gene luxS related to the synthesis of AI-2 in V. parahaemolyticus Vp2015094 was knocked out by homologous recombination with suicide plasmid. The effect of luxS on the biological characteristics of V. parahaemolyticus was determined by comparing the growth, AI-2 activity, motility, biofilm formation ability, and antibiotic resistance between the wildtype strain and the luxS deletion mutant. Compared with wildtype strain, the production of AI-2, the motility and biofilm formation ability, antimicrobial resistance, and conjugation frequency of luxS deletion mutant strain were decreased. The transcriptome sequencing showed that the transcriptional levels of many genes related to motility, biofilm formation, antimicrobial resistance, and conjugation were significantly downregulated after luxS deletion. CONCLUSIONS: Quorum sensing system LuxS/AI-2-related gene luxS in V. parahaemolyticus Vp2015094 played an important role in growth characteristics, biofilm formation, antimicrobial resistance, and resistance genes' transfer.

Antibody aggregation can lead to reduced Protein A binding capacity and low step yield.

Protein A affinity chromatography has been widely used for antibody capture and initial purification. In general, the yield of this step is relatively high (i.e., >90%). However, recently while purifying a bispecific antibody (bsAb) in appended IgG format, the Protein A capture step experienced low yield (i.e., ∼80%). It was found that the target bsAb started appearing in flow-through at a relatively low load density, suggesting that a portion of the expressed bsAb has compromised Protein A binding capability. Further studies indicated that the bsAb in flow-through was mainly in aggregate form. In addition, normal Protein A step yield was restored when the column was loaded with bsAb monomer. Thus, all the evidence pointed to the fact that aggregate with compromised binding capacity was the cause of low Protein A step yield in this case.

Cloning, Expression, and Functional Characterization of FUT1, a Key Gene for Histo-Blood Group Antigens Synthesis in Crassostrea gigas.

Histo-blood group antigens (HBGAs) comprise a family of cell-surface carbohydrates that are considered norovirus-specific binding receptors or ligands. HBGA-like molecules have also been detected in oysters as common norovirus carriers, although the pathway involved in the synthesis of these molecules in oysters has yet to be elucidated. We isolated and identified a key gene involved in the synthesis of HBGA-like molecules, FUT1, from Crassostrea gigas, named CgFUT1. Real-time quantitative polymerase chain reaction analysis showed that CgFUT1 mRNA was expressed in the mantle, gill, muscle, labellum, and hepatopancreatic tissues of C. gigas, with the hepatopancreas exhibiting the highest expression level. A recombinant CgFUT1 protein with a molecular mass of 38.0 kDa was expressed in Escherichia coli using a prokaryotic expression vector. A eukaryotic expression plasmid was constructed and transfected into Chinese hamster ovary (CHO) cells. The expression of CgFUT1 and membrane localization of type H-2 HBGA-like molecules in CHO cells were detected using Western blotting and cellular immunofluorescence, respectively. This study indicated that CgFUT1, expressed in C. gigas tissues, can synthesize type H-2 HBGA-like molecules. This finding provides a new perspective for analyzing the source and synthetic pathway of HBGA-like molecules in oysters.

The genetic basis of the leafy seadragon's unique camouflage morphology and avenues for its efficient conservation derived from habitat modeling.

The leafy seadragon certainly is among evolution's most "beautiful and wonderful" species aptly named for its extraordinary camouflage mimicking its coastal seaweed habitat. However, limited information is known about the genetic basis of its phenotypes and conspicuous camouflage. Here, we revealed genomic signatures of rapid evolution and positive selection in core genes related to its camouflage, which allowed us to predict population dynamics for this species. Comparative genomic analysis revealed that seadragons have the smallest olfactory repertoires among all ray-finned fishes, suggesting adaptations to the highly specialized habitat. Other positively selected and rapidly evolving genes that serve in bone development and coloration are highly expressed in the leaf-like appendages, supporting a recent adaptive shift in camouflage appendage formation. Knock-out of bmp6 results in dysplastic intermuscular bones with a significantly reduced number in zebrafish, implying its important function in bone formation. Global climate change-induced loss of seagrass beds now severely threatens the continued existence of this enigmatic species. The leafy seadragon has a historically small population size likely due to its specific habitat requirements that further exacerbate its vulnerability to climate change. Therefore, taking climate change-induced range shifts into account while developing future protection strategies.

The Imbalance Between Intestinal Th17 and Treg Cells Is Associated with an Incomplete Immune Reconstitution During Long-Term Antiretroviral Therapy in Patients with HIV.

Studies assessing the gut mucosal immune balance in HIV-infected patients using intestinal samples are scarce. In this study, we used intestinal mucosal specimens from the ileocecal region of seven immunological nonresponders (INRs), nine immunological responders (IRs), and six HIV-negative controls. We investigated T helper 17 (Th17) and T regulatory (Treg) cell counts and their ratio, zonula occludens-1 (ZO-1), intestinal fatty acid-binding protein (I-FABP), tumor necrosis factor-α, CD4+ T cell counts, HIV DNA, and cell-associated HIV RNA. The results showed that INRs had lower Th17 and higher Treg cell counts than IR, resulting in a significant difference in the Th17/Treg ratio between IRs and INRs. In addition, INRs had lower ZO-1 and higher I-FABP levels than IRs. The Th17/Treg ratio was positively associated with ZO-1 and negatively associated with I-FABP levels. There was a positive correlation between Th17/Treg ratio and CD4+ T cell counts and a negative correlation between the Th17/Treg ratio and HIV DNA in the intestine. Our study suggests that the imbalance of Th17/Treg in the intestine is a characteristic of incomplete immune reconstitution to antiretroviral therapy and is associated with intestinal damage.

Microbial profiles and immune responses in seahorse gut and brood pouch under chronic exposure to environmental antibiotics.

Ocean antibiotics pose substantial risks to the adaptation and lifespan of marine organisms. Seahorses are unique owing to the occurrence of brood pouches, male pregnancy, and loss of gut-associated lymphatic tissues and spleen, which lead to increased sensitivity to environmental changes. This study evaluated the changes in microbial diversity and immune responses within the gut and brood pouch in the lined seahorse Hippocampus erectus under chronic exposure to environmental levels of triclosan (TCS) and sulfamethoxazole (SMX), which are common antibiotics in coastal regions. The results showed that microbial abundance and diversity within the gut and brood pouch of seahorses were significantly changed following antibiotics treatment, with the expression of core genes involved in immunity, metabolism, and circadian rhythm processes evidently regulated. Notably, the abundance of potential pathogens in brood pouches was considerably increased upon treatment with SMX. Transcriptome analysis revealed that the expression of toll-like receptors, c-type lectins, and inflammatory cytokine genes in brood pouches was significantly upregulated. Notably, some essential genes related to male pregnancy significantly varied after antibiotic treatment, implying potential effects on seahorse reproduction. This study provides insights into the physiological adaptation of marine animals to environmental changes resulting from human activity.

Molecular crosstalk between circadian clock and cancer and therapeutic implications.

The circadian clock governs activity of many physiological processes, thereby playing a pivotal role in human health. Circadian disruption is closely associated with cancer development; in particular, recent discoveries have provided strong evidence supporting specific functions of different molecular clock components in either promoting or inhibiting tumorigenesis. This narrative review aims to summarize the existing data on molecular connections between the clock and cancer. These results along with future efforts pave the road to targeting the circadian clock as a novel pathway for therapeutic intervention. Given the implications of chrono-nutrition interventions such as time-restricted feeding in extending lifespan, chrono-nutrition may have preventive and therapeutic applications for individuals with and at-risk of age-related diseases including cancer.

Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle.

Hepatocellular carcinoma (HCC) remains a global health challenge whose incidence is growing worldwide. Previous evidence strongly supported the notion that the circadian clock controls physiological homeostasis of the liver and plays a key role in hepatocarcinogenesis. Despite the progress, cellular and molecular mechanisms underpinning this HCC-clock crosstalk remain unknown. Addressing this knowledge gap, we show here that although the human HCC cells Hep3B, HepG2, and Huh7 displayed variations in circadian rhythm profiles, all cells relied on the master circadian clock transcription factors, BMAL1 and CLOCK, for sustained cell growth. Down-regulating Bmal1 or Clock in the HCC cells induced apoptosis and arrested cell cycle at the G2/M phase. Mechanistically, we found that inhibiting Bmal1/Clock induced dysregulation of the cell cycle regulators Wee1 and p21 which cooperatively contribute to tumor cell death. Bmal1/Clock knockdown caused downregulation of Wee1 that led to apoptosis activation and upregulation of p21 which arrested the cell cycle at the G2/M phase. Collectively, our results suggest that the circadian clock regulators BMAL1 and CLOCK promote HCC cell proliferation by controlling Wee1 and p21 levels, thereby preventing apoptosis and cell cycle arrest. Our findings shed light on cellular impact of the clock proteins for maintaining HCC oncogenesis and provide proof-of-principle for developing cancer therapy based on modulation of the circadian clock.

Increased Prevalence of Thyroid Nodules Across Nearly 10 Years in Shanghai, China.

OBJECTIVE: This study aimed to determine whether the prevalence of thyroid nodules (TNs) increased due to modern lifestyles or other factors, despite the advances in screening and diagnostic tools. METHODS: This study included 3474 pairs of participants, who were matched by gender and age (±3 years) from two cross-sectional sampling surveys: (1) the program on the iodine nutritional status and related health status of residents in Shanghai in 2009; (2) the thyroid disease screening program for adults in Shanghai between 2017 and 2018. The prevalence of TNs and thyroid diseases in 2009 and 2017-2018 were compared, and the potential risk factors of TNs were detected. RESULTS: The prevalence of TNs in 2009 was 28.9%: 22.5% in males and 34.5% in females. In 2017, this increased to 43.8%: 37.9% in males and 49.1% in females. The prevalence of TNs significantly increased from 2009 to 2017 (odds ratio, 1.486; 95% confidence interval, 1.238-1.786). In addition, female gender, thyroid disease history, and age were the main risk factors for TNs after adjusting for confounders in the logistic regression across the time period. CONCLUSION: The prevalence of TNs significantly increased across nearly 10 years in Shanghai.

Immunogenetic losses co-occurred with seahorse male pregnancy and mutation in tlx1 accompanied functional asplenia.

In the highly derived syngnathid fishes (pipefishes, seadragons & seahorses), the evolution of sex-role reversed brooding behavior culminated in the seahorse lineage's male pregnancy, whose males feature a specialized brood pouch into which females deposit eggs during mating. Then, eggs are intimately engulfed by a placenta-like tissue that facilitates gas and nutrient exchange. As fathers immunologically tolerate allogenic embryos, it was suggested that male pregnancy co-evolved with specific immunological adaptations. Indeed, here we show that a specific amino-acid replacement in the tlx1 transcription factor is associated with seahorses' asplenia (loss of spleen, an organ central in the immune system), as confirmed by a CRISPR-Cas9 experiment using zebrafish. Comparative genomics across the syngnathid phylogeny revealed that the complexity of the immune system gene repertoire decreases as parental care intensity increases. The synchronous evolution of immunogenetic alterations and male pregnancy supports the notion that male pregnancy co-evolved with the immunological tolerance of the embryo.

Exploring the relationships between team leader's conflict management styles and team passion: From the emotional perspective.

From the emotional perspective, this study explores how team leader's conflict management styles affect team passion. A theoretical model is constructed which describes the mediating role of positive team emotional climate and the moderating impact of team emotional intelligence. We collect 101 teams paired data including 101 team leaders and 383 team members to test theoretical model. It is shown that leader's cooperative conflict management style has a significant positive effect on both positive team emotional climate and team passion. Meanwhile, positive team emotional climate plays a mediating role between leader's cooperative conflict management style and team passion. In addition, team emotional intelligence has a moderating effect between leader's cooperative style and positive team emotional climate. This study not only provides a new perspective for follow-up research but also expands the research scope of impacts of conflict management styles. In addition, this study forms the underlying mechanism of team leader's conflict management styles on team passion from the emotional perspective and investigates the mediating effect and moderating effect of emotional variable, which broadens the research on the mechanisms of conflict management styles on team outcomes to a certain extent.