Mercury-induced toxicity: Mechanisms, molecular pathways, and gene regulation.

Mercury is a well-known neurotoxicant for humans and wildlife. The epidemic of mercury poisoning in Japan has clearly demonstrated that chronic exposure to methylmercury (MeHg) results in serious neurological damage to the cerebral and cerebellar cortex, leading to the dysfunction of the central nervous system (CNS), especially in infants exposed to MeHg in utero. The occurrences of poisoning have caused a wide public concern regarding the health risk emanating from MeHg exposure; particularly those eating large amounts of fish may experience the low-level and long-term exposure. There is growing evidence that MeHg at environmentally relevant concentrations can affect the health of biota in the ecosystem. Although extensive in vivo and in vitro studies have demonstrated that the disruption of redox homeostasis and microtube assembly is mainly responsible for mercurial toxicity leading to adverse health outcomes, it is still unclear whether we could quantitively determine the occurrence of interaction between mercurial and thiols and/or selenols groups of proteins linked directly to outcomes, especially at very low levels of exposure. Furthermore, intracellular calcium homeostasis, cytoskeleton, mitochondrial function, oxidative stress, neurotransmitter release, and DNA methylation may be the targets of mercury compounds; however, the primary targets associated with the adverse outcomes remain to be elucidated. Considering these knowledge gaps, in this article, we conducted a comprehensive review of mercurial toxicity, focusing mainly on the mechanism, and genes/proteins expression. We speculated that comprehensive analyses of transcriptomics, proteomics, and metabolomics could enhance interpretation of "omics" profiles, which may reveal specific biomarkers obviously correlated with specific pathways that mediate selective neurotoxicity.

Abnormal circadian rhythm of heart rate variability and their association with symptoms in patients with major depressive disorder.

BACKGROUND: Heart rate variability (HRV) is often reduced in patients with major depressive disorder (MDD) and is linked to symptoms. However, prior studies have mainly focused on short-term HRV, with limited exploration of the 24-h HRV circadian rhythm, despite its ability to comprehensively capture overall HRV distribution and dynamic fluctuations. In this study, we investigated the circadian rhythms of 24-h HRV indices in patients with MDD and their associations with symptom severity. METHODS: We recorded 24-h electrocardiograms in 73 patients with MDD (53 in major depressive episode and 20 in remission period) and 31 healthy controls. An extended cosine model was used to model the circadian rhythm of six HRV indices by five parameters: the mesor, amplitude, duty cycle, curve smoothness, and acrophase. Symptom severity was evaluated using the Hamilton Depression Scale and Hamilton Anxiety Scale. RESULTS: Compared with the control group, patients with MDD had a significantly smaller SampEn mesor, higher HF duty cycle, and lower heart rate (HR) duty cycle. They also had a significantly higher curve smoothness for HR, RMSSD, and HF. The mesor for SampEn, along with the curve smoothness for HR and ln RMSSD, were associated with certain symptoms in patients with MDD. LIMITATIONS: The cross-sectional design and psychiatric treatment of most patients with MDD limited our findings. CONCLUSION: Patients with MDD exhibit abnormal HRV circadian rhythms that are associated with symptoms. Moreover, 24-h ECG monitoring may potentially serve as an adjunct value to objectively evaluate clinical symptoms in these patients.

ERCC3-Related Genes May Aid in the Prognostic and Immunotherapeutic Analysis of Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) has high morbidity and mortality worldwide. Excision repair cross-complement 3 (ERCC3), a key functional gene in the nucleotide excision repair (NER) pathway, is commonly mutated or overexpressed in cancers and is thought to be a key gene contributing to the development of HCC. The characteristics of immune cell infiltration in the global tumor microenvironment (TME) mediated by ERCC3 and its related key genes in HCC are still unclear. The aim of this study was to integrate the role of ERCC3-related key genes in assessing the TME cell infiltration characteristics, immunotherapy efficacy, and prognosis of HCC patients. This study provides a theoretical basis for the study of immunological mechanisms and prognosis prediction in HCC. METHODS: The HCC cohort from the TCGA database included 50 normal samples and 374 tumor samples to compare the differences in ERCC3-related gene expression and prognosis between liver tumor tissues and normal liver tissues and to analyze the extent to which different genes infiltrated TME cells by quantifying the relative abundance of 24 cells through single-sample genome enrichment analysis (ssGSEA). A risk score associated with the ERCC3 gene was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression model. RESULTS: The expression of 11 ERCC3-related genes was significantly upregulated in HCC tumor tissues compared to normal liver tissues, and high expression of these genes was significantly associated with poor prognosis in HCC patients. The key genes (11 ERCC3-related genes) were closely associated with the nucleic acid reduction signaling pathway in nucleic acid metabolism and the viral oncogenic pathway, suggesting that these key genes may play a role in tumor cell proliferation, migration, and invasion, as well as in the pathogenesis of virus-associated HCC. In addition, the infiltration characteristics of TME immune cells in normal and tumor tissues were different. Immune and mesenchymal activity was significantly lower in tumor tissues than in healthy liver tissues. This study revealed that key genes were significantly positively correlated with CTLA4 and enriched in central memory CD4 T cells, effector memory CD4 T cells, activated CD4 T cells, and type 2 T helper cells. The prognostic model constructed by regression analysis could better distinguish patients into high-risk and low-risk groups, and the survival analysis showed that the survival time of patients with high-risk score subtypes was significantly lower than that of patients with low-risk scores and that the high-risk group contained higher levels of immune-suppressive cells, which may be a mediator of immune escape. Moreover, multivariate analyses showed that the risk score profile is a reliable and unbiased biomarker for assessing the prognosis of HCC patients, and its value in predicting the outcome of immunotherapy was also confirmed. CONCLUSION: This study revealed a novel genetic signature that is significantly associated with TME cell infiltration and prognosis in HCC patients. It demonstrated that the combined action of multiple key genes associated with ERCC3 plays a crucial role in shaping the diversity and complexity of TME cell infiltrates. Evaluating the combined characteristics of multiple key genes associated with ERCC3 can help predict the outcome of immunotherapy in patients and provide new potential targets for immuno-individualized therapeutic studies on HCC.

Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results.

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181 .

Seawater Chlorella sp. biofilm for mariculture effluent polishing under environmental combined antibiotics exposure and ecological risk evaluation based on parent antibiotics and transformation products.

Mariculture effluent polishing with microalgal biofilm could realize effective nutrients removal and resolve the microalgae-water separation issue via biofilm scraping or in-situ aquatic animal grazing. Ubiquitous existence of antibiotics in mariculture effluents may affect the remediation performances and arouse ecological risks. The influence of combined antibiotics exposure at environment-relevant concentrations towards attached microalgae suitable for mariculture effluent polishing is currently lack of research. Results from suspended cultures could offer limited guidance since biofilms are richer in extracellular polymeric substances that may protect the cells from antibiotics and alter their transformation pathways. This study, therefore, explored the effects of combined antibiotics exposure at environmental concentrations towards seawater Chlorella sp. biofilm in terms of microalgal growth characteristics, nutrients removal, anti-oxidative responses, and antibiotics removal and transformations. Sulfamethoxazole (SMX), tetracycline (TL), and clarithromycin (CLA) in single, binary, and triple combinations were investigated. SMX + TL displayed toxicity synergism while TL + CLA revealed toxicity antagonism. Phosphorus removal was comparable under all conditions, while nitrogen removal was significantly higher under SMX and TL + CLA exposure. Anti-oxidative responses suggested microalgal acclimation towards SMX, while toxicity antagonism between TL and CLA generated least cellular oxidative damage. Parent antibiotics removal was in the order of TL (74.5-85.2 %) > CLA (60.8-69.5 %) > SMX (13.5-44.1 %), with higher removal efficiencies observed under combined than single antibiotic exposure. Considering the impact of residual parent antibiotics, CLA involved cultures were identified of high ecological risks, while medium risks were indicated in other cultures. Transformation products (TPs) of SMX and CLA displayed negligible aquatic toxicity, the parent antibiotics themselves deserve advanced removal. Four out of eight TPs of TL could generate chronic toxicity, and the elimination of these TPs should be prioritized for TL involved cultures. This study expands the knowledge of combined antibiotics exposure upon microalgal biofilm based mariculture effluent polishing.

Clinical characteristics of acute myeloid leukaemia patients with a large number of azurophilic granules: A single-centre retrospective study.

Large amounts of azurophilic granules are considered to be a morphological feature of acute promyelocytic leukaemia (APL). However, a small percentage of acute myeloid leukaemia (AML) patients also have a large number of azurophilic granules. A large cohort of 3210 AML patients in our hospital was screened to identify AML patients who had a large number of azurophilic granules. The clinical parameters of these patients were collected and compared with typical AML patients (control Group 1) and APL patients (control Group 2). The incidence of AML with a large number of azurophilic granules was 1.26%. The fibrinogen and D-dimer levels of patients in the study group were more similar to those of patients in control Group 2, as was the incidence of bleeding events. Additionally, patients in the study group had higher FLT3-ITD and NPM1 mutation rates than patients in control Group 1. Finally, patients in the study group had a higher 30-day mortality rate than those in control Group 2 (24.2% vs. 9.09%) and showed a higher 30-day mortality trend than those in control Group 1. Therefore, we should pay more attention to the prevention of coagulation dysfunction and bleeding events for these patients.

Relationship between ruminative style and adolescent depression.

BACKGROUND: The role of rumination in depression remains controversial. We aimed to establish the ruminative tendency style theory (RTST), discuss the occurrence of depression in adolescents with rumination as the core, and explore the different associations between adolescent ruminative tendency, ruminative style, and depression. METHODS: This study employed an online questionnaire survey of 1110 Chinese adolescents aged 12-17 years, assessing ruminative tendency, ruminative style, stressful life events, depressive state, depressive trait, the Big Five personality traits, and social support. Conditional process analysis was used to test the chain mediation effect with Ruminative Style as a moderator. After screening for the predictor variables, a logistic regression risk prediction model was established and validated internally. RESULTS: The chain mediation effect of ruminative tendency and depressive trait between stressful life events and depressive state was significant, with the indirect effect accounting for 63.4%. Ruminative Style negatively moderated the relationship between Ruminative Tendency and Depressive Trait (ß=-0.053，P＜0.001). The risk prediction model for depressive state showed good calibration and clinical utility. Area under the curve values for the validation and training sets were 0.926 and 0.927, respectively. CONCLUSION: Different associations may exist between adolescent ruminative tendency, ruminative style, and depression, and the proposal of ruminative style is of great significance for intervention in adolescent depression.

Activation of polyamine catabolism promotes glutamine metabolism and creates a targetable vulnerability in lung cancer.

Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and cancer cell growth. Polyamine metabolism is frequently dysregulated and considered a therapeutic target in cancer. However, targeting polyamine metabolism as monotherapy often exhibits limited efficacy, and the underlying mechanisms are incompletely understood. Here we report that activation of polyamine catabolism promotes glutamine metabolism, leading to a targetable vulnerability in lung cancer. Genetic and pharmacological activation of spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme of polyamine catabolism, enhances the conversion of glutamine to glutamate and subsequent glutathione (GSH) synthesis. This metabolic rewiring ameliorates oxidative stress to support lung cancer cell proliferation and survival. Simultaneous glutamine limitation and SAT1 activation result in ROS accumulation, growth inhibition, and cell death. Importantly, pharmacological inhibition of either one of glutamine transport, glutaminase, or GSH biosynthesis in combination with activation of polyamine catabolism synergistically suppresses lung cancer cell growth and xenograft tumor formation. Together, this study unveils a previously unappreciated functional interconnection between polyamine catabolism and glutamine metabolism and establishes cotargeting strategies as potential therapeutics in lung cancer.

Analysis of influencing factors of serum SCCA elevation in 309 CAP patients with normal CEA,NSE and CYFRA21-1.

Introduction: Squamous cell carcinoma antigen (SCCA) is one of the auxiliary diagnostic indicators of lung squamous cell carcinoma, and an increase in serum SCCA can predict the occurrence of lung squamous cell carcinoma. However, whether SCCA is also elevated in pneumonia patients without malignancy is still not clear. Therefore, we studied influencing factors of elevated serum SCCA in patients with community-acquired pneumonia. Methods: We retrospectively enrolled 309 patients who were admitted to the Respiratory department with normal serum Carcinoembryonic antigen (CEA), Neuron specific enolase (NSE), and Cytokeratin 19 fragment (CYFRA21-1) level and were diagnosed with community-acquired pneumonia (CAP). The patients' serum SCCA level, body temperature, age, sex, white blood cell (WBC) count, hypersensitive C-reactive protein (Hs-CRP) level, and serum amyloid A (SAA) were recorded. Logistic regression models were used to analyze the risk factors of SCCA elevation. The dose-response relationship between temperature and risk of SCCA increase was analyzed using Restricted cubic splines (RCS). Results: Of the 309 patients, 143(46.3%) showed elevated SCCA levels. The logistic regression analysis revealed a significant influence of age and body temperature on elevated SCCA (P<0.05) levels. For every one-year increase in age, the probability of elevated SCCA decreased by 3% [OR=0.97,95%CI:0.95,0.99].For every 1°C increase in body temperature, the risk of elevated SCCA increased by 2.75 times [OR=3.75,95%CI:2.55,5.49].The patients were sorted into quartiles based on body temperature. Compared with patients in the Q1 of body temperature group, patients in the Q3 group were at 7.92 times higher risk [OR=7.92, 95%CI:3.27,19.16].and the risk of elevated SCCA was increased by 22.85 times in the Q4 group [OR=23.85,95%CI:8.38,67.89] after adjusting for age, gender, Hs-CRP, SAA, and WBC. RCS analysis showed there was a linear relationship between temperature index and risk of elevated SCCA. Conclusion: In summary, for CAP patients with normal CEA,NSE and CYFRA21-1 level, age and body temperature are influencing factors of SCCA elevation. Higher body temperature has a strong association with the occurrence of SCCA elevation.

Characterizing complete mitochondrial genome of Aquilegia amurensis and its evolutionary implications.

BACKGROUND: Aquilegia is a model system for studying the evolution of adaptive radiation. However, very few studies have been conducted on the Aquilegia mitochondrial genome. Since mitochondria play a key role in plant adaptation to abiotic stress, analyzing the mitochondrial genome may provide a new perspective for understanding adaptive evolution. RESULTS: The Aquilegia amurensis mitochondrial genome was characterized by a circular chromosome and two linear chromosomes, with a total length of 538,736 bp; the genes included 33 protein-coding genes, 24 transfer RNA (tRNA) genes and 3 ribosomal RNA (rRNA) genes. We subsequently conducted a phylogenetic analysis based on single nucleotide polymorphisms (SNPs) in the mitochondrial genomes of 18 Aquilegia species, which were roughly divided into two clades: the European-Asian clade and the North American clade. Moreover, the genes mttB and rpl5 were shown to be positively selected in European-Asian species, and they may help European and Asian species adapt to environmental changes. CONCLUSIONS: In this study, we assembled and annotated the first mitochondrial genome of the adaptive evolution model plant Aquilegia. The subsequent analysis provided us with a basis for further molecular studies on Aquilegia mitochondrial genomes and valuable information on adaptive evolution in Aquilegia.

High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.

Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.

Rapid assays of SARS-CoV-2 virus and noble biosensors by nanomaterials.

The COVID-19 outbreak caused by SARS-CoV-2 in late 2019 has spread rapidly across the world to form a global epidemic of respiratory infectious diseases. Increased investigations on diagnostic tools are currently implemented to assist rapid identification of the virus because mass and rapid diagnosis might be the best way to prevent the outbreak of the virus. This critical review discusses the detection principles, fabrication techniques, and applications on the rapid detection of SARS-CoV-2 with three categories: rapid nuclear acid augmentation test, rapid immunoassay test and biosensors. Special efforts were put on enhancement of nanomaterials on biosensors for rapid, sensitive, and low-cost diagnostics of SARS-CoV-2 virus. Future developments are suggested regarding potential candidates in hospitals, clinics and laboratories for control and prevention of large-scale epidemic.

EBV-positive Nodal T-Cell and NK-Cell Lymphoma: A Study of 26 Cases Including a Subset With Strong CD30 Expression Mimicking Anaplastic Large Cell Lymphoma.

Epstein-Barr virus (EBV)-positive nodal T-cell and NK-cell lymphoma is a rare neoplasm of cytotoxic T-cell or NK-cell lineage. Here, we report 26 cases affecting 14 men and 12 women with a median age of 52 years. All patients presented with disease involving multiple lymph nodes, and 20 of 22 (91%) fully staged patients had advanced Ann Arbor stage disease. Spleen, liver, and bone marrow were involved in 70%, 50%, and 52% of cases, respectively. These patients had a dismal prognosis with a median survival of 30 days. Histologically, lymph nodes were replaced by lymphoma in a diffuse pattern. Lymphoma cells were variable in size and large cell morphology was seen in 62% of cases. The neoplastic cells were CD4-/CD8- in 14 (54%) cases and CD4-/CD8+ in 12 (46%) cases. CD56 was positive in 14 (54%) cases. CD30 was positive in 20 (77%) cases; a strong and diffuse pattern was observed in 14 (54%) cases, mimicking, in part, anaplastic large cell lymphoma (ALCL). CD30 expression was associated with younger age and large cell morphology. In summary, EBV+ nodal T-cell and NK-cell lymphoma is an aggressive disease with a poor prognosis. These neoplasms are heterogeneous at the morphologic and immunophenotypic levels. Diffuse and strong expression of CD30 could potentially lead to a misdiagnosis of ALCL if EBV evaluation is not performed. Distinguishing between EBV+ nodal T-cell and NK-cell lymphoma from ALCL is important because treatment strategy and prognosis differ. CD30 expression offers a potential therapeutic target for patients with this aggressive disease.

AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial.

BACKGROUND: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9. METHODS: This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing. FINDINGS: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery. INTERPRETATION: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.

Liver Injury Induced by Exposure to Polystyrene Microplastics Alone or in Combination with Cadmium in Mice Is Mediated by Oxidative Stress and Apoptosis.

Microplastics (MPs) have been considered an emerging environmental pollutant which, when combined with toxic metals, enter the circulatory system of mammals and eventually cause damage. Therefore, it is important to study the toxicity of the mixture of MPs and heavy metals for evaluating risk assessment of mammals. In the present study, the toxicological effects of different concentrations of polystyrene (PS)-MPs alone or in combination with cadmium chloride (CdCl2) during chronic exposure (8 weeks) were evaluated using intragastric administration in mice. Using comparative analysis, it was revealed that PS-MPs alone or in combination with Cd could destroy the normal structural morphology of liver tissue and increase the levels of two biochemical indicators of liver damage, thereby inducing changes in antioxidant and hyperoxide capacities. In addition, PS-MPs and/or Cd activated the antioxidant signaling pathway Nrf2-Keap1 and affected the endogenous apoptosis signaling pathway p53-Bcl-2/Bax, thus promoting apoptosis. These findings suggested that exposure to MPs alone or in combination with Cd led to adverse effects on the liver. Furthermore, it was revealed that co-exposure to MPs and Cd reduced Cd toxicity, thereby highlighting the possibility MPs may act as carriers of other toxic substances and coordinate with them. Therefore, evaluating the synergistic or anti-agonistic effects of MPs on the toxicity and bioavailability of xenobiotics is in the future critical in environmental toxicological studies.

Effects of staged multiple phytohormones application on capillary-driven attached Chlorella sp. biofilm.

Comparing with single phytohormone application, applying multiple phytohormones to microalgae-based wastewater treatment systems can offer more extensive growth-promoting and stress-protecting effects for microalgae, yet the advantage of stress-relieving salicylic acid (SA) under combined phytohormones application scenario has not been exploited. Employing the improved capillary-driven attached microalgae culturing device (CD-PBR) previously used for single phytohormone application, this study compared the effects of mixed and single phytohormone(s) addition under as low as 10-7 M dosage. In order to make the best of SA for its stress-relieving property, postponed SA addition combined with applying other phytohormone(s) at the beginning of microalgae cultivation was also investigated. Combination of 10-6 M 6-benzylaminopurine (6-BA) with 10-7 M SA was sufficient for enhancing growth-promoting effects and anti-oxidative responses for attached Chlorella sp., while indole-3-acetic acid (IAA) addition was unnecessary. Combination of 6-BA addition at the beginning while postponed SA addition on Day 4 could further sustain such beneficial effects, while removing up to 99.7% total nitrogen (TN) and 97.9% total phosphorus (TP) from the bulk liquid. These results provided innovative strategies on mixed phytohormones addition for microalgae.

Effects of environmental microplastic exposure on Chlorella sp. biofilm characteristics and its interaction with nitric oxide signaling.

Microalgal biofilm is promising in simultaneous pollutants removal, CO2 fixation, and biomass resource transformation when wastewater is used as culturing medium. Nitric oxide (NO) often accumulates in microalgal cells under wastewater treatment relevant abiotic stresses such as nitrogen deficiency, heavy metals, and antibiotics. However, the influence of emerging contaminants such as microplastics (MPs) on microalgal intracellular NO is still unknown. Moreover, the investigated MPs concentrations among existing studies were mostly several magnitudes higher than in real wastewaters, which could offer limited guidance for the effects of MPs on microalgae at environment-relevant concentrations. Therefore, this study investigated three commonly observed MPs in wastewater at environment-relevant concentrations (10-10,000 µg/L) and explored their impacts on attached Chlorella sp. growth characteristics, nutrients removal, and anti-oxidative responses (including intracellular NO content). The nitrogen source NO3--N at 49 mg/L being 20 % of the nitrogen strength in classic BG-11 medium was selected for MPs exposure experiments because of least intracellular NO accumulation, so that disturbance of intracellular NO by nitrogen availability could be avoided. Under such condition, 10 µg/L polyethylene (PE) MPs displayed most significant microalgal growth inhibition comparing with polyvinyl chloride (PVC) and polyamide (PA) MPs, showing extraordinarily low chlorophyll a/b ratios, and highest superoxide dismutase (SOD) activity and intracellular NO content after 12 days of MPs exposure. PVC MPs exposed cultures displayed highest malonaldehyde (MDA) content because of the toxic characteristics of organochlorines, and most significant correlations of intracellular NO content with conventional anti-oxidative parameters of SOD, CAT (catalase), and MDA. MPs accelerated phosphorus removal, and the type rather than concentration of MPs displayed higher influences, following the trend of PE > PA > PVC. This study expanded the knowledge of microalgal biofilm under environment-relevant concentrations of MPs, and innovatively discovered the significance of intracellular NO as a more sensitive indicator than conventional anti-oxidative parameters under MPs exposure.

Prognosis influence of additional chromosome abnormalities in newly diagnosed acute promyelocytic leukemia with t(15;17)(q24;q21).

OBJECTIVES: In patients with acute promyelocytic leukemia (APL), additional chromosomal abnormalities (ACAs) are prognostic indicators. However, the clinical features of ACAs were not systematically reported in Chinese patients. Therefore, we enrolled a large cohort of APLs to demonstrate the clinical characteristics and prognostic value of ACAs. METHODS: 268 patients with newly diagnosed APL with t(15;17)(q24;q21) were retrospectively enrolled, and their clinical characteristics and the predictive value of ACAs were assessed between patients with the presence and absence of ACAs. RESULTS: APL patients with and without ACAs did not differ significantly in their clinical features or treatment response and clinical outcomes like overall survival (OS) and disease-free survival (DFS). It appeared to be substantially associated with worse OS in APL patients with trisomy 8, which was the most common ACA, although DFS was unaffected. Interestingly, the presence of ACAs or trisomy 8 affected OS and DFS in the subgroup of patients aged ≥60 years; by contrast, ACAs had no effect on OS or DFS in any treatment subgroup (ATRA + ATO/RIF or ATRA + ATO/RIF + CH or ATRA + CH), except for the ATRA + ATO/RIF + CH treatment subgroup, where their impact on DFS was less favorable. CONCLUSIONS: Our results suggested that OS and DFS were unaffected by ACAs. Nonetheless, in the subgroup of patients older than 60, the existence of ACAs or trisomy 8 appeared to impact OS and DFS negatively. Individuals with t(15;17) alone had a higher DFS and were more susceptible to ATRA + ATO/RIF + CH than individuals with t(15;17) ACAs.