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HER2 signaling is activated in response to somatic HER2 mutations, which are often found in invasive lobular breast cancer (ILC) and are associated with poor prognosis. Tyrosine kinase inhibitors (TKIs) have demonstrated considerable antitumor activity in patients with HER2-mutated advanced breast cancer (BC). Further, several clinical trials have indicated that HER2-targeted antibody-drug conjugates (ADCs) exhibit promising efficacy in lung cancer with HER2 mutations, and the efficacy of ADCs against HER2-mutated BC is currently being evaluated. Several preclinical studies have demonstrated that the therapeutic efficacy of ADCs in HER2-mutated cancer can be enhanced by the addition of irreversible TKIs, but the potential of such a combined treatment regimen for the treatment of HER2-mutated BC has not been reported. Herein, we describe a case in which a patient with estrogen receptor-positive/HER2-negative metastatic ILC with 2 activating HER2 mutations (D769H and V777L) exhibited a significant and durable response to anti-HER2 treatment with pyrotinib (an irreversible TKI) in combination with ado-trastuzumab emtansine, which was administered after multiple lines of therapy that had resulted in disease progression. Further, based on the evidence from the present case, TKI plus ADC seems to be a promising combination anti-HER2 regimen for patients with HER2-negative/HER2-mutated advanced BC, although further rigorous studies are warranted to confirm these findings.

Ankylosing spondylitis (AS) is a chronic inflammatory disease, might carry a high risk of irritable bowel syndrome (IBS) due to abnormal gut microbiota or inflammatory reaction.We conducted a 14-year retrospective cohort study based on Taiwan's National Health Insurance Research Database (NHIRD). A total of 4007 patients with newly diagnosed AS (outpatient visits≧3 times, or hospitalization≧1 time) and 988,084 non-AS comparisons were enrolled during 2000-2012. To ensure baseline comparability, the propensity score was matched by age, gender, comorbidities, and other possible confounders. The outcome was the incidence of IBS, followed up to the end of 2013. Cox proportional hazard model calculated adjusted hazard ratio (aHR) and the cumulative incidence of both groups was analyzed by the Kaplan-Meier method.After propensity score matching, baseline demographic characteristics were comparable between AS patients and the comparison group. The crude HR for IBS in the AS group was significantly higher 2.41 (95%C.I. = 1.84-3.16) than comparison group. After adjusting for possible confounders, adjusted HR was 2.50 (95%C.I. = 1.91-3.29). The cumulative incidence of IBS in AS was significantly higher than non-AS comparisons during the 14-year follow-up (P 0.001).This nationwide population-based cohort study showed that patients with AS have higher risks of IBS than those of the non-AS comparison group.

Cerebral vasculitis is a long-standing but flourishing and fadeless research topic. Infections are a frequent cause of cerebral vasculitis, vital to diagnose due to involvement of specific anti-infection treatments. A 65-year-old man visited the hospital for his neurological symptoms without obvious inducements. After admission, radiological examination and comprehensive conventional microbiological tests (CMTs) revealed suspected intracranial infectious vasculitis. Metagenomic next-generation sequencing (mNGS) and reverse transcription-polymerase chain reaction further confirmed that his cerebral vasculitis was caused by Talaromyces marneffei (T. marneffei) and Aspergillus niger (A. niger) co-infection. The patient’s final diagnosis changed from initial herpetic encephalitis, due to the past history of cephalosome and facial herpes and non-significant antiviral therapeutic effects, to fungal cerebral vasculitis. The patient was discharged after use of targeted antifungal therapies on day 18 of his admission, and his associated symptoms disappeared completely at follow-up 3 weeks later. We first illustrated the presence of uncommon cerebral vasculitis caused by T. marneffei and A. niger in a human immunodeficiency virus-positive patient. In clinically suspected patients with infectious cerebral vasculitis, mNGS should be performed to detect potential pathogens if CMTs may not provide useful pathogenic clues, highlighting the importance of mNGS in the diagnosis and treatment of infectious diseases.

DEHP (di(2-ethylhexyl) phthalate) is an endocrine disruptor commonly found in plastic products that has been associated with reproduction alterations, but the effect of DEHP on toxicity is still widely unknown. Using DEHP concentrations of 10, 1, and 0.1 mg/L, we showed that DEHP reduced the reproductive capacity of Caenorhabditis elegans after 72 hr. of exposure. DEHP exposure reduced the reproductive capacity in terms of decreased brood sizes, egg hatchability (0.1, 1 and 10 mg/L), and egg-laying rate (1 and 10 mg/L), and increased numbers of fertilized eggs in the uterus (1 and 10 mg/L). DEHP also caused damage to gonad development. DEHP decreased the total number of germline cells, and decreased the relative area of the gonad arm of all exposure groups, with worms in the 1 mg/L DEHP exposure group having the minimum gonad arm area. Additionally, DEHP caused a significant concentration‐dependent increase in the expression of unc-86. Autophagy and ROS contributed to the enhancement of DEHP toxicity in reducing reproductive capacity, and glutathione peroxidase and superoxide dismutase were activated as the antioxidant defense in this study. Hence, we found that DEHP has a dual effect on nematodes. Higher concentration (10 mg/L) DEHP can inhibit the expression of autophagy genes (atg-18, atg-7, bec-1, lgg-1 and unc-51), and lower concentrations (0.1 and 1 mg/L) can promote the expression of autophagy genes. Our data highlight the potential environmental risk of DEHP in inducing reproductive toxicity toward the gonad development and reproductive capacity of environmental organisms.

This systematic review and meta-analysis study investigates the predictive and prognostic value of PIK3CA mutations for HER2-positive breast cancer treated with tyrosine kinase inhibitors (TKIs). A search of the Medline, Embase, and Cochrane Library databases yielded 17 eligible studies (1706 patients). In 10 neoadjuvant studies, the pathological complete response rate was significantly higher in wild-type PIK3CA (WT) patients than in mutated PIK3CA (MT) patients (OR = 0.45; 95% CI = 0.31-0.65; P 0.001). In five metastasis studies, the pooled objective response rate was significantly higher in WT patients than in MT patients (OR = 0.40; 95% CI = 0.23-0.70; P = 0.001). Four metastasis studies indicated that PIK3CA mutations had a marginally significant relationship with poor progression-free survival and overall survival. Thus, PIK3CA mutations have predictive value for the treatment response of early/advanced-stage HER2-positive breast cancer treated with TKI-containing regimens.

Nanoplastics represented by nanopolystyrene (NPS) and its chemically modified derivatives are environmentally ecotoxicological hotpots in recent years, but their toxicity and underlying mechanisms have not been fully identified. Here we employed Caenorhabditis elegans as an animal model to systematically compare the toxicity between nanopolystyrene and its 4 chemically modified derivatives (PS-PEG, PS-COOH, PS-SOOOH and PS-NH

Neurotransmission related signals are involved in the control of response to toxicants. We here focused on the tyramine and the glutamate related signals to determine their roles in regulating nanoplastic toxicity in Caenorhabditis elegans. In the range of μg/L, exposure to nanopolystyrene (100 nm) increased the expression of tdc-1 encoding a tyrosine decarboxylase required for synthesis of tyramine, and decreased the expression of eat-4 encoding a glutamate transporter. Both TDC-1 and EAT-4 could act in the neurons to regulate the nanopolystyrene toxicity. Meanwhile, neuronal RNAi knockdown of tdc-1 induced a susceptibility to nanopolystyrene toxicity, and neuronal RNAi knockdown of eat-4 induced a resistance to nanopolystyrene toxicity. In the neurons, TYRA-2 functioned as the corresponding receptor of tyramine and acted upstream of MPK-1 signaling to regulate the nanopolystyrene toxicity. Moreover, during the control of nanopolystyrene toxicity, GLR-4 and GLR-8 were identified as the corresponding glutamate receptors, and acted upstream of JNK-1 signaling and DBL-1 signaling, respectively. Our results demonstrated the crucial roles of tyramine and glutamate related signals in regulating the toxicity of nanoplastics in organisms.

The potential adverse effects of nanoplastics have gradually gained significant attention. Herein, we employed Caenorhabditis elegans to investigate the possible neurotoxic effects of nanopolystyrene particles on the development and function of D-type GABAergic motor neurons. Nanopolystyrene (1000 μg L−1) induced the neurodegeneration of D-type motor neurons in wild-type nematodes, and nanopolystyrene (≥100 μg L−1) further induced the neurodegeneration phenotype in nematodes with a mutation in sod-3, encoding a Mn-SOD or acs-22, which governs the functional state of the intestinal barrier. Meanwhile, nanopolystyrene (≥10 μg L−1) decreased head thrash and body bend, and nanopolystyrene (≥100 μg L−1) altered forward and backward movements in wild-type nematodes. Moreover, nanopolystyrene (≥1 μg L−1) decreased head thrash and body bend and nanopolystyrene (≥10 μg L−1) affected forward and backward movements in sod-3 or acs-22 mutant nematodes. Along with the neurotoxicity observed in nanopolystyrene-exposed nematodes, nanopolystyrene exposure induced a dynamic autophagy induction. RNAi knockdown of lgg-1 encoding a key regulator of autophagy induced susceptibility to the neurotoxic effects of nanopolystyrene particles on the development and function of D-type motor neurons, implying the association of dynamic autophagy induction with the neurotoxicity induced by nanopolystyrene particles. Our results highlight the potential neurotoxicity of long-term nanoplastic exposure in organisms.

Background The response of organisms to nanoplastic exposure has gradually received the attention. Nevertheless, the role of neurons in response to nanoplastic exposure and the underlying mechanism are still largely unclear. We here examined the role of neuronal JNK MAPK signaling in response to low-dose of polystyrene (100 nm) in Caenorhabditis elegans. Results Exposure to nanopolystyrene in the range of μg/L could increase the expression of genes (jkk-1, mek-1, and jnk-1) encoding JNK MAPK signaling pathway. Meanwhile, RNAi knockdown of any of these genes induced a susceptibility to nanopolystyrene toxicity. In the neurons, SNB-1/synaptobrevin was identified as the downstream target of JNK-1/JNK, suggesting the alteration in neurotransmitter signals in nanopolystyrene-exposed nematodes. In nanopolystyrene-exposed nematodes, JNK-1 modulated TBH-1-mediated octopamine signal and CAT-2-mediated dopamine signal. TBH-1 and CAT-2 further regulated the response to nanopolystyrene by affecting the function of corresponding intestinal octopamine receptors (SER-6 and OCTR-1) and intestinal dopamine receptor (DOP-1). In the intestine, DOP-1 regulated the response to nanopolystyrene by activating the downstream signaling cascade in p38 MAPK signaling pathway. Conclusions Exposure to low-dose of nanopolystyrene could induce the response of neuronal JNK MAPK signaling pathway in nematodes. Our data further highlight the crucial role of neuronal JNK MAPK signaling-activated alteration in octopamine and dopamine signals in regulating the response to nanopolystyrene in organisms.

The possible adverse effects of nanoplastics have received the great attention recently; however, their effects at environmentally relevant concentration on organisms are still largely unclear. We here employed Caenorhabditis elegans to investigate the combinational effects of titanium dioxide nanoparticles (TiO2-NPs) and nanopolystyrene particles at environmentally relevant concentrations on organisms. In wild-type nematodes, prolonged exposure to nanopolystyrene particles (1 μg/L) could enhance the toxicity of TiO2-NPs (1 μg/L) in decreasing locomotion behavior and in inducing intestinal reactive oxygen species (ROS) production. Meanwhile, combinational exposure to TiO2-NPs (1 μg/L) and nanopolystyrene particles (1 μg/L) altered the molecular basis for oxidative stress in wild-type nematodes. Moreover, prolonged exposure to nanopolystyrene particles (0.1 μg/L) could further enhance the toxicity of TiO2-NPs (1 μg/L) in decreasing locomotion behavior and in inducing intestinal ROS production in sod-3 mutant nematodes. Our data suggest the potential role of nanopolystyrene particles at environmentally relevant concentrations in enhancing the toxicity of ENMs in the environment.

We showed previously that 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a ligand to type 2 imidazoline receptor (I2R) exerts neuroprotective effects in ischemia stroke via an unknown mechanism. The present study was to investigate whether 2-BFI can protect the neurovascular unit (NVU) using a rat model of 90 min focal cerebral ischemia.Rats were randomly divided into three groups: thesham-operated group; the vehicle control group and the 2-BFI group which received 2-BFI (3 mg/kg) immediately after the start of middle cerebralartery occlusion (MCAO). Neurological deficit score, infarct size, apoptosis level, brain water content and Evans Blue extravasation were assessed at 24 h after stroke. Expressions of occludin and zonula occludens 1 (ZO-1), collagen IV, aquaporin-4 (AQP-4), matrix metalloproteinase-9 (MMP-9) and MMP-2 were assessed by Western blotting.2-BFI treatment was associated with significant improvement of neurological performance and decreased infarct volume at 24 h after stroke. Apoptosis level reduced significantly by 2-BFI compared to the vehicle group (34.3 ± 5.4% vs 56.1 ± 7.9%, p 0.05). Significant decreased of brain water content (79.5 ± 2.6% vs 84.62 ± 2%, p 0.05) and Evans Blue extravasation (1.2 ± 0.5 vs 2.5 ± 0.41 µg/g, p 0.05) of ipsilateral hemisphere was observed in 2-BFI group compared to vehicle group. Expressions of occludin, ZO-1 and collagen IV were significantly higher while MMP-9 level significantly lower in 2-BFI group. AQP-4 and MMP-2 showed no difference between 2-BFI and the vehicle groups.These results suggest that the neuroprotective effects of 2-BFI in acute ischemic brain damage are at least partly due to the drug's ability to improve the functions of NVU.

ERK signaling is one of the important mitogen-activated protein kinases (MAPKs). However, the role of ERK signaling in the regulation of response to engineered nanomaterial exposure is still largely unclear. In this study, using in vivo assay system of Caenorhabditis elegans, we investigated the function of ERK signaling in response to graphene oxide (GO) exposure and the underlying molecular mechanism. GO exposure increased the expression of MEK-2/MEK and MPK-1/ERK in the ERK signaling pathway. Mutation of mek-2 or mpk-1 resulted in a susceptibility to GO toxicity. Both the MEK-2 and the MPK-1 acted in neurons to regulate the response to GO exposure, and the neuronal expression of MEK-2 or MPK-1 caused a resistance to GO toxicity. In the neurons, SKN-1b/Nrf acted downstream of the MPK-1, and AEX-3, a guanine exchange factor for GTPase, further acted downstream of the SKN-1b to regulate the response to GO exposure. Therefore, a signaling cascade of MEK-2-MPK-1-SKN-1b/-AEX-3 was identified in the neurons required for the regulation of response to GO exposure. Moreover, genetic interaction assay demonstrated that the neuronal ERK signaling-mediated signaling pathway and the intestinal p38 MAPK-mediated signaling pathway functioned synergistically in the regulation of response to GO exposure. Our results highlight the crucial function of the neuronal ERK signaling in the regulation of response to nanomaterial exposure in organisms.

The potential adverse effects of graphene oxide (GO) on organisms have received great attention. However, the underlying molecular mechanisms for response to GO exposure are still largely unclear. Canonical Wnt/β-catenin signaling is an evolutionarily conserved signaling, and plays a key role in the development. Using assay system of Caenorhabditis elegans, we investigated the potential involvement of canonical Wnt/β-catenin signaling pathway in the regulation of response to GO. GO exposure caused the damage on the functions of both primary and secondary targeted organs by dysregulating the expression of β-catenin BAR-1, APR-1 and GSK-3 in APC complex, Dishevelled proteins of DSH-1, and DSH-2, and Frizzled receptors of MOM-5 and CFZ-2 in the Wnt/β-catenin signaling pathway. Based on genetic evidence, we further raised a signaling cascade of MOM-5/CFZ-2-DSH-1/DSH-2-APR-1/GSK-3-BAR-1 in the Wnt/β-catenin signaling pathway in the regulation of GO toxicity. The homeobox protein EGL-5, an important downstream target of Wnt/β-catenin signaling, regulated GO toxicity by modulating expression of the genes required for the control of oxidative stress. Moreover, β-catenin BAR-1 acted in parallel with insulin or p38 MAPK signaling to regulate the GO toxicity. Therefore, our results suggest the crucial function of Wnt/β-catenin signaling pathway in the regulation of GO toxicity in organisms.

Purpose: This study aimed to characterize the microvascular and structural changes in the macular that occur in white matter hyperintensities (WMH) using optical coherence tomographic angiography. We also aimed to explore the association between macular microvascular and structural changes with focal markers of brain tissue on MRI in WMH using the Fazekas scale. Methods: This study enrolled healthy participants who were stroke- and dementia-free. MRI was used to image the cerebral white matter lesions, and Fazekas scale was used to evaluate the severity of the white matter lesions. Optical coherence tomography angiography (OCT-A) was used to image the radial peripapillary capillaries (RPCs), macular capillary plexuses [superficial capillary plexus (SCP) and deep capillary plexus (DCP)] and thickness around the optic nerve head, peripapillary retinal nerve fiber layer (pRNFL). Results: Seventy-four participants were enrolled and divided into two groups according to their Fazekas score (Fazekas scores ≤ 1 and ≥2). Participants with Fazekas score ≥2 showed significantly reduced RPC density (P = 0.02) and DCP density (P = 0.012) when compared with participants with Fazekas score ≤ 1. Participants with Fazekas score ≥2 showed reduced pRNFL (P = 0.004) when compared to participants with Fazekas score ≤ 1. Fazekas scores were significantly associated with the pRNFL thickness (Rho = -0.389, P = 0.001), RPC density (Rho = -0.248, P = 0.035), and DCP density (Rho = -0.283, P = 0.015), respectively. Conclusions: Microvascular impairment and neuro-axonal damage are associated with the disease cascade in WMH. We have shown that RPC and DCP densities are significantly affected, and these impairments are associated with the severity of the disease and cognitive function. OCT-A could be a useful tool in quantifying the retinal capillary densities in WMH.

microRNAs (miRNAs) usually act post-transcriptionally to suppress the expression of many targeted genes. However, the response of miRNAs to nanoplastics is still unclear. We here employed Caenorhabditis elegans to investigate the response of miRNAs to 100 nm nanopolystyrene at a predicted environmental concentration (1 μg/L). After exposure from L1-larvae to adult day-3, we found that 7 miRNAs (4 down-regulated (mir-39, mir-76, mir-794, and mir-1830) and 3 up-regulated (mir-35, mir-38, and mir-354)) were dysregulated by nanopolystyrene. Expressions of these 7 miRNAs were dose-dependent in nematodes exposed to 1–100 μg/L nanopolystyrene. Among these 7 miRNAs, we found that only mir-35, mir-38, mir-76, mir-354, and mir-794 were involved in the regulation of response to nanopolystyrene based on phenotypic analysis of both transgenic strains and mutant nematodes. Overexpression of mir-35, mir-38, or mir-354 induced a resistance to nanopolystyrene toxicity, and overexpression of mir-76 or mir-794 induced a susceptibility to nanopolystyrene toxicity, which suggested that these 5 miRNAs mediated a protective response to nanopolystyrene. Gene ontology and KEGG analysis further implied that mir-35, mir-38, mir-76, mir-354, and mir-794 were associated with various biological processes and signaling pathways. Our results suggest the crucial role of a certain number of miRNAs in response to nanopolystyrene after long-term and low-dose exposure in organisms.

The potential adverse effects of nanoplastics, such as nanopolystyrene, have received the great attention recently. However, the molecular response of organisms to nanoplastics is still largely unknown. In this study, we employed Caenorhabditis elegans as an animal model to investigate the long non-coding RNAs (lncRNAs) in response to long-term exposure to low-dose nanopolystyrene (100 nm). Based on Hiseq 2000 sequencing and qRT-PCR confirmation, we identified 36 lncRNAs (21 down-regulated lncRNAs and 15 up-regulated lncRNAs) in response to nanopolystyrene (1 μg/L). Using intestinal reactive oxygen species (ROS) production and locomotion behavior as endpoints, we found that RNAi knockdown of linc-2, linc-9, or linc-61 induced a susceptibility to nanopolystyrene toxicity, and RNAi knockdown of linc-18 or linc-50 induced a resistance to nanopolystyrene toxicity. Meanwhile, nanopolystyrene (1 μg/L) increased expressions of linc-2, linc-9, linc-18, and linc-61 and decreased linc-50 expression, suggesting that these 5 lncRNAs mediated two different responses to nanopolystyrene exposure. Bioinformatical analysis implied that these 5 lncRNAs were associated with multiple biological processes and signaling pathways. Our results demonstrated the crucial roles of lncRNAs in response to long-term exposure to low-dose nanopolystyrene in organisms.

Caenorhabditis elegans is a useful animal model to assess nanoplastic toxicity. Using polystyrene nanoparticles (PS-NPs) as the example of nanoplastics, we found that exposure to PS-NPs (1–100 μg/L) from L1-larvae for 6.5 days increased expression of cbp-1 encoding an acetyltransferase. The susceptibility to PS-NPs toxicity was observed in cbp-1(RNAi) worms, suggesting that CBP-1-mediated histone acetylation regulation reflects a protective response to PS-NPs. The functions of CBP-1 in intestine, neurons, and germline were required for formation of this protective response. In intestinal cells, CBP-1 controlled PS-NPs toxicity by modulating functions of insulin and p38 MAPK signaling pathways. In neuronal cells, CBP-1 controlled PS-NPs toxicity by affecting functions of DAF-7/TGF-β and JNK MAPK signaling pathways. In germline cells, CBP-1 controlled PS-NPs toxicity by suppressing NHL-2 activity, and NHL-2 further regulated PS-NPs toxicity by modulating insulin communication between germline and intestine. Therefore, our data suggested that the CBP-1-mediated histone acetylation regulation in certain tissues is associated with the induction of protective response to PS-NPs in C. elegans.

The potential toxicity of nanoplastics to environmental organisms has gradually received great attention recently. We employed the in vivo assay system of Caenorhabditis elegans to investigate the possible transgenerational toxicity of nanopolystyrene particles and the underlying cellular mechanisms. After prolonged exposure, we observed the toxicity of nanopolystyrene particles at concentrations higher than 10 μg L−1. The transgenerational toxicity was further detected in nematodes exposed to nanopolystyrene particles at concentrations higher than 100 μg L−1. This observed transgenerational toxicity of nanopolystyrene particles might be mainly due to the translocation of nanopolystyrene particles into reproductive organs such as the gonad, which potentially in turn led to the transfer of nanopolystyrene particles to the next generation. Leachates from nanopolystyrene particles at concentrations in the range of μg L−1 did not contribute to the development of this transgenerational toxicity. Enhancement of intestinal permeability and extension of defecation cycle length provide the explanation for the observed accumulation and translocation of nanopolystyrene particles in reproductive organs. Therefore, our results demonstrate the potential transgenerational toxicity of nanopolystyrene particles in the range of μg L−1 in environmental organisms.

Separation and partial purification of polysaccharides from fungi or mushrooms are difficult and have become the main bottleneck in the development of a commercially viable process. In this study, an aqueous two-phase system (ATPS) composed of short chain alcohols and salts was developed for the separation and partial purification of polysaccharides and other bioactive constituents from Cordyceps sinensis (CS). The results showed that ATPS not only purified CS polysaccharides (CSPS) with the removal of 99.1% cell debris, 80% proteins, 90.7% pigments, and 61.3% nucleic acids, but also simultaneously recovered CSPS, adenosine, and mannitol up to 96.6%, 100%, and 88.4%, respectively. Compared with traditional purification methods, the coupling of ethanol/Na2CO3 ATPS with ultrafiltration decreased the protein, nucleic acid, and pigment contents in the purified CSPS by 344%, 192%, and 290%, respectively. Therefore, this environmentally friendly method could have potential applications in large-scale separation of multiple bioactive constituents from fungi in the future.

The responses of different organs are important for organisms against the toxicity of environmental toxicants. So far, the neuronal response to nanoplastic exposure and the underlying mechanisms are still largely unclear. Due to the sensitivity to environmental exposures, we here employed Caenorhabditis elegans as an animal model to examine the role of ERK MAPK signaling pathway in the neurons to regulate the response to nanopolystyrene (100 nm). Nanopolystyrene exposure in the range of μg/L could significantly increase expressions of genes (lin-45, mek-2, and mpk-1) encoding ERK MAPK signaling pathway. Nanopolystyrene at the predicted environmental concentration of 1 μg/L could only significantly increase the mpk-1 expression. Meanwhile, RNAi knockdown of any of these genes caused a susceptibility to nanopolystyrene toxicity. ERK/MPK-1 acted in the neurons to regulate the response to nanopolystyrene. Moreover, three genes (ins-4, ins-39, and daf-28) encoding insulin peptides were identified as the downstream targeted genes of neuronal mpk-1 in regulating the response to nanopolystyrene. In nanopolystyrene exposed nematodes, neuronal RNAi knockdown of ins-4, ins-39, or daf-28 decreased expression of intestinal daf-2 encoding insulin receptor and increased expression of intestinal daf-16 encoding FOXO transcriptional factor. Therefore, the neuronal ERK MAPK signaling responded to nanopolystyrene by modulating the insulin signaling-mediated communication between neurons and intestine in nematodes. Our findings are helpful for understanding the molecular basis of neuronal response to nanopolystyrene in organisms.

Nanopolystyrene particles have been widely used in many fields. However, the molecular responses of organisms to nanopolystyrene particles at predicted environmentally relevant concentrations are still largely unclear. Caenorhabditis elegans is employed herein to investigate the molecular response of p38 mitogen-activated protein kinase (MAPK) signaling to nanoplastic particles (1 µg L-1 ) and the underlying molecular mechanism. In wild-type nematodes, prolonged exposure (from L1-larvae to adult day 3) to nanopolystyrene particles increases the expression of pmk-1 encoding a p38 MAPK. Mutation of pmk-1 induces a susceptibility to nanopolystyrene toxicity, suggesting that the p38 MAPK signaling mediates a protective response to nanopolystyrene particles. PMK-1 functions in the intestine to act upstream of two transcriptional factors (ATF-7 and SKN-1), which can further act upstream of XBP-1, a key regulator of endoplasmic reticulum unfolded protein response (ER UPR), to regulate the response to nanopolystyrene particles. PMK-1, ATF-7, SKN-1, and XBP-1 are all required for the induction of intestinal ER UPR in nematodes exposed to nanopolystyrene particles. Therefore, the intestinal p38 MAPK signaling may mediate a protective response to nanopolystyrene particles by activating XBP-1-mediated ER UPR. The results herein highlight the importance of molecular response in the intestine of organisms to nanopolystyrene particles.

We previously demonstrated that administering 2-(2-benzofuranyl)-2-imidazolin (2-BFI), an imidazoline I2 receptor agonist, immediately after ischemia onset can protect the brain from ischemic insult. However, immediate administration after stroke is difficult to realize in the clinic. Thus, the therapeutic time window of 2-BFI should be determined. Sprague-Dawley rats provided by Wenzhou Medical University in China received right middle cerebral artery occlusion for 120 minutes, and were treated with 2-BFI (3 mg/kg) through the caudal vein at 0, 1, 3, 5, 7, and 9 hours after reperfusion. Neurological function was assessed using the Longa's method. Infarct volume was measured by 2,3,5-triphenyltetrazolium chloride assay. Morphological changes in the cortical penumbra were observed by hematoxylin-eosin staining under transmission electron microscopy . The apoptosis levels in the ipsilateral cortex were examined with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The protein expression of Bcl-2 and BAX was detected using immunohistochemistry. We found the following: Treatment with 2-BFI within 5 hours after reperfusion obviously improved neurological function. Administering 2-BFI within 9 hours after ischemia/reperfusion decreased infarct volume and alleviated apoptosis. 2-BFI administration at different time points after reperfusion alleviated the pathological damage of the ischemic penumbra and reduced the number of apoptotic neurons, but the protective effect was more obvious when administered within 5 hours. Administration of 2-BFI within 5 hours after reperfusion remarkably increased Bcl-2 expression and decreased BAX expression. To conclude, 2-BFI shows potent neuroprotective effects when administered within 5 hours after reperfusion, seemingly by up-regulating Bcl-2 and down-regulating BAX expression. The time window provided clinical potential for ischemic stroke by 2-BFI.

Quantum dots (QDs), considered as a type of excellent semiconductor nanomaterial, are widely employed and have a number of important applications. However, QDs have the potential to produce adverse effects and toxicity with the underlying molecular mechanisms not well understood. Herein, Caenorhabditis elegans was used for in vivo toxicity assessment to detect the reproductive toxicity of CdTe QDs. We found that exposure to CdTe QDs particles (≥ 50 mg/L) resulted in a defect in reproductive capacity, dysfunctional proliferation and differentiation, as well as an imbalance in oogenesis by reducing the number of cells in pachytene and diakinesis. Further, we identified a SPO-11 and PCH-2 mediated toxic mechanism and a GLP-1/Notch mediated protective mechanism in response to CdTe QDs particles (≥ 50 mg/L). Taken together, these results demonstrate the potential adverse impact of CdTe QDs (≥ 50 mg/L) exposure on oogenesis and provide valuable data and guidelines for evaluation of QD biocompatibility.

In this study, we employed Caenorhabditis elegans with acs-22 mutation to examine the in vivo effect of functional deficit in intestinal barrier on toxicity and translocation of nanopolystyrene particles. Mutation of acs-22 leads to deficit in intestinal barrier. After prolonged exposure, nanopolystyrene particles at concentrations ≥1 μg/L could cause toxicity on acs-22 mutant nematodes. acs-22 mutation resulted in translocation of nanopolystyrene particles into targeted organs through intestinal barrier in nanopolystyrene particles (1 μg/L) exposed nematodes. After prolonged exposure, nanopolystyrene particles (1 μg/L) dysregulated expressions of some genes required for the control of oxidative stress and activated expression of Nrf signaling pathway. Therefore, under certain pathological conditions, our results suggest the potential toxicity of nanoplastic particles at predicted environmental concentration on organisms after long-term exposure.

Highly efficient interfacial enzymatic hydrolysis of oil was achieved in a three-liquid-phase system, wherein the substrate constituted one of the phases. The enlarged interfacial area and relieved product inhibition were responsible for the high catalytic efficiency. Convenient product isolation and the high reusability of the enzyme were also demonstrated.

Sulfonate modified polystyrene is potentially used in medical application; however, the effect of sulfonate modification on polystyrene toxicity is still largely unclear. We here compared the neurotoxicity between pristine and sulfonate modified nanopolystyrene particles in nematode Caenorhabditis elegans. Exposure to nanopolystyrene (35 nm) caused neurotoxicity on locomotion behaviors (head thrash, body bend, forward movement, and backward movement) and sensory perception behaviors (chemotaxis to NaCl or diacetyl). Exposure to nanopolystyrene also induced the damage on development of dopaminergic neurons as reflected by relative fluorescence intensity, number of discontinuous dendrite, and number of abnormal cell body. Moreover, we found that sulfonate modification effectively enhanced the neurontoxicity of nanopolystyrene on locomotion behaviors, sensory perception behaviors, and development of dopaminergic neurons. Our results highlight the possibility of sulfonate modification in increasing neurotoxicity of nanopolystyrene exposure on environmental organisms.

Although amino modified nanopolystyrene could cause toxicity on environmental organisms, the effect of amino modification on nanopolystyrene toxicity is still largely unclear. We here employed Caenorhabditis elegans as an animal model to compare the effects between pristine and amino modified nanopolystyrene particles in inducing reproductive toxicity. Nanopolystyrene (35 nm) could cause the damage on gonad development as indicated by the endpoints of number of total germline cells, length of gonad arm, and relative area of gonad arm. Nanopolystyrene exposure also reduced the reproductive capacity as reflected by the endpoints of brood size and number of fertilized eggs in uterus. Moreover, amino modification enhanced nanopolystyrene toxicity on both the gonad development and the reproductive capacity. Additionally, induction of germline apoptosis and formation of germline DNA damage contributed to the enhancement of nanopolystyrene toxicity in reducing reproductive capacity by amino modification. Our results highlight the potential environmental risk of amino modified nanopolystyrene in inducing reproductive toxicity on gonad development and reproductive capacity of environmental organisms.

To solve the problem of the dynamic variation of wave force diameter of pile foundation for offshore wind turbines, wave force and moment of large diameter pile foundation can be calculated. In this paper, simulation technique is used to calculate the wave force and moment of different large diameter pile foundation, and the base shear force and moment of the interval 20-degree phase angle are obtained by the base line of the pile. Under the action of a certain load, the complete stress variation of the pile foundation is obtained. According to the basic principle of diffraction theory, the process curve of large diameter pile, and analysis of wave force, diffraction force changes in a certain period of time interval. The results show that the wave after the large diameter pile formed around the vortex, large diameter pile base shear, and moment dynamic change is nonlinear in a complete cycle, the diameter of the pile increases by 0.5 m, and the wave force increases by about 5%, the results show that it provides certain reference value for the offshore pile foundation pile with large diameter primary site. Some significant results for practical application are discussed.

In this study, we investigated the possible involvement of Wnt signals in the control of graphene oxide (GO) toxicity using the in vivo assay system of Caenorhabditis elegans. In nematodes, the Wnt ligands, CWN-1, CWN-2, and LIN-44, were found to be involved in the control of GO toxicity. Mutation of cwn-1 or lin-44 gene induced a resistant property to GO toxicity and resulted in the decreased accumulation of GO in the body of nematodes, whereas mutation of cwn-2 gene induces a susceptible property to GO toxicity and an enhanced accumulation of GO in the body of nematodes. Genetic interaction assays demonstrated that mutation of cwn-1 or lin-44 was able to suppress the susceptibility to GO toxicity shown in the cwn-2 mutants. Loss-of-function mutations in all three of these Wnt ligand genes resulted in the resistance of nematodes to GO toxicity. Moreover, the Wnt ligands might differentially regulate the toxicity and translocation of GO through different mechanisms. These findings could be important in understanding the function of Wnt signals in the regulation of toxicity from environmental nanomaterials.

Background: A thermostable lipase MAS1 from marine Streptomyces sp. strain was considered as a potential biocatalyst for industrial application, but its production level was relatively low. Here, the effect of chaperones co-expression on the secretory expression of lipase MAS1 in Pichia pastoris was investigated. Result: Co-expression of protein disulfide isomerase (PDI), HAC1 and immunoglobulin binding protein could increase the expression level of lipase MAS1, whereas co-expression of Vitreoscilla hemoglobin showed a negative effect to the lipase MAS1 production. Among them, PDI co-expression increased lipase MAS1 expression level by 1.7-fold compared to the control strain harboring only the MAS1 gene. Furthermore, optimizing production of lipase MAS1 with Pichia pastoris strain X-33/MAS1-PDI in a 30-L bioreactor were conducted. Lower induction temperature was found to have a benefit effect for lipase MAS1 production. Lipase activity at 24 and 22°C showed 1.7 and 2.1-fold to that at 30°C, respectively. Among the induction pH tested, the highest lipase activity was obtained at pH 6.0 with activity of 440 U/mL after 144 h fermentation. Conclusion: Our work showed a good example for improving the production of recombinant enzymes in Pichia pastoris via chaperon co-expression and fermentation condition optimization. Normal 0 21 false false false EN-US ZH-CN X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Tabla normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.5pt; mso-bidi-font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-font-kerning:1.0pt; mso-ansi-language:EN-US; mso-fareast-language:ZH-CN;}

To investigate whether curcumin regulates Notch signaling to cause neuroprotection and neurogenesis after focal ischemia reperfusion injury.Focal ischemia reperfusion injury was modeled in rats by occluding the middle cerebral artery. These animals were given either curcumin (300 mg/kg) or corn oil (vehicle) by intraperitoneal injection starting 1 h after stroke and continuing for 7 d. In parallel, sham-operated control animals received vehicle. All animals were killed on day 12. The different treatment groups were compared in terms of neurobehavioral deficits, BrdU incorporation, and levels of doublecortin (DCX) and Notch intracellular domain (NICD) using immunohistochemistry, immunofluorescence and Western blotting.Animals treated with curcumin showed significantly smaller neurobehavioral deficits than vehicle-treated animals after 3, 7, and 12 d of reperfusion (all p 0.05). Tissue sections from curcumin-treated animals contained significantly greater numbers of BrdU-positive cells (p 0.05) and BrdU/DCX-positive cells (p 0.01), as well as significantly higher NICD levels (p 0.01).Curcumin may protect from focal cerebral ischemia reperfusion injury as well as stimulate neurogenesis by activating the Notch signaling pathway.

Immobilization of lipase MAS1 from marine Streptomyces sp. strain W007 and its application in catalyzing esterification of n-3 polyunsaturated fatty acids (PUFA) with glycerol were investigated. The resin XAD1180 was selected as a suitable support for the immobilization of lipase MAS1, and its absorption ability was 75mg/g (lipase/resin ratio) with initial buffer pH value of 8.0. The thermal stability of immobilized MAS1 was improved significantly compared with that of the free lipase. Immobilized MAS1 had no regiospecificity in the hydrolysis of triolein. The highest esterification degree (99.31%) and TAG content (92.26%) by immobilized MAS1-catalyzed esterification were achieved under the optimized conditions, which were significantly better than those (82.16% and 47.26%, respectively) by Novozym 435. More than 92% n-3 PUFA was incorporated into TAG that had similar fatty acids composition to the substrate (n-3 PUFA). The immobilized MAS1 exhibited 50% of its initial activity after being used for five cycles.