Up-regulating GABA transporter-3 in the zona incerta prevents surgery-induced memory impairment in mice.

Clinical surgery can lead to severe neuroinflammation and cognitive dysfunctions. It has been reported that astrocytes mediate memory formation and postoperative cognitive dysfunction (POCD), however, the thalamic mechanism of astrocytes in mediating POCD remains unknown. Here, we report that reactive astrocytes in zona incerta (ZI) mediate surgery-induced recognition memory impairment in male mice. Immunostaining results showed that astrocytes are activated with GABA transporter-3 (GAT-3) being down-expressed, and neurons were suppressed in the ZI. Besides, our work revealed that reactive astrocytes caused increased tonic current in ZI neurons. Up-regulating the expression of GAT-3 in astrocytes ameliorates surgery-induced recognition memory impairment. Together, our work demonstrates that the reactive astrocytes in the ZI play a crucial role in surgery-induced memory impairment, which provides a new target for the treatment of surgery-induced neural dysfunctions.

EEF1D stabilized by SRSF9 promotes colorectal cancer via enhancing the proliferation and metastasis.

Colorectal cancer (CRC) is the third most common cancer and causes high mortality worldwide. Although CRC has been studied widely, the molecular mechanism is not completely known. Eukaryotic translation elongation factor 1 delta (EEF1D) participates in the progression of various tumors, however, the effect of EEF1D on CRC remains unclear. Here, we aimed to identify the potential mechanism of EEF1D in CRC. The expression levels of EEF1D were assessed in CRC samples. Functional analysis of EEF1D in CRC was detected in vitro and in vivo. The regulatory mechanism of EEF1D was identified with RNA immunoprecipitation, RNA pull-down assay, and proteomics analysis. Our findings confirmed that EEF1D was upregulated in human CRC tissues. Functionally, EEF1D overexpression accelerated cell proliferation and metastasis, whereas EEF1D knockdown inhibited cell proliferation and metastasis both in vitro and in vivo CRC models. Furthermore, we showed that EEF1D was upregulated by SRSF9 via binding to 3'UTR of EEF1D mRNA. EEF1D knockdown reversed the malignant phenotype induced by SRSF9 overexpression. These findings demonstrated that EEF1D promotes CRC progression, and EEF1D may be a molecular target against CRC.

Associations of incident female breast cancer with long-term exposure to PM2.5 and its constituents: Findings from a prospective cohort study in Beijing, China.

This study aimed to investigate the association between long-term exposure to fine particulate matter (PM2.5) and its constituents (black carbon (BC), ammonium (NH4+), nitrate (NO3-), organic matter (OM), inorganic sulfate (SO42-)) and incident female breast cancer in Beijing, China. Data from a prospective cohort comprising 85,504 women enrolled in the National Urban Cancer Screening Program in Beijing (2013-2019) and the Tracking Air Pollution in China dataset are used. Monthly exposures were aggregated to calculate 5-year average concentrations to indicate long-term exposure. Cox models and mixture exposure models (weighted quantile sum, quantile-based g-computation, and explanatory machine learning model) were employed to analyze the associations. Findings indicated increased levels of PM2.5 and its constituents were associated with higher breast cancer risk, with hazard ratios per 1-µg/m3 increase of 1.02 (95% confidence interval (CI): 1.01, 1.03), 1.39 (95% CI: 1.16, 1.65), 1.28 (95% CI: 1.12, 1.46), 1.15 (95% CI: 1.05, 1.24), 1.05 (95% CI: 1.02, 1.08), and 1.15 (95% CI: 1.07, 1.23) for PM2.5, BC, NH4+, NO3-, OM, and SO42-, respectively. Exposure-response curves demonstrated a monotonic risk increase without an evident threshold. Mixture exposure models highlighted BC and SO42- as key factors, underscoring the importance of reducing emissions of these pollutants.

Higher disease burden and lower utilization in mongolian with breast cancer: a 9-year retrospective cohort study of 18.19 million adults in China.

BACKGROUND: Whether health inequalities of disease burden and medical utilization exist by ethnicity in Asian breast cancer (BC) patients remains unclear. We aim to measure ethnic disparities in disease burden and utilization among Mongolian and Han female breast cancer patients in China. MATERIALS AND METHODS: Based on data extracted from Inner Mongolia Regional Health Information Platform, a retrospective cohort study was established during 2012-2021. Disease burden including incidence, 5-year prevalence, mortality, survival rate, and medical cost were analyzed and compared between Han and Mongolian patients. RESULTS: A total of 34,878 female patients (mean [SD] age, 52.34 [10.93] years) were included among 18.19 million Chinese, and 4,315 [12.03%] participants were Mongolian. Age-standardized rates of incidence are 32.68 (95% CI: 20.39-44.98) per 100,000. Higher age-specific incidence and 5-year prevalence were observed in Mongolian than in Han. The cost of breast cancer annually per capita was significantly lower for Mongolian than Han in FBC ($1,948.43 [590.11-4 776.42] vs. $2,227.35 [686.65-5,929.59], P<0.001). Mongolian females showed higher all-cause mortality (30.92, [95% CI: 28.15-33.89] vs. 27.78, [95% CI: 26.77-28.83] per 1,000, P=0.036) and breast cancer-specific mortality (18.78, [95% CI: 16.64-21.13] vs. 15.22, [95% CI: 14.47-16.00] per 1,000, P=0.002) than Han females. After adjusting covariates, Mongolian were associated with increased all-cause mortality (HR, 1.21, [95% CI, 1.09-1.34]; P<0.001) and breast cancer-specific mortality (HR, 1.31, [95% CI, 1.14-1.49]; P<0.001). CONCLUSION: The findings of this cohort study highlight a higher level of disease burden with unmet medical demand in Mongolian patients, suggesting that more practical efforts should be made for the minority. Further research is needed to explore the concrete mechanisms of the disparities as well as eliminate health disproportion.

Ultrasensitive Optical Detection and Elimination of Residual Microtumors with a Postoperative Implantable Hydrogel Sensor for Preventing Cancer Recurrence.

In vivo optical imaging of trace biomarkers in residual microtumors holds significant promise for cancer prognosis but poses a formidable challenge. Here, a novel hydrogel sensor is designed for ultrasensitive and specific imaging of the elusive biomarker. This hydrogel sensor seamlessly integrates a molecular beacon nanoprobe with fibroblasts, offering both high tissue retention capability and an impressive signal-to-noise ratio for imaging. Signal amplification is accomplished through exonuclease I-mediated biomarker recycling. The resulting hydrogel sensor sensitively detects the biomarker carcinoembryonic antigen with a detection limit of 1.8 pg mL-1 in test tubes. Moreover, it successfully identifies residual cancer nodules with a median diameter of less than 2 mm in mice bearing partially removed primary triple-negative breast carcinomas (4T1). Notably, this hydrogel sensor is proven effective for the sensitive diagnosis of invasive tumors in post-surgical mice with infiltrating 4T1 cells, leveraging the role of fibroblasts in locally enriching tumor cells. Furthermore, the residual microtumor is rapidly photothermal ablation by polydopamine-based nanoprobe under the guidance of visualization, achieving ≈100% suppression of tumor recurrence and lung metastasis. This work offers a promising alternative strategy for visually detecting residual microtumors, potentially enhancing the prognosis of cancer patients following surgical interventions.

Correlation of IVIM/DKI Parameters with Hypoxia Biomarkers in Fibrosarcoma Murine Models: Direct Control of MRI and Pathological Sections.

RATIONALE AND OBJECTIVES: To investigate whether intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) parameters correlate with hypoxia biomarkers, namely hypoxia inducible factor-1ɑ (HIF-1ɑ), carbonic anhydrase IX (CAIX), and pimonidazole (PIMO), in fibrosarcoma (FS) murine models. MATERIALS AND METHODS: A model of 30 FS nude mice was established. All mice underwent magnetic resonance imaging (MRI) scans after which the IVIM (standard apparent diffusion coefficient [standard ADC], pure diffusion coefficient [D], pseudo-diffusion coefficient [D*], and perfusion fraction [f]) and DKI parameters (mean diffusion [MD], mean kurtosis [MK]) were obtained. Based on an MRI-pathology controlled method, correlations between each MRI parameter and hypoxia biomarkers were assessed by Pearson or Spearman tests. An independent sample t-test or Wilcoxon's rank sum test, and receiver operating characteristic curves were used to identify whether MRI parameters could differentiate between high and low expressions of hypoxia biomarkers. RESULTS: The IVIM/DKI parameters showed varying degrees of correlation with HIF-1α, CAIX, and PIMO expression. Among them, the D, f, and MK values could confirm HIF-1α expression, while D, f, and MK values could assess CAIX expression. Finally, standard D and MK values could evaluate PIMO expression levels. CONCLUSION: IVIM and DKI parameters can be used to reflect hypoxic biomarkers of FS and have the potential to detect tumor hypoxia.

Cubosomes-assisted transdermal delivery of doxorubicin and indocyanine green for chemo-photothermal combination therapy of melanoma.

Melanoma is a highly aggressive form of skin cancer with limited therapeutic options. Chemo-photothermal combination therapy has demonstrated potential for effectively treating melanoma, and transdermal administration is considered the optimal route for treating skin diseases due to its ability to bypass first-pass metabolism and enhance drug concentration. However, the stratum corneum presents a formidable challenge as a significant barrier to drug penetration in transdermal drug delivery. Lipid-nanocarriers, particularly cubosomes, have been demonstrated to possess significant potential in augmenting drug permeation across the stratum corneum. Herein, cubosomes co-loaded with doxorubicin (DOX, a chemotherapeutic drug) and indocyanine green (ICG, a photothermal agent) (DOX-ICG-cubo) transdermal drug delivery system was developed to enhance the therapeutic efficiency of melanoma by improving drug permeation. The DOX-ICG-cubo showed high encapsulation efficiency of both DOX and ICG, and exhibited good stability under physiological conditions. In addition, the unique cubic structure of the DOX-ICG-cubo was confirmed through transmission electron microscopy (TEM) images, polarizing microscopy, and small angle X-ray scattering (SAXS). The DOX-ICG-cubo presented high photothermal conversion efficiency, as well as pH and thermo-responsive DOX release. Notably, the DOX-ICG-cubo exhibited enhanced drug permeation efficiency, good biocompatibility, and improved in vivo anti-melanoma efficacy through the synergistic effects of chemo-photothermal therapy. In conclusion, DOX-ICG-cubo presented a promising strategy for melanoma treatment.

Two parallel medial prefrontal cortex-amygdala pathways mediate memory deficits via glutamatergic projection in surgery mice.

The neural circuit mechanisms underlying postoperative cognitive dysfunction (POCD) remain elusive. We hypothesized that projections from the medial prefrontal cortex (mPFC) to the amygdala are involved in POCD. A mouse model of POCD in which isoflurane (1.5%) combined with laparotomy was used. Virally assisted tracing techniques were used to label the relevant pathways. Fear conditioning, immunofluorescence, whole-cell patch-clamp recordings, and chemogenetic and optogenetic techniques were applied to investigate the role of mPFC-amygdala projections in POCD. We find that surgery impairs memory consolidation but not retrieval of consolidated memories. In POCD mice, the glutamatergic pathway from the prelimbic cortex to the basolateral amygdala (PL-BLA) shows reduced activity, whereas the glutamatergic pathway from the infralimbic cortex to the basomedial amygdala (IL-BMA) shows enhanced activity. Our study indicates that the hypoactivity in the PL-BLA pathway interrupts memory consolidation, whereas the hyperactivity in the IL-BMA promotes memory extinction, in POCD mice.

EPO has multiple positive effects on astrocytes in an experimental model of ischemia.

Erythropoietin (EPO) has neuroprotective effects in central nervous system injury models. In clinical trials EPO has shown beneficial effects in traumatic brain injury (TBI) as well as in ischemic stroke. We have previously shown that EPO has short-term effects on astrocyte glutamatergic signaling in vitro and that administration of EPO after experimental TBI decreases early cytotoxic brain edema and preserves structural and functional properties of the blood-brain barrier. These effects have been attributed to preserved or restored astrocyte function. Here we explored the effects of EPO on astrocytes undergoing oxygen-glucose-deprivation, an in vitro model of ischemia. Measurements of glutamate uptake, intracellular pH, intrinsic NADH fluorescence, Na,K-ATPase activity, and lactate release were performed. We found that EPO within minutes caused a Na,K-ATPase-dependent increase in glutamate uptake, restored intracellular acidification caused by glutamate and increased lactate release. The effects on intracellular pH were dependent on the sodium/hydrogen exchanger NHE. In neuron-astrocyte co-cultures, EPO increased NADH production both in astrocytes and neurons, however the increase was greater in astrocytes. We suggest that EPO preserves astrocyte function under ischemic conditions and thus may contribute to neuroprotection in ischemic stroke and brain ischemia secondary to TBI.

Prognostic value of preoperative platelet-related parameters and plasma fibrinogen in patients with non-muscle invasive bladder cancer after transurethral resection of bladder tumor.

Aim: To investigate the prognostic value of preoperative mean platelet volume (MPV), MPV/lymphocyte ratio (MPVLR), MPV/platelet count ratio and plasma fibrinogen in patients with non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). Methods: A total of 371 patients who underwent TURBT were enrolled. The main end points were disease-free survival (DFS) and overall survival (OS). Results: MPVLR, tumor size, tumor number and pathological grade were independent risk factors for postoperative DFS. Age and pathological grade were independent risk factors for postoperative OS. Conclusion: MPVLR is an independent risk factor for DFS in NMIBC patients and could be used as a parameter to predict postoperative tumor recurrence in patients after TURBT.

The current study investigated the prognostic value of preoperative mean platelet volume (MPV), MPV/lymphocyte ratio (MPVLR), MPV/platelet count ratio (MPVPCR) and plasma fibrinogen (PF) in peripheral blood of patients with non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). Included were 371 patients who underwent TURBT and were followed up. A high level of PF indicated worse survival and age and pathological grade were independent risk factors for postoperative survival. High levels of MPV, MPVLR and MPVPCR were associated with recurrence. MPVLR, tumor size, tumor number and pathological grade were independent risk factors for postoperative recurrence. MPVLR could be used as a parameter to predict postoperative tumor recurrence in patients after TURBT.

Multifunctional platinum(IV) complex bearing HDAC inhibitor and biotin moiety exhibits prominent cytotoxicity and tumor-targeting ability.

Despite the wide clinical use of platinum drugs in cancer treatment, their severe side effects and lack of tumor selectivity seriously limit their further clinical application. To address the limitations of the current platinum drugs, herein a multifunctional platinum(IV) compound 1 containing a histone deacetylase (HDAC) inhibitor (4-phenylbutyric acid, 4-PBA) and a tumor-targeting group (biotin) has been designed and prepared. An in vitro cytotoxicity study indicated that compound 1 exhibits comparable or superior cytotoxicity to cisplatin against the tested cancer cell lines, but greatly reduced toxicity in human normal liver LO2 cells, implying the potential tumor-targeting ability of compound 1. Molecular docking results indicate that compound 1 can effectively interact with a biotin-specific receptor (streptavidin) through its biotin moiety, enabling potential tumor-targeting capability. Further studies indicated that compound 1's cytotoxicity stems from inducing DNA damage via the mitochondrial apoptotic pathway and inhibiting HDACs. Consequently, this compound can not only take advantage of the tumor selectively of biotin to improve its tumor-targeting ability but also strengthen its anticancer activity via simultaneously targeting DNA and HDACs.

Prognostic value of preoperative inflammation-based predictors in patients with bladder carcinoma after radical cystectomy.

AIMS: Emerging evidence has related inflammation-based biomarkers to numerous carcinomas, including bladder carcinoma (BC). However, the role of inflammatory biomarkers in the prognosis of BC remains inconclusive. This study aimed to compare preoperative plasma fibrinogen (PF) and other inflammatory biomarkers such as the platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), C-reactive protein (CRP) level, and serum albumin level to predict the prognosis of patients with BC. METHODS: This article focused on a retrospective analysis of 175 patients with newly diagnosed BC who were admitted to our hospital from March 2005 to March 2016. Of these BC patients, 136 had undergone radical cystectomy (RC). RESULTS: According to multivariate analysis, high PF level was an independent predictor of overall survival (OS) in 136 BC patients receiving RC (HR = 3.759; P = 0.011), but not for all 175 BC patients. Combining the NLR and PF values showed higher predictive accuracy for OS than NLR or PF alone (P < 0.05). Additionally, for 136 BC patients who had undergone RC, a close relationship was found between high PF levels (≥3.39 g/L) and lymph node metastasis (P = 0.011) and clinical T stage (P = 0.015). Furthermore, PF was a superior prognostic factor compared with the LMR, PLR, CRP, and albumin values in 136 BC patients who had undergone RC (P < 0.001). CONCLUSIONS: The preoperative PF level may be a prognostic biomarker; and when combined with the NLR, it can improve the predictive ability of the survival of BC patients, particularly of BC patients who underwent RC.

Optical Activation of TrkB Signaling.

Brain-derived neurotrophic factor, via activation of tropomyosin receptor kinase B (TrkB), plays a critical role in neuronal proliferation, differentiation, survival, and death. Dysregulation of TrkB signaling is implicated in neurodegenerative disorders and cancers. Precise activation of TrkB signaling with spatial and temporal resolution is greatly desired to study the dynamic nature of TrkB signaling and its role in related diseases. Here we develop different optogenetic approaches that use light to activate TrkB signaling. Utilizing the photosensitive protein Arabidopsis thaliana cryptochrome 2, the light-inducible homo-interaction of the intracellular domain of TrkB in the cytosol or on the plasma membrane is able to induce the activation of downstream MAPK/ERK and PI3K/Akt signaling as well as the neurite outgrowth of PC12 cells. Moreover, we prove that such strategies are generalizable to other optical homo-dimerizers by demonstrating the optical TrkB activation based on the light-oxygen-voltage domain of aureochrome 1 from Vaucheria frigida. The results open up new possibilities of many other optical platforms to activate TrkB signaling to fulfill customized needs. By comparing all the different strategies, we find that the cryptochrome 2-integrated approach to achieve light-induced cell membrane recruitment and homo-interaction of intracellular domain of TrkB is most efficient in activating TrkB signaling. The optogenetic strategies presented are promising tools to investigate brain-derived neurotrophic factor/TrkB signaling with tight spatial and temporal control.

Zweigelt and Niagara skin extracts suppress cyclobutane pyrimidine dimer formation due to UV irradiation in NHEK cells: first attempt.

The grape skins after pressing the juice are a major problem for winery. However, because it contains a large amount of polyphenols, development of effective usages are expected to construct sustainable waste use. In this study, we examined whether grape skin extract is effective for recovery of DNA damage caused by UV irradiation. Extract from Zweigelt and Niagara skin was prepared by methanol, and UV irradiation was performed at 10 mJ/cm2 (250 nm) and 15 mJ/cm2 (290 nm) using human normal skin cells. As results, the decreased cell viability due to UV irradiation was improved by adding Niagara or Zweigelt skin extract. On the other hand, cyclobutane pyrimidine dimer production due to UV irradiation decreased significantly by Niagara or Zweigelt extract. In addition, the effects of grape skin extracts on the expression of sirtuin gene were also examined.

Impact of Intraoperative Infusion and Postoperative PCIA of Dexmedetomidine on Early Breastfeeding After Elective Cesarean Section: A Randomized Double-Blind Controlled Trial.

Objective: Few studies have investigated the effects of dexmedetomidine (DEX) on breastfeeding after cesarean delivery. A randomized double-blind controlled trial was conducted to investigate whether the administration of DEX, immediately after delivery and for patient-controlled intravenous analgesia (PCIA), can be beneficial for breastfeeding. Patients and Methods: One hundred sixty parturients scheduled for elective cesarean section under spinal anesthesia were randomly allocated to the DEX group (a loading dose of DEX was pumped at 0.5 µg/kg within 10 min, followed by a further infusion of DEX at 0.5 µg/kg/h until the end of the surgery and PCIA for 2 days with DEX plus sufentanil) or the standard care group (infusion saline intraoperatively, and PCIA for 2 days with sufentanil). The number of days required to switch to exclusive breastfeeding within six weeks of delivery, the time to first lactation and breast milk volume on day 1 and day 2 after delivery were recorded. Recovery quality, comfort, anxiety, depression, postoperative analgesia, and adverse reactions of parturients were also assessed. Results: Compared with the standard care group, parturients in the DEX group could be converted to exclusive breastfeeding earlier (11 [14] vs 8 [10] days, log-rank P=0.025), the first lactation time was sooner (28.38 [13.82] vs 33.79 [14.85] hrs, P=0.024), and the amount of breast milk on the second day after delivery increased (P=0.012). There was no difference between the two groups in postpartum uterine contraction pain, but postpartum rest and movement VAS scores and recovery quality score in the DEX group were better than those in the standard care group (all P<0.05). Moreover, the hospital anxiety and depression scale and anxiety subscale score on the second day after delivery and the comfort score on the third day after delivery in the DEX group were significantly better than those in the standard care group (5 [5] vs 6 [8], 2 [2] vs 3 [3], 83.58 [6.75] vs 80.48 [6.58]; P=0.013, P=0.005, P=0.006, respectively). The incidence of adverse events, such as bradycardia, vomiting, hypersomnia, hypertension and hypotension, was not significantly different between the DEX and standard care groups (6.9% vs 2.7%, 5.6% vs 13.7%, 4.2% vs 0%, 5.6% vs 2.7%, 11.1% vs 8.2%; P=0.275, P=0.158, P=0.366, P=0.681, P=0.556, respectively), except more parturients experienced nausea in the standard care group than in the DEX group (28.8% vs 11.1%, P=0.012). Furthermore, there was no difference in Neonatal Behavioral Neurological Assessment scores on the first and second days after delivery between the DEX and standard care groups (38 [3] vs 37 [2], 38.5 [2] vs 38 [2]; P=0.173, P=0.312, respectively). Conclusion: The application of DEX in the perioperative period of cesarean section was not only conducive to the early conversion of infant feeding to exclusive breastfeeding but could also improve the recovery quality and comfort of the parturient, optimize analgesia, shorten the time to first lactation, and increase lactation. Clinical Trials Registration: NCT03805945.

Effects of Hyaluronic Acid on Stability of Bleomycin Foam.

BACKGROUND: Bleomycin (BLM) foam sclerotherapy is effective in the treatment of venous malformations (VMs). Foam stability is influenced by factors such as sclerosant concentration, viscosity, and liquid-gas ratio. OBJECTIVE: To investigate whether hyaluronic acid (HA) could increase the stability of BLM foam and to evaluate the safety and efficacy of HA-BLM foam. MATERIALS AND METHODS: Experiment: BLM 6.0 IU + human serum albumin (HSA, 2, 1.95, 1.90, and 1.85 mL, respectively) + 1% HA (0, 0.05, 0.10, and 0.15 mL, respectively) + air 6 mL to create foam using the Tessari method. The foam half-life (FHL) was used to evaluate foam stability. Clinical study: Twenty-eight patients with head and neck VMs were enrolled between June 2018 and August 2019 treated by HA-BLM foam to evaluate the safety and efficacy. RESULTS: The FHL of the BLM foam was 8.46, 8.95, 10.45, and 14.51 minutes, respectively. All patients achieved significant efficacy, and no obvious side effects were observed. CONCLUSION: Addition of HA could improve the stability of BLM foam.

HDAC2 hyperexpression alters hippocampal neuronal transcription and microglial activity in neuroinflammation-induced cognitive dysfunction.

BACKGROUND: Inflammation can induce cognitive dysfunction in patients who undergo surgery. Previous studies have demonstrated that both acute peripheral inflammation and anaesthetic insults, especially isoflurane (ISO), are risk factors for memory impairment. Few studies are currently investigating the role of ISO under acute peri-inflammatory conditions, and it is difficult to predict whether ISO can aggravate inflammation-induced cognitive deficits. HDACs, which are essential for learning, participate in the deacetylation of lysine residues and the regulation of gene transcription. However, the cell-specific mechanism of HDACs in inflammation-induced cognitive impairment remains unknown. METHODS: Three-month-old C57BL/6 mice were treated with single versus combined exposure to LPS injected intraperitoneally (i.p.) to simulate acute abdominal inflammation and isoflurane to investigate the role of anaesthesia and acute peripheral inflammation in cognitive impairment. Behavioural tests, Western blotting, ELISA, immunofluorescence, qRT-PCR, and ChIP assays were performed to detect memory, the expressions of inflammatory cytokines, HDAC2, BDNF, c-Fos, acetyl-H3, microglial activity, Bdnf mRNA, c-fos mRNA, and Bdnf and c-fos transcription in the hippocampus. RESULTS: LPS, but not isoflurane, induced neuroinflammation-induced memory impairment and reduced histone acetylation by upregulating histone deacetylase 2 (HDAC2) in dorsal hippocampal CaMKII+ neurons. The hyperexpression of HDAC2 in neurons was mediated by the activation of microglia. The decreased level of histone acetylation suppressed the transcription of Bdnf and c-fos and the expressions of BDNF and c-Fos, which subsequently impaired memory. The adeno-associated virus ShHdac2, which suppresses Hdac2 after injection into the dorsal hippocampus, reversed microglial activation, hippocampal glutamatergic BDNF and c-Fos expressions, and memory deficits. CONCLUSIONS: Reversing HDAC2 in hippocampal CaMKII+ neurons exert a neuroprotective effect against neuroinflammation-induced memory deficits.

Extensive genomic recoding by codon-pair deoptimization selective for mammals is a flexible tool to generate attenuated vaccine candidates for dengue virus 2.

The four serotypes of dengue virus (DENV) are the leading etiologic agent of disease caused by arthropod-borne viruses (arboviruses) in the world, with billions at risk of DENV infection spread by infected mosquitoes. DENV causes illness ranging from dengue fever (DF) to life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). DENV proliferates well in two different host systems, an invertebrate mosquito vector and vertebrate primate host, which have a distinct difference in their preference of codon pairs (CP) for translation (different "codon pair bias"). Consequently, arboviruses must delicately balance the use of codon pairs between mammals and arthropods, which presents an Achilles' heel that we have exploited by specifically shifting the codon pair preference in the E and NS3 ORFs away from mammals while keeping the CPB favorable for mosquito ORFs. Here we report that recoding of the ORFs has led to variants that were over-attenuated in rhesus macaques although induction of protective antibodies in animals vaccinated with the smallest recoded ORF (E) was observed. The flexibility of our synthetic vaccine design (by decreasing the number of unfavorable CPs in the E ORF), allowed us to construct two new vaccine candidates (EhminA and EhminB) with intermediate attenuation in cell culture and neonatal mice, a result demonstrating proof of concept. New DENV vaccine candidates are being developed based on selective attenuation by dramatic recoding, with flexibility in balancing the attenuation and immunogenicity by marrying rational design and empirical modification.

Nonylphenol diethoxylate inhibits apoptosis induced in PC12 cells.

Nonylphenol and short-chain nonylphenol ethoxylates such as NP2 EO are present in aquatic environment as wastewater contaminants, and their toxic effects on aquatic species have been reported. Apoptosis has been shown to be induced by serum deprivation or copper treatment. To understand the toxicity of nonylphenol diethoxylate, we investigated the effects of NP2 EO on apoptosis induced by serum deprivation and copper by using PC12 cell system. Nonylphenol diethoxylate itself showed no toxicity and recovered cell viability from apoptosis. In addition, nonylphenol diethoxylate decreased DNA fragmentation caused by apoptosis in PC12 cells. This phenomenon was confirmed after treating apoptotic PC12 cells with nonylphenol diethoxylate, whereas the cytochrome c release into the cytosol decreased as compared to that in apoptotic cells not treated with nonylphenol diethoxylates. Furthermore, Bax contents in apoptotic cells were reduced after exposure to nonylphenol diethoxylate. Thus, nonylphenol diethoxylate has the opposite effect on apoptosis in PC12 cells compared to nonylphenol, which enhances apoptosis induced by serum deprivation. The difference in structure of the two compounds is hypothesized to be responsible for this phenomenon. These results indicated that nonylphenol diethoxylate has capability to affect cell differentiation and development and has potentially harmful effect on organisms because of its unexpected impact on apoptosis. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1389-1398, 2016.

Large-scale recoding of an arbovirus genome to rebalance its insect versus mammalian preference.

The protein synthesis machineries of two distinct phyla of the Animal kingdom, insects of Arthropoda and mammals of Chordata, have different preferences for how to best encode proteins. Nevertheless, arboviruses (arthropod-borne viruses) are capable of infecting both mammals and insects just like arboviruses that use insect vectors to infect plants. These organisms have evolved carefully balanced genomes that can efficiently use the translational machineries of different phyla, even if the phyla belong to different kingdoms. Using dengue virus as an example, we have undone the genome encoding balance and specifically shifted the encoding preference away from mammals. These mammalian-attenuated viruses grow to high titers in insect cells but low titers in mammalian cells, have dramatically increased LD50s in newborn mice, and induce high levels of protective antibodies. Recoded arboviruses with a bias toward phylum-specific expression could form the basis of a new generation of live attenuated vaccine candidates.