Search

Vaccines are known to function as themost effective interventional therapeutics for controlling infectious diseases, including polio, smallpox, rabies, tuberculosis, influenza and SARS-CoV-2. Smallpox has been eliminated completely and polio is almost extinct because of vaccines. Rabies vaccines and Bacille Calmette-Gueérin (BCG) vaccines could effectively protect humans against respective infections. However, both influenza vaccines and COVID-19 vaccines are unable to eliminate these two infectious diseases of their highly variable antigenic sites in viral proteins. Vaccine effectiveness (VE) could be negatively influenced (i.e., interfered with) by immune imprinting of previous infections or vaccinations, and repeated vaccinations could interfere with VE against infections due to mismatch between vaccine strains and endemic viral strains. Moreover, VE could also be interfered with when more than one kind of vaccine is administrated concomitantly (i.e., co-administrated), suggesting that the VE could be modulated by the vaccineinduced immunity. In this review, we revisit the evidence that support the interfered VE result from immune imprinting or repeated vaccinations in influenza and COVID-19 vaccine, and the interference in co-administration of these two types of vaccines is also discussed. Regarding the development of next-generation COVID-19 vaccines, the researchers should focus on the induction of crossreactive T-cell responses and naive B-cell responses to overcome negative effects from the immune system itself. The strategy of co-administrating influenza and COVID-19 vaccine needs to be considered more carefully and more clinical data is needed to verify this strategy to be safe and immunogenic. [ABSTRACT FROM AUTHOR]

Among the current five Variants of Concern, infections caused by SARS-CoV-2 B.1.617.2 (Delta) variant are often associated with the greatest severity. Despite recent advances on the molecular basis of elevated pathogenicity using recombinant proteins, the architecture of intact Delta virions remains veiled. Moreover, pieces of molecular evidence for the detailed mechanism of S-mediated membrane fusion are missing. Here, we showed the pleomorphic nature of Delta virions from electron beam inactivated samples and reported the in situ structure and distribution of S on the authentic Delta variant. We also captured the virus-virus fusion events, which provided pieces of structural evidence for Delta's attenuated dependency on cellular factors for fusion activation, and proposed a model of S-mediated membrane fusion. Besides, site-specific glycan analysis revealed increased oligomannose-type glycosylation of native Delta S than that of the WT S. Together, these results disclose distinctive factors of Delta being the most virulent SARS-CoV-2 variant. [ABSTRACT FROM AUTHOR]

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression. [ABSTRACT FROM AUTHOR]

Background: In 2020, a new coronavirus, SARS-CoV-2, quickly spread worldwide within a few months. Although coronaviruses typically infect the upper or lower respiratory tract, the virus RNA can be detected in plasma. The risk of transmitting coronavirus via transfusion of blood products remains. As more asymptomatic infections are identified in COVID-19 cases, blood safety has become particularly important. Methylene blue (MB) photochemical technology has been proven to inactivate lipid-enveloped viruses with high efficiency and safety. The present study aimed to investigate the SARS-CoV-2 inactivation effects of MB in plasma.Methods: The SARS-CoV-2 virus strain was isolated from Zhejiang University. The live virus was harvested from cultured VERO-E6 cells, and mixed with MB in plasma. The MB final concentrations were 0, 1, 2, and 4 μM. The "BX-1 AIDS treatment instrument" was used at room temperature, the illumination adjusted to 55,000 ± 0.5 million Lux, and the plasma was irradiated for 0, 2, 5, 10, 20, and 40 mins using light at a single wavelength of 630 nm. Virus load changes were measured using quantitative reverse transcription- PCR.Results: BX-1 could effectively eliminate SARS-CoV-2 within 2 mins in plasma, and the virus titer declined to 4.5 log10 TCID50 (median tissue culture infectious dose)/mL.Conclusion: BX-1 is based on MB photochemical technology, which was designed to inactivate HIV-1 virus in plasma. It was proven to be safe and reliable in clinical trials of HIV treatment. In this study, we showed that BX-1 could also be applied to inactivate SARS-CoV-2. During the current outbreak, this technique it has great potential for ensuring the safety of blood transfusions, for plasma transfusion therapy in recovering patients, and for preparing inactivated vaccines. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo. [ABSTRACT FROM AUTHOR]

Background. Elite controller refers to a patient with human immunodeficiency virus infection with an undetected viral load in the absence of highly active antiretroviral therapy. Studies on gene expression and regulation in these individuals are limited but significant, and have helped researchers and clinicians to understand the interrelationships between HIV and its host. Methods. We collected CD4 T-cell samples from two elite controllers (ECs), two HIV-positive infected patients (HPs), and two healthy controls (HCs) to perform second-generation transcriptome sequencing. Using the Cufflinks software, we calculated the Fragments Per Kilobase of transcript per Million fragments mapped (FPKM) and identified differentially expressed (DE) mRNAs and long non-coding RNAs (lncRNAs), with corrected P value < 0.05 (based on a false discovery rate (FDR) < 0.05). We then constructed a protein-protein interaction network using cytoHubba and a long non-coding RNA-mRNA co-expression network based on the Pearson correlation coefficient. Results. In total, 1109 linear correlations of DE lncRNAs targeting DE mRNAs were found and several interesting interactions were identified as being associated with viral infections and immune responses within the networks based on these correlations. Among these lncRNA-mRNA relationships, hub mRNAs including HDAC6, MAPK8, MAPK9, ATM and their corresponding annotated co-expressed lncRNAs presented strong correlations with the MAPK-NF-kappa B pathway, which plays a role in the reactivation and replication of the virus. Conclusions. Using RNA-sequencing, we systematically analyzed the expression profiles of lncRNAs and mRNAs from CD4+ T cells from ECs, HPs, and HCs, and constructed a co-expression network based on the relationships among DE transcripts and database annotations. This was the first study to examine gene transcription in elite controllers and to study their functional relationships. Our results provide a reference for subsequent functional verification at the molecular or cellular level. [ABSTRACT FROM AUTHOR]

The differentiation and response of CD8+ T cells is vital in host defense against human immunodeficiency virus type 1 (HIV-1). MicroRNA (miR)-155 is an important regulator of T cell differentiation. However, the profile of miR-155 in HIV-1 infected individuals and its association with CD8+ T cell differentiation remain to be fully elucidated. The present cross-sectional study was performed involving 63 HIV-1-infected patients undergoing highly active antiretroviral therapy (HAART), 31 HAART-naïve patients and 35 healthy controls. The levels of miR-155 in CD8+ T cells were detected using reverse transcription-quantitative polymerase chain reaction analysis. Subsets of CD8+ T cell differentiation were detected using flow cytometry. The results revealed that the discord controllers and HAART-naïve patients showed higher percentages of effector and effector memory cells, and lower percentages of naïve cells (P<0.05). The levels of miR-155 in CD8+ T cells from the HIV-1-infected patients were higher, particularly in the discord controllers and HAART naïve patients (P<0.01). The expression levels of miR-155 were positively correlated with the percentages of effector and effector memory CD8+ T cells, and negatively correlated with the percentages of naïve and central memory CD8+ T cells (P<0.01). Taken together, these findings suggested that the levels of miR-155 in CD8+ T cells of patients with HIV-1 were increased and associated with CD8+ T cell differentiation. [ABSTRACT FROM AUTHOR]

Recently, novel variants of H5 highly pathogenic avian influenza viruses (AIVs) have been frequently isolated from poultry and wild birds in Asia, Europe and North America. Live poultry markets (LPMs) play an important role in the dissemination of influenza viruses. Four H5N2 AIVs were isolated from poultry during surveillance of AIVs in LPMs in Eastern China, in 2015. Whole-genome sequencing, combined with phylogenetic and antigenic analyses were performed to characterize these viruses. These H5N2 viruses had undergone extensive reassortment resulting in two genetic groups of viruses in poultry. These viruses exhibited slightly pathogenicity in mice, and replicated without prior adaptation. The continued circulation of these novel H5N2 viruses may represent a threat to human health. [ABSTRACT FROM AUTHOR]

Background: H5N2 avian influenza viruses (AIVs) can infect individuals that are in frequent contact with infected birds. In 2013, we isolated a novel reassortant highly pathogenic H5N2 AIV strain [A/duck/Zhejiang/6DK19/2013(H5N2) (6DK19)] from a duck in Eastern China. This study was undertaken to understand the adaptive processes that led enhanced replication and increased virulence of 6DK19 in mammals. 6DK19 was adapted to mice using serial lung-to-lung passages (10 passages total). The virulence of the wild-type virus (WT-6DK19) and mouse-adapted virus (MA-6DK19) was determined in mice. The whole-genome sequences of MA-6DK19 and WT-6DK19 were compared to determine amino acid differences. Findings: Amino acid changes were identified in the MA-DK19 PB2 (E627K), PB1 (I181T), HA (A150S), NS1 (seven amino acid extension "WRNKVAD" at the C-terminal), and NS2 (E69G) proteins. Survival and histology analyses demonstrated that MA-6DK19 was more virulent in mice than WT-6DK19. Conclusion: Our results suggest that these substitutions are involved in the enhanced replication efficiency and virulence of H5N2 AIVs in mammals. Continuing surveillance for H5N2 viruses in poultry that are carrying these mutations is required. [ABSTRACT FROM AUTHOR]

Macrophages are major targets of human immunodeficiency virus (HIV) and can act as long-term reservoirs of the virus. Chronic HIV-1 infection is associated with dysregulated inflammation. Recepteur d'origine nantais (RON) is expressed in tissue resident macrophages and functions to maintain inflammatory homeostasis. The present study aimed to compare the expression of RON on HIV-positive and - negative participants, and to investigate the mechanism by which HIV-1 influences the expression and function of RON in the JLTRG T cell line. The levels of RON and the RON ligand, macrophage-stimulating protein (MSP), in the peripheral blood of HIV-1-positive patients that were receiving (n=22) or not receiving highly active anti-retroviral therapy (HAART) (n=82) and 37 healthy control participants were determined by enzyme-linked immunosorbent assay. Expression of RON and MSP in the JLTRG T cell line was assessed by western blotting and the subcellular location was analyzed by fluorescence microscopy. JLTRG cells were co-cultured with a cell line that stably expresses HIV, H9/HTLV-IIIB, and alterations in the levels of RON and nuclear factor-κB (NF-κB) in JLTRG cells were assessed by western blotting. The expression of RON and MSP were significantly different in the serum of HIV-1- positive patients that were receiving HAART compared with those not receiving H AART (P<0.05) a nd healthy control patients (P<0.01). RON was detected in JLTRG cells, and was shown to be downregulated by HIV-1 infection. HIV-1 infection of JLTRG cells also reduced NF-κB phosphorylation. Thus, HIV-1 was shown to downregulate the expression and phosphorylation of RON by targeting the NF-κB pathway. [ABSTRACT FROM AUTHOR]

Background: Co-infection of hepatitis virus is common in human immunodeficiency virus (HIV) infected adults in China. But little is known about hepatitis virus co-infection in pediatric HIV-infected subjects. The study aimed to investigate the impact of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co-infection and highly active antiretroviral therapy (HAART) on liver function of pediatric HIV-infected subjects. Materials and Methods: A cohort study including 101 pediatric HIV-infected subjects with HBV/HCV co-infection and 44 pediatric comparators with HIV mono-infection was carried out in Henan Province of China from September 2011 to September 2012. All patients received HAART for 1-year. HBV and HCV infection was determined by antibody tests. HIV RNA load, CD4+ T-cell counts and liver function were determined before and after HAART. The Student's t-test or a one-way ANOVA was used for normally distributed values and A Mann-Whitney U-test was performed for values without normal distribution using SPSS statistical package 18.0 (SPSS Inc.). Results: After HAART for 1-year, the median levels of viral load were decreased to lower limit of detection in 90.34% pediatric HIV-infected subjects with/without HBV/HCV co-infection (P < 0.001), and CD4+ T-cell counts increased significantly (P < 0.001). Compared with the pre-HAART, mean level of alanine aminotransferase (ALT) in each group had a significant increase after HAART (P < 0.01). The mean levels of ALT and aspartate aminotransferase (AST) in nevirapine (NVP) based HAART group increased significantly after HAART (P < 0.01). Mean change values of ALT and AST were significantly higher in the NVP based regimen group than in the efavirenz (EFV) based regimen group (P < 0.01). For HIV/ HBV/HCV co-infected patients, mean change values of ALT and AST in NVP-based HAART group was significantly higher than that in EF V-based HAART group (P < 0.01). Conclusion: Highly active antiretroviral therapy can damage liver function in pediatric HIV-infected subjects, especially in those with HBV/HCV co-infection. NVP was more harmful to liver function of pediatric HIV-infected subjects than EFV. [ABSTRACT FROM AUTHOR]

Domestic ducks are natural reservoirs of avian influenza viruses and serve as reassortant hosts for new virus subtypes. We isolated 2 novel influenza A(H5N8) viruses from domestic ducks in eastern China, sequenced their genomes, and tested their pathogenicity in chickens and mice. Circulation of these viruses may pose health risks for humans. [ABSTRACT FROM AUTHOR]

We assessed a colloidal gold immunochromatographic assay (GICA) for rapid detection of influenza A (H7N9) and compared it with reverse-transcription-polymerase chain reaction (RT-PCR) and viral culture. Samples from 35 H7N9 infected patients were collected, including 45 throat swab samples, 56 sputum samples, and 39 feces samples. All samples were tested by GICA, viral culture, and RT-PCR. GICA specifically reacted with recombinant HA proteins, virus lysates, and clinical samples fromH7 subtype viruses. Compared with RT-PCR, GICA demonstrated low sensitivity (33.33%) but high specificity (97.56%). The positive rate of GICA tests for samples collected in the period from 8 to 21 days after contact with poultry was much higher than those for samples collected before or after this period. Compared with viral culture, GICA showed sensitivity of 91.67% and specificity of 82.03%. Sputum specimens weremore likely to test positive for H7N9 virus than samples from throat swabs and feces. The GICA-based H7 test is a reliable, rapid, and convenient method for the screening and diagnosis of influenza A (H7N9) disease, especially for the sputum specimens with high viral load. It may be helpful in managing H7N9 epidemics and preliminary diagnosis in early stages in resource-limited settings. [ABSTRACT FROM AUTHOR]

Objective: The aims of this study were to systematically review epidemiological characteristics in older people living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (PLWHA) in low endemic areas of the People's Republic of China, analyze the causes of death and mortality, and provide a basis for targeted prevention in these populations. Methods: Nine counties representative of the distribution and epidemiological factors of the HIV epidemic in Zhejiang Province were selected, and data from 1,115 HIV-positive individuals, including 196 older people (⩾50 years), who were confirmed as PLWHA from January 1, 2000 to December 31, 2012, were retrospectively analyzed. Results: The proportion of older PLWHA increased from 0% in 2000 to 22.45% in 2012. Sexual transmission was the main route, accounting for 82.65% of infections in this group. Compared with the younger group (range from 14 to 49 years old), the older group had significantly lower CD4+ cell counts (291.64 versus 363.63; P<0.001) when first diagnosed, and more of this group presented in the AIDS state with opportunistic infections (51.02% versus 34.06%; P<0.001). In the older group, 25 (12.76%) patients died directly of AIDS and 171 (87.24%) were censored, and in the younger group 50 (5.44%) patients died directly of AIDS and 869 (94.56%) were censored. Estimated survival time since HIV diagnosis in the older group was 11.54±0.49 years (95% confidence interval [CI] 10.59-12.50), while in the younger group it was 13.85±0.46 years (95% CI 12.94-14.76), the log rank (Mantel-Cox) test gave a chi-square value of 3.83, and there was significant difference between the groups (P<0.05). Conclusion: The number of older PLWHA increased steadily over the study period in low HIV endemic provinces of a developing country. Later discovery and preexisting disease perhaps contributed to a shorter estimated survival time for older PLWHA and higher mortality. [ABSTRACT FROM AUTHOR]

Objective: The development of a human immunodeficiency virus (HIV)-1 promoter reporter system is critical for investigating transcription activity of the virus. We designed a modified overlap extension PCR method for single round site-directed mutagenesis of the long terminal repeat (LTR) segment of HIV-1. Methods: The procedure consists of overlap extension PCR, DpnI digestion, and product transformation. Wild-type and serial sequence deletion clones of HIV-1 LTR were constructed. βasal transcription activity was also measured. Results: The overall efficiency for obtaining the desired products was 53.2%. The reporter assay indicated the importance of the second NF-κβ cis-element and surrounding regions in mediating the regulation of HIV-1 transcription. Conclusion: The technique we investigated is suitable for highthroughput functional studies of virus-host interaction. [ABSTRACT FROM AUTHOR]

Objective: To explore whether expression of dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and reactivation of human immunodeficiency virus type 1 (HIV-1) provirus in dendritic cells (DCs) occur through similar or common signaling pathways. Methods: Phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells were used as the in vitro model of DCs. The activation of the DC-SIGN promoter and HIV-1 5' long-term repeat (LTR) sequence induced by interleukin 4 (IL-4) in differentiated THP-1 cells was studied using luciferase reporter plasmids. The regulatory signaling pathways were identified using specific inhibitors, and the activity of the DC-SIGN promoter and HIV-1 5'LTR was detected. Results: HIV-1 5'LTR was activated by IL-4-induced signaling pathways but much weaker than DC-SIGN promoter. IL-4-induced activation of HIV-1 5'LTR was mainly through the nuclear factor kappalight- chain-enhancer of activated B cells (NF-êB) pathway, which was also involved in activation of the DC-SIGN promoter. The extracellular signal-regulated kinase (ERK) pathway, which was the main pathway for DC-SIGN promoter activation, also played an important role in HIV-1 5'LTR activation. Conclusion: Our study suggests that the activation of the DC-SIGN promoter and HIV-1 5'LTR may share NF-êB and ERK-signaling pathways. [ABSTRACT FROM AUTHOR]

Cortical dysplasia (CD), a frequent pathological substrate of pediatric epilepsy surgery patients, has a number of similarities with immature cortex, such as reduced Mg2+ sensitivity of N-methyl-D-aspartate (NMDA) receptors and the persistence of subplate-like neurons and undifferentiated cells. Because γ-aminobutyric acid (GABA) is the main neurotransmitter in early cortical development, we hypothesized increased GABA receptor-mediated synaptic function in CD tissue. Infrared videomicroscopy and whole-cell patch clamp recordings were used to characterize the morphology and electrophysiological properties of immature and normal-appearing neurons in slices from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy in children (0.2–14 years). In addition, we examined spontaneous and evoked synaptic activity, as well as responses to exogenous GABA application. We demonstrate both the presence of immature pyramidal neurons and networks in young CD tissue and the predominance of GABA synaptic activity. In addition, spontaneous GABA depolarizations frequently induced action potentials, supporting a potential excitatory role of GABA in CD. Evoked synaptic responses mediated by GABA were also prominent, and bath application of 4-aminopyridine induced rhythmic depolarizations that were blocked by bicuculline. Finally, responses to exogenous application of GABA had depolarized reversal potentials in severe compared to mild and non-CD cases. The present data support the hypothesis that CD shares features of immature cortex, with predominant and potentially excitatory GABAA receptor-mediated neurotransmission. These results could partially explain the increased excitability of the cortical network in pediatric CD. [ABSTRACT FROM AUTHOR]

Dopamine (DA) modulates glutamate neurotransmission in the striatum. Abnormal DA modulation has been implicated in neurological and psychiatric disorders. The development of DA transporter knock-down (DAT-KD) mice has permitted modeling of these disorders and has shed new light on DA modulation. DAT-KD mice exhibit increased extracellular DA, hyperactivity, and alterations in habituation. We used whole cell patch-clamp recordings from visually identified striatal neurons in slices to examine the effects of DAT-KD on corticostriatal transmission. Electrophysiological recordings from medium-sized spiny neurons in the dorsal striatum revealed alterations in both amplitude and frequency, of spontaneous glutamate receptor-mediated synaptic currents in cells from DAT-KD mice. Furthermore, kinetic analyses revealed that these currents had shorter half-amplitude durations and faster decay times. In contrast, GABA-receptor–mediated synaptic currents were not altered. Striatal neurons from DAT-KD mice also responded differently to amphetamine, cocaine, and DA D2-receptor agonists or antagonists compared with wildtype (WT) littermate controls. In WTs amphetamine and cocaine reduced the frequency of spontaneous glutamate currents and these effects appeared to be mediated by activation of D2 receptors. In contrast, in DAT-KD mice either no changes or only small increases in frequency occurred. D2-receptor agonists or antagonists also had opposing effects in WT and DAT-KD mice. Together, these results indicate that chronically increased extracellular DA produces long-lasting changes in corticostriatal communication that may be mediated by changes in D2-receptor function. These findings have implications for understanding mechanisms underlying attention deficit hyperactivity disorder and Tourette's syndrome and may provide insights into novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

The apoptosis of lens epithelial cells has been proposed as the common basis of cataract formation, with oxidative stress as the major cause. This study was performed to investigate the protective effect of the herbal constituent parthenolide against oxidative stress-induced apoptosis of human lens epithelial (HLE) cells and the possible molecular mechanisms involved. HLE cells (SRA01-04) were incubated with 50 μM H2O2 in the absence or presence of different doses of parthenolide (10, 20 and 50 μM). To study apoptosis, the cells were assessed by morphologic examination and Annexin V-propidium iodide double staining flow cytometry; to investigate the underlying molecular mechanisms, the expression of caspase-3 and caspase-9 were assayed by Western blot and quantitative RT-PCR, and the activities of caspase-3 and caspase-9 were measured by a Chemicon caspase colorimetric activity assay kit. Stimulated with H2O2 for 18 h, a high fraction of HLE cells underwent apoptosis, while in the presence of parthenolide of different concentrations, dose-dependent blocking of HLE cell apoptosis was observed. The expression of caspase-3 and caspase-9 induced by H2O2 in HLE cells was significantly reduced by parthenolide both at the protein and mRNA levels, and the activation of caspase-3 and caspase-9 was also suppressed by parthenolide in a dose-dependent manner. In conclusion, parthenolide prevents HLE cells from oxidative stress-induced apoptosis through inhibition of the activation of caspase-3 and caspase-9, suggesting a potential protective effect against cataract formation.Cell Research (2007) 17:565–571 doi: 10.1038/cr.2007.6; published online 6 March 2007 [ABSTRACT FROM AUTHOR]

Trigeminal motoneurons relay the final output signals generated within the oral-motor pattern generating circuit(s) to muscles for execution of various motor patterns. In recent years, these motoneurons were shown to possess voltage dependent nonlinear membrane properties that allow them to actively participate in sculpting their final output. A complete understanding of the factors controlling trigeminal motoneuronal (TMN) discharge during oral-motor activity requires, at a minimum, a detailed understanding of the palette of ion channels responsible for membrane excitability and a determination of whether these ion channels are targets for modulation. Toward that end, we studied in detail the properties of calcium channels in TMNs and their susceptibility to modulation by 5-HT in rat brain slices. We found that based on pharmacological and voltage-dependent properties, high-voltage-activated (HVA) N-type [ω-conotoxin GVIA (ω-CgTX)]-sensitive, and to a lesser extent P/Q-type [ω-agatoxin IVA (ω-Aga IVA)]-sensitive, calcium channels make up the majority of the whole cell calcium current. 5-HT (5.0 μM) decreased HVA current by 31.3 ± 2.2%, and the majority of this suppression resulted from reduction of current flow through N- and P/Q-type calcium channels. In contrast, 5-HT had no effect on low-voltage-activated (LVA) current amplitude in TMNs. HVA calcium current inhibition was mimicked by 5-CT, a 5-HT1 receptor agonist, and by R(+)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), a specific 5-HT1A agonist. The effects of 5-HT were blocked by the 5-HT1A antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide (NAN-190) but not by ketanserin, a 5-HT2/1C antagonist. Under current clamp, ω-CgTX and 5-HT were most effective in suppressing the mAHP and both increased the spike frequency and input/output gain in response to current injection. Calcium current modulation by 5-HT1A receptors likely is an important mechanism to fine tune the input/output gain of TMNs in response to small incoming synaptic inputs and accounts for some of the previously reported effects of 5-HT on TMN excitability during tonic and burst activity during oral-motor behavior. [ABSTRACT FROM AUTHOR]

The functional and biophysical properties of a persistent sodium current (I(NaP)) previously proposed to participate in the generation of subthreshold oscillations and burst discharge in mesencephalic trigeminal sensory neurons (Mes V) were investigated in brain stem slices (rats, p7-p12) using whole cell patch-clamp methods. I(NaP) activated around -76 mV and peaked at -48 mV, with V1/2 of -58.7 mV. Ramp voltage-clamp protocols showed that I(NaP) undergoes time- as well as voltage-dependent inactivation and recovery from inactivation in the range of several seconds (tau(onset) = 2.04 s, tau(recov) = 2.21 s). Riluzole (< or =5 microM) substantially reduced I(NaP), membrane resonance, postinhibitory rebound (PIR), and subthreshold oscillations, and completely blocked bursting, but produced modest effects on the fast transient Na+ current (I(NaT)). Before complete cessation, burst cycle duration was increased substantially, while modest and inconsistent changes in burst duration were observed. The properties of the I(NaT) were obtained and revealed that the amplitude and voltage dependence of the resulting "window current" were not consistent with those of the observed I(NaP) recorded in the same neurons. This suggests an additional mechanism for the origin of I(NaP). A neuronal model was constructed using Hodgkin-Huxley parameters obtained experimentally for Na+ and K+ currents that simulated the experimentally observed membrane resonance, subthreshold oscillations, bursting, and PIR. Alterations in the model g(NaP) parameters indicate that I(NaP) is critical for control of subthreshold and suprathreshold Mes V neuron membrane excitability and burst generation. [ABSTRACT FROM AUTHOR]

The authors discuss the study conducted by W. D. Leavitt and colleagues regarding sulfur isotope fractionations and cell-specific sulfate reduction rate on the single electron donor for Desulfovibrio vulgaris Hildenborough, a model sulfate reducer. The authors note the role of the study in revealing the shared dependency of sulfate reduction rate and isotope fractionations for microbial metabolism. Moreover, the authors cite the association of the study in marine sediment relationships.