Analyzing Gene Expression Profile in K562 Cells Exposed to Sodium Valproate Using Microarray Combined with the Connectivity Map Database

To explore the mechanism underlying antileukaemia effect of sodium valproate, the growth and survival of the K562 cell line were investigated. Global profiles of gene expression in K562 cells exposed to sodium valproate were assessed and validated. The differentially expressed genes identified were further used to query the connectivity map database to retrieve a ranked list of compounds that act on the same intracellular targets as sodium valproate. A significant increase in cell apoptosis and a change in gene expression profile were observed in valproate-exposed K562 cells. The significant enrichment analysis of gene ontology terms for the differentially expressed genes showed that these genes were involved in many important biological processes. Eight differentially expressed genes involved in apoptosis were verified by quantitative real-time PCR. The connectivity map analysis showed gene expression profile in K562 cells exposed to sodium valproate was most similar to that of HDACi and PI3K inhibitors, suggesting that sodium valproate might exert antileukaemic action by inhibiting HDAC as well as inhibiting PI3K pathway. In conclusion, our data might provide clues to elucidate the molecular and therapeutic potential of VPA in leukaemia treatment, and the connectivity map is a useful tool for exploring the molecular mechanism of drug action

Utjecaj sastava podloge na povećanje biomase micelija i proizvodnje egzopolimera s pomoću gljive Hericium erinaceus CZ-2

In this work, the effects of medium composition and fermentation parameters on the simultaneous production of mycelial biomass and exopolymer by medicinal mushroom Hericium erinaceus CZ-2 were investigated in shake flask cultures using one-factor-at-a-time method and orthogonal array design. Results showed that the most suitable carbon, nitrogen, mineral sources, and cofactors for the mycelial biomass and exopolymer production were: corn flour combined with 1 % glucose, yeast extract, KH2PO4 and corn steep liquor. The intuitive analysis of orthogonal array design results indicated that the effects of nutritional requirement on the mycelial growth of Hericium erinaceus CZ-2 were in regular sequence of corn flour combined with 1 % glucose > yeast extract > corn steep liquor > KH2PO4, and those on exopolymer production were in the order of corn flour combined with glucose > KH2PO4 > yeast extract > corn steep liquor. The maximal yield of mycelial biomass (16.07 g/L) was obtained when the composition of the culture medium was (in g/L): corn flour 30, glucose 10, yeast extract 3, KH2PO4 1, CaCO3 0.5, and 15 mL/L of corn steep liquor; while the maximal exopolymer yield (1.314 g/L) was achieved when the composition of medium was (in g/L): corn flour 30, glucose 10, yeast extract 5, KH2PO4 3, CaCO3 0.5, and 15 mL/L of corn steep liquor. In the 15-litre scale-up fermentation, the maximum mycelial biomass yield of 20.50 g/L was achieved using the optimized medium.U ovom je radu ispitan utjecaj sastava podloge i uvjeta fermentacije na istodobnu proizvodnju biomase micelija i egzopolimera s pomoću ljekovite gljive Hericium erinaceus CZ-2. Pokusi su provedeni na kulturama uzgojenim na tresilici, primjenom jednofaktorske metode i ortogonalnog modela. Rezultati su pokazali da su najbolji izvori dušika, minerala i kofaktora za proizvodnju biomase micelija i egzopolimera kukuruzno brašno s 1 % glukoze, ekstrakt kvasca, KH2PO4 i kukuruzni ekstrakt. Analizom ortogonalnog modela utvrđeno je da na povećanje micelija redom utječu: kukuruzno brašno s 1 % glukoze, zatim ekstrakt kvasca, kukuruzni ekstrakt i KH2PO4, a na proizvodnju egzopolimera kukuruzno brašno s glukozom, zatim KH2PO4, ekstrakt kvasca te kukuruzni ekstrakt. Najveći je prinos biomase micelija (16,07 g/L) postignut s ovim sastavom podloge (u g/L): kukuruzno brašno 30, glukoza 10, ekstrakt kvasca 3, KH2PO4 1, CaCO3 0,5 i 15 mL/L kukuruznog ekstrakta, a najveći je prinos egzopolimera (1,314 g/L) dobiven korištenjem podloge (u g/L) od: kukuruznog brašna 30, glukoze 10, ekstrakta kvasca 5, KH2PO4 3, CaCO3 0,5 i 15 mL/L kukuruznog ekstrakta. Povećanjem obujma fermentacije na 15 L dobiven je najveći prinos biomase micelija od 20,50 g/L pri optimalnim uvjetima

Lentiviral Vector-Mediated SHC3 Silencing Exacerbates Oxidative Stress Injury in Nigral Dopamine Neurons by Regulating the PI3K-AKT-FoxO Signaling Pathway in Rats with Parkinson’s Disease

Background/Aims: Parkinson’s disease (PD) is a prevalent disease that leads to motor and cognitive disabilities, and oxidative stress (OS) injury was found to be related to the etiology of PD. Increasing evidence has shown that SHC3 is aberrantly expressed in neurons. The current study examines the involvement of SHC3 silencing in OS injury in the nigral dopamine neurons in rats with PD via the PI3K-AKT-FoxO signaling pathway. Methods: To study the mechanisms and functions of SHC3 silencing in PD at the tissue level, 170 rats were selected, and a lentivirus-based packaging system was designed to silence SHC3 expression in rats. Furthermore, PC12 cells were selected for in vitro experimentation. To evaluate the effect of SHC3 silencing in nigral dopamine neuronal growth, an MTT assay, propidium iodide (PI) single staining and Annexin V-PI double staining were performed to detect cell viability, cell cycle progression and cell apoptosis, respectively. Results: SHC3 shRNA led to decreased SOD and MDA levels and enhanced GSH activity, indicating that SHC3 silencing leads to motor retardation. SHC3 silencing repressed the extent of Akt and FoxO phosphorylation, thereby inhibiting the PI3K-AKT-FoxO signaling pathway. Furthermore, in cell experiments, SHC3 silencing suppressed PC12 cell proliferation and cell cycle progression, whereas it enhanced cell apoptosis. Conclusion: The current study provides evidence suggesting that SHC3 silencing may aggravate OS injury in nigral dopamine neurons via downregulation of the PI3K-AKT-FoxO signaling pathway in PD rats

Expressão não equilibrada do receptor de hidrocarboneto arílico nos linfócitos T CCR6+ CD4+ e CD4+ CD25+ do sangue periférico na artrite reumatoide

ResumoObjetivoAnalisar o papel do receptor de hidrocarboneto arílico (AhR) nos linfócitos T CCR6+ CD4+ e CD4+ CD25+ no sangue periférico de pacientes com artrite reumatoide (AR).MétodosFoi aplicada citometria de fluxo para determinar a proporção de células AhR positivas em linfócitos CCR6+ CD4+ e CD4+ CD25+ do sangue periférico e células mononucleares periféricas de cada indivíduo. Os níveis de expressão relativa de ácido ribonucleico mensageiro (do inglês ribonucleic acid, RNAm,) de AhR e RNAm de enzima de primeiro estágio essencial para o AhR (CYP1A1) foram testados por reação em cadeia de polimerase (do inglês polymerase chain reaction, PCR,) em tempo real.ResultadosA percentagem de células AhR positivas nas células mononucleares do sangue periférico foi maior no grupo com AR do que nos indivíduos saudáveis [(35,23±10,71)% vs. (18,83±7,32)%, (p<0,01)]. Os níveis de expressão de AhR e CYP1A1 estavam aumentados em pacientes com AR quando comparados com os controles [(3,71±1,63) vs. (2,00±1,27), p=0,002; (2,62±2,08) vs. (0,62±0,29), p<0,01, respectivamente]. Em pacientes com AR, a percentagem de células AhR positivas nos linfócitos T CD4+ CD25+ foi significativamente inferior à dos controles [17,90 (6,10±80,10)]% vs. (52,49±19,18)%, p < 0,01]; em controles saudáveis, a percentagem de células AhR positivas nos linfócitos T CD4+ CD25+ foi significativamente mais elevada do que nos linfócitos T CCR6+ CD4+ e também foi significativamente maior do que nas células mononucleares do sangue periférico (do inglês peripheral blood mononuclear cells, PBMC,) [(52,49±19,18)% vs. (23,18±5,62)% vs. (18,06±7,80)%, X 2=24,03, p < 0,01]; em pacientes com AR, a percentagem de células AHR positivas nos linfócitos T CCR6+ CD4+ era significativamente maior em comparação com os linfócitos T CD4+ CD25+ e PBMC (46,02±14,68)% vs. [17,90 (6,10±80.10)]% vs. (34,22±10,33)%, X 2=38,29, p<0,01]; no entanto, não foi encontrada correlação estatisticamente significativa entre os dados clínicos e células AhR positivas em linfócitos T CCR6+ CD4+ e CD4+ CD25+.ConclusãoO Ahr pode participar do progresso patológico da AR ao controlar a diferenciação de linfócitos Th17 e Treg no sangue periférico.AbstractObjectiveThe goal of this study was to analyze the role of aryl hydrocarbon receptor in peripheral blood CCR6+ CD4+ and CD4+ CD25+T cells of patients with rheumatoid arthritis.MethodsFlow cytometry was applied to determine the proportion of AhR positive cells in CCR6+ CD4+T, CD4+ CD25+T and peripheral blood peripheral mononuclear cells from each subject. AhR mRNA and CYP1A1 mRNA relative expression levels were tested by real‐time PCR.ResultsThe percentage of AhR positive cells in peripheral blood mononuclear cells was higher in RA group than that in healthy cases [(35.23±10.71) % vs. (18.83±7.32) %, (p<0.01)]. The expression levels of AhR and CYP1A1 were both increased in patients with RA while compared to controls [(3.71±1.63) vs. (2.00±1.27), p=0.002; (2.62±2.08) vs. (0.62±0.29), p<0.01, respectively]. In RA patients, the percentage of AhR positive cells in CD4+CD25+T cells was significantly lower than that from controls [17.90(6.10±80.10)]% vs. (52.49±19.18)%, p<0.01]; In healthy controls, the percentage of AhR positive cells in CD4+CD25+T cells was significantly higher than that in CCR6+CD4+T cells, and was also significantly higher than that in PBMCs [(52.49±19.18)% vs. (23.18±5.62)% vs. (18.06±7.80)%, X2=24.03, p<0.01]; in RA patients, the percentage of AhR positive cells in CCR6+CD4+T cells was significantly increased than that in CD4+CD25+T cells and PBMCs (46.02±14.68)% vs. [17.90 (6.10±80.10)] %vs. (34.22±10.33)%, X2=38.29, p<0.01]; Nevertheless, no statistically significant relationship was found between clinical data and AhR positive cells in CCR6+CD4+T and CD4+ CD25+T cells.ConclusionAhR may participate in the pathological progress of RA by controlling the differentiation of Th17 and Treg cells in peripheral blood

Mega-TTS: Zero-Shot Text-to-Speech at Scale with Intrinsic Inductive Bias

Scaling text-to-speech to a large and wild dataset has been proven to be highly effective in achieving timbre and speech style generalization, particularly in zero-shot TTS. However, previous works usually encode speech into latent using audio codec and use autoregressive language models or diffusion models to generate it, which ignores the intrinsic nature of speech and may lead to inferior or uncontrollable results. We argue that speech can be decomposed into several attributes (e.g., content, timbre, prosody, and phase) and each of them should be modeled using a module with appropriate inductive biases. From this perspective, we carefully design a novel and large zero-shot TTS system called Mega-TTS, which is trained with large-scale wild data and models different attributes in different ways: 1) Instead of using latent encoded by audio codec as the intermediate feature, we still choose spectrogram as it separates the phase and other attributes very well. Phase can be appropriately constructed by the GAN-based vocoder and does not need to be modeled by the language model. 2) We model the timbre using global vectors since timbre is a global attribute that changes slowly over time. 3) We further use a VQGAN-based acoustic model to generate the spectrogram and a latent code language model to fit the distribution of prosody, since prosody changes quickly over time in a sentence, and language models can capture both local and long-range dependencies. We scale Mega-TTS to multi-domain datasets with 20K hours of speech and evaluate its performance on unseen speakers. Experimental results demonstrate that Mega-TTS surpasses state-of-the-art TTS systems on zero-shot TTS, speech editing, and cross-lingual TTS tasks, with superior naturalness, robustness, and speaker similarity due to the proper inductive bias of each module. Audio samples are available at https://mega-tts.github.io/demo-page

Electronically phase separated nano-network in antiferromagnetic insulating LaMnO3/PrMnO3/CaMnO3 tricolor superlattice

Strongly correlated materials often exhibit an electronic phase separation (EPS) phenomena whose domain pattern is random in nature. The ability to control the spatial arrangement of the electronic phases at microscopic scales is highly desirable for tailoring their macroscopic properties and/or designing novel electronic devices. Here we report the formation of EPS nanoscale network in a mono-atomically stacked LaMnO3/CaMnO3/PrMnO3 superlattice grown on SrTiO3 (STO) (001) substrate, which is known to have an antiferromagnetic (AFM) insulating ground state. The EPS nano-network is a consequence of an internal strain relaxation triggered by the structural domain formation of the underlying STO substrate at low temperatures. The same nanoscale network pattern can be reproduced upon temperature cycling allowing us to employ different local imaging techniques to directly compare the magnetic and transport state of a single EPS domain. Our results confirm the one-to-one correspondence between ferromagnetic (AFM) to metallic (insulating) state in manganite. It also represents a significant step in a paradigm shift from passively characterizing EPS in strongly correlated systems to actively engaging in its manipulation

Prevalence of syphilis infection in different tiers of female sex workers in China: implications for surveillance and interventions

<p>Abstract</p> <p>Background</p> <p>Syphilis has made a dramatic resurgence in China during the past two decades and become the third most prevalent notifiable infectious disease in China. Female sex workers (FSWs) have become one of key populations for the epidemic. In order to investigate syphilis infection among different tiers of FSWs, a cross-sectional study was conducted in 8 sites in China.</p> <p>Methods</p> <p>Serum specimens (n = 7,118) were collected to test for syphilis and questionnaire interviews were conducted to obtain socio-demographic and behavioral information among FSWs recruited from different types of venues. FSWs were categorized into three tiers (high-, middle- and low-tier FSWs) based on the venues where they solicited clients. Serum specimens were screened with enzyme-linked immunosorbent assay (ELISA) for treponemal antibody followed by confirmation with non-treponemal toluidine red unheated serum test (TRUST) for positive ELISA specimens to determine syphilis infection. A logistic regression model was used to determine factors associated with syphilis infection.</p> <p>Results</p> <p>Overall syphilis prevalence was 5.0% (95%CI, 4.5-5.5%). Low-tier FSWs had the highest prevalence (9.7%; 95%CI, 8.3-11.1%), followed by middle-tier (4.3%; 95%CI, 3.6-5.0%, <it>P </it>< 0.001) and high-tier FSWs (2.2%; 95%CI, 1.6-2.9%, <it>P </it>< 0.001). Factors independently associated with syphilis infection included older age, lower education level, geographic location, lower tier of typology, and injection drug use.</p> <p>Conclusions</p> <p>This multi-site survey showed a high prevalence of syphilis infection among FSWs and substantial disparities in syphilis prevalence by the tier of FSWs. The difference in syphilis prevalence is substantial between different tiers of FSWs, with the highest rate among low-tier FSWs. Thus, current surveillance and intervention activities, which have low coverage in low-tier FSWs in China, should be further examined.</p