Furthermore, deficiency of BCO2 resulted in inactivation of mitochondrial MnSOD enzyme, excessive production of reactive oxygen species, and elevation of protein levels of stimulator of interferon genes (STING) and interferon regulatory factor 3 (IRF3) in the hypothalamus. The data suggest that BCO2 is essential for hypothalamic mitochondrial dynamics. BCO2 deficiency induces mitochondrial fragmentation and mitochondrial oxidative stress, which may lead to mitochondrial DNA release into the cytosol and subsequently sensing by activation of the STING-IRF3 signaling pathway in the mouse hypothalamus.

To investigate (1) whether measurement of the critical shoulder angle (CSA) is still reliable in some nonstandard anteroposterior radiographs; and (2) whether the ratio of the transverse to longitudinal diameter of the glenoid projection (RTL) could be used to determine the reliability of the CSA in nonstandard anteroposterior radiographs.

The authors analyzed radiology records from 2017 to 2019 for patients with computed tomography (CT) scans of the shoulder. According to the Suter-Henninger classification system, each CT scan underwent 3-dimensional (3D) reconstructions to obtain 8 digitally reconstructed radiographs (DRRs), including 1 type A1 film and 7 type D1 films with different rotation angles. CSA and RTL were measured on all films, and 2 blinded reviewers evaluated DRRs. The relationship between RTL and CSA was determined by Pearson correlation test. The threshold value was determined by receiver operating characteristic (ROC) analyses using RTL as predictors and defined reliable CSA as criterioon (RTL) is of good predictive value in defining the reliability of the CSA in malposition films. Based on the results, the CSA can be considered reliable if its RTL is <0.25.

III, retrospective cohort study investigating a diagnostic test.

III, retrospective cohort study investigating a diagnostic test.A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has been confirmed as having the capacity to transmit from humans to humans, causing acute respiratory distress syndrome (ARDS) and acute lung injury. Angiotensin converting enzyme-2 (ACE2) is known to be expressed on type II pneumocytes. As a counter-regulatory arm of the renin-angiotensin system (RAS), ACE2 plays critical roles in the pathogenesis of ARDS and acute lung injury. The affinity of the spike protein receptor binding domain (RBD) of SARS-CoV-2 for human ACE2 (hACE2) largely determines the degree of clinical symptoms after infection by SARS-CoV-2. Previous studies have shown that regulating the ACE2/RAS system is effective in the treatment of severe acute respiratory syndrome coronavirus (SARS-CoV)-induced ARDS and acute lung injury. Since ACE2 is the host cell receptor for both SARS-CoV-2 and SARS-CoV, regulating the ACE2/RAS system may alleviate ARDS and acute lung injury caused by SARS-CoV-2 as well as SARS-CoV. Vitamin D was found to affect ACE2, the target of SARS-CoV-2; therefore, we propose that vitamin D might alleviate ARDS and acute lung injury induced by SARS-CoV-2 by modulating ACE2.

To evaluate and compare the effectiveness of four types of non-pharmaceutical interventions (NPIs) to contain the time-varying effective reproduction number (Rt) of coronavirus disease-2019 (COVID-19).

This study included 1,908,197 confirmed COVID-19 cases from 190 countries between 23 January and 13 April 2020. The implemented NPIs were categorised into four types mandatory face mask in public, isolation or quarantine, social distancing and traffic restriction (referred to as mandatory mask, quarantine, distancing and traffic hereafter, respectively).

The implementations of mandatory mask, quarantine, distancing and traffic were associated with changes (95% confidence interval, CI) of -15.14% (from -21.79% to -7.93%), -11.40% (from -13.66% to -9.07%), -42.94% (from -44.24% to -41.60%) and -9.26% (from -11.46% to -7.01%) in the Rt of COVID-19 when compared with those without the implementation of the corresponding measures. Distancing and the simultaneous implementation of two or more types of NPIs seemed to be associated with a greater decrease in the Rt of COVID-19.

Our study indicates that NPIs can significantly contain the COVID-19 pandemic. Distancing and the simultaneous implementation of two or more NPIs should be the strategic priorities for containing COVID-19.

Our study indicates that NPIs can significantly contain the COVID-19 pandemic. Distancing and the simultaneous implementation of two or more NPIs should be the strategic priorities for containing COVID-19.

Nipah virus (NiV) infection, often fatal in humans, is primarily transmitted in Bangladesh through the consumption of date palm sap contaminated by Pteropus bats. Person-to-person transmission is also common and increases the concern of large outbreaks. This study aimed to characterize the molecular epidemiology, phylogenetic relationship, and the evolution of the nucleocapsid gene (N gene) of NiV.

We conducted molecular detection, genetic characterization, and Bayesian time-scale evolution analyses of NiV using pooled Pteropid bat roost urine samples from an outbreak area in 2012 and archived RNA samples from NiV case patients identified during 2012-2018 in Bangladesh.

NiV-RNA was detected in 19% (38/456) of bat roost urine samples and among them; nine N gene sequences were recovered. We also retrieved sequences from 53% (21 out of 39) of archived RNA samples from patients. Phylogenetic analysis revealed that all Bangladeshi strains belonged to NiV-BD genotype and had an evolutionary rate of 4.64 × 10

substitutions/site/year. The analyses suggested that the strains of NiV-BD genotype diverged during 1995 and formed two sublineages.

This analysis provides further evidence that the NiV strains of the Malaysian and Bangladesh genotypes diverged recently and continue to evolve. More extensive surveillance of NiV in bats and human will be helpful to explore strain diversity and virulence potential to infect humans through direct or person-to-person virus transmission.

This analysis provides further evidence that the NiV strains of the Malaysian and Bangladesh genotypes diverged recently and continue to evolve. More extensive surveillance of NiV in bats and human will be helpful to explore strain diversity and virulence potential to infect humans through direct or person-to-person virus transmission.

The increasing incidence of fluoroquinolones (FQ) resistance may lower its efficacy in preventing UTI following transrectal ultrasound-guided prostate biopsy (TRUS-PB). We assessed the efficacy and safety of FQ and fosfomycin-trometamol (FT) in patients undergoing TRUS-PB.

A prospective observational study was conducted between April 2017 and June 2019 and enrolled men undergoing TRUS-PB and receiving a single-dose of FQ (FQ-arm) or FT (FT-arm) for UTI prophylaxis per physician’s choice. The primary efficacy endpoint was self-reported TRUS-PB UTI. We assessed baseline factors associated with UTI with logistic regression.

A total of 222 men were enrolled, 141/222 (64%) received FQ, and 81/222 (36%) FT. The median age was 67.6 years [IQR, 61.4-72.1] and the Charlson score was 3 [IQR, 3-5]. The overall incidence of self-reported TRUS-PB UTI was 12% (24/197, (95%CI, 8%-17%)) 15% (17/116, (95% CI, 10%-17%)) in FQ-arm, versus 9% (7/81, 95% CI (5%-13%)) in FT-arm (RR = 0.55 (95% CI, 0.22-1.40), p-value = 0.209). No baseline characteristic was significantly associated with TRUS-PB UTI. Safety was similar between the arms the rate of the reported adverse event was 31% (36/116, (95% CI, 25%-37%) in the FQ-arm versus 36% (28/81, (95% CI, 28%-41%)) in the FT-arm (RR = 1.17 (95% CI, 0.64-2.15), p = 0.602).

TRUS-PB UTI prophylaxis with FT and FQ has similar efficacy and safety. A randomized comparison of these two antibiotics is warranted.

TRUS-PB UTI prophylaxis with FT and FQ has similar efficacy and safety. A randomized comparison of these two antibiotics is warranted.

This study was performed to investigate whether an intravenous (IV) strategy based on new-generation midline catheters is an efficacious alternative to a conventional IV strategy consisting of peripheral venous catheters and central venous catheters, for patients needing IV therapy exceeding 5 days.

This was a prospective, randomized, controlled study. Patients requiring more than 5 days of IV treatment were randomized to either a midline catheter-based IV strategy or a conventional strategy. The primary endpoint was the composite of the insertion of a central venous catheter (CVC) or the need for four or more peripheral venous catheter (PVC) insertions. The secondary outcomes included catheter dwell times and reasons for premature removal.

One hundred and twenty patients were included. The fraction of patients receiving four or more PVCs or having a CVC inserted was 12/58 (21%) in the midline group versus 38/58 (66%) in the conventional group (p <  0.001); the number needed to treat was 2.2. The median overall catheter dwell time was 7 days (range 0-60 days) in the midline group and 4 days (range 0-84 days) in the conventional group (p =  0.002).

In patients requiring more than 5 days of IV therapy, a midline catheter strategy reduced the need for insertion of a CVC or four or more PVCs.

In patients requiring more than 5 days of IV therapy, a midline catheter strategy reduced the need for insertion of a CVC or four or more PVCs.In a single day, six of 150 (4%) asymptomatic visitors were diagnosed with COVID-19 at a hospital with a universal masking policy. Two inpatients (contacts) subsequently developed symptoms. More rigorous protective measures during visitation periods may need to be included in infection control practices to reduce nosocomial transmissions.Long noncoding RNAs act essential regulators in cervical cancer progression. Our study aimed to investigate the underlying function and molecular mechanisms of LINC00657 in cervical cancer. QRT-PCR results indicated that LINC00657 was significantly decreased in cervical cancer. Gain-and loss-of-function experiments were performed in SiHa and HeLa. Functional assays demonstrated that LINC00657 inhibited cervical cancer cell growth, migration and invasion. Moreover, miR-20a-5p was confirmed as a target of LINC00657. Furthermore, miR-20a-5p promoted the development of cervical cancer via targeting RUNX3. DR5 acts as a vital promoter in activating NK cells and is a downstream target of RUNX3. We found that LINC00657 overexpression promoted the cytotoxic activity of NK cells via regulating RUNX3/DR5 axis. Therefore, LINC00657 suppressed cervical cancer progression via inducing miR-20a-5p/RUNX3/DR5 mediated NK cell tolerance. In conclusion, LINC00657 was identified as a novel tumor-suppressor in cervical cancer and could function as a potential therapeutic target for clinical treatment.Colorectal cancer (CRC) is the leading cause of cancer death worldwide. CRC therapeutic strategies include surgical resection, chemotherapy, radiotherapy, and other approaches. However, patients with metastatic CRC have worse prognoses. In recent years, T-cell-based immunotherapy has elicited promising responses in B-cell malignancies, melanoma, and lung cancer, but most CRC patients are resistant to immunotherapy, chemotherapy, and targeted therapy. Immune checkpoint inhibitors have shown encouraging results in non-small cell lung cancer, melanoma, and other cancers, but immune checkpoint blockade is only effective for CRC subset with microsatellite instability. Other immunotherapies, such as cytokines, cancer vaccines, small molecules, oncolytic viruses, and chimeric antigen-receptor therapy, are currently in use against CRC. This review analyzes recent developments in immunotherapy for CRC treatment as well as the challenges in overcoming resistance.Hepatocellular carcinoma (HCC) is a prevalent human malignancy with high morbidity worldwide. Hepatocarcinogenesis is a complex multistep process, and its underlying molecular mechanisms remain largely unknown. Recently, long non-coding RNAs (lncRNAs), a class of newly discovered molecules, have been revealed as essential regulators in the development of HCC. HCC-associated lncRNAs affect multiple malignant phenotypes by modulating gene expression or protein activity. Moreover, the dysregulation of lncRNAs in the liver is also associated with diseases predisposing to HCC, such as chronic viral infection, nonalcoholic steatohepatitis, and liver fibrosis/cirrhosis. A deeper understanding of the lncRNA regulatory network in the multistep processes of HCC development will provide new insights into the diagnosis and treatment of HCC. In this review, we introduce the biogenesis and function of lncRNAs and summarize recent knowledge on how lncRNAs regulate the malignant hallmarks of HCC, such as uncontrolled cell proliferation, resistance to cell death, metabolic reprogramming, immune escape, angiogenesis, and metastasis. We also review emerging insights into the role of lncRNAs in HCC-associated liver diseases. Finally, we discuss the potential applications of lncRNAs as early diagnostic biomarkers and therapeutic targets.Cancer immunotherapy holds tremendous promise as a strategy for eradicating solid tumors, and its therapeutic effect highly relies on sufficient CD8+ T cells infiltration. Here, we demonstrate that ultrasound stimulated microbubble cavitation (USMC) promotes tumor perfusion, thereby increasing CD8+ T cells infiltration and anti-PD-L1 antibody delivery, then further enhancing the PD-L1 blockade of MC38 colon cancer in mice. Firstly, we optimized the mechanic index (MI) of ultrasound, and found that USMC with MI of 0.4 (equal to peak negative pressure of 0.8 MPa) significantly improved the peak intensity and area under curve of tumor contrast-enhanced ultrasound. Also, flow cytometry exhibited higher percentage of infiltrating CD8+ T cells in the USMC (MI = 0.4)-treated tumors than that of the control. We further explored the combination therapy of optimized USMC with anti-PD-L1 antibody. The combination therapy enhanced tumor perfusion and even led to the tumor vascular normalization. More importantly, flow cytometry showed that the combination not only increased the percentage and absolute number of tumor infiltrating CD8+ T cells, but also promoted the expression of Ki67 as well as the secretions of IFN γ and granzyme B, therefore, the combination therapy achieved greater tumor growth inhibition and longer survival than that of the monotherapies. These suggest that USMC is a promising therapeutic modality for combining immune checkpoint blockade against solid tumors.Colorectal cancer (CRC) is one of the most common malignancies worldwide and is associated with poor prognosis and high mortality. Despite advances in treatment with chemotherapy, CRC remains a major cause of drug resistance-related cancer deaths. One of the main reasons for such resistance is dysregulation of Mcl-1 expression. In this study, we identified LZT-106 as a novel kinase inhibitor that was able to bind to CDK9 with potent inhibitory ability, and indirectly regulate the expression of Mcl-1. However, different regulatory profiles were observed between LZT-106 and the well-studied CDK9 inhibitor flavopiridol with regards to Mcl-1 inhibition. Via Western blotting, real-time PCR and immunoprecipitation, we confirmed that LZT-106 was also able to target GSK-3β signaling and facilitate the degradation of Mcl-1. And LZT-106 was shown to synergize with ABT-199 to induce apoptosis even in the RKO cell line that overexpressed Mcl-1. Finally, LZT-106 significantly inhibited tumor growth in a xenograft mouse model with minimal toxicity. Overall, our findings suggest that LZT-106 is a promising candidate drug for the treatment of patients with CRC.Despite recent advances in cancer immunotherapy, the efficacy of colorectal cancer (CRC) immunotherapy regimens is limited. This study evaluated the combined effect of an anti-PD-1 antibody and a platelet-derived growth factor receptor inhibitor (imatinib) on CRC progression using an orthotopic transplanted mouse model that reproduced the three histological phenotypes of CRC (inflamed-, excluded-, and desert-type). The frequency of each of these phenotypes in 196 human CRC tissue samples was also evaluated. Excluded-type CRC had the highest frequency in human tissue samples. In the mouse model, imatinib suppressed stromal reaction and increased sensitivity to anti-PD-1 treatment in excluded-type CRC. Antitumor effect was observed in mice with excluded-type tumors only after concomitant administration of anti-PD-1 antibody and imatinib. Immunohistological analysis revealed a reduction in stromal volume and an increase in the number of CD8-positive T cells in the tumor nest following combination therapy. RNA sequencing revealed significant activation of immune-related pathways and suppression of stromal-related pathways in transplanted tumors treated with combination therapy compared with tumors treated with anti-PD-1 antibody monotherapy. This combination therapy may prove effective for CRC cases that are unresponsive to anti-PD-1 antibody monotherapy.We mathematically model the uptake of phosphorus by a soil community consisting of a plant and two bacterial groups copiotrophs and oligotrophs. Four equilibrium states emerge, one for each of the species monopolising the resource and dominating the community and one with coexistence of all species. We show that the dynamics are controlled by the ratio of chemical adsorption to bacterial death permitting either oscillatory states or quasi-steady uptake. We show how a steady state can emerge which has soil and plant nutrient content unresponsive to increased fertilization. However, the additional fertilization supports the copiotrophs leading to community reassembly. Our results demonstrate the importance of time-series measurements in nutrient uptake experiments.The interplay between the dengue virus and the innate immune response is not fully understood. Here, we use deterministic and stochastic approaches to investigate the dynamics of the interaction between the interferon-mediated innate immune response and the dengue virus. We aim to develop a quantitative representation of these complex interactions and predict their system-level dynamics. Our simulation results predict bimodal and bistable dynamics that represent viral clearance and virus-producing states. Under normal conditions, we determined that the viral infection outcome is modulated by the innate immune response and the positive-strand viral RNA concentration. Additionally, we tested system perturbations by external stimulation, such as the direct induction of the innate immune response by interferon, and a therapeutic intervention consisting of the direct application of mRNA encoding for several interferon-stimulated genes. Our simulation results suggest optimal regimes for the studied intervention approaches.As protection against infectious disease, immunity is conferred by one of two main defense mechanisms, namely (i) resistance generated by previous infection (known as natural immunity) or (ii) by being vaccinated (known as artificial immunity). To analyze, a modified SVIRS epidemic model is established that integrates the effects of the durability of protection and imperfectness in the framework of the human decision-making process as a vaccination game. It is supposed that immunized people become susceptible again when their immunity expires, which depends on the duration of immunity. The current theory for most voluntary vaccination games assumes that seasonal diseases such as influenza are controlled by a temporal vaccine, the immunity of which lasts for only one season. Also, a novel perspective is established involving an individual’s immune system combined with self-interest to take the vaccine and natural immunity obtained from infection by coupling a disease-spreading model with an evolutionary game approach over a long period. Numerical simulations show that the longer attenuation helps significantly to control the spread of disease. Also discovered is the entire mechanism of active and passive immunities, in the sense of how they coexist with natural and artificial immunity. Thus, the prospect of finding the optimal strategy for eradicating a disease could help in the design of effective vaccination campaigns and policies.

Tuberculosis (TB) remains a major public health problem. SH3RF1 and SH3RF2 are candidate genes with multiple single-nucleotide polymorphisms (SNPs) that have the potential to participate in Mycobacterium infection via activation of the JNK signaling pathway. In this case-control study, we aimed to investigate the association of five SH3RF1 and SH3RF2 SNPs with susceptibility to TB in the Western Chinese population.

A total of 900TB patients and 1534 healthy control subjects were enrolled in our study. All samples used were obtained from the Bio-Bank of resources of Tuberculosis Research in the Department of Laboratory Medicine, West China Hospital, Sichuan University, China. SNP genotyping was conducted using a commercial custom-by-design 2×48-Plex SNPscan Kit.

The rs758037 variant of the SH3RF2 gene was found to be associated with decreased TB risk based on allelic effects (p=0.00001, OR=0.731, 95% CI=0.641-0.833) and three genetic models (padd=0.00001, pdom=0.0003, prec=0.0007) after the data were controlled for age and gender and underwent Bonferroni correction. The rs4913057 variant of the SH3RF2 gene was found to be associated with increased TB risk in a dominant model (p=0.021, OR 1.260, 95% CI 1.065-1.490). No significant association was observed between other SNPs and TB risk.

These findings indicate that polymorphisms in the SH3RF2 gene are involved in susceptibility to TB in the Western Chinese population.

These findings indicate that polymorphisms in the SH3RF2 gene are involved in susceptibility to TB in the Western Chinese population.

Malaria is a global public health burden due to large number of annual infections and casualties caused by its hematological complications. The bark of Annickia polycarpa is an effective anti-malaria agent in African traditional medicine. However, there is no standardization parameters for A. polycarpa. The anti-malaria properties of its leaf are also not known.

To standardize the ethanol leaf extract of A. polycarpa (APLE) and investigate its anti-malaria properties and the effect of its treatment on hematological indices in Plasmodium berghei infected mice in the Rane’s test.

Malaria was induced by inoculating female ICR mice with 1.0×10

P. berghei-infected RBCs in 0.2mL (i.p.) of blood. Treatment was commenced 3 days later with APLE 50, 200, 400mg/kg p.o., Quinine 30mg/kg i.m. (Standard drug) or sterile water (Negative control) once daily per group for 4 successive days. Anti-malarial activity and gross malaria indices such as hyperparasitemia, mean change in body weight and mean survival time (MST)stituents especially, aporphine and oxoaporphine alkaloids.

These results indicate that APLE possessed significant anti-malaria, immunomodulatory, erythropoietic and hematinic actions against malaria infection. APLE also has the ability to revoke deleterious physiological alteration produced by malaria and hence, promote clinical cure. These properties of APLE are due to its constituents especially, aporphine and oxoaporphine alkaloids.

Prasachandaeng (PSD) remedy is a famous antipyretic drug for adults and children in Thai traditional medicine used and is described in Thailand’s National List of Essential Medicine. Relationship between the taste of this herbal medicine, ethnopharmacological used and its pharmacological properties was reviewed.

Since there has been no scientific report on the antipyretic activity of PSD, aim of this study was to investigate the efficacy related antipyretic drug of the remedy and its 12 herbal ingredients. It involved quality evaluation of raw materials, extraction of PSD and its ingredients, in vitro evaluation of their inhibitory activities on fever mediators, i.e. NO and PGE

production in murine macrophage (RAW 264.7) cell line stimulated by lipopolysaccharide, and its stability study of the 95% ethanolic extract of PSD remedy.

PSD remedy was extracted by maceration with 50% and 95% ethanol (PSD50 and PSD95), by decoction with distilled water (PSDW), and hydrolysis of PSDW with 0.1N HCl (PSDH). The of PSD remedy and some of its ingredients, were better than ACP in reducing fever. PSD should be further studied using in vivo models and clinical trials to support its use as an antipyretic drug in Thai traditional medicine.

The results suggested that the 95% ethanolic extracts of PSD remedy and some of its ingredients, were better than ACP in reducing fever. PSD should be further studied using in vivo models and clinical trials to support its use as an antipyretic drug in Thai traditional medicine.

Callicarpa japonica Thunb., as an herbal medicine has been used for the treatment of inflammatory diseases in China and Korea.

Ultra performance liquid chromatography-photodiode array-quadrupole time-of-flight mass spectrometer (UPLC-PDA-QTof MS) was used to detect the major phenylethanoid glycosides in the C. japonica extract. BALB/c mice were intraperitoneally sensitized by ovalbumin (OVA) (on days 0 and 7) and challenged by OVA aerosol (on days 11-13) to induce airway inflammatory response. The mice were also administered with C. japonica Thunb. (CJT) (20 and 40mg/kg Per oral) on days 9-13. CJT pretreatment was conducted in lipopolysaccharide (LPS)-stimulated RAW264.7 or phorbol 12-myristate 13-acetate (PMA)-stimulated A549cells.

CJT administration significantly reduced the secretion of Th2 cytokines, TNF-α, IL-6, immunoglobulin E (IgE) and histamine, and the recruitment of eosinophils in an OVA-exposed mice. In histological analyses, the amelioration of inflammatory cell influx and mucus secretion were observed with CJT. The OVA-induced airway hyperresponsiveness (AHR), iNOS expression and NF-κB activation were effectively suppressed by CJT administration. In addition, CJT led to the upregulation of HO-1 expression. In an in vitro study, CJT pretreatment suppressed the LPS-induced TNF-α secretion in RAW264.7cells and attenuated the PMA-induced IL-6, IL-8 and MCP-1 secretion in A549cells. These effects were accompanied by downregulated NF-κB phosphorylation and by upregulated HO-1 expression.

These results suggested that CJT has protective activity against OVA-induced airway inflammation via downregulation of NF-κB activation and upregulation of HO-1, suggesting that CJT has preventive potential for the development of allergic asthma.

These results suggested that CJT has protective activity against OVA-induced airway inflammation via downregulation of NF-κB activation and upregulation of HO-1, suggesting that CJT has preventive potential for the development of allergic asthma.

Hypericum perforatum L. has been widely used as a natural antidepressant. However, it is unknown whether it is effective in treating infection-induced neuropsychiatric disorders.

In order to evaluate the effectiveness of H. perforatum against infection with neurotropic parasite Toxoplasma gondii, which has been linked to neuropsychiatric disorders, this study investigated the anti-Toxoplasma activity using in vitro models.

Dried alcoholic extracts were prepared from three Hypericum species H. perforatum, H. erectum, and H. ascyron. H. perforatum extract was further separated by solvent-partitioning. Hyperforin and hypericin levels in the extracts and fractions were analyzed by high resolution LC-MS. Anti-Toxoplasma activities were tested in vitro, using cell lines (Vero and Raw264), murine primary mixed glia, and primary neuron-glia. Toxoplasma proliferation and stage conversion were analyzed by qPCR. Infection-induced damages to the host cells were analyzed by Sulforhodamine B cytotoxicity assay (Vero) glial cells against infection-induced damages. Further study is warranted to establish in vivo efficacy.

To investigate the effect of processed Aconiti tuber (PAT) administered during or after the time of conditioned place preference (CPP) training on the extinction and reinstatement of morphine-priming CPP in rats. The dynorphin level in rats’ nucleus accumbens (NAc) is detected as a target of the Dynorphin/Kappa Opioid Receptor (KOR) system for the possible mechanism.

Eight groups of rats were subcutaneously (s.c.) injected with morphine (10mg/kg) (on days 2,4,6,8) or saline (1ml/kg) (on days 3,5,7,9) alternately for 8 days. Five groups, including groups (Mor+Water, Mor+PAT (1.0/3.0g/kg) (S) and Sal+PAT(1.0/3.0g/kg)), were orally given distilled water or PAT 1.0 or 3.0g/kg daily on days 1-8 during CPP training while other three groups, including groups (Sal+Water and Mor+PAT (1.0/3.0g/kg)(P), were given distilled water or PAT daily from day 10 until CPP was extinct. Morphine 1mg/kg (s.c.) was used to reinstate the extinct CPP and the CPP scores were recorded. The dynorphin concentration in nucleus accumbend during or after CPP training did not affect morphine-priming reinstatement of morphine induced CPP. 3) Dynorphin/KOR system might be a target to regulate morphine-induced CPP extinction but not reinstatement.Since 2004, tattooing products have been recognized as such by French law. A tattooist must declare his activity to the ARS (French regional health agency). A tattooist is legally compelled to undergo training sessions on occupational safety and hygienic requirements and to deliver his certificate to the ARS. A tattooist commits himself to preliminarily informing his customers of the risks they possibly incur and of the precautions to be taken. He also commits himself to complying with general rules and regulations and with good practices of hygiene and safety; lastly, he signs an agreement pertaining to waste disposal (DASRI). Contrary to pharmaceutical products, tattooing products are not subject to authorization prior to their commercialization. Any adverse effect after tattooing must be the subject of a declaration addressed to the ANSM (French health products safety agency) by the customer, the tattooist or a health professional.The death of retinal ganglion cells (RGCs) during acute glaucoma causes progressive degeneration of the retinal nerve and irreversible blindness. Astaxanthin (AST) is a type of xanthophyll carotenoids and naturally synthesized by multiple halobios. It has been reported to protect the retina from acute glaucoma due to its anti-oxidative and anti-neuroinflammatory properties. However, the mechanism underlying this process remains unclear. We designed a mouse model with acute glaucoma and AST was administered by oral gavage. Hematoxylin and eosin staining was utilized to evaluate the condition of retina and the number of ganglion cells was counted. QRT-PCR was performed to evaluate the mRNA levels of Bax and Bcl2 while Western blot assay was used to determine the protein levels of Bax, Bcl2, Nrf2 and HO-1. AST protected the retinal integrity of mice with acute glaucoma. The apoptosis of RGCs induced by ischemia and reperfusion was repressed by AST. The protective functions of AST on the retinal and ganglion cells decreased with the knock-down of Nrf2. AST promoted the activation of Nrf2 and Ho-1 in the RGCs of the model mice. AST protected the RGCs from apoptosis during acute glaucoma and alleviated the severe retinopathy symptoms through the Nrf2/Ho-1 pathway.Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia – an animal model of migraine – and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of URB937 in animal models of acute and chronic migraine. We evaluated the effects of URB937 in two rat models that capture aspects of acute and chronic migraine, and are based on single or repeated administration of the vasodilating drug, nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured mRNA levels of neuropeptides and pro-infin neuropeptide and cytokine transcription. The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways.Antibodies possess multiple biologically relevant features that have been engineered into new therapeutic formats. Two examples include the adaptable specificity of their variable (Fv) region and the extension of plasma circulation times through their crystallizable (Fc) region. Since the invention of the single chain variable fragment (scFv) in 1988, antibody variable regions have been re-engineered into a wide variety of multifunctional nanostructures. Among these strategies, peptide-mediated self-assembly of variable regions through heterologous expression has become a powerful method to produce homogenous, functional biomaterials. This manuscript reviews recent reports of antibody fragments assembled through fusion with peptides and proteins, including elastin-like polypeptides (ELPs), collagen-like polypeptides (CLPs), albumin, transmembrane proteins, leucine zippers, silk protein, and viruses. This review further discusses the current clinical status of engineered antibody fragments and challenges to overcome.

To compare the correlations among the R1ρ, R2, and R2* relaxation rates with liver iron concentration (LIC) in the assessment of rat liver iron content and explore the application potential of R1ρ in assessing liver iron content.

Iron dextran (dosage of 0, 25, 50, 100, and 200mg/kg body weight) was injected into 35 male rats to increase the amount of iron storage in the liver. After one week, all rats were euthanized with isoflurane. A portion of the largest hepatic lobe was extracted to quantify the LIC by inductively coupled plasma, and the remaining liver tissue was stored in 4% buffered paraformaldehyde for 24h before MRI. Spin-lock preparation with a RARE (rapid acquisition with relaxation enhancement) readout (9 different spin-lock times and 7 different spin-lock frequencies (FSLs)) and multi-echo UTE (ultrashort TE) pulses were developed to quantify R1ρ and R2 * on a Bruker 11.7T MR system. For comparisons with R1ρ and R2*, R2 was acquired using the CPMG sequence.

Mean R1ρ values displayed disperther confirming previous findings. The results demonstrated that R1ρ at high FSL might serve as a complementary imaging biomarker for liver iron overload quantification.Palliative care research raises a host of ethical concerns. Obtaining informed consent from seriously ill patients and their families is often perceived as an additional burden. Alternative approaches to traditional written informed consent reflects the changing nature of modern trial design, embracing real-world effectiveness and pragmatic clinical trials with those who are seriously ill. Ethicists, clinical investigators, and regulatory bodies have acknowledged the challenges to rigorous, meaningful, and generalizable research across diverse patient populations in real-world settings. The purpose of this paper is to describe how these clinical trial designs have driven innovation in methods for achieving informed consent, with a focus on palliative care research. In this paper, we describe, and provide examples of consent waivers and three types of alternative approaches to consent, including broadcast notification, and integrated and targeted consent. We also present our experiences in an ongoing palliative care clinical trial, specifically using broadcast notification. Working with participants and regulatory oversight organizations, investigators can address the limits of traditional written informed consent and adopt innovative consent models to advance the science of palliative care. Research is now needed to determine the impact of these differing consent models on clinical trial recruitment, enrollment, and retention, as well as participants’ informed understanding of their research participation using such models.The induction of vomiting by activation of mechanisms protecting the body against ingested toxins is not confined to natural products but can occur in response to manmade medicinal and non-medicinal products such as liquid cleaning products where it is a commonly reported adverse effect of accidental ingestion. The present study examined the utility of an historic database (>30 years old) reporting emetic effects of 98 orally administered liquid cleaning formulations studied in vivo (canine model) to objectively identify the main pro-emetic constituents and to derive a predictive model. Data were analysed by categorizing the formulation constituents into 10 main groups followed by using multivariate correlation, partial least squares and recursive partitioning analysis. Using the ED50 we objectively identified high ionic strength, non-ionic surfactants (alcohol ethoxylate) and alkaline pH as the main pro-emetic factors. Additionally, a mathematical model was developed which allows prediction of the ED50 based on formulation. The limitations of the use of historic data and the model are discussed. The results have practical applications in new product formulation and safety but additionally the principles underpinning this in silico study have wider applicability in demonstrating the potential utility of such archival data in current research contributing to animal replacement.Deoxynivalenol (DON), a trichothecene mycotoxin, has attracted global attention due to its prevalence and substantial effects on animal and human health. DON induces the upregulation of intracellular reactive oxygen species (ROS) by disrupting the normal mitochondrial functionality, which causes oxidative stress, cell apoptosis, and even severe disorders. The aim of present work is to develop a simple, convenient, and in situ method for monitoring ROS and evaluating DON-mediated oxidative stress. Herein, polyethylene glycol-modified CdSe@ZnS quantum dots (QDs) were employed as simple and convenient nanoprobe for ROS imaging and oxidative stress evaluating induced by DON in living cells. The results demonstrated 5 ppm QDs nanoprobe can be easily loaded into cells via endocytosis without readily observable oxidative effects. Once in presence of DON, the augmented ROS directly oxidize the QDs nanoprobe, which leads to the destruction of the QDs structure and quenched fluorescence. According to the weakened fluorescence intensity (FI), the oxidative damage mediated by DON can be rapidly monitored and found that the oxidative stress was the most severe when the DON concentration exceeded 10 ppm. The developed QDs nanoprobe is also suitable for assessing other mycotoxins and chemicals. We hope it will be beneficial for the early screening of toxic and harmful substances in in vitro toxicology.The dramatic rise in the global occurrence of obesity and associated diseases calls for new strategies to promote weight loss. However, while the beneficial effects of weight loss are well known, rapid loss of fat mass can also lead to the endogenous release of liposoluble molecules with potential harmful effects, such as persistent organic pollutants (POP). The aim of this study was to evaluate the impact of a polyphenol-rich cranberry extract (CE) on POP release and their potential deleterious effects during weight loss of obese mice. C57BL/6 J mice were fed an obesogenic diet with or without a mixture of POP for 12 weeks and then changed to a low-fat diet to induce weight loss and endogenous POP release. The POP-exposed mice were then separated in two groups during weight loss, receiving either CE or the vehicle. Unexpectedly, despite the higher fat loss in the CE-treated group, the circulating levels of POP were not enhanced in these mice. Moreover, glucose homeostasis was further improved during CE-induced weight loss, as revealed by lower fasting glycemia and improved glucose tolerance as compared to vehicle-treated mice. Interestingly, the CE extract also induced changes in the gut microbiota after weight loss in POP-exposed mice, including blooming of Parvibacter, a member of the Coriobacteriaceae family which has been predicted to play a role in xenobiotic metabolism. Our data thus suggests that the gut microbiota can be targeted by polyphenol-rich extracts to protect from increased POP exposure and their detrimental metabolic effects during rapid weight loss.NhaA antiporters are secondary integral membrane protein critical for maintaining the Na+/H+ cell homeostasis, as a result, they regulate fundamental processes like cell volume and intracellular pH. Exploration of the structural and functional properties can assist to make them effective human drug targets and mechanisms of salt-resistance in plants. NhaA proteins are integrated into cytoplasmic and intracellular membranes, transport 2H+/Na + across the membrane by the canonical alternating access mechanism. There are mutagenesis studies have done on Ec-NhaA predicting residues crucial for function and structure. The unique NhaA structural fold is formed in the middle of the membrane by two transmembrane segments (TMs), TM IV and XI which cross each other creating a delicate electrostatically balanced environment for the binding of Na+/H+. Previously, Asp164, Asp163 and Asp133 residues have been proposed as crucial for Na+/Li + binding on the based on crystal structure and mutation-based studies. However, the pathway and the binding sites for the two protons are still elusive and debatable. This review will provide comprehensive details on various mutations constructed in Ec-NhaA by different research groups using site-directed or random mutagenesis techniques. The selected residues for mutations are located on the sites which are more suspected to have a crucial role in function and structure on NhaA. This information on the single platform would accelerate further studies on the structure-function relationship on NhaA as well as will facilitate to predict the role of Na+/H+ antiporters in human diseases.The study examined the influence of sex on the alterations occurring with ageing in rat lymph node (LN) T cell compartment. In female and male rats the decrease in LN T cell counts was followed by a shift in CD4+/CD8+ T cell ratio towards CD8+ T cells, which was more prominent in males than in females. With ageing, in both major LN T cell subpopulations naïve (recent thymic emigrants and mature naïve cells) to memory/activated T cell ratio shifted to the side of memory/activated cells in female, and particularly in male rats. The frequency of regulatory CD25+Foxp3+ cells increased among LN CD4+/CD8+ T cells with ageing, reflecting, at least partly, an enhanced conversion of effector T cells into regulatory cells. This was also more prominent in male rats. The more prounounced increase in LN oxidative damage and the expression levels of proinflammatory cytokines in male rats with ageing, most likely contributed to the greater frequency of proinflammatory, replicatively senescent CD28- cells expressing CD11b (innate cell marker), among T cells of old male rats compared with age-matched females. The increase in LN oxidation/proinflammatory state with ageing was also consistent with the accumulation of exhausted PD-1high cells among T lymphocytes, particularly prominent among CD8+ T cells from male rats. Finally, by calculating a summary score for the key ageing-relevant parameters (an ageing index), a faster development of the deleterious changes in the T cell compartment occurring with ageing was confirmed in male rat LNs. Additionally, the study pointed to indices of LN T cell compartment ageing which correlate with those in peripheral blood.Aging is often associated with declines in language production. For example, compared to younger adults, older adults experience more tip-of-the-tongue (TOT) states, show decreased speed and accuracy in naming objects, and have more pauses and fillers in speech, all of which indicate age-related increases in retrieval difficulty. While prior work has suggested that retrieval difficulty may be phonologically based, it is unclear whether there are age-related differences in the organization of phonological information per se or whether age-related difficulties may arise from accessing that information. Here we used fMRI to investigate the neural and behavioral basis of phonological neighborhood denisty (PND) effects on picture naming across the lifespan (N=91, ages 20-75). Consistent with prior work, behavioral results revealed that higher PND led to faster picture naming times and higher accuracies overall, and that older adults were less accurate in their responses. Consistent with the behavioral analyses, fMRI analyses showed that increasing PND was associated with decreased activation in auditory and motor language regions, including bilateral superior temporal gyri and bilateral precentral gyri. Interestingly, although there were age-related increases in functional activation to picture naming, there were no age-related modulations of neural sensitivity to PND. Overall, these results suggest that having a large cohort of phonological neighbors facilitates language production, and although aging is associated with increases in language production difficulty, sensitivity to phonological features during language production is stable across the lifespan.Functional MRI signals can be heavily influenced by systemic physiological processes in addition to local neural activity. For example, widespread hemodynamic fluctuations across the brain have been found to correlate with natural, low-frequency variations in the depth and rate of breathing over time. Acquiring peripheral measures of respiration during fMRI scanning not only allows for modeling such effects in fMRI analysis, but also provides valuable information for interrogating brain-body physiology. However, physiological recordings are frequently unavailable or have insufficient quality. Here, we propose a computational technique for reconstructing continuous low-frequency respiration volume (RV) fluctuations from fMRI data alone. We evaluate the performance of this approach across different fMRI preprocessing strategies. Further, we demonstrate that the predicted RV signals can account for similar patterns of temporal variation in resting-state fMRI data compared to measured RV fluctuations. These findings indicate that fluctuations in respiration volume can be extracted from fMRI alone, in the common scenario of missing or corrupted respiration recordings. The results have implications for enriching a large volume of existing fMRI datasets through retrospective addition of respiratory variations information.Benign prostatic hyperplasia (BPH) is a progressive proliferative disease, the incidence of which is constantly increasing due to aging of population. In this research, a hexokinase-II enzyme inhibiting agent, lonidamine – the use of which is limited in BPH treatment due to high hepatic toxicity observed after three months of treatment – was selected as an active agent, based on its mechanism of action in treating BPH. The aim of this study was to evaluate in vivo therapeutic efficacy and hepatic toxicity of lipid-polymer hybrid nanoparticles of lonidamine in a rat BPH model created in rat prostates. After local injections of hybrid nanoparticles of lonidamine were administered to the rat prostates, hyperplasic structures of prostates were evaluated in terms of prostatic index values, immunohistochemical evaluations, and histopathological findings. Liver blood enzyme values were also determined to specify hepatic toxicity. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) reaction and histopathological methods to determine intravital degenerative destruction in liver. Through this study, lonidamine-loaded hybrid nanoparticles were found to reduce the hepatic toxicity and increase therapeutic efficiency of lonidamine. Therefore, lonidamine-entrapped hybrid nanoparticles may provide a promising, and very safe, drug delivery strategy in the treatment of BPH.Valproic acid (VPA) remarkably promotes the differentiation of adipose tissue-derived stem cells (ASCs) to mature neuronal cells through nitric oxide (NO) signaling due to up-regulated inducible NO synthase (iNOS) as early as within 3 days. Here, we investigated mechanisms of VPA-promoted neuronal differentiation of ASCs concerning the NO-citrulline cycle, the metabolic cycle producing NO. Cultured rat ASCs were differentiated to mature neuronal cells rich in dendrites and expressing a neuronal marker by treatments with VPA at 2 mM for 3 days and subsequently with the neuronal induction medium for 2 h. Inhibitor (α-methyl-d, l-aspartic acid, MDLA) of arginosuccinate synthase (ASS), a key enzyme of the NO-citrulline cycle, abolishes intracellular NO increase and VPA-promoted neuronal differentiation in ASCs. l-Arginine, the substrate of iNOS, restores the promotion effect of VPA, being against MDLA. Immunocytochemistry showed that ASS and iNOS were increased in ASCs expressing neurofilament medium polypeptide (NeFM), a neuronal marker, by VPA and NIM synergistically. Real-time RT-PCR analysis showed that mRNAs of Ass and arginosuccinate lyase (Asl) in the NO-citrulline cycle were increased by VPA. Chromatin immunoprecipitation assay indicated that Ass and Asl were up-regulated by VPA through the acetylation of their associated histone. From these results, it was considered that VPA up-regulated the whole NO-citrulline cycle, which enabled continuous NO production by iNOS in large amounts for potent iNOS-NO signaling to promote neuronal differentiation of ASCs. This may also indicate a mechanism enabling short-lived NO to function conveniently as a potent signaling molecule that can disappear quickly after its role.

Radiotherapy is the most important therapeutic measure against glioblastoma multiforme (GBM), which is regarded as the most common and highly lethal type of brain cancer. Nevertheless, most relapses originate in the close vicinity of the irradiated target volume. Genistein is a natural product that can suppress the invasive potential of cancer cells. In this study, DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-proficient and -deficient GBM cells were selected for in vitro and in vivo studies to investigate the inhibiting effects of genistein on radiation-induced invasion and migration and the corresponding mechanism.

GBM cell lines with or without genistein pre-treatment were irradiated with X-rays. Cell survival was determined using colony formation assay and the rate of cellular proliferation was analyzed with a real-time cell electronic sensing system. For in vitro study, invasion and migration abilities were evaluated via wound-healing and transwell assays, while protein expression was determined with western blotting.