High frequency of CD4+ CXCR5+ TFH cells in patients with immune-active chronic hepatitis B

Background

T follicular helper (TFH) cells are a special subpopulation of T helper cells and can regulate humoral immune responses. This study examined whether the frequency of CD4⁺CXCR5⁺ TFH cells could be associated with active immunity in chronic hepatitis B (CHB) patients.

Methodology and Findings

The frequencies of peripheral blood CD4⁺CXCR5⁺ TFH cells, inducible T cell costimulator (ICOS), and/or programmed death 1 (PD-1) positive CD4⁺CXCR5⁺ TFH cells in immune-active (IA), immune-tolerant (IT) CHB, and healthy controls (HC) were characterized by flow cytometry analysis. The effect of adevofir dipivoxil treatment on the frequency of CD4⁺CXCR5⁺ TFH cells, the concentrations of serum IL-2, IFN-γ, TNF-α, IL-4, IL-6, IL-10, IL-21, ALT, AST, HBsAg, HBsAb, HBeAg, HBeAb and HBV loads in IA patients were determined. The potential association of the frequency of CD4⁺CXCR5⁺ TFH cells with clinical measures was analyzed. In addition, the frequency of splenic and liver CD4⁺CXCR5⁺ TFH cells in HBV-transgenic mice was examined. We found that the frequency of CD4⁺CXCR5⁺ TFH cells in IA patients was significantly higher than that of IT patients and HC, and the percentages of CD4⁺CXCR5⁺ TFH in IA patients were positively correlated with AST. Furthermore, the percentages of ICOS⁺, PD-1⁺, and ICOS⁺PD-1⁺ in CD4⁺CXCR5⁺ TFH cells in CHB patients were significantly higher than that of HC. Treatment with adefovir dipivoxil reduced the frequency of CD4⁺CXCR5⁺ TFH, PD-1⁺CD4⁺CXCR5⁺ TFH cells and the concentrations of HBsAg and HBeAg, but increased the concentrations of HBsAb, HBeAb, IL-2 and IFN-γ in IA patients. Moreover, the frequency of splenic and liver CD4⁺CXCR5⁺ TFH cells in HBV-transgenic mice was higher than that of wild-type controls.

Conclusions

These data indicate that CD4⁺CXCR5⁺ TFH cells may participate in the HBV-related immune responses and that high frequency of CD4⁺CXCR5⁺ TFH cells may be a biomarker for the evaluation of active immune stage of CHB patients.     

Discovery of a piperazine urea based compound as a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist

We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.     

Pyridazine-derived γ-secretase modulators

SAR of a novel series of pyridazine-derived γ-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain the levels of total Aβ. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat.     

利用数码相机和Photoshop软件非破坏性测定叶面积的简便方法

采用数码相机获取叶片的数字图像,用Photoshop图像处理软件计算叶面积,并与目前常用的剪纸法和叶面积仪测定法进行比较分析。结果表明,本方法和上述传统测定方法测定结果存在极显著线性相关;不同拍摄分辨率、单位叶面积存贮像素个数和拍摄角度对测定结果无显著影响。和其它方法相比,本方法具有准确、快速、成本低廉、适合非破坏性动态连续观测等优点,适用于植物生理生态学研究中叶面积的测定。     

Strain improvement of <Emphasis Type="Italic">Trichoderma viride</Emphasis> for increased cellulase production by irradiation of electron and <Superscript>12</Superscript>C<Superscript>6+</Superscript>-ion beams

Objectives

To improve cellulase production and activity, Trichoderma viride GSICC 62010 was subjected to mutation involving irradiation with an electron beam and subsequently with a ¹²C⁶⁺-ion beam.

Results

Mutant CIT 626 was the most promising cellulase producer after preliminary and secondary screening. Soluble protein production and cellulase activities were increased mutifold. The optimum temperature, pH and culture time for the maximum cellulase production of the selected mutant were 35 °C, pH 5 and 6 days. The highest cellulase production was obtained using wheat bran. The prepared cellulases from T. viride CIT 626 had twice the hydrolytic performance with sawdust (83 %) than that from the parent strain (42.5 %). Furthermore, molecular studies demonstrated that there were some key mutation sites suggesting that some amino acid changes in the protein caused by base mutations had led to the enhanced cellulase production and activity.

Conclusions

Mutagenesis with electron and ¹²C⁶⁺-ion beams could be developed as an effective tool for improvement of cellulase producing strains.

     

Effectiveness of steam inhalation and nasal irrigation for chronic or recurrent sinus symptoms in primary care: a pragmatic randomized controlled trial

Background:Systematic reviews support nasal saline irrigation for chronic or recurrent sinus symptoms, but trials have been small and few in primary care settings. Steam inhalation has also been proposed, but supporting evidence is lacking. We investigated whether brief pragmatic interventions to encourage use of nasal irrigation or steam inhalation would be effective in relieving sinus symptoms.Methods:We conducted a pragmatic randomized controlled trial involving adults (age 18–65 yr) from 72 primary care practices in the United Kingdom who had a history of chronic or recurrent sinusitis and reported a “moderate to severe” impact of sinus symptoms on their quality of life. Participants were recruited between Feb. 11, 2009, and June 30, 2014, and randomly assigned to 1 of 4 advice strategies: usual care, daily nasal saline irrigation supported by a demonstration video, daily steam inhalation, or combined treatment with both interventions. The primary outcome measure was the Rhinosinusitis Disability Index (RSDI). Patients were followed up at 3 and 6 months. We imputed missing data using multiple imputation methods.Results:Of the 961 patients who consented, 871 returned baseline questionnaires (210 usual care, 219 nasal irrigation, 232 steam inhalation and 210 combined treatment). A total of 671 (77.0%) of the 871 participants reported RSDI scores at 3 months. Patients’ RSDI scores improved more with nasal irrigation than without nasal irrigation by 3 months (crude change −7.42 v. −5.23; estimated adjusted mean difference between groups −2.51, 95% confidence interval −4.65 to −0.37). By 6 months, significantly more patients maintained a 10-point clinically important improvement in the RSDI score with nasal irrigation (44.1% v. 36.6%); fewer used over-the-counter medications (59.4% v. 68.0%) or intended to consult a doctor in future episodes. Steam inhalation reduced headache but had no significant effect on other outcomes. The proportion of participants who had adverse effects was the same in both intervention groups.Interpretation:Advice to use steam inhalation for chronic or recurrent sinus symptoms in primary care was not effective. A similar strategy to use nasal irrigation was less effective than prior evidence suggested, but it provided some symptomatic benefit. Trial registration: ISRCTN, no. 88204146.Rhinosinusitis probably affects more than 25 million Americans and 2.5 million Canadians.¹ Quality of life of patients with chronic or recurrent sinusitis has been reported to be similar to congestive heart disease and chronic pulmonary disease.² Antibiotics are prescribed for nearly all patients with sinusitis,³ but the evidence is modest⁴ and an international priority is to contain antibiotic resistance.⁵ Steam inhalation is widely advocated in rhinosinusitis, but a Cochrane review of steam for the “common cold” found equivocal evidence,⁶ and a recent primary care trial found no benefit and some harm (mild thermal injury) for pragmatic advice to inhale steam twice daily for a range of respiratory tract infections.⁷ The Cochrane review of nasal saline irrigation reported benefit.⁸ However, most of the trials were small, mainly from secondary care settings, and the review documented symptom data from only 129 participants, with high heterogeneity. Two small randomized controlled trials included some participants from primary care settings.^9,10 One of the studies compared a gravity-based nasal irrigation device with routine care among 76 participants mainly from primary care settings; it found that symptoms improved very little in the control group (by 1 point on the Rhinosinusitis Disability Index [RSDI] converted to a 100-point scale), as compared with a 14-point improvement in the irrigation group.⁹ The other (published since the Cochrane review) compared a positive-pressure squeeze bottle with saline nasal spray among 121 volunteers from various sources and found an 8.5-point improvement in the control group, as compared with a 15-point improvement in the irrigation group.¹⁰We conducted a large pragmatic randomized controlled trial of the effectiveness of brief advice to use nasal irrigation or steam inhalation in routine primary care for chronic or recurrent sinus symptoms.     

Isolation and characterization of cardiac progenitor cells from myocardial right atrial appendage tissue

Resident cardiac stem cells, known as “cardiogenic progenitor cells” (CPCs), are a heterogeneous population of immature cells residing in the myocardium and capable of self-renewal and differentiation into cardiomyocyte-like and vascular-like cells. CPCs are usually isolated by long enzymatic digestion of heart tissue and selection with stem cell markers. However, long exposure to enzymatic digestion and the small size of a myocardial sample significantly hinder acquiring a large number of viable cells. To avoid these problems, we developed a method based on CPC growth ex vivo and subsequent immunomagnetic selection.