Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response

Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4⁺ T cells in the lung. PA-specific CD4⁺ T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity.     

Novel HLA-A2-restricted human metapneumovirus epitopes reduce viral titers in mice and are recognized by human T cells

Human metapneumovirus (HMPV) is a major cause of morbidity and mortality from acute lower respiratory tract illness, with most individuals seropositive by age five. Despite the presence of neutralizing antibodies, secondary infections are common and can be severe in young, elderly, and immunocompromised persons. Preclinical vaccine studies for HMPV have suggested a need for a balanced antibody and T cell immune response to enhance protection and avoid lung immunopathology. We infected transgenic mice expressing human HLA-A*0201 with HMPV and used ELISPOT to screen overlapping and predicted epitope peptides. We identified six novel HLA-A2 restricted CD8⁺ T cell (T_CD8) epitopes, with M_39–47 (M39) immunodominant. Tetramer staining detected M39-specific T_CD8 in lungs and spleen of HMPV-immune mice. Immunization with adjuvant-formulated M39 peptide reduced lung virus titers upon challenge. Finally, we show that T_CD8 from HLA-A*0201 positive humans recognize M39 by IFNγ ELISPOT and tetramer staining. These results will facilitate HMPV vaccine development and human studies.     

AAV-CRISPR Gene Editing Is Negated by Pre-existing Immunity to Cas9

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幼儿不同跑步着地方式的生物力学特征

文题释义：跑：跑是双脚交替接触地面的周期性运动，但跑有一个双脚都离开地面的腾空期。幼儿在 1 岁多开始学习跑步，最初是走跑结合的移动方式，由于身体发育不完善，下肢力量弱，平衡能力差，容易摔倒；到 2.5岁，幼儿跑步的腾空阶段明显；到 6岁，早期跑步的特点基本消失。 着地方式：指的是人体在跑步着地阶段足部接触地面的方式，一般分为3种方式：分别为足跟着地(fore foot strike)，跟骨先接触地面；全足着地(mid foot strike)，全脚掌着地，即足跟与前足同时接触地面；前足着地(rear foot strike)：前足部首先接触地面。 背景：成年人跑步着地方式一直是国内外学者研究的重点，而幼儿跑步的着地方式也是不容忽视的内容。 目的：运用生物力学方法探究幼儿在跑步过程中，不同着地方式下的运动学和动力学指标的差异，为幼儿正确的跑步着地方式提供科学依据。 方法：在北京市海淀区某公立幼儿园中随机抽取幼儿74名，按年龄分为3岁组、4岁组、5岁组，采用BTS红外动作捕捉系统、Kistler三维测力台和VIXTA录像解析系统同步采集幼儿跑步过程中不同着地方式下的运动学、动力学数据；运用Anybody 5.2仿真建模软件计算下肢肌肉力量指标。试验前向受试者父母详细解释并签署知情同意书，试验方案符合北京师范大学的相关伦理要求。 结果与结论：①3岁组全足着地的比例最高，足跟着地的比例最低，5岁组全足着地的比例最低，足跟着地的比例最高；前足着地者的蹬伸时间大于足跟着地(P < 0.01)和全足着地(P < 0.05)；②着地时刻，踝屈曲角度足跟着地者大于前足着地(P < 0.01)和全足着地者(P < 0.05)，全足着地者大于前足着地(P < 0.05)；前足着地者髋内收-外展角度、最大髋内收-外展角、髋内-收外展的关节变化量及最大膝内收-外展角速度大于足跟着地(P < 0.01)和全足着地者(P < 0.05)；前足着地者的踝屈伸最小值大于足跟着地者(P < 0.05)，而最大髋内收-外展角速度小于足跟着地者(P < 0.05)；③足跟着地和全足着地者的腓骨短肌、腓骨长肌、第三腓骨肌的肌力大于前足着地者(P < 0.05)，前足着地者的股中间肌、股外侧肌下束、股外侧肌上束、股内侧肌下束、股内侧肌上束、股内侧肌中束肌力均大于足跟着地(P < 0.01)和全足着地者(P < 0.05)；④结果提示：在3-6岁阶段，幼儿多采用足跟或全足着地模式进行奔跑，以满足自己在跑步过程的稳定性，随着年龄的增长，逐渐出现前足着地方式的跑步模式；前足着地能够动用更多髋关节和膝关节额状面的运动来维持人体运动中的稳定，足跟着地和全足着地能够动用更多的小腿前侧和后侧的肌力，而前足着地动用更多的大腿前侧肌力。 ORCID: 0000-0002-8337-3931(赵盼超) 中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程     

阴道锥体训练联合生物反馈盆底肌治疗尿失禁老年人盆底肌康复研究现状

目的研究阴道锥体训练联合生物反馈盆底肌治疗尿失禁老年人的临床疗效及对盆底肌的影响。方法选取84例从2016年9月至2018年3月本院收治的尿失禁老年患者进行研究,以随机抽签法将其均分为联合组及对照组,每组42例。对照组予以常规盆底肌训练治疗,联合组则予以阴道锥体训练联合生物反馈盆底肌治疗。对比两组在临床疗效、治疗前后盆底肌力情况、治疗前后尿动力学参数指标水平以及生活质量变化情况等方面的差异。结果联合组与对照组在总有效率方面比较,前者高于后者(P<0.05)。治疗后联合组盆底肌力分级为Ⅳ级、Ⅴ级的人数占比相比对照组较高(P<0.05)。治疗后联合组与对照组在VLPP、PMUC水平方面比较,前者高于后者(P<0.05)。治疗后联合组与对照组I-QOL评分相比治疗前较高,且联合组相比对照组较高(P<0.05)。结论阴道锥体训练联合生物反馈盆底肌治疗老年尿失禁患者的疗效显著,有利于促进盆底肌力的恢复,且有效改善患者尿动力学参数,提高生活质量,具有较高的临床推广应用价值。     

Vibratory stimulus to the masseter muscle impairs the oral fine motor control during biting tasks

PurposeTo investigated the effect of vibratory stimulus on masseter muscles during oral fine motor biting tasks.MethodsSixteen healthy individuals (age: 24.5 ± 2.4 years) participated in experiment I during which the participants were asked to “hold and split” half a roasted peanut placed on a force transducer with their front teeth. The participant performed ten series with ten trials of the “hold and split” behavioral task while vibratory stimulus was applied on the masseter muscle every alternate series. Further, fourteen participants participated (age: 25.2 ± 4.8 years) in experiment II during which they performed a series each of the behavioral task at baseline, an adjusted baseline without and with vibration as well as with and without visual feedback. Hold and split forces along with the variability of hold force and duration and force rate during the split were measured.ResultsThe results of the study showed an increase in the magnitude of the hold force (P = 0.002), force rate during the split (P < 0.001) and a significant decrease in the duration of split (P < 0.001) due to the vibratory stimulus. However, there was no significant effect of the vibratory stimulus on the variability of hold forces (P = 0.879) or mean split force (P = 0.683) during the “hold and split” behavioral task. The results of experiment II also showed an increase in hold force due to the vibratory stimulus (P < 0.001).ConclusionsVibratory stimulus to the masseter muscles impairs the oral force control during a standardized biting task and provide further insight into the sensorimotor regulation of the masticatory system.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A

Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.

Myostatin (MSTN) is a secreted signaling molecule that normally acts to limit skeletal muscle growth (for review, see ref. 1). Mice lacking MSTN exhibit dramatic increases in muscle mass throughout the body, with individual muscles growing to about twice the normal size (2). MSTN appears to play two distinct roles in regulating muscle size, one to regulate the number of muscle fibers that are formed during development and a second to regulate the growth of those fibers postnatally. The sequence of MSTN has been highly conserved through evolution, with the mature MSTN peptide being identical in species as divergent as humans and turkeys (3). The function of MSTN has also been conserved, and targeted or naturally occurring mutations in MSTN have been shown to cause increased muscling in numerous species, including cattle (3–5), sheep (6), dogs (7), rabbits (8), rats (9), swine (10), goats (11), and humans (12). Numerous pharmaceutical and biotechnology companies have developed biologic agents capable of blocking MSTN activity, and these have been tested in clinical trials for a wide range of indications, including Duchenne and facioscapulohumeral muscular dystrophy, inclusion body myositis, muscle atrophy following falls and hip fracture surgery, age-related sarcopenia, Charcot–Marie–Tooth disease, and cachexia due to chronic obstructive pulmonary disease, end-stage kidney disease, and cancer.The finding that certain inhibitors of MSTN signaling can increase muscle mass even in Mstn^−/− mice revealed that the function of MSTN as a negative regulator of muscle mass is partially redundant with at least one other TGF-β family member (13, 14), and subsequent studies have identified activin A as one of these cooperating ligands (15, 16). MSTN and activin A share many key regulatory and signaling components. For example, the activities of both MSTN and activin A can be modulated extracellularly by naturally occurring inhibitory binding proteins, including follistatin (17, 18) and the follistatin-related protein, FSTL-3 or FLRG (19, 20). Moreover, MSTN and activin A also appear to share receptor components. Based on in vitro studies, MSTN is capable of binding initially to the activin type II receptors, ACVR2 and ACVR2B (also called ActRIIA and ActRIIB) (18) followed by engagement of the type I receptors, ALK4 and ALK5 (21). In previous studies, we presented genetic evidence supporting a role for both ACVR2 and ACVR2B in mediating MSTN signaling and regulating muscle mass in vivo. Specifically, we showed that mice expressing a truncated, dominant-negative form of ACVR2B in skeletal muscle (18) or carrying deletion mutations in Acvr2 and/or Acvr2b (13) have significantly increased muscle mass. One limitation of the latter study, however, was that we could not examine the consequence of complete loss of both receptors using the deletion alleles, as double homozygous mutants die early during embryogenesis (22). Moreover, the roles that the two type I receptors, ALK4 and ALK5, play in regulating MSTN and activin A signaling in muscle in vivo have not yet been documented using genetic approaches. Here, we present the results of studies in which we used floxed alleles for each of the type II and type I receptor genes in order to target these receptors alone and in combination in muscle fibers. We show that these receptors are functionally redundant and that signaling through each of these receptors contributes to the overall control of muscle mass.     

The effect of Benson’s relaxation response on sleep quality and anorexia in cancer patients undergoing chemotherapy: A randomized controlled trial

Background and objectivesPatients with cancer experience many side effects due to its nature and usual treatments. Sleep disorders and anorexia are the most commonly reported symptoms in cancer patients undergoing chemotherapy. The present study aimed to investigate the effect of Benson's Relaxation Response (BRR) on sleep quality and anorexia in cancer patients undergoing chemotherapy.Methodology and participantsIn the present clinical trial, a total of 84 patients were enrolled and randomly divided into two groups of experimental and control. Benson's relaxation response was administered to the experimental group twice a day over 5 consecutive days. Data was collected using St. Mary's Hospital Sleep Questionnaire (SMHSQ) and anorexia questionnaire with Visual Analog Scale (VAS).ResultsThe results of our study showed a significant improvement in the sleep quality in the experimental group at 24 (p = 0.02) and 48 (p = 0.001) hours after the intervention compared to the control group. Benson's relaxation response (BRR) also had a significant effect on the anorexia in the experimental group at 24 (7.5 ± 1.6) and 48 (6.9 ± 2.1) hours after the intervention compared to the control group. No side effects were reported during the study and follow-up period.ConclusionBenson's relaxation response as a complementary method may improve sleep quality and anorexia in cancer patients undergoing chemotherapy. Further studies with greater sample size and longer follow-up period are needed to confirm the current findings.