Identification of a novel HLA-B allele, HLA-B*3713, in a Chinese individual

A novel human leukocyte antigen (HLA) class I allele, HLA-B*3713, has been identified in a Chinese individual. The HLA-B*3713 allele differs from the closest matching allele B*370101 by one nucleotide substitutions in exon 3 at nt 527(T-->A), resulting in an amino acid change from Val (GTG) to Glu (GAG) at codon 152.     

MRI signal intensity of anterior cruciate ligament graft after transtibial versus anteromedial portal technique (TRANSIG): A randomised controlled clinical trial

BackgroundTwo primary surgical femoral drilling techniques are used to reconstruct the anterior cruciate ligament (ACL): the transtibial (TT) technique and the anteromedial portal (AMP) technique. Currently there is no consensus on which surgical technique elicits the best clinical and functional outcomes. MRI-derived measures of the signal intensity (SI) of the ACL graft have been described as an independent predictor of graft properties. The purpose of this study was to assess MRI-derived SI measurements of the ACL graft one year after ACL reconstruction, in order to compare graft maturation of both AMP and TT ACL reconstruction techniques.MethodsThis randomised controlled trial included 33 patients admitted for primary unilateral ACL reconstruction. Primary outcome was MRI Signal intensity ratio (SIR) of the ACL graft one year after ACL reconstruction. Differences in MRI SIR were assessed on two MRI sequencies: sagittal Proton Density Turbo Spin Echo weighted images (PDTSE) and 3D T2 Gradient Echo (T2*) weighted images. Analysis of interobserver and intraobserver variability was conducted for the SIR measurements.ResultsNo difference in signal intensity of the graft was found between the TT and AMP techniques one year after ACL reconstruction (PDTSE p = 0.665, T2* p = 0.957). Both interobserver and intraobserver variability showed strong agreement (ICC 0.64–0.94).ConclusionNo differences in signal intensity of the graft on MRI were seen between the femoral drilling techniques one year after ACL reconstruction, suggesting similar graft maturation at that time. Follow-up studies are needed to determine whether graft intensity changes in the long term.Level of evidenceTherapeutic study with level of evidence I.     

HLA-dependent variations in human immunodeficiency virus Nef protein alter peptide/HLA binding

In human immunodeficiency virus (HIV) infection, sequence variations within defined cytotoxic T lymphocyte (CTL) epitopes may lead to escape from CTL recognition. In a previous report, we have shown that the variable central region of HIV Nef protein (amino acids 73–144) that contains potential CTL epitopes, can escape the CTL response. We suggested that this non recognition occurs through a variety of mechanisms. In particular, we provided evidence that HIV Nef sequences recovered from HLA-A11-expressing individuals have alterations in the major anchor residues essential for binding of the two Nef epitopes (amino acids 73–82 and 84–92) to the HLA-A11 molecule. Here, we investigate in more detail whether variations in autologous Nef sequences affect HLA binding, leading to CTL escape. Potential epitopes were sought by testing Nef peptides containing the HLA-A11-specific motif or related motifs. We confirmed that only the two previously described epitopes identified in cytolysis tests have optimal reactivity with the HLA-A11 molecule. We then sequenced several viral variants from donors that do not express the HLA-A11 molecule and compared the variability of these epitopes with those obtained from HLA-A11-expressing individuals. One substitution (Leu⁸⁵) found in the sequences isolated from both populations increase the reactivity of the HLA-A11-restricted epitope 84–92, and might explain the difference in immunogenicity observed between the two HLA-A11-restricted epitopes from HLA-A11⁺ individuals. In addition, selective variations were only detected in virus isolated from HLA-A11-expressing individuals. Furthermore, examination of the association of variant peptides with the HLA-A11 molecule demonstrated that a single substitution within the minimal epitope could not always completely abrogate HLA binding, suggesting that multiple alterations within a particular epitope may accumulate during disease progression, allowing the virus to escape CTL recognition.     

Bioactive natural compounds against human coronaviruses: a review and perspective

Coronaviruses (CoVs), a family of enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, unusually large RNA genome, and unique replication capability. CoVs are known to cause various potentially lethal human respiratory infectious diseases, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the very recent coronavirus disease 2019 (COVID-19) outbreak. Unfortunately, neither drug nor vaccine has yet been approved to date to prevent and treat these diseases caused by CoVs. Therefore, effective prevention and treatment medications against human coronavirus are in urgent need. In the past decades, many natural compounds have been reported to possess multiple biological activities, including antiviral properties. In this article, we provided a comprehensive review on the natural compounds that interfere with the life cycles of SARS and MERS, and discussed their potential use for the treatment of COVID-19.     

Roles of TGF-β signaling pathway in tumor microenvirionment and cancer therapy

Transforming growth factor β (TGF- β) signaling pathway has pleiotropic effects on cell proliferation, differentiation, adhesion, senescence, and apoptosis. TGF-β can be widely produced by various immune or non-immune cells and regulate cell behaviors through autocrine and paracrine. It plays essential roles in biological processes including embryological development, immune response, and tumor progression. Few cell signalings can contribute to so many pleiotropic functions as the TGF- β signaling pathway in mammals. The significant function of TGF-β signaling in tumor progression and evasion leading it to draw great attention in scientific and clinical research. Understanding the mechanism of TGF- β signaling provides us with chances to potentiate the effectiveness and selectivity of this therapeutic method. Herein, we review the molecular and cellular mechanisms of TGF-β signaling in carcinomas and tumor microenvironment. Then, we enumerate main achievements of TGF-β blockades used or being evaluated in cancer therapy, providing us opportunities to improve therapeutical approaches in the tumor which thrive in a TGF-β-rich environment.     

Copaiba oil suppresses inflammation in asthmatic lungs of BALB/c mice induced with ovalbumin

Asthma is a chronic inflammatory disease that represents high hospitalizations and deaths in world. Copaiba oil (CO) is popularly used for relieving asthma symptoms and has already been shown to be effective in many inflammation models. This study aimed to investigate the immunomodulatory relationship of CO in ovalbumin (OVA)-induced allergic asthma. The composition of CO sample analyzed by GC and GC–MS and the toxicity test was performed in mice at doses of 50 or 100 mg/kg (by gavage). After, the experimental model of allergic asthma was induced with OVA and mice were orally treated with CO in two pre-established doses. The inflammatory infiltrate was evaluated in bronchoalveolar lavage fluid (BALF), while cytokines (IL-4, IL-5, IL-17, IFN-γ, TNF-α), IgE antibody and nitric oxide (NO) production was evaluated in BALF and lung homogenate (LH) of mice, together with the histology and histomorphometry of the lung tissue. CO significantly attenuated the number of inflammatory cells in BALF, suppressing NO production and reducing the response mediated by TH2 and TH17 (T helper) cells in both BALF and LH. Histopathological and histomorphometric analysis confirmed that CO significantly reduced the numbers of inflammatory infiltrate in the lung tissue, including in the parenchyma area. Our results indicate that CO has an effective in vivo antiasthmatic effect.     

Probiotics modulate the microbiota–gut–brain axis and improve memory deficits in aged SAMP8 mice

ProBiotic-4 is a probiotic preparation composed of Bifidobacterium lactis, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus acidophilus. This study aims to investigate the effects of ProBiotic-4 on the microbiota–gut–brain axis and cognitive deficits, and to explore the underlying molecular mechanism using senescence-accelerated mouse prone 8 (SAMP8) mice. ProBiotic-4 was orally administered to 9-month-old SAMP8 mice for 12 weeks. We observed that ProBiotic-4 significantly improved the memory deficits, cerebral neuronal and synaptic injuries, glial activation, and microbiota composition in the feces and brains of aged SAMP8 mice. ProBiotic-4 substantially attenuated aging-related disruption of the intestinal barrier and blood–brain barrier, decreased interleukin-6 and tumor necrosis factor-α at both mRNA and protein levels, reduced plasma and cerebral lipopolysaccharide (LPS) concentration, toll-like receptor 4 (TLR4) expression, and nuclear factor-κB (NF-κB) nuclear translocation in the brain. In addition, not only did ProBiotic-4 significantly decreased the levels of γ-H2AX, 8-hydroxydesoxyguanosine, and retinoic-acid-inducible gene-I (RIG-I), it also abrogated RIG-I multimerization in the brain. These findings suggest that targeting gut microbiota with probiotics may have a therapeutic potential for the deficits of the microbiota–gut–brain axis and cognitive function in aging, and that its mechanism is associated with inhibition of both TLR4-and RIG-I-mediated NF-κB signaling pathway and inflammatory responses.     

Novel approach for real-time monitoring of carrier-based DPIs delivery process via pulmonary route based on modular modified Sympatec HELOS

An explicit illustration of pulmonary delivery processes (PDPs) was a prerequisite for the formulation design and optimization of carrier-based DPIs. However, the current evaluation approaches for DPIs could not provide precise investigation of each PDP separately, or the approaches merely used a simplified and idealized model. In the present study, a novel modular modified Sympatec HELOS (MMSH) was developed to fully investigate the mechanism of each PDP separately in real-time. An inhaler device, artificial throat and pre-separator were separately integrated with a Sympatec HELOS. The dispersion and fluidization, transportation, detachment and deposition processes of pulmonary delivery for model DPIs were explored under different flow rates. Moreover, time-sliced measurements were used to monitor the PDPs in real-time. The Next Generation Impactor (NGI) was applied to determine the aerosolization performance of the model DPIs. The release profiles of the drug particles, drug aggregations and carriers were obtained by MMSH in real-time. Each PDP of the DPIs was analyzed in detail. Moreover, a positive correlation was established between the total release amount of drug particles and the fine particle fraction (FPF) values (R² = 0.9898). The innovative MMSH was successfully developed and was capable of illustrating the PDPs and the mechanism of carrier-based DPIs, providing a theoretical basis for the design and optimization of carrier-based DPIs.     

Conditional reprogramming: next generation cell culture

Long-term primary culture of mammalian cells has been always difficult due to unavoidable senescence. Conventional methods for generating immortalized cell lines usually require manipulation of genome which leads to change of important biological and genetic characteristics. Recently, conditional reprogramming (CR) emerges as a novel next generation tool for long-term culture of primary epithelium cells derived from almost all origins without alteration of genetic background of primary cells. CR co-cultures primary cells with inactivated mouse 3T3-J2 fibroblasts in the presence of RHO-related protein kinase (ROCK) inhibitor Y-27632, enabling primary cells to acquire stem-like characteristics while retain their ability to fully differentiate. With only a few years’ development, CR shows broad prospects in applications in varied areas including disease modeling, regenerative medicine, drug evaluation, drug discovery as well as precision medicine. This review is thus to comprehensively summarize and assess current progress in understanding mechanism of CR and its wide applications, highlighting the value of CR in both basic and translational researches and discussing the challenges faced with CR.     

胃泌素和胃泌素受体与大肠癌的关系

目的探讨胃泌素和胃泌素受体与大肠癌的关系。方法采用ＲＩＡ测定大肠癌患者（ｎ＝３０）、良性疾病患者（ｎ＝２０）手术前后和正常人（ｎ＝２２）血清胃泌素含量；用免疫组化检测大肠癌组织、癌旁组织及远癌组织中胃泌素受体的表达。结果①大肠癌患者术前血清胃泌素水平显著升高，术后２周基本恢复正常（Ｐ＜０．０５）；②癌组织和癌旁组织中胃泌素受体阳性率高于远癌组织（Ｐ＜０．０５）。结论胃泌素可作为大肠癌诊断与预后判断的参考指标，癌旁组织虽无组织形态学改变，但胃泌素受体阳性率高，暗示此处组织可能已处于癌前状态，在切除范围允许的条件下直肠癌远端切缘以＞３ｃｍ为宜