Reduced inhibitory synaptic transmission onto striatopallidal neurons may underlie aging-related motor skill deficits.

Human beings are living longer than ever before and aging is accompanied by an increased incidence of motor deficits, including those associated with the neurodegenerative conditions, Parkinson's disease (PD) and Huntington's disease (HD). However, the biological correlates underlying this epidemiological finding, especially the functional basis at the synapse level, have been elusive. This study reveals that motor skill performance examined via rotarod, beam walking and pole tests is impaired in aged mice. This study, via electrophysiology recordings, further identifies an aging-related reduction in the efficacy of inhibitory synaptic transmission onto dorsolateral striatum (DLS) indirect-pathway medium spiny neurons (iMSNs), i.e., a disinhibition effect on DLS iMSNs. In addition, pharmacologically enhancing the activity of DLS iMSNs by infusing an adenosine A2A receptor (A2AR) agonist, which presumably mimics the disinhibition effect, impairs motor skill performance in young mice, simulating the behavior in aged naïve mice. Conversely, pharmacologically suppressing the activity of DLS iMSNs by infusing an A2AR antagonist, in order to offset the disinhibition effect, restores motor skill performance in aged mice, mimicking the behavior in young naïve mice. In conclusion, this study identifies a functional inhibitory synaptic plasticity in DLS iMSNs that likely contributes to the aging-related motor skill deficits, which would potentially serve as a striatal synaptic basis underlying age being a prominent risk factor for neurodegenerative motor deficits.

Nanofiber Peptides for Bacterial Trapping: A Novel Approach to Antibiotic Alternatives in Wound Infections.

The pervasive employment of antibiotics has engendered the advent of drug-resistant bacteria, imperiling the well-being and health of both humans and animals. Infections precipitated by such multi-resistant bacteria, especially those induced by methicillin-resistant Staphylococcus aureus (MRSA), pervade hospital settings, constituting a grave menace to patient vitality. Antimicrobial peptides (AMPs) have garnered considerable attention as a potent countermeasure against multidrug resistant bacteria. In preceding research endeavors, an insect-derived antimicrobial peptide is identified that, while possessing antimicrobial attributes, manifested suboptimal efficacy against drug-resistant Gram-positive bacteria. To ameliorate this issue, this work enhances the antimicrobial capabilities of the initial ß-hairpin AMPs by substituting the structural sequence of the original AMPs with variant lengths of hydrophobic amino acid-hydrophilic amino acid repeat units. Throughout this endeavor, this work has identified a number of peptides that possess highly effective antibacterial characteristics against a wide range of bacteria. Additionally, some of these peptides have the ability to self-assemble into nanofibers, which then build networks in a distinctive manner to capture bacteria. Consequently, they represent prospective antibiotic alternatives for addressing wound infections engendered by drug-resistant bacteria.

A novel glycine-rich peptide from Zophobas atratus, coleoptericin B, targets bacterial membrane and protects against Klebsiella pneumoniae-induced mastitis in mice.

OBJECTIVES: The growing occurrence of bacterial resistance has spawned the development of novel antimicrobial agents. Antimicrobial peptides, a class of small molecules with antimicrobial activity, have been regarded as the ideal alternatives to antibiotics. METHODS: In this study, we amplified a new type of Zophobas atratus coleoptericin (denoted coleoptericin B) through rapid amplification of cDNA ends (RACE) PCR and expressed recombinant Z. atratus coleoptericin B (rZA-col B) by prokaryotic expression. Subsequently, we evaluated the antimicrobial effect and biocompatibility of rZA-col B in vivo, investigated its antimicrobial mechanism, and assessed its therapeutic effect in a murine model of mastitis caused by MDR Klebsiella pneumoniae. RESULTS: The in vivo studies demonstrated that rZA-col B possesses broad-spectrum antimicrobial activity against both Gram-positive and Gram-negative bacteria. It exhibited less than 1.5% haemolysis and 10% cytotoxicity, even at a concentration of 128 µM. Additionally, rZA-col B had a minimal risk of inducing drug resistance. Furthermore, rZA-col B could disrupt the integrity of bacterial membranes, induce membrane permeabilization and ultimately lead to bacterial death. Importantly, rZA-col B also alleviated mastitis caused by MDR K. pneumoniae in a murine model by enhancing bacterial clearance, reducing neutrophil infiltration, decreasing TNF-α and IL-1ß expression, and protecting the mammary barrier. CONCLUSIONS: rZA-col B may be a promising antibacterial agent to combat MDR bacterial infection.

Novel Plasma Proteomic Biomarkers for Early Identification of Induction Chemotherapy Beneficiaries in Locoregionally Advanced Nasopharyngeal Carcinoma.

Background: Induction chemotherapy (IC) can alleviate locoregionally advanced nasopharyngeal carcinoma (LA-NPC), but effectiveness differs between patients, toxicity is problematic, and effective blood-based IC efficacy predictors are lacking. Here, we aimed to identify biomarkers for early identification of IC beneficiaries. Methods: Sixty-four pairs of matched plasma samples collected before and after IC from LA-NPC patients including 34 responders and 30 non-responders, as well as 50 plasma samples of healthy individuals, were tested using data-independent acquisition mass spectrometry. The proteins associated with clinical traits or IC benefits were investigated by weighted gene co-expression network analysis (WGCNA) and soft cluster analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional annotations were performed to determine the potential function of the identified proteins. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of candidate biomarkers in predicting IC beneficiaries. Results: Compared with healthy individuals, 1027 differentially expressed proteins (DEPs) were found in the plasma of LA-NPC patients. Based on feedback from IC outcomes, 463 DEPs were identified in the pre-IC plasma between responders and non-responders. A total of 1212 DEPs represented the proteomic changes before and after IC in responders, while 276 DEPs were identified in post-IC plasma between responders and non-responders. WGCNA identified nine protein co-expression modules correlated with clinical traits. Soft cluster analysis identified four IC benefits-related protein clusters. Functional enrichment analysis showed that these proteins may play a role in IC via immunity, complement, coagulation, glycosaminoglycan and serine. Four proteins differentially expressed in all group comparisons, paraoxonase/arylesterase 1 (PON1), insulin-like growth factor-binding protein 3 (IGFBP-3), rheumatoid factor D5 light chain (v-kappa-3) and RNA helicase (DDX55), were associated with clinical traits or IC benefits. A four-protein model accurately identified potential IC beneficiaries (AUC=0.95) while diagnosing LA-NPC (AUC=0.92), and the prediction performance was verified using the models to confirm the effective IC (AUC=0.97) and evaluate IC outcome (AUC=0.94). Conclusion: The plasma protein profiles among IC responders and non-responders were different. PON1, IGFBP3, v-kappa-3 and DDX55 could serve as potential biomarkers for early identification of IC beneficiaries for individualised treatment of LA-NPC.

A Novel ß-Hairpin Peptide Z-d14CFR Enhances Multidrug-Resistant Bacterial Clearance in a Murine Model of Mastitis.

The widespread prevalence of antimicrobial resistance has spawned the development of novel antimicrobial agents. Antimicrobial peptides (AMPs) have gained comprehensive attention as one of the major alternatives to antibiotics. However, low antibacterial activity and high-cost production have limited the applications of natural AMPs. In this study, we successfully expressed recombinant Zophobas atratus (Z. atratus) defensin for the first time. In order to increase the antimicrobial activity of peptide, we designed 5 analogues derived from Z. atratus defensin, Z-d13, Z-d14C, Z-d14CF, Z-d14CR and Z-d14CFR. Our results showed that Z-d14CFR (RGCRCNSKSFCVCR-NH2) exhibited a broad-spectrum antimicrobial activity to both Gram-positive bacteria and Gram-negative bacteria, including multidrug-resistant bacteria. It possessed less than 5% hemolysis and 10% cytotoxicity, even at a high concentration of 1 mg/mL. Antimicrobial mechanism studies indicated that Z-d14CFR performed antimicrobial effect via inhibiting biofilm formation, disrupting bacterial membrane integrity and inducing cellular contents release. Furthermore, Z-d14CFR showed a great therapeutic effect on the treatment of multidrug-resistant Escherichia coli (E. coli) infection by enhancing bacterial clearance, decreasing neutrophils infiltration and the expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) in a murine model of mastitis. Our findings suggest that Z-d14CFR could be a promising candidate against multidrug-resistant bacteria.

A novel three-microRNA signature for predicting survival in patients with nasopharyngeal carcinoma.

BACKGROUND/PURPOSE: Nasopharyngeal carcinoma (NPC) is a malignant neoplasm of the head and neck. This study aims to use integrated bioinformatics technologies to develop a predictive miRNA-signature correlated with the prognosis of NPC. MATERIALS AND METHODS: Initially, the differentially expressed miRNAs (DEMs) in NPC were identified, and then DEMs related to the prognosis of NPC were further screened. Subsequently, the relatively important DEMs identified by random forest algorithm were used to construct a predictive signature by multivariate COX regression analysis. Moreover, PCA, Kaplan-Meier analysis, time-dependent ROC analysis, and univariate and multivariate COX regression analysis were performed to evaluate the ability of the signature in risk identification and prognosis prediction in NPC. RESULTS: Hsa-miR-29c, hsa-miR-30e and hsa-miR-93 were selected from DEMs to construct a signature, and their abnormal expression was significantly associated with poor prognosis of NPC. The average AUC values of 1- to 5-year OS, DFS and DMFS predicted by the signature were all above 0.7, and showed better clinical independence than other indexes. In addition, 295 differentially expressed mRNAs could be used as potential target genes of the 3 DEMs. Among them, 56 differentially expressed mRNAs were related to PFS. GO and KEGG enrichment analysis indicated that the poor prognosis of NPC was related to the abnormality of chromosomes, cytokines, and chemokines. CONCLUSION: We constructed a three-miRNA signature with good independent performance in predicting the prognosis for NPC. This study may lay the foundation for exploring new therapeutic targets and improving survival outcomes in NPC patients.

Construction of prediction model of inflammation related genes in idiopathic pulmonary fibrosis and its correlation with immune microenvironment.

Background: The role of inflammation in the formation of idiopathic pulmonary fibrosis (IPF) has gained a lot of attention recently. However, the involvement of genes related to inflammation and immune exchange environment status in the prognosis of IPF remains to be further clarified. The objective of this research is to establish a new model for the prediction of the overall survival (OS) rate of inflammation-related IPF. Methods: Gene Expression Omnibus (GEO) was employed to obtain the three expression microarrays of IPF, including two from alveolar lavage fluid cells and one from peripheral blood mononuclear cells. To construct the risk assessment model of inflammation-linked genes, least absolute shrinkage and selection operator (lasso), univariate cox and multivariate stepwise regression, and random forest method were used. The proportion of immune cell infiltration was evaluated by single sample Gene Set Enrichment Analysis (ssGSEA) algorithm. Results: The value of genes linked with inflammation in the prognosis of IPF was analyzed, and a four-genes risk model was constructed, including tpbg, Myc, ffar2, and CCL2. It was highlighted by Kaplan Meier (K-M) survival analysis that patients with high-risk scores had worse overall survival time in all training and validation sets, and univariate and multivariate analysis highlighted that it has the potential to act as an independent risk indicator for poor prognosis. ROC analysis showed that the prediction efficiency of 1-, 3-, and 5-year OS time in the training set reached 0.784, 0.835, and 0.921, respectively. Immune infiltration analysis showed that Myeloid-Derived Suppressor Cells (MDSC), macrophages, regulatory T cells, cd4+ t cells, neutrophils, and dendritic cells were more infiltrated in the high-risk group than in the low-risk group. Conclusion: Inflammation-related genes can be well used to evaluate the IPF prognosis and impart a new idea for the treatment and follow-up management of IPF patients.

TCF1 in T cell immunity: a broadened frontier.

TCF1 and its homologue LEF1 are historically known as effector transcription factors downstream of the WNT signalling pathway and are essential for early T cell development. Recent advances bring TCF1 into the spotlight for its versatile, context-dependent functions in regulating mature T cell responses. In the cytotoxic T cell lineages, TCF1 is required for the self-renewal of stem-like CD8+ T cells generated in response to viral or tumour antigens, and for preserving heightened responses to checkpoint blockade immunotherapy. In the helper T cell lineages, TCF1 is indispensable for the differentiation of T follicular helper and T follicular regulatory cells, and crucially regulates immunosuppressive functions of regulatory T cells. Mechanistic investigations have also identified TCF1 as the first transcription factor that directly modifies histone acetylation, with the capacity to bridge transcriptional and epigenetic regulation. TCF1 also has the potential to become an important clinical biomarker for assessing the prognosis of tumour immunotherapy and the success of viral control in treating HIV and hepatitis C virus infection. Here, we summarize the key findings on TCF1 across the fields of T cell immunity and reflect on the possibility of exploring TCF1 and its downstream transcriptional programmes as therapeutic targets for improving antiviral and antitumour immunity.

Screening and identification of potential novel lipid biomarkers for non-small cell lung cancer using ultra-high performance liquid chromatography tandem mass spectrometry.

Lung cancer is characterized by a high incidence rate and low survival rate. It is important to achieve early diagnosis of the disease. We applied ultra-high performance liquid chromatography tandem mass spectrometry to screen plasma lipid spectrum in non-small cell lung cancer (NSCLC) patients, healthy controls (HC), and community-acquired pneumonia (CAP) patients. Modeling employing orthogonal partial least squares-discriminant analysis combined with t-test was used to screen the differential lipids. Logistic regression analysis was used to establish the diagnostic model, while the accuracy was verified by 10-fold cross-validation. The results showed that the abnormal metabolism of lipid in NSCLC mainly comprised fatty acid metabolism, phospholipid metabolism, and glyceride metabolism. Four potential biomarkers, including LPC (14:0/0:0), LPI (14:1/0:0), DG (14:0/18:2/0:0), and LPC (16:1/0:0), were fitted by the receiver operating characteristic curve model with the area under curve (AUC) value of 0.856, and the specificity and sensitivity were 87.0 and 78.0%, respectively. The results of cross validation showed that the AUC value of the model was 0.812, the sensitivity was 72.9%, and the specificity was 82.6%. The positive rate of four potential lipid biomarkers in this study (>60.0%) was higher than that of existing tumor biomarkers in the clinical application. We investigated the plasma lipid profile of NSCLC patients and identified lipid biomarkers with potential diagnostic values. From the lipidomics perspective, our study may lay a foundation for the biomarker-based early diagnosis of lung cancer.

Research status and prospects of acupuncture for prevention and treatment of chemo- and radiotherapy-induced salivary gland dysfunction in head and neck cancer.

Salivary gland dysfunction (SGD) induced by chemo- and radiotherapy for head and neck cancer (HNC) has always been a difficult problem in modern medicine. The quality of life of a large number of HNC patients is severely impaired by SGD such as xerostomia and dysphagia. In recent years, several studies have found that acupuncture can improve patients' salivary secretion, but it has not yet been approved as an alternative therapy for SGD. For this reason, we collected the clinical study reports on acupuncture in the treatment of SGD induced by chemo- and radiotherapy in HNC patients in the past 20 years, and analyzed and discussed the advantages and disadvantages of these studies with respect to tumor types, group setting, intervention modality, acupoints selection, outcome evaluation, and safety. We believed that acupuncture is beneficial for SGD, but the existing objective evidence is insufficient to support its effectiveness. Therefore, improving the Standards for Reporting Interventions in Clinical Trials of Acupuncture, selecting the optimal combination of acupoints through scientific and rigorous study design, and exploring the potential mechanism of acupuncture in the treatment of diseases combined with the meridian theory may be effective ways to promote the acceptance of acupuncture as an alternative therapy for SGD in future. The significance of this review is to provide a reference for researchers to carry out high-quality clinical trials of acupuncture in the treatment of SGD in future from the perspective of the combination of modern medicine and traditional Chinese medicine.

Different Behaviors of a Glycine Receptor Channel Pore Residue between Wild-Type-Mimicking and Disease-Type-Mimicking Formats.

The glycine receptor (GlyR) is a neurotransmitter-gated chloride channel that mediates fast inhibitory neurotransmission, predominantly in the spinal cord and brain stem. Mutations of the GlyR are the major cause of hereditary hyperekplexia. Site-specific cysteine substitution followed by labeling with a fluorophore has previously been used to explore the behaviors of the hyperekplexia-related 271 (19') residue of the GlyR. However, this manipulation dramatically compromises sensitivity toward the agonist glycine and alters the pharmacological effects of various agents in manners similar to those of the hyperekplexia-causing R19'Q/L mutations, raising the question whether what is reported by the substituted and modified residue faithfully reflects what actually happens to the wild-type (WT) residue. In this study, a mechanism-rescuing second-site mutation was introduced to create a WT-mimicking GlyR (with the 19' residue cysteine substitution and modification still in place), in which the sensitivity toward glycine and pharmacological effects of various agents were restored. Further experiments revealed stark differences in the behaviors upon the various pharmacological treatments and consequently the underlying mechanisms of the 19' residue between this WT-mimicking GlyR and the GlyR without the mechanism rescue, which is correspondingly defined as the disease-type (DT)-mimicking GlyR. The data presented in this study warn generally that caution is required when attempting to deduce the behaviors of a WT residue from data based on substituted or modified residues that alter protein structure and function. Extra measures, such as rescuing mechanisms via alternative means as presented in this study, are needed to mitigate this challenge.

Identifying Prognostic Significance of RCL1 and Four-Gene Signature as Novel Potential Biomarkers in HCC Patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant disease, and it is characterized by rapid progression and low five-year survival rate. At present, there are no effective methods for monitoring the treatment and prognosis of HCC. METHODS: The transcriptome and gene expression profiles of HCC were obtained from the Cancer Genome Atlas (TCGA) program, International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. The random forest method was applied to construct a four-gene prognostic model based on RNA terminal phosphate cyclase like 1 (RCL1) expression. The Kaplan-Meier method was performed to evaluate the prognostic value of RCL1, long noncoding RNAs (AC079061, AL354872, and LINC01093), and four-gene signature (SPP1, MYBL2, TRNP1, and FTCD). We examined the relationship between RCL1 expression and immune cells infiltration, tumor mutation burden (TMB), and microsatellite instability (MSI). RESULTS: The results of multiple databases indicated that the aberrant expression of RCL1 was associated with clinical outcome, immune cells infiltration, TMB, and MSI in HCC patients. Meanwhile, we found that long noncoding RNAs (AC079061, AL354872, and LINC01093) and RCL1 were significantly coexpressed in HCC patients. We also confirmed that the four-gene signature was an independent prognostic factor for HCC patients. Ferroptosis potential index, immune checkpoint molecules, and clinical feature were found to have obvious correlations with risk score. The area under the receiver operating characteristic curve values for the model were 0.7-0.8 in the training set and the validation set, suggesting high robustness of the four-gene signature. We then built a nomogram for facilitating the use in clinical practice. CONCLUSION: Our study demonstrated that RCL1 and a novel four-gene signature can be used as prognostic biomarkers for predicting clinical outcome in HCC patients; and this model may assist in individualized treatment monitoring of HCC patients in clinical practice.

Research status and prospects of biomarkers for nasopharyngeal carcinoma in the era of high­throughput omics (Review).

As a malignant tumor type, nasopharyngeal carcinoma (NPC) is characterized by distinct geographical, ethnic and genetic differences; presenting a major threat to human health in many countries, especially in Southern China. At present, no accurate and effective methods are available for the early diagnosis, efficacious evaluation or prognosis prediction for NPC. As such, a large number of patients have locoregionally advanced NPC at the time of initial diagnosis. Many patients show toxic reactions to overtreatment and have risks of cancer recurrence and distant metastasis owing to insufficient treatment. To solve these clinical problems, high­throughput '­omics' technologies are being used to screen and identify specific molecular biomarkers for NPC. Because of the lack of comprehensive descriptions regarding NPC biomarkers, the present study summarized the research progress that has been made in recent years to discover NPC biomarkers, highlighting the existing problems that require exploration. In view of the lack of authoritative reports at present, study design factors that affect the screening of biomarkers are also discussed here and prospects for future research are proposed to provide references for follow­up studies of NPC biomarkers.

Ectopic Tcf1 expression instills a stem-like program in exhausted CD8+ T cells to enhance viral and tumor immunity.

Exhausted CD8+ T (Tex) cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts. A stem cell-like Tex (Tex-stem) subset can self-renew and differentiate into terminally exhausted (Tex-term) cells. Here, we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor models. Tcf1 overexpression diminished coinhibitory receptor expression and enhanced polycytokine-producing capacity while retaining a heightened responses to checkpoint blockade, leading to enhanced viral and tumor control. Mechanistically, ectopically expressed Tcf1 exploited existing and novel chromatin accessible sites as transcriptional enhancers or repressors and modulated the transcriptome by enforcing pre-existing expression patterns in Tex-stem cells, such as enhanced suppression of Blimp1 and Bim and acquisition of new downstream genes, including Mx1, Tox2, and Runx3. These findings reveal a pronounced impact of ectopic Tcf1 expression on Tex functional restoration and highlight the therapeutic potential of harnessing Tcf1-enforced transcriptional programs.

ß-catenin and γ-catenin are dispensable for T lymphocytes and AML leukemic stem cells.

The ß-catenin transcriptional coregulator is involved in various biological and pathological processes; however, its requirements in hematopoietic cells remain controversial. We re-targeted the Ctnnb1 gene locus to generate a true ß-catenin-null mutant mouse strain. Ablation of ß-catenin alone, or in combination with its homologue γ-catenin, did not affect thymocyte maturation, survival or proliferation. Deficiency in ß/γ-catenin did not detectably affect differentiation of CD4+T follicular helper cells or that of effector and memory CD8+ cytotoxic cells in response to acute viral infection. In an MLL-AF9 AML mouse model, genetic deletion of ß-catenin, or even all four Tcf/Lef family transcription factors that interact with ß-catenin, did not affect AML onset in primary recipients, or the ability of leukemic stem cells (LSCs) in propagating AML in secondary recipients. Our data thus clarify on a long-standing controversy and indicate that ß-catenin is dispensable for T cells and AML LSCs.

Physiological Functions of Heat Shock Proteins.

Heat shock proteins (HSPs) are molecular chaperones involved in a variety of life activities. HSPs function in the refolding of misfolded proteins, thereby contributing to the maintenance of cellular homeostasis. Heat shock factor (HSF) is activated in response to environmental stresses and binds to heat shock elements (HSEs), promoting HSP translation and thus the production of high levels of HSPs to prevent damage to the organism. Here, we summarize the role of molecular chaperones as anti-heat stress molecules and their involvement in immune responses and the modulation of apoptosis. In addition, we review the potential application of HSPs to cancer therapy, general medicine, and the treatment of heart disease.

[Four kinds of operative methods for subtalar arthrodesis in treating old calcaneal fracture].

OBJECTIVE: To explore clinical efficacy of four surgical methods for subtalar joint fusion and internal fixation in treating old calcaneal fractures. METHODS: From March 2014 to November 2017, 25 patients (26 feet) with old calcaneal fractures treated with four surgical methods of subtalar arthrodesis were retrospectively analyzed, including subtalar joint fusion in situ for 2 patients (2 feet), subtalar articular strut bone graft fusion for 6 patients (6 feet), subtalar joint fusion with calcaneus V-shaped osteotomy for 6 patients(6 feet), and subtalar bone graft fusion with calcaneus cuneiform osteotomy for 11 patients (11 feet). They aged from 23 to 70 years old with an average of (36.7±5.8) years old, and the courses of disease ranged from 3 to 35 months with an average of (9.5±5.1) months. Postoperative complications were observed, talar tilt angle, calcaneus Böhler angle, Gissane angle, and the heel height were compared before and after surgery at 12 months. VAS score and American Orthopaedic Foot and Ankle Society(AOFAS) score were employed to evaluate clinical efficacy at 12 months after surgery. RESULTS: Twenty-one patients (21 feet) were followed up for 13 to 34 months with an average of (20.1±3.7) months, four patients(5 feet) were lost to follow-up. Two patients were underwent surgical incision rupture, 1 patient occurred fracture nonunion, and no complications such as fracture nonunion, loosening or fracture of internal fixation occurred in the other patients. There were significant differences between preoperative and postoperative in talar tilt angle[(5.3±2.4)° vs (11.2±4.6)°, t=7.24, P<0.05], calcaneus Böhler angle[(5.4±2.7)° vs(25.5±5.3)°, t=11.2, P<0.05], Gissane angle[(89.4±9.6)° vs (122.0±5.2)°, t=8.13, P<0.05], and heel height[(28.5±5.1) mm vs(47.1±3.7) mm, t=6.45, P<0.05]. VAS score was decreased from 5.2±1.0 before operation to 1.6±0.7 at 12 months after operation(t=5.12, P<0.05); AOFAS score was improved from 52.4±6.4 to 86.2±5.2 at 12 months after operation(t=6.41, P<0.05); 14 feet got excellent results, 4 good , 2 moderate and 1 poor. CONCLUSIONS: Subtalar joint fusion in situ, subtalar articular strut bone graft fusion, subtalar joint fusion with calcaneus V-shaped osteotomy, and subtalar bone graft fusion with calcaneus cuneiform osteotomy are effective operation methods for old calcaneal fractures, which have advantages of relieving pain, correcting deformity of calcaneal, improving foot function. Reasonable selection and treatment is the key to ensure the efficacy.

Bystander responses impact accurate detection of murine and human antigen-specific CD8 T cells.

Induction of memory CD8 T cells is important for controlling infections such as malaria HIV/AIDS, and for cancer immunotherapy. Accurate assessment of antigen (Ag)-specific CD8 T-cells is critical for vaccine optimization and defining correlates of protection. However, conditions for determining Ag-specific CD8 T-cell responses ex-vivo using ICS may be variable, especially in humans with complex antigens. Here, we used an attenuated whole parasite malaria vaccine model in humans and various experimental infections in mice to show that the duration of antigenic stimulation and timing of brefeldin A (BFA) addition influences the magnitude of Ag-specific and bystander T cell responses. Indeed, following immunization with an attenuated whole sporozoite malaria vaccine in humans, significantly higher numbers of IFN-γ producing memory CD8 T-cells comprised of antigen specific and bystander responses were detected by increasing the duration of Ag-stimulation prior to addition of BFA. Mechanistic analyses of virus-specific CD8 T-cells in mice revealed that the increase in IFNg producing CD8 T-cells was due to bystander activation of Ag-experienced memory CD8 T-cells, and correlated with the proportion of Ag-experienced CD8 T-cells in the stimulated populations. Incubation with anti-cytokine antibodies (ex. IL-12) improved accuracy in detecting bona-fide memory CD8 T-cell responses suggesting this as the mechanism for the bystander activation. These data have important implications for accurate assessment of immune responses generated by vaccines intended to elicit protective memory CD8 T-cells.

[Bone and soft tissue combined with surgery for the treatment soft flatfoot combined with painful navicular bone].

OBJECTIVE: To explore short-term clinical effects of bone and soft tissue combined with surgery for the treatment of soft flatfoot accompanied with painful navicular bone. METHODS: From May 2015 to August 2017, 16 patients (16 feet) with navicular bone soft flatfoot accompanied with painful navicular bone were treated with bone and soft tissues operation (gastrocnemius release, medial displacement calcaneal osteotomy, and excision of accessory navicular with reconstruction of posterior tibial tendon). Among them, there were 9 males (9 feet) and 7 females (7 feet), aged from 22 to 48 years old with an average of (32.0±3.4) years old. The duration of diseases ranged from 6 months to 5 years with an average of (2.4±1.7) years. The postoperative complications were observed, talocalcaneal angle, the first metatarsal horn of the talus, arch height, angle of inclination and calcaneal valgus before and after operation at 12 months were compared. VAS score and AOFAS score after operation at 12 months were applied to evaluate pain relief and function. RESULTS: All patients were followed up for an average of (18.4±3.5) months(13~25 months). The incisions of patients were healed at grade A without wound infection, nonunion or delayed union, internal fixation fracture or loosening and other complications. Medial pain of foot was disappeared and motor ability was restored at 12 months after operation. Arch height, angle of inclination and the first metatarsal horn of the talus of lateral X-ray before operation and after operation at 12 months on weight-bearing foot were(21.51±1.20)°vs(31.01±1.62)°, (10.71±1.52)°vs(22.12±2.11)°, (15.61±1.41)°vs(5.10±1.20)°; talocalcaneal angle, the first metatarsal horn of the talus of AP X-ray before operation and after operation at 12 months on weight-bearing foot were (36.12±2.21) ° vs (22.12±2.61)°, (13.41±1.51)°vs(4.30±0.91)°; calcaneal valgus of axial X-ray before operation and after operation at 12 months on weight-bearing foot were (10.80±1.21)°vs(3.92±1.81)°; there were statistical difference in imaging indicators between preoperation and 12 months after operation. VAS score was significantly decreased from (6.21±2.31) before operation to (1.82±0.56) at 12 months after operation (t=2.64, P<0.05). AOFAS score was obviously increased from (51.2±5.6)before operation to (87.1±4.7)at 12 months after operation (t=3.43, P<0.05). CONCLUSIONS: Bone and soft tissue operation (namely, gastrocnemius release, medial displacement calcaneal osteotomy, and excision of accessory navicular with reconstruction of posterior tibial tendon) could obviously relieve foot pain, improve foot appearance and function in patients with navicular bone soft flatfoot complicated with painful navicular bone, and has certain clinical efficacy.

Lactoferrin: Major Physiological Functions and Applications.

Lactoferrin (lactotransferrin; Lf) is an iron-binding glycoprotein and one of the most important bioactivators in milk and other external secretions. It has numerous biological roles, including the regulation of iron absorption and modulation of immune responses, and has anti-microbial, anti-viral, antioxidant, anti-cancer, and anti-inflammatory activities. Lf regulates the quantity of iron absorbed in the intestine via its role in iron transport and can also chelate iron, directly or indirectly. Notably, it has been used as an adjuvant therapy for some intestinal diseases. It is now used in nutraceuticalsupplemented infant formula and other food products. This article reviews the content, distribution, physiologic functions and current applications of Lf, and aims to shed light on future prospects for additional applications of Lf.