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BACKGROUND: At present osteoporosis has come into view as a major health concern. Skeletal diseases typified by weak and fragile bones have imposed threats of fissure. Hydroxyapatite (HAP) is known to induce osteoblast like differentiation and provide mechanical strength, hence, used in bone tissue engineering; whereas, Nigella sativa has also demonstrated potential to treat bone and muscle diseases. This study was aimed to develop potential orthopedic scaffold exploiting natural resources of Saudi Arabia which can be used as prospective tissue engineering implant. METHODS: The bone scaffold was developed by grafting biogenic HAP with N. sativa essential oil. N. sativa was applied for boosting osteogenesis and to stimulate antimicrobial potential. Antimicrobial potential was investigated utilizing S. aureus bacteria. Spectroscopic and surface characters of N. sativa grafted HAP scaffolds were analyzed using Fourier-transform infrared spectroscopy, X-ray crystallography and Scanning electron microscopy. To ensure biocompatibility of scaffolds; we selected C2C12 cell-lines; best model to study mechanistic pathways related to osteoblasts and myoblasts differentiation. RESULTS: Grafting of HAP with N. sativa did not affect typical spherical silhouette of nanoparticles. Characteristically; protein loaded polynucleated myotubes are result of in vitro myogenesis of C2C12 myoblasts in squat serum environment. CONCLUSION: It is first study of unique combination of N. sativa and HAP scaffold as a possible candidate of implantation for skeletal muscles regeneration. Outcome of this finding revealed N. sativa grafted HAP enhance differentiation significantly over that of HAP. The proposed scaffold will be an economical natural material for hard and soft tissue engineering and will aid in curing skeletal muscle diseases. Our findings have implications for treatment of muscular/bone diseases. GRAPHIC ABSTRACT: [Image: see text]

Objectives Subacute combined degeneration (SCD) is a demyelinating disease commonly caused by vitamin B12 deficiency. Several studies have been reported SCD could be accompanied by anemia. However, the correlation between anemia and clinical severity of SCD patients is unclear. In this study, we aim to analyze the clinical characteristics of SCD concomitant with anemia, and investigate the effect of anemia in predicting the severity of SCD. Methods A total 42 patients were included in the study. Clinical, laboratory, radiological findings, and outcomes from the patients were analyzed. All patients were treated with vitamin B12 for no less than 6 months and a functional disability rating scale was used to evaluate severity of neurological impairment at the time of admission and 3 and 6 months after admission in our study. Results 85.7% patients had macrocytosis. Decreased serum vitamin B12 levels were found in 27 patients (64.3%). MRI showed long-segment abnormality on the spinal cord in 22 patients. No differences in rating score were found in patients grouped by sex, age, clinical course, serum vitamin B12, or MRI manifestations at the time of admission or at the follow-up visits. Negative correlation was seen between hemoglobin levels and the clinical severity scores on admission. Conclusion Not all patients with SCD concomitant with anemia had decreased serum vitamin B12 level. The inverse correlation between hemoglobin level and clinical severity suggests the degree of anemia can help in evaluating the extent of neurologic impairment.

The aim of this study was to determine the prevalence, serovar distribution, antimicrobial resistance, and genotypic analyses of the dominating serovars of Salmonella in chickens from a national study in Korea. Between 2017 and 2018, a total of 550 chicken samples were collected from the top 12 integrated broiler chicken operations in Korea. Salmonella was isolated from 117 (32.5%) chicken feces and 19 (10.0%) retail chicken meat sources. Ten serovars were identified, and the most common Salmonella serovar was Salmonella ser. Albany (50 isolates, 36.8%), followed by S. Enteritidis (38 isolates, 27.9%), and S. Montevideo (23 isolates, 16.9%) isolated from 6, 10, and 6 operations, respectively. A total of 35 (25.7%) isolates were with the ACSSuTN (ampicillin, chloramphenicol, streptomycin, sulfisoxazole, tetracycline, and nalidixic acid) resistance pattern, with high prevalence of this resistance pattern in S. Albany (29 isolates, 58.0%). A total of 35 PFGE types were identified among Salmonella isolates of the serovars Albany, Enteritidis, Virchow, Montevideo, and Senftenberg, while 11 distinct types of PFGE patterns were found among S. Albany isolates, which showed an overall homology similarity of higher than 85%. Among these 35 PFGE types, 22 PFGE types corresponded to 32 isolates from samples limited to one operation, and the other 13 PFGE types corresponded to 72 isolates from samples widely distributed among different operations. These results highlighted rapid colony dissemination of multidrug-resistant S. Albany in chicken all over Korea after it first appeared in 2016; furthermore, the spread of Salmonella colonies between various integrated operations was common, and several operations played an important role in Salmonella carriage and transmission in Korea.

Objective To analyze the clinical characteristics and outcomes of patients diagnosed with acquired neuromyotonia and who were treated with tacrolimus. Methods A single center, retrospective study was performed on patients with acquired meuromyotonia whose treatment included tacrolimus. The clinical information, antibody tests, and electromyography results were reviewed. The Numeric Rating Scale for pain and modified Rankin scale were used to quantify outcomes. Results This study included four patients who presented with fasciculation or myokymia in their limbs. Electromyography suggested peripheral nerve hyperexcitability. Autoantibodies including contactin-associated protein 2 (CASPR2), leucine-rich glioma inactivated protein 1 (LGl1) or IgLON5 antibody were detected in three patients, and another patient had Sjogren's syndrome. Initial treatment included membrane-stabilizing drugs and/or corticosteroids. Tacrolimus was administered at a dose of 3 mg once daily to all patients. All patients showed clinical improvement after the treatment. No recurrence was observed after gradual tapering or discontinuation of therapy during follow-up. Conclusions Tacrolimus may be a therapeutic option for acquired neuromyotonia. Further studies on tacrolimus in larger patient cohort should be performed.

Extended-spectrum cephalosporin (ESC) resistance investigated in Salmonella and E. coli from the same chicken was to improve the understanding of the inter-species transmission of ESC resistance determinants in Salmonella and E. coli from a single chicken individual. Fifteen (13.6%) farms and 44 (8.0%) chicken individuals were positive for ESC-resistant E. coli and/or Salmonella, 8 farms (7.3%) and 12 (2.2%) individuals were simultaneously positive for ESC-resistant E. coli and Salmonella. The genetic diversity of ESC resistance determinants in E. coli and Salmonella was observed. Most E. coli isolates (67.6%) produced CTX-M-type of blaCTX-M-55, and 9 isolates (24.3%) produced CMY-type of blaCMY-2. Most Salmonella isolates (94.1%) produced blaCTX-M-15. Two broiler chicken farms were simultaneously positive for blaCMY-2- and blaCTX-M-15-harboring E. coli and Salmonella isolates. Whole-plasmid sequence for the transferable plasmid harboring blaCMY-2 showed genomic diversity of the plasmids from Salmonella and E. coli sourced from the same chicken. The genetic arrangement of blaCMY-2 in Salmonella was IS1294b-ΔISEcp1-blaCMY-2-blc-sugE and ISEcp1-blaCMY-2-blc-sugE in E. coli located on multi-host plasmids of IncI1-pST-2 and IncI1-pST-12. In conclusion, the study illustrates the genetic diversity of ESC resistance determinants in E. coli and Salmonella in a single chicken. Considering the possibility of transmission of antimicrobial resistance to humans through the food chain, a large reservoir of ESC resistance in chicken which could be co-infected with ESC-resistant E. coli and Salmonella poses a serious risk of potential transmission of ESC-resistant E. coli and Salmonella, and their transferable ESC resistant gene, to human simultaneously.

The importance of employee green behavior (EGB) to an enterprise’s green development goal is increasingly emphasized in many industries. However, to date promoting EGB through interaction, namely between individuals and organizations, has not been a central concern. Therefore, from the perspective of the person-organization fit, this study considers the psychological distance between employees and the organization as a moderating variable, exploring the mechanisms of values fit, needs-supplies fit, and demands-abilities fit on green behaviors as within and outside the scope of employee responsibility. After collecting the results of questionnaires from 412 employees, our hypotheses were tested using the Structural Equation Model (SEM). The results show that (1) person-organization fit can effectively promote EGB in the workplace. However, different types of person-organization fit have different influencing paths and effect-strengths on employees’ task-related green behavior and proactive green behavior. (2) Values fit has the greatest incentive effect on EGB, followed by demands-abilities fit, while needs-supplies fit promotes only eco-helping behavior. (3) Psychological distance has a significant moderating effect on the relationship between the person-organization fit and EGB. The effect of person-organization fit on EGB is enhanced when employees are close with less emotional distance, while the effect is weakened in the case of close expectation distance. Finally, this study provides suggestions for enterprise managers providing ways to motivate EGB through the selection and allocation of human resources.

High-dose steroids, the first-line therapy for acute attacks in neuromyelitis optica spectrum disorder (NMOSD), were ineffective in a proportion of NMOSD attacks. This study aimed to explore possible predictors of high-dose steroid resistance. Demographics and disease characteristics of acute attacks were compared between those who responded to high-dose intravenous methylprednisolone (IVMP) and those resistant to IVMP. In total, 197 attacks in 160 patients were identified in our NMOSD registry. Compared with responders, attacks resistant to high-dose steroids tended to have a higher proportion of previous history of immunosuppressive use (25.5 vs. 15.5%, p = 0.080). Significantly higher levels of proteins in the cerebrospinal fluid (CSF) were found in non-responders than in responders [485.5 (388–656) vs. 387 (291.5–532) mg/L, p = 0.006]. More active lesions were found in the brain stem of non-responders (8 attacks in 55, 14.5%), especially in the pons (7.3%) and medulla (14.5%), as opposed to responders (7 patients in 142, 4.9%). Multivariable logistic regression showed that resistance to high-dose steroid treatment was associated with previous immunosuppressant use [odds ratio (OR), 2.31; 95% confidence interval (CI) 1.002–5.34, p = 0.049], CSF protein level above 450 mg/L (OR 3.42, 95% CI 1.72–6.82, p < 0.001), and active lesions in the brainstem (OR 3.80, 95% CI 1.17–12.32, p = 0.026). In conclusion, NMOSD patients with previous use of immunosuppressants, higher levels of CSF protein, and active lesions in the brainstem are more likely to respond poorly to high-dose IVMP alone during an acute attack.

Salmonella is a type of zoonotic bacteria that represents an economic and public health concern worldwide. Difficulties in sample collection from migratory birds mean little is known about their importance as a reservoir of Salmonella. The present study evaluated the prevalence and potential risk of Salmonella enterica in migratory birds. From 2012–2017, 3661 cloacal swabs from migratory birds were collected in South Korea and tested to isolate S. enterica. Strains were tested for antimicrobial resistance and the presence of virulence genes. Thirty-six S. enterica strains, including S. enterica serovar Typhimurium (n = 19), S. Berta (n = 16), and S. Virchow (n = 1), were isolated from 34 birds. Two migratory birds were simultaneously co-infected with two serotypes. S. enterica was isolated from the Mallard duck, Northern pintail, Eurasian wigeon, Spot-billed duck, Eastern great egret, and Intermediate egret. S. Virchow was resistant to ciprofloxacin, with a point mutation (Ser-83-Phe) in the gyrA gene. Ten virulence genes were detected; sixteen strains were positive for all ten virulence genes. Salmonella was isolated from different migratory bird species and geographic locations with up to 100 % similarity of PFGE type. Eight S. Virchow strains taken from migratory birds, poultry farms, and chicken meat showed the same PFGE type. Salmonella was transmitted across species, space, and time in migratory birds. These birds may play a role in the dispersal of pathogenic and antimicrobial-resistant Salmonella and sporadic Salmonella infections in poultry; therefore, they may represent a direct or indirect public health threat.

Indoleamine 2,3-dioxygenase 1 (IDO1), which degrades the essential amino acid tryptophan, exerts immunosuppressive functions and serves a crucial role in multiple types tumor progression, including non-small-cell lung cancer (NSCLC) and melanoma. Recent studies have reported that T-cell exhaustion is increased during tumor progression, which impairs the antitumor immune response. However, the association between IDO1 and T-cell exhaustion during tumor progression remains unknown. The present study evaluated the effect of IDO1 on T-cell exhaustion in lung cancer mice. The present study demonstrated that IDO1 knockdown by small interfering RNA in the LLC cell line inhibited T-cell exhaustion. Furthermore, the role of IDO1 in T-cell exhaustion during lung cancer progression was determined in an in vivo mouse model using IDO1 short hairpin RNA (shRNA). The results demonstrated that inhibition of IDO1 activity by shRNA administration in vivo significantly delayed the onset and growth of tumors. In addition, the expression levels of the inhibitory receptors programmed death-1 (PD-1) and B and T lymphocyte attenuator (BTLA) were increased in T-cells from the lung tumor-bearing mice, whereas interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) levels in serum were decreased compared with the control mice. However, no difference in the absolute number of T cells was observed, including CD4+ and CD8+ T cells. In addition, IDO1 knockdown by shRNA inhibited T-cell exhaustion in lung tumor-bearing mice, which was characterized by decreased expression of PD-1 and BTLA on T cells. By contrast, IL-2 and TNF-α levels in serum were increased in IDO1-shRNA-treated mice. By using a shRNA approach, the present study demonstrated that IDO1 activity may be involved in tumor growth, and that IDO1 silencing may inhibit tumor progression by impeding the process of T-cell exhaustion.

Background: In December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan and rapidly spread throughout China. The immune response is likely to be highly involved in the pathological process of coronavirus disease 2019 (COVID-19). However, information on specific changes of immune response in COVID-19 are limited. Methods: Demographic and clinical data of all confirmed cases with COVID-19 on admission at Tongji Hospital from January 10 to February 12, 2020, were collected and analyzed. The expression of lymphocytes, lymphocyte subsets, infection related biomarkers and inflammatory cytokines were analyzed and compared between severe cases and non-severe patients. Findings: Of the 452 patients with COVID-19 recruited from January 10 to February 12, 2020, 286 were diagnosed as severe infection. The median age was 58 years and 235 were male. 201 patients had chronic diseases and a higher percentage in the severe cases. The most common symptoms were fever, shortness of breath, expectoration, and fatigue. Severe cases tend to have higher white blood cell and neutrophil lymphopenia ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. Most of severe cases demonstrated elevated levels of infection-related biomarkers, and inflammatory cytokines. The numbers of B cells, T cells and NK cells was significantly decreased in patients with COVID-19, and more severely decreased in the severe cases. T cells were shown to be most affected by SARS-CoV-2, and more hampered in severe cases. Both helper T cells and suppressor T cells in patients with COVID-19 were below normal levels. Helper T cells tend to be more affected in severe cases. The percentage of naive helper T cells increased and memory helper T cells decreased in severe cases. Patients with COVID-19 have lower level of regulatory T cells, and more obviously damaged in severe cases. Interpretation: SARS-CoV-2 might mainly act on lymphocytes, especially T lymphocytes, and induce a cytokine storm in the body, generate a series of immune responses. Surveillance of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis and treatment of COVID-19. Funding Statement: None. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study was performed in accordance with Tongji Hospital Ethics Committee (IRB ID: TJ-C20200121). Written informed consent was waived by the Ethics Commission of the designated hospital for emerging infectious disease.

Nephroblastoma overexpressed protein (NOV/CCN3), the early discovered member of the CCN family, has recently been suggested to be involved in a number of inflammatory processes, including wound healing, alveolar epithelial cell inflammation, cancer metastasis, and macrophage foam cell formation. However, the role of CCN3 in rheumatoid arthritis (RA), a classic autoimmune and inflammatory disease, remains elusive. RA is a chronic systemic autoimmune disease that eventually leads to cartilage and bone destruction and joint dysfunction. In this study, we investigated the potential of serum CCN3 as a biomarker for RA. The serum levels of CCN3 were measured by ELISA. The clinical and laboratory parameters were collected from a clinical record system, and disease activity was determined by joint disease activity score 28 (DAS28). Our results showed that the serum levels of CCN3 were significantly increased in RA patients compared to healthy controls. Furthermore, the CCN3 level was positively correlated with DAS28 (CRP), DAS28 (ESR), and the level of anti-CCP Ab, an autoantibody highly specific for RA. Furthermore, CCN3 showed a positive correlation with inflammatory cytokine IL-6, while no significant correlation with TNF-α was observed. These data suggest that CCN3 plays an important role in the development of RA and might be a potential disease activity biomarker for RA.

Salmonella enterica serovar Gallinarum (S. Gallinarum) can cause fowl typhoid, a severe systemic disease responsible for considerable economic losses. Chicken pathogenicity test is the traditional method for assessing the virulence of S. Gallinarum. However, this method is limited by several factors, including ethical considerations, costs, and the need for specialized facilities. Hence, we established a chicken embryo lethality assay (ELA) model to determine the virulence of S. Gallinarum. Three virulent and three avirulent representative strains, which were confirmed by the chicken pathogenicity test, were used to perform the ELA. The most significant difference between the virulent and avirulent strains could be observed when 13-day-old embryos were inoculated via the AC route and incubated for 5 days. Based on a 50% embryo lethal dose (ELD50), isolates considered to be virulent had a Log10ELD50 of ≤ 4.0, moderately virulent strains had a Log10ELD50 of 4.0-6.1, and avirulent isolates had a Log10ELD50 of ≥ 6.1. Different abilities to invade the liver of embryos were found between the virulent and avirulent strains by a growth curve experiment in vitro. The maximum colony-forming units (CFU) of the virulent strain was about 10,000 times higher than that of the avirulent strain in the liver at 5 days post infection. The ELA results of 42 field strains showed that thirty-two strains (76.2%) were virulent, nine were moderately virulent (21.4%), and one strain was avirulent (2.4%). In conclusion, these results suggest that the ELA can be used as an alternative method to assess the virulence of S. Gallinarum, which will contribute to the study of virulence genes, virulence evolution, pathogenic mechanisms and vaccine development.

Background. Hypertrophic pachymeningitis (HP) is generally regarded as a rare inflammatory disease, which results in a diffuse thickening of the dura mater. We retrospectively collected data from patients with HP. Methods. A total of 16 patients with HP were included in our study. The clinical features, laboratory evaluation, imaging findings, treatment, and outcome were reviewed. Results. Of the 16 cases, half were male, with a mean age of 52.6±13.2 years. The mean duration from onset to diagnosis was 8.6 months. The most frequent presenting symptoms in HP cases were a recurrently chronic headache (81.3%) and multiple cranial nerve injury (50%). Antineutrophil cytoplasmic antibody- (ANCA-) related HP was found in 5 cases and IgG4-related HP in 1 case. The intracranial pressure was elevated in 4 cases. The cerebrospinal fluid (CSF) had lymphocytosis in 5 cases and increased protein in 12 cases. Immunoglobulins (IgG, IgA, and IgM) and protein showed linear relationships in the CSF. On magnetic resonance imaging (MRI), localized or diffuse dura maters were thickened in all cases. HP combined with subacute subdural hemorrhage or hypertrophic spinal pachymeningitis was also observed in individual cases. Biopsy of the dura mater in one case showed amounts of inflammatory cells infiltrating, with an increased percentage of IgG4-positive plasma cells. Of all cases referring to glucocorticoid treatment, the symptoms have improved significantly in 10 cases. In other 6 cases, mycophenolate mofetil or azathioprine was added. All patients showed clinical improvement at the follow-up visits. Conclusion. The clinical characters of HP are chronic onset, recurrently chronic headache, and multiple cranial nerves paralysis. Inflammatory changes in CSF caused by intrathecal synthesis of immunoglobulin, characteristic dural enhancement on MRI, and pathologic biopsy are all helpful for diagnosis. The addition of immunosuppressant, especially mycophenolate mofetil, is a good choice for steroid-resistance HP.

Rationale: Ischemic white matter damage frequently results in myelin loss, accompanied with microglial activation. We previously found that directing microglia towards an anti-inflammatory phenotype provided a beneficial microenvironment and helped maintain white matter integrity during chronic cerebral hypoperfusion. However, the molecular mechanisms underlying microglial polarization remain elusive. Methods: Hypoperfusion induced white matter damage mice model and lipopolysaccharide (LPS) induced primary cultured microglia were established. Autophagy activation in microglia was detected both in vivo and in vitro by immunofluorescence, Western blot and electron microscopy. Autophagy inhibitors/agonist were administrated to investigate the role of autophagic process in modulating microglial phenotypes. Quantitative real time-polymerase chain reaction and Western blot were carried out to investigate the possible pathway. Results: We identified rapid accumulation of autophagosomes in primary cultured microglia exposed to LPS and within activated microglia during white matter ischemic damage. Autophagy inhibitors switched microglial function from pro-inflammatory to anti-inflammatory phenotype. Furthermore, we found TLR4, one of the major receptors binding LPS, was most highly expressed on microglia in corpus callosum during white matter ischemic damage, and TLR4 deficiency could mimic the phenomenon in microglial functional transformation, and exhibit a protective activity in chronic cerebral hypoperfusion. Whereas, the anti-inflammatory phenotype of microglia in TLR4 deficiency group was largely abolished by the activation of autophagic process. Finally, our transcriptional analysis confirmed that the up-regulation of STAT1 and down-regulation of STAT6 in microglia exposure to LPS could be reversed by autophagy inhibition. Conclusion: These results indicated that TLR4-dependent autophagy regulates microglial polarization and induces ischemic white matter damage via STAT1/6 pathway.

Background Salmonella is a major zoonotic food-borne pathogen that persists on poultry farms, and animals undergo reinfection with endemic strains. The present study aimed to investigate the characteristics and dissemination of antimicrobial-resistant Salmonella within and between broiler farms that used enrofloxacin and those that did not. Results Cloacal and environmental (litter, feed, and water) samples from two selected flocks in each of 12 farms owned by the same company were collected three times over a 30-day period of two production cycles during 2015–2016. The rate of Salmonella isolation was 7.8% (123/1584). Nine Salmonella serotypes (116 isolates) and seven untypable isolates were identified, and Salmonella Montevideo was the most prevalent serotype. Azithromycin-resistant (17.9%) and colistin-resistant (3.3%) isolates were detected, and multidrug-resistant isolates (43.1%) were also observed. No isolate was resistant to enrofloxacin or ciprofloxacin; however, intermediate resistance to enrofloxacin was significantly higher (P

Right heart catheterization is commonly used to measure right ventricle hemodynamic parameters and is the gold standard for pulmonary arterial hypertension diagnosis; however, it is not suitable for patients’ long-term follow-up. Non-invasive echocardiography and nuclear medicine have been applied to measure right ventricle anatomy and function, but the guidelines for the usefulness of clinical parameters remain to be established. The goal of this study is to identify reliable clinical parameters of right ventricle function in pulmonary arterial hypertension patients and analyze the relationship of these clinical parameters with the disease severity of pulmonary arterial hypertension. In this study, 23 normal subjects and 23 pulmonary arterial hypertension patients were recruited from January 2015 to March 2016. Pulmonary arterial hypertension patients were classified into moderate and severe pulmonary arterial hypertension groups according to their mean pulmonary arterial pressure levels. All the subjects were subjected to physical examination, chest X-ray, 12-lead electrocardiogram, right heart catheterization, two-dimensional echocardiography, and technetium 99m (99mTc) myocardial perfusion imaging. Compared to normal subjects, the right heart catheterization indexes including right ventricle systolic pressure, right ventricle end diastolic pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, pulmonary vascular resistance, and right ventricle end systolic pressure increased in pulmonary arterial hypertension patients and were correlated with mean pulmonary arterial pressure levels. Echocardiography parameters, including tricuspid regurgitation peak velocity, tricuspid regurgitation pressure gradient, tricuspid annular plane systolic excursion and fractional area, right ventricle-myocardial performance index, were significantly associated with the mean pulmonary arterial pressure levels in pulmonary arterial hypertension patients. Furthermore, myocardial perfusion imaging was not observed in the normal subjects but in pulmonary arterial hypertension patients, especially severe pulmonary arterial hypertension subgroup, and showed potential diagnostic properties for pulmonary arterial hypertension. In conclusion, mean pulmonary arterial pressure levels are correlated with several right heart catheterization and echocardiography markers in pulmonary arterial hypertension patients; echocardiography and 99mTc myocardial perfusion can be used to evaluate right ventricle performance in pulmonary arterial hypertension patients. Impact statement In this study, we analyzed the clinical parameters for evaluating RV function, including right ventricle catheterization (RHC), echocardiography, and technetium 99m (99mTc) myocardial perfusion imaging (MPI) in normal Asian subjects and PAH patients ( n = 23 for each group). Our results demonstrated that six RHC indexes, four echocardiography indexes and MPI index were significantly altered in PAH patients and correlated with the levels of mean pulmonary arterial pressure. Importantly, we evaluated the diagnostic performance of MPI and found that MPI has a strong diagnostic accuracy in PAH patients. The findings from this study will be of interest to clinical investigators who make diagnosis and therapeutic strategies for PAH patients.

PEDV remains one of the most important swine diseases that infects pigs of all ages. It causes devastating viral enteric disease in piglets with a high mortality rate, leading to significant threats and huge economic loss to the pork industry. In this study, a transcriptomic shotgun sequencing (RNA-Seq) procedure was used to study gene responses against PEDV infection. Genome-wide analysis of differentially expressed genes (DEGs) was performed in Vero E6 cells post-PEDV infection. mTOR signaling pathway activator-MHY1485, and inhibitor-PP242 were used to study the antiviral function. Results revealed that the IRF3 was significantly up-regulated post-PEDV infection. Although most of the IFN-regulatory and –related genes evaluated in this study were either down-regulated or remained unchanged, IL11 behaved significantly up-regulated, with the peak at 16 hpi. Nearly 90% of PEDV infections were suppressed in the PP242 pretreated cells whereas the reverse effect was observed in the MYH1485 pretreated cells. Results indicated that the mTOR signaling pathway played a vital role in the PEDV antiviral regulation in the Vero E6 cells. Future studies will contribute to better understand the cellular antiviral mechanism against PEDV., Highlights • RNA-Seq was used to study gene responses against PEDV infection. • Genome-wide analysis of DEGs was performed in Vero E6 cells post-PEDV infection. • The mTOR signaling pathway activator and inhibitor can affect the PEDV infection rate.

Background and Purpose— White matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model. Methods— Chronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis. Results— Disruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post–bilateral carotid artery stenosis–induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720’s effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling. Conclusions— Our study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.

Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) specifically infects the epithelial cells in the midgut of silkworm and causes them to death, which negatively affects the sericulture industry. In order to determine the midgut response at the protein levels to the virus infection, differential proteomes of the silkworm midgut responsive to BmCPV infection were identified with isobaric tags for relative and absolute quantitation (iTRAQ) labeling followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). 193, 408, 189 differentially expressed proteins (DEPs) were reliably quantified by iTRAQ analysis in the midgut of BmCPV-infected and control larvae at 24, 48, 72 h post infection (hpi) respectively. KEGG enrichment analysis showed that Oxidative phosphorylation, amyotrophic lateral sclerosis, Toll-like receptor signaling pathway, steroid hormone biosynthesis were the significant pathways (Q value ≤ 0.05) both at 24 and 48 hpi. qRT-PCR was used to further verify gene transcription of 30 DEPs from iTRAQ, showing that the regulations of 24 genes at the transcript level were consistent with those at the proteomic level. Moreover, the cluster analysis of the three time groups showed that there were seven co-regulated DEPs including BGIBMGA002620-PA, which was a putative p62/sequestosome-1 protein in silkworm. It was upregulated at both the mRNA level and the proteomic level and may play an important role in regulating the autophagy and apoptosis (especially apoptosis) induced by BmCPV infection. This was the first report using an iTRAQ approach to analyze proteomes of the silkworm midgut against BmCPV infection, which contributes to understanding the defense mechanisms of silkworm midgut to virus infection. Significance The domesticated silkworm, Bombyx mori, is renowned for silk production as well as being a traditional lepidopteron model insect served as a subject for morphological, genetic, physiological, and developmental studies. Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) specifically infects the epithelial cells in the midgut of silkworm and causes the silkworm to death, which negatively affects the sericulture industry. Studies on insect antiviral immunity and on interactive mechanisms between host cells and BmCPV are in their infancy and remain insufficient. In order to obtain an overall view of silkworm response to BmCPV infection, we performed a proteomic analysis of the midgut of silkworm responses to BmCPV infection by iTRAQ. This was the first report using an iTRAQ approach to analyze proteomes of the silkworm midgut against BmCPV infection, which contributes to understanding the defense mechanisms of silkworm midgut to virus infection.

Background Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Proteins associated with acute LVO pathogenesis and endothelial function may appear in blood samples of AIS patients due to LVO, thus permitting development of blood-based biomarkers for its diagnosis and prognosis. Methods This study is a single-center, retrospective, observational case–control trial. Consecutive patients who presented at the Department of Neurology of Tongji Hospital were recruited from July 2016 to April 2018. In the discovery phase, a proteomic approach with iTRAQ-based LC–MS/MS was used to investigate the altered proteomic pattern in plasma from patients with AIS due to LVO. In the validation study, Western blots was used to identify biomarkers associated with stroke diagnosis as well as their prognostic value associated with different collateral statuses. Results For this exploratory study, the proteomic analysis of plasma from 40 patients with AIS due to LVO and 20 healthy controls revealed seven differentially expressed proteins with a 1.2/0.83-fold or greater difference between groups. The four elevated proteins, PPBP (1.58 ± 0.78 vs 0.98 ± 0.37; P Conclusions The identified 4-biomarker panel could provide diagnostic aid to the existing imaging modalities for AIS due to LVO, and the prognostic value of IGF2, LYVE1, and THBS1 was proved in predicting functional outcomes related to collateral status. Trial registration ClinicalTrials.gov NCT 03122002. Retrospectively registered April 20, 2017. URL of trial registry record: https://www.clinicaltrials.gov/ct2/show/NCT03122002?term=NCT+03122002&rank=1

Background Neuromyelitis optica spectrum disorder (NMOSD) refers to a range of autoimmune inflammatory demyelinating diseases affecting the optic nerves, spinal cord, and periependymal regions of the brain. Classical NMOSD is characterized by the presentation of autoantibodies against the water channel aquaporin-4 (AQP4). However, a subset of patients fulfilling the clinical criteria for NMOSD is negative for AQP4-IgG but positive for autoantibodies against myelin oligodendrocyte glycoprotein (MOG); these patients are associated with different clinical manifestations and pathogenesis. Methods Patients who received a first diagnosis of NMOSD were reviewed retrospectively between April 2015 and December 2018. Patients were classified according to the presence of AQP4-IgG and MOG-IgG in serum and/or cerebrospinal fluid. Clinical characteristics, magnetic resonance imaging findings, disease severity, and serum C3 and C4 levels at the first episode were compared between the groups. Results The NMOSD patients with AQP4-IgG and MOG-IgG demonstrated specific, differential clinical features. The AQP4-IgG group featured more women, the presentation of transverse myelitis attacks and simultaneous occurrence of optic neuritis and transverse myelitis were more common, and intrathecal synthesis was more evident. The MOG-IgG group featured younger patients, more acute disseminated encephalomyelitis (ADEM) or ADEM-like attacks, more frequent cerebrospinal fluid pleocytosis, and a better overall outcome. C3 levels were significantly lower in AQP4-IgG-positive patients and higher in MOG-IgG-positive patients relative to healthy controls. C4 levels were significantly lower in the AQP4-IgG-positive NMOSD group when compared to both MOG-IgG-positive patients and controls. C3 and C4 were then combined in a receiver operating characteristic model. The area under the curve of the model was calculated to differentiate the AQP4-IgG-positive group from the MOG-IgG-positive group was 0.787, which was considered moderately predictive. Conclusion The combination of C3 and C4 could assist in the differential diagnosis of AQP4-IgG-positive NMOSD from MOG-IgG-positive NMOSD.

Supplemental Digital Content is available in the text, Rationale: Risk factors of cerebral venous sinus thrombosis (CVST) are usually divided into acquired risks (e.g., trauma and pregnancy) and genetic risks (inherited thrombophilia). It is essential but not easy to identify the exact one for each patient. Patient concerns: A 14-year-old male patient was admitted in our hospital because of progressively exacerbated severe headache and vomiting for 3 days, accompanied by transient weakness once in his right leg. Diagnosis: CVST due to hyperhomocysteinemia with cystathionine-β-synthase (CBS) gene mutation. Interventions: Persistent oral anticoagulant therapy. Outcomes: Follow-ups at 4 months and 1 year showed that the patient's symptoms alleviated and did not recur, accompanied with improved MRV image; however, the cranial MRV image did not display as a completely normal one. Lessons: We recommend that in case of thrombophilic state, serum homocysteine (Hcy), folic acid, and vitamin B12 levels should be routinely screened; when serum Hcy level is extremely high, congenital diseases caused by gene mutations should be considered. We firstly discovered a new mutation of CBS c.949A>G which had not been reported before.

Rhabdomyolysis could be caused by various mechanisms including autoimmune reaction. Here, we reported a case of 76-year-old-woman diagnosed with aquaporin-4 (AQP4) IgG positive neuromyelitis optica spectrum disorder (NMOSD) following rhabdomyolysis. After a review of literature, we propose that physical injury of skeletal muscle cells may lead to the production of AQP4 IgG and this AQP4 IgG might further decrease in the stability of skeletal muscle cells creating a positive feedback loop. HyperCKemia might be an inducement of NMOSD.

Interleukin-33 (IL-33), a member of the IL-1 superfamily, has been shown to play a critical role in many diseases through regulating the immune cell responses, including myeloid-derived suppressor cells (MDSCs). Our previous study demonstrated that IL-33 might play a protective role in kidney injury in gout patients by regulating the lipid metabolism. However, the role of IL-33in the development of MSU-induced inflammation remains elusive. In this study, an increased IL-33 expression was observed in gout patients, which was positively correlated with inflammatory marker CRP. To explore the effects and mechanisms of the increased IL-33 expression in the gout patients, the anti-ST2 antibody and exogenous recombinant IL-33 were used in MSU-induced peritonitis animal model that mimics human gout. Compared with control group, mice with exogenous recombinant IL-33 significantly ameliorated the inflammatory cells infiltration, while blockage of IL-33 signaling by anti-ST2 had no effect on the development of MSU-induced peritonitis. Furthermore, the crucial inflammatory cytokine IL-1β was markedly decreased in IL-33-treated mice. Besides that, a large number of anti-inflammatory MDSCs with CD11b+Gr1intF4/80+ phenotype was observed in the IL-33-treated mice, and adoptive transfer of IL-33-induced MDSCs (CD11b+Gr1intF4/80+) markedly inhibited the IL-1β production in MSU-induced peritonitis. In conclusion, our data provide clear evidences that the increased expression of IL-33 in the gout patients might be due to a cause of self-negative regulation, which inhibits the development of MSU-induced inflammation through expanding MDSCs. Thus, IL-33 might serve as a promising therapeutic target for gout.

Gout is a common metabolic disease in humans, and it is due to persistently elevated levels of uric acid in the blood. At high levels, uric acid crystallizes and the crystals deposit in joints and surrounding tissues, resulting in an attack of gout. Interestingly, the gout attack can spontaneously resolve within a few days. However, the self-limited mechanism of gout remains elusive. It has been demonstrated that CD14 plays an important role in self-remission of gout. In this study, we found that the proportion of CD14-positive PBMCs was decreased in gout patients when compared with healthy controls and the serum sCD14 level was also considerably decreased in gout patients in comparison to healthy controls. In addition, sCD14 levels were positively correlated with CRP levels. Furthermore, the effect of MSU on the levels of CD14 in healthy volunteer’s PBMC was explored in in vitro experiment. The results showed that CD14 expression on macrophage and sCD14 levels in the culture supernatants were significantly decreased after MSU treatment. However, there was no significance in the levels of membrane CD14 and sCD14 in healthy volunteer’s PBMC stimulated by LPS. Taken together, these results suggest that CD14 might play an important role in self-remission of gout.

The cDNA of a biphenyl hydrolase-like (BPHL) protein from Bombyx mori was cloned via rapid amplification of cDNA ends and submitted to GenBank under accession number JN020647 . The full-length BmBPHL cDNA was 1161 bp, with four exons and three introns. It consisted of a 208 bp 5′-terminal untranslated region (UTR) and a 191 bp 3′-UTR with three polyadenylation signal sequences AATAAA and a poly(A) tail. The BmBPHL cDNA encodes a 253–amino acid polypeptide with a theoretical isoelectric point of 8.67 and a predicted molecular weight of 28.9 kDa. The deduced amino acid sequence of BmBPHL contained an abhydrolase _ 6 domain and the Gly-X-Ser-X-Gly motif that is characteristic of serine hydrolases. Sequence comparison showed that BmBPHL is 51% identical to Tribolium castaneum BPHL and 50% identical to Nasonia vitripennis BPHL. Phylogenetic analysis revealed that BmBPHL is grouped with insect BPHL proteins, separating from vertebrate BPHLs. The BmBPHL mRNA transcripts were mainly detected in hemolymph and fat body using fluorescent quantitative real-time PCR. In addition, infection with B. mori cytoplasmic polyhedrosis virus (BmCPV) upregulated the relative BmBPHL expression in the hemolymph and midgut. Therefore, BmBPHL may have an important function in the response of silkworms to BmCPV infection.

Fontan surgery is a widely used palliative procedure that significantly improves the survival period of patients with complex congenital heart disease (CHD). However, it does not decrease postoperative complication rate. Previous studies suggested that elevated mean pulmonary artery pressure (mPAP) and vascular resistance lead to decreased exercise tolerance and myocardial dysfunction. Therapy with endothelial receptor antagonists (Bosentan) has been demonstrated to improve the patients' prognosis. A double-blind, randomized controlled trial was performed to explore the efficacy of Bosentan in treating patients who underwent the Fontan procedure. Eligible participants were randomly divided into Bosentan group and control group. Liver function was tested at a local hospital and the results were reported to the phone inspector every month. If the results suggested abnormal liver function, treatment would be adjusted or terminated. All the participants finished the follow-up study, with no patients lost to follow-up. Unblinding after 2-year follow-up, no mortality was observed in either group. However, secondary end-points were found to be significantly different in the comparable groups. The cardiac function and 6-min walking distance in the Bosentan group were significantly superior to those in the control group (P=0.018 and P=0.027). Bosentan could improve New York Heart Association (NYHA) functional status and improve the results of the 6-min walking test (6MWT) in Fontan patients post-surgery, and no other benefits were observed. Furthermore, a primary meta-analysis study systematically reviewed all the similar clinical trails worldwide and concluded an overall NYHA class improvement in Fontan patients who received Bosentan treatments.

The aim of the present study was to investigate variation in antimicrobial resistance in Clostridium perfringens (C. perfringens) isolated from chickens after withdrawal of antimicrobial growth promoters (AGPs), and to investigate the correlation between the presence of toxin genes (cpb2, netB, and tpeL) and antimicrobial resistance. Altogether, 162 isolates of C. perfringens were obtained from chickens displaying clinical signs of necrotic enteritis (n = 65) and from healthy chickens (n = 97) in Korea during 2010&ndash, 2016. Compared to before AGP withdrawal, increased antimicrobial resistance or MIC50/MIC90 value was observed for nine antimicrobials including penicillin, tetracycline, tylosin, erythromycin, florfenicol, enrofloxacin, monensin, salinomycin, and maduramycin. Significantly (p &lt, 0.05) higher resistance to gentamicin, clindamycin, and virginiamycin was found in isolates from chickens with necrotic enteritis compared to those from healthy chickens. tpeL gene was not detected in C. perfringens isolates from healthy chickens. A correlation between toxin gene prevalence and antibiotic resistance was found in the C. perfringens isolates. Because the usage of antimicrobials may contribute to the selection of both resistance and toxin genes, these can potentially make it challenging to control antimicrobial resistance in pathogenic colonies. Therefore, a more complete understanding of the interplay between resistance and virulence genes is required.

The main purpose of this research was to evaluate the element distribution in the edible viscera of Tibetan pigs and to clarify its correlation with soils, drinking water and feed. A total of 55 chemical elements were simultaneously quantified. P, K, Na, Mg, Ca, Fe and Zn were the most abundant elements in the analyzed viscera. The general distribution of all element concentrations in the viscera of Tibetan pigs was such that liver > kidney > small intestine > heart = lung = large intestine > stomach. Comparison with national and international allowable limits of toxic elements indicates that consumption of Tibetan pig viscera presents potential health risks. Spearman correlation analysis reveals that significantly (p

Introduction Microglial activation plays a crucial role in the pathology of ischemic stroke. Recently, we demonstrated that fingolimod (FTY720) exerted neuroprotective effects via immunomodulation in ischemic white matter damage induced by chronic cerebral hypoperfusion, which was accompanied by robust microglial activation. In this study, we assessed the pro-angiogenic potential of FTY720 in a murine model of acute cortical ischemic stroke. Methods The photothrombotic (PT) method was used to induce cortical ischemic stroke in mice. We evaluated cortical damage, behavioral deficits, microglial polarization, and angiogenesis to identify the neuroprotective effects and possible molecular mechanisms of FTY720 in acute ischemic stroke. Results In vivo, a reduction in neuronal loss and improved motor function were observed in FTY720-treated mice after PT stroke. Immunofluorescence staining revealed that robust microglial activation and the associated neuroinflammatory response in the peri-infarct area were ameliorated by FTY720 via its ability to polarize microglia toward the M2 phenotype. Furthermore, both in vivo and in vitro, angiogenesis was enhanced in the microglial M2 phenotype state. Behaviorally, a significant improvement in the FTY720-treated group compared to the control group was evident from days 7 to 14. Conclusions Our research indicated that FTY720 treatment promoted angiogenesis via microglial M2 polarization and exerted neuroprotection in PT ischemic stroke.

Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) is a major pathogen of the economic insect silkworm, Bombyx mori. Virus-encoded microRNAs (miRNAs) have been proven to play important roles in host-pathogen interactions. In this study we identified a BmCPV-derived miRNA-like 21 nt small RNA, BmCPV-miR-1, from the small RNA deep sequencing of BmCPV-infected silkworm larvae by stem-loop quantitative real-time PCR (qPCR) and investigated its functions with qPCR and lentiviral expression systems. Bombyx mori inhibitor of apoptosis protein (BmIAP) gene was predicted by both target prediction software miRanda and Targetscan to be one of its target genes with a binding site for BmCPV-miR-1 at the 5' untranslated region. It was found that the expression of BmCPV-miR-1 and its target gene BmIAP were both up-regulated in BmCPV-infected larvae. At the same time, it was confirmed that BmCPV-miR-1 could up-regulate the expression of BmIAP gene in HEK293T cells with lentiviral expression systems and in BmN cells by transfecting mimics. Furthermore, BmCPV-miR-1 mimics could up-regulate the expression level of BmIAP gene in midgut and fat body in the silkworm. In the midgut of BmCPV-infected larvae, BmCPV-miR-1 mimics could be further up-regulated and inhibitors could lower the virus-mediated expression of BmIAP gene. With the viral genomic RNA segments S1 and S10 as indicators, BmCPV-miR-1 mimics could up-regulate and inhibitors down-regulate their replication in the infected silkworm. These results implied that BmCPV-miR-1 could inhibit cell apoptosis in the infected silkworm through up-regulating BmIAP expression, providing the virus with a better cell circumstance for its replication.

Communities are virtually ubiquitous in real-world networks, and the statistic of modularity index Q is the classical measurement for community detection algorithms. However, the relationship between the modularity property and network multilever micro-scale structures is still not clear. In this paper, we study community detection results both in artificial and real-life complex networks by constructing different order null networks, and the results uncover that how micro-structures (such as degree distribution, assortativity and clustering coefficient) affect community properties. Meanwhile, we also propose two novel null networks (increasing or decreasing community structures) to verify the robustness of different community detection algorithms. Our results indicate that the modularity index Q is not a suitable statistic to measure the weak community property which is widely available in empirical networks. Our findings can not only be used to test the robustness of different community detection methods, but also be helpful to uncover the correlation of network structures between microcosmic and mesoscopic scales.

The present study describes the case of a 2.5-year-old girl with double patent ductus arteriosus (PDA) that was successfully treated following interventional and surgical treatment. Bilateral ductus arteriosus is a very rare condition, which is assumed to occur when the branchial-type arterial system transforms into the mammalian-type arterial system during the development of the aorta and its branches. This case was misdiagnosed as ordinary PDA by echocardiography prior to the first surgery and the surgery was not successful because of poor accessibility. Enhanced computed tomography subsequently showed situs solitus, atrial situs, levocardia, right-sided aortic arch with right-sided descending aorta, an isolated left subclavian artery and double PDA. Interventional treatment was performed and intraoperative aortic arch angiography showed that the descending aorta was the origin of the first funnel-type PDA (PDA-1). The left subclavian artery was not connected to the aorta but was connected to the pulmonary artery with a very narrow winding duct, which was PDA-2. Interventional treatment via PDA-2 also failed because passing a guidewire through the twisted PDA-2 was difficult. The child was immediately transferred to the surgical operation room for double PDA ligation and left subclavian artery reconstruction under median thoracotomy. The surgical procedure succeeded and the patient recovered quickly. The failure of the interventional treatment may be attributed to the difficulty in establishing a path. The soft tip of the hardened guidewire was relatively long. If the hardened part of the wire was sent to the appropriate place to support the pathway, the soft tip would be forced to enter the vertebrobasilar artery system. A similar problem was encountered when the left subclavian artery was selected for intervention. Shortening the length of the soft tip of the hardened guidewire may have enabled smooth completion of the establishment of the pathway. However, this type of hardened guidewire requires specific production.

To compare the clinical, imaging, and arthroscopic characteristics of the torn discoid lateral meniscus (TDLM) in patients greater than 40 years of age with matched controls. One hundred and ninety-four older patients (211 knees) who underwent arthroscopic surgery for a TDLM were consecutively recruited (Group 1). Another 211 age- and sex-matched controls with a torn semilunar lateral meniscus were included in this study (Group 2). Statistical analyses were used to determine the differences in the clinical, imaging, and arthroscopic characteristics between the two groups. In our series, more severe medial meniscal extrusion on magnetic resonance imaging was present in Group 1 than in Group 2 and more serious osteoarthritic changes were observed in both the medial and lateral compartments in Group 1. Under the same conditions, chondral lesions in the knee were more serious in Group 1 than in Group 2 when patients were subgrouped according to the presence of a horizontal tear or complex tear. In the present study, older patients with a torn discoid lateral meniscus exhibited greater and more severe medial meniscal extrusion and more serious osteoarthritis. Therefore, knees with a discoid lateral meniscus displaying medial meniscal extrusion should be monitored carefully with long-term follow-up, because a medial meniscal extrusion may increase the risk of progression to degenerative osteoarthritis of the medial compartment. Regarding the clinical relevance, these findings will be helpful in further revealing that a torn discoid lateral meniscus may affect not only the cartilage in the lateral compartment but also the cartilage in the medial compartment and medial meniscal extrusion. III.

Bcl-2 is an anti-apoptotic gene that is frequently overexpressed in human cancers. G3139 is an antisense oligonucleotide against bcl-2 that has shown limited efficacy in clinical trials. Here, we report the synthesis of a new antisense oligonucleotide containing additional chemical modifications and its delivery using nanoparticles. An oligonucleotide G3139-GAP was synthesized, which has 2’-O-methyl nucleotides at the 5’ and 3’ ends based on a “gapmer” design. Furthermore, G3139-GAP was incorporated into lipid nanoparticles (LNPs) composed of DOTAP/egg PC/cholesterol/Tween 80. The LNP-loaded G3139-GAP was evaluated in A549 lung cancer cells both in vitro and in a murine xenograft model for biological activity and therapeutic efficacy. The LNPs showed excellent colloidal and serum stability, and high encapsulation efficiency for G3139-GAP. They have a mean particle diameter and zeta potential of 134 nm and 9.59 mV, respectively. G3139-GAP-LNPs efficiently downregulated bcl-2 expression in A549 cells, as shown by 40% and 83% reduction in mRNA and protein levels, respectively. Furthermore, G3139-GAP-LNPs were shown to inhibit tumor growth, prolong survival, and downregulate tumor bcl-2 expression in an A549 murine xenograft tumor model. These data indicate that G3139-GAP-LNPs have excellent anti-tumor efficacy and warrant further evaluation.

Supplemental Digital Content is available in the text, Background and purpose: Whether the direct aspiration approach of thrombectomy for recanalization in patients with acute ischemic stroke has a similar efficacy and safety compared to the stent-retriever remains uncertain. Methods: We conducted a meta-analysis of 9 studies obtained through PubMed and Embase database searches to determine whether successful recanalization rate, good functional outcome at 3 months (modified Rankin score, mRS≤2), procedure time from groin puncture to maximal revascularization and procedure-related adverse events differed between patients who underwent the direct aspiration and those receiving stent-retriever for recanalization in acute cerebral infarction. Results: There was no significant difference between the direct aspiration group and the stent-retriever group in rate of successful recanalization (summary odds ratio [OR], 0.86 [95% confidence interval (CI), 0.45–1.52]; P = .60), but a better functional outcomes in the direct aspiration group at 3 months defined as a mRS score of 0 to 2 (OR, 0.77; 95% CI, 0.66–0.97; P = .03). Furthermore, the direct aspiration patients compared with the stent-retriever patients had a tendency of shorter procedural time (Mean difference [MD], -8.77 [95% CI, from-18.90 to 1.37]; P = .09). Finally, there were less adverse events especially in symptomatic intracerebral hemorrhage (sICH) (OR, 0.56; 95% CI, 0.33–0.98; P = .04) and embolization to a new territory (ENT) (OR, 0.49; 95% CI, 0.28–0.84; P = .01) in the direct aspiration group when compared with the stent-retriever group, although no difference between them in the rate of any ICH (OR, 0.81; 95% CI, 0.41–1.60; P = .54). Conclusions: The results support that the direct aspiration technique for those acute ischemic stroke patients may have better functional outcomes, less procedure related-adverse events and a tendency of faster revascularization time as compared to the stent-retriever thrombectomy, with a similar successful recanalization rate. However, major limitations of current evidence (mainly from retrospective and observational studies and a small number of patients population) indicate a need for adequately powered, multicenter randomized controlled trials (RCT) to answer this question.

Newcastle disease virus (NDV) and Salmonella Pullorum have significant damaging effects on the poultry industry, but no previous vaccine can protect poultry effectively. In this study, a recombinant-attenuated S. Pullorum strain secreting the NDV hemagglutinin-neuraminidase (HN) protein, C79-13ΔcrpΔasd (pYA-HN), was constructed by using the suicide plasmid pREasd-mediated bacteria homologous recombination method to form a new bivalent vaccine candidate against Newcastle disease (ND) and S. Pullorum disease (PD). The effect of this vaccine candidate was compared with those of the NDV LaSota and C79-13ΔcrpΔasd (pYA) strains. The serum hemagglutination inhibition antibody titers, serum immunoglobulin G (IgG) antibodies, secretory IgA, and stimulation index in lymphocyte proliferation were increased significantly more (p 0.05). Moreover, the novel strain provides 60% and 80% protective efficacy against the NDV virulent strain F48E9 and the S. Pullorum virulent strain C79-13. In summary, in this study, a recombinant-attenuated S. Pullorum strain secreting NDV HN protein was constructed. The generation of the S. Pullorum C79-13ΔcrpΔasd (pYA-HN) strain provides a foundation for the development of an effective living-vector double vaccine against ND and PD.

Background: Cellular damage initiated by reactive oxygen species (ROS) is the main cause of numerous severe diseases and therefore for this reason, the natural antioxidants have note worthy significance in human health. Capsaicin possesses noteworthy analgesic and anti-inflammatory properties. It also possesses healing effects for treatment of arthritis, diabetic neuropathy, gastric lesions, and cardiac excitability that is why it is incorporated in creams and gels. Objective: The present study was carried out to estimate the in vitro antioxidant and ROS scavenging activities of capsaicin against muscle precursor cells. Till date,no investigation has been carried out to study the effect of capsaicin on myoblasts.Materials and methods: Herein, the cytotoxicity was induced by endotoxin lipopolysaccharide (LPS) to analyze the effect of capsaicin on LPS induced inflammation and apoptosis on muscle cells. To find out the toxicity of endotoxin, myoblasts were exposed to different concentrations of LPS, viability and morphology was checkedby the means of CCK-8 test and microscopy, respectively. Apoptotic cell death was examined by fluorescence staining. Additionally, LPS-induced apoptosis was determined by mRNAexpression of calpain, caspase-3 and tumor necrosisfactor alpha (TNF-α), and were quantified by qRT-PCR. Results: The outcome of the presentstudy demonstrated that LPS stimulation generatestoxicity in dose-dependent manner. Pre-treatmentof myoblasts with capsaicin can considerably alleviate LPS-induced inflammation. Conclusion: In conclusion, this study indicates that dietetic supplementation of capsicum may help to alleviate/reduce the inflammatory effects and is therefore potent source of natural antioxidant agent which can be utilized to control muscle related diseases, such as myotube atrophy. Abbreviation used: AMP: Adenosine monophosphate, AO/EB: Acridine orange / Ethidium bromide, ATL: T-cell leukemi, CAP: Capsaicin, CCK-8: Cell counting Kit-8, CLSM: Laser Scanning Microscopy, DCF-DA: 2', 7'-dichlorofluorescein diacetate, DMEM: Dulbecco's modified Eagle's medium, DPPH: α, α-diphenyl-β-picrylhydrazyl, FBS: Fetal bovine serum, KA: Kainic acid, LPS: Lipopolysaccharide, MDA: Malondialdehyde, NF-kB: Nuclear factor kgene binding, PBS: Phosphate buffer saline, pNA: p-nitroanilide, RNW: RNase free water, ROS: Reactive oxygen species, TNF-α: Tumor necrosis factor alpha, TRPV1: Transient receptor potential vanilloid 1