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Rabies is a viral disease that is nearly 100% fatal once clinical signs and symptoms develop. Post-exposure prophylaxis can efficiently prevent rabies, and antibody (Ab) induction by vaccination or passive immunization of human rabies immunoglobulin (HRIG) or monoclonal antibodies (mAbs) play an integral role in prevention against rabies. In addition to their capacity to neutralize viruses, antibodies exert their antiviral effects by antibody-dependent cellular cytotoxicity (ADCC), which plays an important role in antiviral immunity and clearance of viral infections. For antibodies against rabies virus (RABV), evaluation of ADCC activity was neglected. Here, we developed a robust cell-based reporter gene assay (RGA) for the determination of the ADCC activity of anti-RABV antibodies using CVS-N2c-293 cells, which stably express the glycoprotein (G) of RABV strain CVS-N2c as target cells, and Jurkat cells, which stably express FcγRⅢa and nuclear factor of activated T cells (NFAT) reporter gene as effector cells (Jurkat/NFAT-luc/FcγRⅢa cells). The experimental parameters were carefully optimized, and the established ADCC assay was systematically validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q2 guideline. We also evaluated the ADCC activity of anti-RABV antibodies, including mAbs, HRIG, and vaccine induced antisera, and found that all test antibodies exhibited ADCC activity with varied strengths. The established RGA provides a novel method for evaluating the ADCC of anti-RABV antibodies.

Mathematical ability is moderately heritable, and it is a complex trait which can be evaluated in several different categories. A few genetic studies have been published on general mathematical ability. However, no genetic study focused on specific mathematical ability categories. In this study, we separately performed genome-wide association studies (GWASs) on 11 mathematical ability categories in 1 146 students from Chinese elementary schools. We identified 7 genome-wide significant single nucleotide polymorphisms (SNPs) with strong linkage disequilibrium (LD) among each other (all r2>0.8) associated with mathematical reasoning ability (top SNP: rs34034296,p=2.01×10−8, nearest gene: CUB and Sushi multiple domains 3, CSMD3). We replicated one SNP (rs133885) from 585 SNPs previously reported to be associated with general mathematical ability associated with division ability in our data (p=1.053×10−5). In the gene- and gene-set enrichment analysis by MAGMA, we found three significant enrichments of associations with three mathematical ability categories for three genes. We also observed four significant enrichments of associations with four mathematical ability categories for three gene sets. Our results suggest new candidate genetic loci for the genetics of mathematical ability.

Reading disability exhibited defects in different cognitive domains, including word reading fluency, word reading accuracy, phonological awareness, rapid automatized naming and morphological awareness. To identify the genetic basis of Chinese reading disability, we conducted a genome-wide association study (GWAS) of the cognitive traits related to Chinese reading disability in 2284 unrelated Chinese children. Among the traits analyzed in the present GWAS, we detected one genome-wide significant association (p 5 × 10

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of uncut Roux‐en‐Y reconstruction after distal gastrectomy for patients with gastric carcinoma.

BACKGROUND Intronic (TTTCA)n insertions in the SAMD12, TNRC6A, and RAPGEF2 genes have been identified as causes of familial cortical myoclonic tremor with epilepsy. OBJECTIVE To identify the cause of familial cortical myoclonic tremor with epilepsy pedigrees without (TTTCA)n insertions in SAMD12, TNRC6A, and RAPGEF2. METHODS Repeat-primed polymerase chain reaction, long-range polymerase chain reaction, and Sanger sequencing were performed to identify the existence of a novel (TTTGA)n insertion. Targeted long-read sequencing was performed to confirm the accurate structure of the (TTTGA)n insertion. RESULTS We identified a novel expanded intronic (TTTGA)n insertion at the same site as the previously reported (TTTCA)n insertion in SAMD12. This insertion cosegregated with familial cortical myoclonic tremor with epilepsy in 1 Chinese pedigree with no (TTTCA)n insertion. In the targeted long-read sequencing of 2 patients and 1 asymptomatic carrier in this pedigree, with 1 previously reported (TTTCA)n -insertion-carrying patient as a positive control, a respective total of 302, 159, 207, and 50 on-target subreads (predicated accuracy: ≥90%) spanning the target repeat expansion region were generated. These sequencing data revealed the accurate repeat expansion structures as (TTTTA)114-123 (TTTGA)108-116 in the pedigree and (TTTTA)38 (TTTCA)479 in (TTTCA)n -insertion-carrying patient. CONCLUSION The targeted long-read sequencing helped us to elucidate the accurate structures of the (TTTGA)n and (TTTCA)n insertions. Our finding offers a novel possible cause for familial cortical myoclonic tremor with epilepsy and might shed light on the identification of genetic causes of this disease in pedigrees with no detected (TTTCA)n insertion in the reported causative genes. © 2019 International Parkinson and Movement Disorder Society.

Objective. We aimed to study the longitudinal associations between genetic risk, change in diet quality, and change in visceral adipose tissue (ΔVAT), abdominal subcutaneous adipose tissue (ΔSAT), and pericardial adipose tissue (ΔPAT). Methods. We analyzed 1,677 Framingham Heart Study participants who had ectopic fat depots measured using computed tomography. We quantified diet quality using a Mediterranean-style diet score (MDS) and genetic risk by depot-specific genetic risk scores (GRSs). Results. Per standard deviation improvement in MDS, there was 50 cm3 (95% CI: 14, 86; p=0.007) less fat accumulation in VAT; 52 cm3 (95% CI: 12, 92; p=0.01) less fat accumulation in SAT; and 1.3 cm3 (95% CI: 0.1, 2.4; p=0.04) less fat accumulation in PAT. No association was observed between GRSs and ΔVAT or ΔSAT. One standard deviation increase in the PAT GRS was associated with 1.2 cm3 (95% CI: 0.1, 2.3; p=0.03) increase in ΔPAT. In participants with higher PAT GRS, those with ΔMDS ≥0 had a favorable change in PAT compared to the counterparts with ΔMDS

Human enterovirus 68 (EVD68) is a primary causative agent for respiratory illness worldwide. Until now, there has been no available medication for treating EVD68-related diseases. Rheum emodin, artemisinin, astragaloside, pseudolaric acid B, oridonin, and erianin are natural extracts from Chinese herbs that have traditionally been used for the treatment and prevention of epidemic diseases. Our results showed that pseudolaric acid B protected cells from EVD68-induced cytopathic effects and decreased viral production. However, the same effects were not observed with rheum emodin, astragaloside, or artemisinin. Pseudolaric acid B inhibited EVD68 production by manipulating the host cell cycle in G2/M phase. Further, either oridonin or erianin related G2/M arrest also inhibited viral production. Due to inducing G2/M phase arrest, pseudolaric acid B, oridonin, and erianin might be good candidates for inhibiting EVD68 production, and Chinese herbs with natural compounds inducing G2/M arrest should be considered for the treatment of EVD68-related diseases.

Background & aims Few molecules are currently verified to be actionable drug targets in cholangiocarcinoma (CCA). Serine/threonine protein phosphatase 5 (PP5) dysregulation is related to several malignancies. However, the role of PP5 in CCA is poorly defined. Methods Colony and tumorsphere formation assays were conducted to establish the role of PP5 in CCA tumorigenesis. Cantharidin (CTD) and norcantharidin (NCTD), both potent PP5 inhibitors, were used in in vitro and in vivo experiments to validate the potential therapeutic role of PP5. Results Increased cell growth, colony formation and tumorsphere formation were observed in PP5-overexpressing CCA cells, whereas PP5 knockdown by shRNA decreased cell growth and colony formation. Tumours from HuCCT1 xenograft-bearing mice treated with PP5-shRNA showed decreased growth and increased AMP-activated protein kinase (AMPK) phosphorylation. Furthermore, CTD treatment decreased cell viability, reduced PP5 activity and enhanced AMPK phosphorylation in CCA cell lines. Overexpressing PP5 or enhancing PP5 activity suppressed AMPK phosphorylation and decreased CTD-induced cell death. Suppressing p-AMPK with siRNA or inhibitors also decreased CTD-induced cell death, suggesting a pivotal role for PP5-AMPK cascades in CCA. Immunoprecipitation revealed that PP5 interacted with AMPK. Importantly, treatment of HuCCT1 xenograft-bearing mice with NCTD, a CTD analogue with a lower systemic toxicity in vivo, suppressed PP5 activity, increased p-AMPK and reduced tumour volume. Conclusions Protein phosphatase 5 negatively regulates AMPK phosphorylation and contributes to CCA aggressiveness; thus, PP5 may be a potential therapeutic target in CCA.

Herein, in-situ high pressure Raman spectra of 7,7,8,8-tetracyanoquinodimethane (TCNQ) have been measured up to 10 GPa, and a first-order phase transition was detected at about 2.3 GPa. An anharmonic coupling (Fermi resonance) between fundamental modes was observed. The relationship of Fermi resonance parameters (intensity ratio, coupling coefficient, frequency separation and frequency separation of unperturbed transition) with pressure was discussed. The frequency separation dominated the decay of the intensity ratio of Fermi resonance doublets, and this would be another character of anharmonic coupling between fundamental modes. Copyright © 2017 John Wiley & Sons, Ltd.

Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib. Ectopic expression of KIAA1524, or pretreatment with the PP2A inhibitor, okadaic acid, suppressed carfilzomib-induced apoptosis and KIAA1524 downregulation in sensitive cells, whereas co-treatment with the PP2A agonist, forskolin, enhanced carfilzomib-induced apoptosis in resistant cells. Mechanistically, carfilzomib affected KIAA1524 transcription through disturbing ELK1 (Elk-1) binding to the KIAA1524 promoter. Moreover, the drug sensitivity and mechanism of carfilzomib in xenograft mouse models correlated well with the effects of carfilzomib on KIAA1524 and p-Akt expression, as well as PP2A activity. Our data disclosed a novel drug mechanism of carfilzomib in leukaemia cells and suggests the potential therapeutic implication of KIAA1524 in leukaemia treatment.

We use cross-correlation of the ambient seismic field to estimate seasonal variations of seismic velocity in the Mississippi Embayment and to determine the underlying physical mechanisms. Our main ...

BACKGROUND Enumerating hematopoietic progenitor cells (HPCs) by using an automated hematology analyzer is a rapid, inexpensive, and simple method for predicting a successful harvest compared with enumerating circulating CD34+ cells. However, the optimal HPC cutoff count and the indicating factors to be considered for improved predicting have not yet been determined. STUDY DESIGN AND METHODS Between 2007 and 2012, a total of 189 consecutive patients who proceeded to peripheral blood stem cell (PBSC) harvesting were retrospectively recruited. Baseline characteristics were analyzed to identify the risk factors for a failed harvest, which were defined as less than 2 × 106 CD34+ cells/kg. Variables identified by multivariate logistic regression and correlation analysis for predicting a successful harvest were subjected to classification and regression tree (CART) analysis. RESULTS PBSCs were successfully harvested in 154 (81.5%) patients. An age of at least 60 years, a diagnosis of a solid tumor, at least five prior chemotherapy cycles, prior radiotherapy, and mobilization with granulocyte–colony-stimulating factor alone or high-dose cyclophosphamide were independent baseline predictors of poor mobilization. In CART analysis, patients with zero to two host risk factors and either higher HPC (≥28 × 106/L) or mononuclear cell (MNC; ≥3.5 × 109/L) counts were categorized as good mobilizers and their harvest success rate was 92.3%. By contrast, 30.3% of harvests were adequate in the patients with three to five host risk factors and lower HPC and MNC counts. CONCLUSION A CART algorithm incorporating host predictors and HPC and MNC counts improves predictions in a successful harvest and might reduce the necessity of monitoring peripheral CD34+ cells.

Background Surgery is the potentially curative treatment for retroperitoneal sarcoma (RS), but complete resectability is frequently a challenge. This study aimed to characterize the clinical features, prognostic factors and treatment outcomes. Methods A cohort of 144 patients with RS was surveyed retrospectively from January 1st, 2000 to July 30th, 2011. The prognostic influence of clinicopathological characteristics as well as treatments on local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS), were examined by univariate and multivariate analyses. A histology-specific nomogram developed by Gronchi et al was used for validation. Results Liposarcoma, leiomyosarcoma, and malignant peripheral sheath tumor (MPNST) were the most common histologies (70%). Multivariate analysis revealed FNCLCC tumor grade was the most significant prognostic factor for OS (P = 0.001) and DMFS (P

Prior studies found bendamustine is efficacious in patients with indolent B-cell non-Hodgkin lymphoma (NHL). To date, no studies have reported the efficacy of bendamustine in a Chinese population. This multicentre phase II trial evaluated the pharmacokinetics (PK), safety and efficacy of bendamustine monotherapy in Chinese patients in Taiwan with pretreated indolent B-cell NHL or mantle cell lymphoma (MCL). For PK assessments, patients were randomized (n = 16; 11 with indolent B-cell NHL and five with MCL) to 90 or 120 mg/m2 of bendamustine for the first cycle. Plasma levels of bendamustine and its two metabolites were analyzed. For efficacy and safety evaluations, bendamustine 120 mg/m2 was given to all patients every 3 weeks starting at cycle 2 for a minimum of a total of six cycles. The median age of patients was 61.7 years, and the majority were men (75%). The median number of prior treatments was 4 (range, 1–9 regimens), and all patients were previously treated with rituximab. Bendamustine plasma concentration peaked near the end of infusion and was rapidly eliminated with a mean elimination half-life (t1/2) of 0.67–0.8 h. Of the evaluable patients (n = 14), the overall response rate was 78.6%, including 7.2% of patients having a complete response. Mean progression-free survival was 27.5 weeks. The most common grade 3–4 adverse events were leucopenia (56.3%), neutropenia (56.3%) and thrombocytopenia (25%). In conclusion, bendamustine was efficacious and well tolerated in Taiwanese patients with indolent NHL and MCL with a similar PK profile to that of other populations. Copyright © 2014 John Wiley & Sons, Ltd.

We provide an introduction to network theory, evidence to support a connection between molecular network structure and neuropsychiatric disease, and examples of how network approaches can expand our knowledge of the molecular bases of these diseases. Without systematic methods to derive their biological meanings and inter-relatedness, the many molecular changes associated with neuropsychiatric disease, including genetic variants, gene expression changes, and protein differences, present an impenetrably complex set of findings. Network approaches can potentially help integrate and reconcile these findings, as well as provide new insights into the molecular architecture of neuropsychiatric diseases. Network approaches to neuropsychiatric disease are still in their infancy, and we discuss what might be done to improve their prospects.