C-Terminus of Progranulin Interacts with the Beta-Propeller Region of Sortilin to Regulate Progranulin Trafficking

Progranulin haplo-insufficiency is a main cause of frontotemporal lobar degeneration (FTLD) with TDP-43 aggregates. Previous studies have shown that sortilin regulates progranulin trafficking and is a main determinant of progranulin level in the brain. In this study, we mapped the binding site between progranulin and sortilin. Progranulin binds to the beta-propeller region of sortilin through its C-terminal tail. The C-terminal progranulin fragment is fully sufficient for sortilin binding and progranulin C-terminal peptide displaces progranulin binding to sortilin. Deletion of the last 3 residues of progranulin (QLL) abolishes its binding to sortilin and also sortilin dependent regulation of progranulin trafficking. Since progranulin haplo-insufficiency results in FTLD, these results may provide important insights into future studies of progranulin trafficking and signaling and progranulin based therapy for FTLD

Characterization of membranes with X-ray ultramicroscopy

Non-invasive characterization and observation of synthetic membranes is an important practice to monitor the performance of membrane process. Primarily there are two techniques&mdash;optical and non-optical for this purpose. Among them, X-ray computed tomography, as a non-optical technique, has been extensively used for the measurement of fibre distribution and air pockets trapped in the modules. However, the micro resolution of most commercial systems has limited its application which can hardly be used for the sub-micro characterization of membrane processes. A novel micro and nano characterization method is introduced in the current work by exploring an innovative development of the X-ray ultramicroscope (XuM) and micro-tomographic techniques. The XuM, based on using a scanning electron microscope as host, provides a new approach to X-ray projection microscopy. It has demonstrated the ability to characterize very small features in objects, down to of order 100 nm, including the use for dry, wet and even liquid samples. It can also distinguish objects with very subtle difference in density.<br /

Using noble gases to trace groundwater evolution and assess helium accumulation in Weihe Basin, central China

The severe shortage of helium resources is an impending global problem. However, the helium accumulation processes and conditions favorable for helium enrichment in reservoirs remain poorly understood, which makes helium exploration challenging. Noble gases are good tracers of subsurface fluids provenance, migration and storage, as well as indicators of the nature and quantity of associated phases. In this study the variation of major gases and noble gases data in Weihe Basin provide us with an excellent opportunity to understand the groundwater evolution and helium accumulation processes. Twelve gas samples collected from wellheads of geothermal wells can be classified into three groups, in which Group A has high concentrations of N2 (58.57% - 91.66%) and He (0.32% - 2.94%); Group B has high contents of CH4 (52.94% and 69.50%) and low concentrations of He (0.057% and 0.062%); Group C has a high content of CH4 (71.70%) and He (2.11%). Helium isotopic ratios are predominantly radiogenic in origin and therefore crustally derived. Measured elemental ratios of noble gases are compared with multiple fractionation models for Group A and B samples, implying that open system heavy oil-water fractionation with excess heavy noble gases has occurred in the basin with Voil/Vwater ratios of 0.06-0.18. The amount of helium in Group A and B samples requires the release of all 4He produced in the crust since 0.30Ma-1.98Ma into the groundwater. The Group C sample requires an additional He flux from adjacent granitic bodies. The accumulation of helium and hydrocarbon in the Weihe Basin can be explained by a 4-stage process. Accumulation of commercially viable helium requires high He flux from source rocks, the existence of a free gas phase of major gas components (CH4 in most cases, N2 or CO2) and minimal major gas addition after formation of the free gas phase

A Randomized Controlled Trial of an Integrated Brain, Body, and Social Intervention for Children With ADHD

Objective: This study evaluated the efficacy of an Integrated Brain, Body, and Social (IBBS) intervention for children with ADHD. Treatment consisted of computerized cognitive remediation training, physical exercises, and a behavior management strategy. Method: Ninety-two children aged 5 to 9 years with ADHD were randomly assigned to 15 weeks of IBBS or to treatment-as-usual. Primary outcome measures included blinded clinician ratings of ADHD symptoms and global clinical functioning. Secondary outcome measures consisted of parent and teacher ratings of ADHD and neurocognitive tests. Results: No significant treatment effects were found on any of our primary outcome measures. In terms of secondary outcome measures, the IBBS group showed significant improvement on a verbal working memory task; however, this result did not survive correction for multiple group comparisons. Conclusion: These results suggest that expanding cognitive training to multiple domains by means of two training modalities does not lead to generalized improvement of ADHD symptomatology

Hybrid minigene splicing assay verifies the pathogenicity of a novel splice site variant in the COL1A1 gene of a chinese patient with osteogenesis imperfecta type I

Abstract(#br)Background(#br)Osteogenesis imperfecta (OI) is a rare genetic bone disease associated with brittle bones and fractures. Among all known types, OI type I is the most common type and characterized by increased bone fragility, low bone mass, distinctly blue-gray sclera, and susceptibility to conductive hearing loss beginning in adolescence. Mutations in genes encoding type I collagen ( COL1A1 and COL1A2 ) contribute to the main pathogenic mechanism of OI.(#br)Methods(#br)Subtle mutation of the COL1A1 gene in the proband was detected by targeted next-generation sequencing (NGS) and confirmed by Sanger sequencing. We then assessed the effect of the mutation on the splicing of the COL1A1 gene by bioinformatics prediction and hybrid minigene splicing assay (HMSA).(#br)Results(#br)A novel splice site mutation c.1821+1 G > C was discovered in the proband by NGS and further confirmed by Sanger sequencing, which was also simultaneously identified from the proband’s mother and elder sister. Bioinformatics predicted that this mutation would result in a disappearance of the 5′ donor splice site in intron 26, thereby leading to abnormal splicing and generation of premature stop codon. The follow-up experimental data generated by HMSA was consistent with this prediction.(#br)Conclusion(#br)Our study identified a novel splice site mutation that caused OI type I in the proband by abnormal splicing and demonstrated that combined applications of NGS, bioinformatics and HMSA are comprehensive and effective methods for diagnosis and aberrant splicing study of OI

EMP3 Overexpression in Primary Breast Carcinomas is not Associated with Epigenetic Aberrations

Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule with important roles in the regulation of apoptosis, differentiation and invasion of cancer cells, but the detailed is largely still unknown. We analyzed the mRNA levels and methylation statuses of EMP3 in 63 primary breast carcinomas and assessed their correlations with clinicopathologic variables. The expression of EMP3 mRNA in primary breast carcinomas was significantly higher than the expression of 20 normal breast tissues (p<10-7). EMP3 overexpression in breast carcinomas was significantly related to histological grade III (p=3.9×10-7), lymph node metastasis (p=0.003), and strong Her-2 expression (p=3.3×10-6). Hypermethylation frequencies of EMP3 were detected in 36.5% of breast carcinomas by methylation-specific polymerase chain reaction. However, no significant correlations were found between methylation status of EMP3 and mRNA expression levels as well as other clinical parameters. In conclusion, EMP3 may be a novel marker of tumor aggressiveness. Overexpression of EMP3 in primary breast carcinoma is not associated with DNA methylation

The prognostic index PRIMA-PI combined with Ki67 as a better predictor of progression of disease within 24 months in follicular lymphoma

BackgroundProgression of disease within 24 months (POD24) is a risk factor for poor survival in follicular lymphoma (FL), and there is currently no optimal prognostic model to accurately predict patients with early disease progression. How to combine traditional prognostic models with new indicators to establish a new prediction system, to predict the early progression of FL patients more accurately is a future research direction.MethodsThis study retrospectively analyzed patients with newly diagnosed FL patients in Shanxi Provincial Cancer Hospital from January 2015 to December 2020. Data from patients undergoing immunohistochemical detection (IHC) were analyzed using χ2 test and multivariate Logistic regression. Also, we built a nomogram model based on the results of LASSO regression analysis of POD24, which was validated in both the training set and validation set, and additional external validation was performed using a dataset (n = 74) from another center, Tianjin Cancer Hospital.ResultsThe multivariate Logistic regression results suggest that high-risk PRIMA-PI group, Ki-67 high expression represent risk factors for POD24 (P&lt;0.05). Next, PRIMA-PI and Ki67 were combined to build a new model, namely, PRIMA-PIC to reclassify high and low-risk groups. The result showed that the new clinical prediction model constructed by PRIMA-PI with ki67 has a high sensitivity to the prediction of POD24. Compared to PRIMA-PI, PRIMA-PIC also has better discrimination in predicting patient’s progression-free survival (PFS) and overall survival (OS). In addition, we built nomogram models based on the results of LASSO regression (histological grading, NK cell percentage, PRIMA-PIC risk group) in the training set, which were validated using internal validation set and external validation set, we found that C-index and calibration curve showed good performance.ConclusionAs such, the new predictive model-based nomogram established by PRIMA-PI and Ki67 could well predict the risk of POD24 in FL patients, which boasts clinical practical value

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Using Laplace transform to solve the viscoelastic wave problems in the dynamic material property tests

In relation to the dynamic tests of materials, the approach to solve the viscoelastic wave propagations in a one dimensional viscoelastic rod was summarized. By conducting Laplace transform, the governing partial differential equations were transformed to ordinary differential equations for the image functions, which were solved analytically with suitable boundary equations. Inversely transforming these image functions gives the results of the stress, velocity, and strain in the bar. Two wave problems occurred in split Hopkinson pressure bar (SHPB) tests are analyzed: 1) the problem of evaluating the internal stress distributions in a viscoelastic specimen; and 2) the problem of stress wave propagations in a viscoelastic bar. Both problems were solved numerically by way of numerical inverse Laplace transform. For the first problem, the special case when the specimen is pure elastic was solved analytically, giving the exact solution to the problem of elastic wave propagation in a sandwich elastic media