Genome sequencing identifies major causes of severe intellectual disability.

Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed. Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.

Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation.

De novo mutations are recognized both as an important source of genetic variation and as a prominent cause of sporadic disease in humans. Mutations identified as de novo are generally assumed to have occurred during gametogenesis and, consequently, to be present as germline events in an individual. Because Sanger sequencing does not provide the sensitivity to reliably distinguish somatic from germline mutations, the proportion of de novo mutations that occur somatically rather than in the germline remains largely unknown. To determine the contribution of post-zygotic events to de novo mutations, we analyzed a set of 107 de novo mutations in 50 parent-offspring trios. Using four different sequencing techniques, we found that 7 (6.5%) of these presumed germline de novo mutations were in fact present as mosaic mutations in the blood of the offspring and were therefore likely to have occurred post-zygotically. Furthermore, genome-wide analysis of "de novo" variants in the proband led to the identification of 4/4,081 variants that were also detectable in the blood of one of the parents, implying parental mosaicism as the origin of these variants. Thus, our results show that an important fraction of de novo mutations presumed to be germline in fact occurred either post-zygotically in the offspring or were inherited as a consequence of low-level mosaicism in one of the parents.

IL-1ß/NF-kb signaling promotes colorectal cancer cell growth through miR-181a/PTEN axis.

To date, the role of miRNA in tumorigenesis has been largely reported. It was found that miR-181a may be involved in the tumorigenesis of colon cancer. The purpose of this study was to investigate the mechanism of miR-181a in colon cancer carcinogenesis. The expression levels of IL-1ß, NF-κB (RelA), and miR-181a in colon cancer tissue were higher than that in normal control tissue when assessed by real-timePCR. In addition, it was found that IL-1ß induced the expression of miR-181a. The expression of PTEN was regulated by IL-1ß-stimulated miR-181a expression. In a PTEN reporter plasmid, miR-181a binding site mutations were introduced. By using a luciferase reporter assay, it was found that wild type reported activity was lower than that of the mutant registration system activity. Furthermore, a siRNA strategy was used to find that IL-1B regulates miR-181a expression via NF-κB and then regulates PTEN expression. Consequently, repression of PTEN by miR-181a promotes colon cancer cell proliferation. Taken together, our data support a critical role for NF-κB-dependent upregulation of miR-181a; this represents a new pathway for the repression of PTEN and the promotion of cell proliferation upon IL-1ß induction.

Modeling and simulating the multi-generation product sales, production and inventory system within the context of quality upgrades.

The rapid development of science and technology has led to an increasing number of high-tech enterprises offering new products through successive generations of product upgrades. This trend presents a new challenge for the sustainable operations of enterprises. Based on the Norton-Bass model, this study begins by constructing a multi-generation product diffusion model within a single enterprise in the context of a monopoly under the quality upgrade scenario. Subsequently, a supply model is established based on this foundation, and these two models are seamlessly integrated using product sales volume as an interface, culminating in a comprehensive sales-supply system. This study analyzes the effects of new-product pricing, quality levels, initial stock, and production capacity on the performance of this system. The system dynamics (SD) method was used to simulate and solve the system in the decentralized and centralized decision-making modes, and the two decision-making modes were compared and analyzed. The research reveals several key findings. i) Comprehensive decision optimization yields enhanced profitability through joint optimization calculation of the multi-generation product diffusion system and the supply adjustment system. ii) consumer price sensitivity significantly affects product quality upgrades and profits. A negative correlation exists between consumer price sensitivity and both factors. The upgrades of product quality should be carefully traded off with consideration of pricing and quality costs. iii) Maximizing profits by maintaining a certain order level of backlog or stock shortage is beneficial for overall enterprise profitability. Additionally, optimal production capacity has been identified as a crucial element in efficient operational inventory management. This study expands the multi-generation product diffusion operational theory and provides valuable theoretical support and decision-making foundations for the sustainable management of enterprises.

Incorporation of styrene enhances recognition of ribonuclease A by molecularly imprinted polymers.

Ribonuclease A (RNase A) is an RNA-cleaving enzyme characterized by its high conformational stability and strong catalytic activity. This enzyme is ubiquitous in living organisms and is difficult to inactivate. In polymerase chain reaction (PCR) RNase activity is removed by adding inhibitors. Molecularly imprinted polymers (MIPs) with high selectivity, high stability, low cost and facile synthesis could prove useful in extraction of target molecules, such as RNase A, from reaction mixtures. In this investigation, MIPs were synthesized from the monomers styrene and polyethyleneglycol 400 dimethacrylate (PEG400DMA) in several different ratios. Styrene as a functional monomer gave MIPs with a higher affinity for RNase A than other functional monomers tested, according to both enzyme-linked immnuosorbent assay (ELISA) and isothermal titration calorimetry (ITC). The optimum volume ratio of styrene/PEG400DMA was 20/100 at 25 degrees C, and this ratio maximized the rebinding efficiency of RNase A to MIPs. Isothermal titration calorimetry was also used, and could be useful to design the composition of molecularly imprinted polymers for various target molecules.

The numerical model of biosorption of Zn2+ and its application to the bio-electro tower reactor (BETR).

A 2-D numerical kinetic model considering flow velocity and adsorption is developed to simulate the bio-electro tower reactor (BETR). This new model considers the adsorbed amount when equilibrium qe as transient variable, which is superior to the old pseudo-first-order and the pseudo-second-order model which regards qe as a constant. We did research on the intensifying effect of electric field upon heavy metal ions adsorption process. The calculation result matches well with the experimental data. BETR is a coupling technique whose mechanism is that outer electric field can enhance the mass transfer rate when the solute is metal ions. Two kinds of carriers, pottery ball and 3-dimensional electrode (3DE), were used to support the biofilm layer; and organic wastewater that contains Zn(2+) is selected as a sample to validate the model. The 3DE carriers can be polarized by outer electric field, but pottery ball cannot. It is found that Zn(2+) transfers faster in 3DE carriers than in pottery ball (insulation materials); and an intensifying coefficientη is introduced to describe this effect in BETR.

Retrospective study of chest wall tumors at a cancer hospital in Nepal.

Primary and metastatic tumors of both soft tissues and bony skeleton, and primary tumors of adjacent organs invading the chest wall constitute chest wall tumors. A retrospective review of all the patients with chest wall tumors was done at BP Koirala Memorial Cancer Hospital (BPKMCH). Primary tumors of breast were excluded. Surgical treatment consisted of wide local excision (WLE). Chest wall reconstruction, if needed, was achieved by a muscular flap +/- prolene mesh +/- omental transposition. Thirty one patients were treated in the period from October 1999 to October 2003. Age of the patients varied from 3 years to 72 years (mean age--38 years). Presenting complaint was mass in 96.8% and pain in 48.4% cases. The mass was 5 cm or less in 34.4%, from 5 to 10 cm in 32.3%, and more than 10 cm in 32.3% cases. The lesions were located in sternal region, anterior, lateral, posterior, and vertebral chest wall in 6.5%, 32.3%, 41.9%, 16.1% and 3.2% respectively. WLE was done in 29 cases. Chest wall reconstruction using both muscular flaps and prolene mesh (15x15 cm) was done in 8 cases. In three of them, where concomitant wedge resection of the lung was done, omental transposition was added. In rest of the cases, primary closure, muscular/myocutaneous flap or skin grafting was done. Minor complications were observed in 31.0% cases, which were managed conservatively. Two patients received adjuvant radiotherapy and four patients--adjuvant chemotherapy. There were no postoperative deaths. The rate of malignancy was 48.4%.