Numerical and Experimental Analysis of Horizontal-Axis Wind Turbine Blade Fatigue Life.

Horizontal-axis wind turbines are the most popular wind machines in operation today. These turbines employ aerodynamic blades that may be oriented either upward or downward. HAWTs are the most common non-conventional source of energy generation. These turbine blades fail mostly due to fatigue, as a large centrifugal force acts on them at high rotational speeds. This study aims to increase a turbine's service life by improving the turbine blades' fatigue life. Predicting the fatigue life and the design of the turbine blade considers the maximum wind speed range. SolidWorks, a CAD program, is used to create a wind turbine blade utilizing NACA profile S814. The wind turbine blade's fatigue life is calculated using Morrow's equation. A turbine blade will eventually wear out due to several forces operating on it. Ansys software is used to analyze these stresses using the finite element method. The fatigue study of wind turbine blades is described in this research paper. To increase a turbine blade's fatigue life, this research study focuses on design optimization. Based on the foregoing characteristics, an improved turbine blade design with a longer fatigue life than the original one is intended in this study. The primary fatigue parameters are the length of a chord twist angle and blade length. The experimental data computed with the aid of a fatigue testing machine are also used to validate the numerical results, and it is found that they are very similar to one another. By creating the most effective turbine blades with the longest fatigue life, this research study can be developed further. The most effective turbine blades with the longest fatigue life can be designed to further this research investigation.

Regulation of Chemosensitivity in Human Medulloblastoma Cells by p53 and the PI3 Kinase Signaling Pathway.

In medulloblastoma, p53 expression has been associated with chemoresistance and radiation resistance and with poor long-term outcomes in the p53-mutated sonic hedgehog, MYC-p53, and p53-positive medulloblastoma subgroups. We previously established a direct role for p53 in supporting drug resistance in medulloblastoma cells with high basal protein expression levels (D556 and DAOY). We now show that p53 genetic suppression in medulloblastoma cells with low basal p53 protein expression levels (D283 and UW228) significantly reduced drug responsiveness, suggesting opposing roles for low p53 protein expression levels. Mechanistically, the enhanced cell death by p53 knockdown in high-p53 cells was associated with an induction of mTOR/PI3K signaling. Both mTOR inhibition and p110α/PIK3CA induction confirmed these findings, which abrogated or accentuated the enhanced chemosensitivity response in D556 cells respectively while converse was seen in D283 cells. Co-treatment with G-actin-sequestering peptide, thymosin ß4 (Tß4), induced p-AKTS473 in both p53-high and p53-low cells, enhancing chemosensitivity in D556 cells while enhancing chemoresistance in D283 and UW228 cells. IMPLICATIONS: Collectively, we identified an unexpected role for the PI3K signaling in enhancing cell death in medulloblastoma cells with high basal p53 expression. These studies indicate that levels of p53 immunopositivity may serve as a diagnostic marker of chemotherapy resistance and for defining therapeutic targeting.

Predicting new drug indications for prostate cancer: The integration of an in silico proteochemometric network pharmacology platform with patient-derived primary prostate cells.

BACKGROUND: Drug repurposing enables the discovery of potential cancer treatments using publically available data from over 4000 published Food and Drug Administration approved and experimental drugs. However, the ability to effectively evaluate the drug's efficacy remains a challenge. Impediments to broad applicability include inaccuracies in many of the computational drug-target algorithms and a lack of clinically relevant biologic modeling systems to validate the computational data for subsequent translation. METHODS: We have integrated our computational proteochemometric systems network pharmacology platform, DrugGenEx-Net, with primary, continuous cultures of conditionally reprogrammed (CR) normal and prostate cancer (PCa) cells derived from treatment-naive patients with primary PCa. RESULTS: Using the transcriptomic data from two matched pairs of benign and tumor-derived CR cells, we constructed drug networks to describe the biological perturbation associated with each prostate cell subtype at multiple levels of biological action. We prioritized the drugs by analyzing these networks for statistical coincidence with the drug action networks originating from known and predicted drug-protein targets. Prioritized drugs shared between the two patients' PCa cells included carfilzomib (CFZ), bortezomib (BTZ), sulforaphane, and phenethyl isothiocyanate. The effects of these compounds were then tested in the CR cells, in vitro. We observed that the IC50 values of the normal PCa CR cells for CFZ and BTZ were higher than their matched tumor CR cells. Transcriptomic analysis of CFZ-treated CR cells revealed that genes involved in cell proliferation, proteases, and downstream targets of serine proteases were inhibited while KLK7 and KLK8 were induced in the tumor-derived CR cells. CONCLUSIONS: Given that the drugs in the database are extremely well-characterized and that the patient-derived cells are easily scalable for high throughput drug screening, this combined in vitro and in silico approach may significantly advance personalized PCa treatment and for other cancer applications.

DNA Methylation Across the Serotonin Transporter Gene Following Marital Separation: A Pilot Study.

BACKGROUND: Marital separation and divorce are stressful life transitions associated with increased risk for a range of poor mental and physical health outcomes. A key task for research in this area is to identify individual differences that may index risk for these adverse outcomes. PURPOSE: To examine the association between DNA methylation across the serotonin transporter gene (SLC6A4) and self-reported emotional distress following marital separation. METHODS: Genomic DNA methylation (from buffy coat fractions of whole blood) was quantified in a sample of 47 adults following a recent marital separation; concurrent with the blood draw, participants completed questionnaires on their psychological adjustment to the separation experience. RESULTS: Relatively greater methylation of SLC6A4 was associated with less subjective separation-related psychological distress, and this association held after accounting for participants' age, length of the relationship, time since the separation, and SLC6A4 genotype, b = -211.99, SE = 94.91, p = .03, 95% CI: -402.22, -25.21. Significantly stronger negative associations were observed between methylation and psychological adjustment among participants who had more recently separated from their former partner. CONCLUSIONS: Although results derived from small samples must be considered preliminary and hypothesis generating, the current study raises new questions about the role of DNA methylation and psychosocial adaptation to stressful life events such as divorce, and the findings can inform future studies in this research area.

Publisher Correction: PhIP-Seq characterization of serum antibodies using oligonucleotide-encoded peptidomes.

The version of this paper originally published contained typesetter-introduced errors in some of the code commands, consisting of conversion of a closing backslash (\) to a forward slash (/). These errors have been corrected in the HTML and PDF versions of the protocol.

PhIP-Seq characterization of serum antibodies using oligonucleotide-encoded peptidomes.

The binding specificities of an individual's antibody repertoire contain a wealth of biological information. They harbor evidence of environmental exposures, allergies, ongoing or emerging autoimmune disease processes, and responses to immunomodulatory therapies, for example. Highly multiplexed methods to comprehensively interrogate antibody-binding specificities have therefore emerged in recent years as important molecular tools. Here, we provide a detailed protocol for performing 'phage immunoprecipitation sequencing' (PhIP-Seq), which is a powerful method for analyzing antibody-repertoire binding specificities with high throughput and at low cost. The methodology uses oligonucleotide library synthesis (OLS) to encode proteomic-scale peptide libraries for display on bacteriophage. These libraries are then immunoprecipitated, using an individual's antibodies, for subsequent analysis by high-throughput DNA sequencing. We have used PhIP-Seq to identify novel self-antigens associated with autoimmune disease, to characterize the self-reactivity of broadly neutralizing HIV antibodies, and in a large international cross-sectional study of exposure to hundreds of human viruses. Compared with alternative array-based techniques, PhIP-Seq is far more scalable in terms of sample throughput and cost per analysis. Cloning and expression of recombinant proteins are not required (versus protein microarrays), and peptide lengths are limited only by DNA synthesis chemistry (up to 90-aa (amino acid) peptides versus the typical 8- to 12-aa length limit of synthetic peptide arrays). Compared with protein microarrays, however, PhIP-Seq libraries lack discontinuous epitopes and post-translational modifications. To increase the accessibility of PhIP-Seq, we provide detailed instructions for the design of phage-displayed peptidome libraries, their immunoprecipitation using serum antibodies, deep sequencing-based measurement of peptide abundances, and statistical determination of peptide enrichments that reflect antibody-peptide interactions. Once a library has been constructed, PhIP-Seq data can be obtained for analysis within a week.

The actin cytoskeletal architecture of estrogen receptor positive breast cancer cells suppresses invasion.

Estrogen promotes growth of estrogen receptor-positive (ER+) breast tumors. However, epidemiological studies examining the prognostic characteristics of breast cancer in postmenopausal women receiving hormone replacement therapy reveal a significant decrease in tumor dissemination, suggesting that estrogen has potential protective effects against cancer cell invasion. Here, we show that estrogen suppresses invasion of ER+ breast cancer cells by increasing transcription of the Ena/VASP protein, EVL, which promotes the generation of suppressive cortical actin bundles that inhibit motility dynamics, and is crucial for the ER-mediated suppression of invasion in vitro and in vivo. Interestingly, despite its benefits in suppressing tumor growth, anti-estrogenic endocrine therapy decreases EVL expression and increases local invasion in patients. Our results highlight the dichotomous effects of estrogen on tumor progression and suggest that, in contrast to its established role in promoting growth of ER+ tumors, estrogen has a significant role in suppressing invasion through actin cytoskeletal remodeling.

Fasting with diabetes: a prospective observational study.

OBJECTIVES: To determine the proportion of diabetic patients who develop adverse glycaemic events when fasting regularly. DESIGN: Prospective observational study conducted at a tertiary care hospital in South Asia. Five hundred and twenty-three patients were assessed for eligibility, and 150 were included in the final analysis. Diabetic patients over 18 years of age who were willing to fast regularly and make a chart of their daily blood sugar levels were included in the study. The main outcome measures were hypoglycaemic and hyperglycaemic events. Frequencies and percentages were calculated for quantitative variables, while mean±SD were documented for qualitative variables. Relative risk was calculated as a measure of association. RESULTS: Of a total of 150 individuals, 10% experienced hypoglycaemia, while 3.3% reported hyperglycaemic episodes. Only 8.7% of the participants discontinued one or more fasts; however, none of them required hospitalisation. There is a negative association between a visit to a physician by diabetic patients before they begin to fast regularly and the risk of developing hypoglycaemia (relative risk 0.73). CONCLUSIONS: Many diabetic patients who fast regularly are at high risk of adverse glycaemic events. Most diabetics do not consult their physicians before fasting to adjust medications and lifestyle. Various strategies should be planned and implemented for the awareness and education of such patients to avoid adverse glycaemic events and subsequent complications.

Oral Rehydration Therapy and Feeding Replaces Total Parenteral Nutrition: A Clinical Vignette.

A 27-year-old patient with spina bifida and a high output loss of water and electrolytes from her ileostomy was successfully liberated from dependency on total parenteral nutrition and intravenous fluid and electrolyte replacement by the use of a rice-based oral rehydration therapy (ORT). This allowed her to return home to the care of her mother. We suggest that ORT can be effective in the context of modern high-technology settings, as well as in resource-poor situations.

Surgical Management of Odontoid Fracture in Elderly.

Odontoid type II fractures are associated with high mortality in the elderly. No formal guidelines are present regarding the treatment of such fractures. Their management can be done either conservatively or surgically, however, surgical treatment is technically demanding and relatively new. We report a case of 75 years old man who presented to our clinical setting, following a history of fall. The CT scan and MRI showed odontoid type II fracture. With time, the neurological deficit got marked and he underwent transoral odontoidectomy and occipitocervical fixation using rods and screws via posterior approach. Patient's neurological condition improved dramatically and on the short term follow up, he had no motor deficit. Our experience suggests that occipitocervical fixation via posterior approach is a viable option for the management of odontoid type II fracture in the geriatric population.

Lesion processing by a repair enzyme is severely curtailed by residues needed to prevent aberrant activity on undamaged DNA.

DNA base excision repair is essential for maintaining genomic integrity and for active DNA demethylation, a central element of epigenetic regulation. A key player is thymine DNA glycosylase (TDG), which excises thymine from mutagenic G·T mispairs that arise by deamination of 5-methylcytosine (mC). TDG also removes 5-formylcytosine and 5-carboxylcytosine, oxidized forms of mC produced by Tet enzymes. Recent studies show that the glycosylase activity of TDG is essential for active DNA demethylation and for embryonic development. Our understanding of how repair enzymes excise modified bases without acting on undamaged DNA remains incomplete, particularly for mismatch glycosylases such as TDG. We solved a crystal structure of TDG (catalytic domain) bound to a substrate analog and characterized active-site residues by mutagenesis, kinetics, and molecular dynamics simulations. The studies reveal how TDG binds and positions the nucleophile (water) and uncover a previously unrecognized catalytic residue (Thr197). Remarkably, mutation of two active-site residues (Ala145 and His151) causes a dramatic enhancement in G·T glycosylase activity but confers even greater increases in the aberrant removal of thymine from normal A·T base pairs. The strict conservation of these residues may reflect a mechanism used to strike a tolerable balance between the requirement for efficient repair of G·T lesions and the need to minimize aberrant action on undamaged DNA, which can be mutagenic and cytotoxic. Such a compromise in G·T activity can account in part for the relatively weak G·T activity of TDG, a trait that could potentially contribute to the hypermutability of CpG sites in cancer and genetic disease.