Miracle-dz/UniFAR-FTUs huggingface dataset:
Hypertension, Dietary Sodium, and Cognitive Decline: Results From the Women's Health Initiative Memory Study.

BACKGROUND To investigate the relationships of hypertension, antihypertensive treatment, and sodium intake on cognitive decline in older women. METHODS Prospective follow-up of 6,426 cognitively intact women aged 65-79 years enrolled in the Women's Health Initiative Memory Study (WHIMS) with a median follow-up of 9.1 years. Dietary sodium intake was determined by food frequency questionnaires. Hypertension was defined as self-report of current drug therapy for hypertension. Blood pressure (BP) control was assessed by treatment for hypertension and clinic measurement of systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg at baseline. Cognitive functioning was assessed annually by global cognitive screening, neurocognitive, and neuropsychiatric evaluations. Cognitive decline was identified by the incidence of mild cognitive impairment (MCI) or probable dementia (PD). Cox proportional hazards analyses were used to calculate hazard ratios (HRs). RESULTS Hypertension was associated with an increased risk for cognitive decline (HR 1.20; 95% confidence interval (CI) 1.04, 1.39; P = 0.02). Among women with antihypertensive medication, those with BP ≥140/90 mm Hg (uncontrolled BP) were at highest risk for developing cognitive decline (HR 1.30; 95% CI 1.05, 1.60) compared to women without treatment and BP <140/90mm Hg (controlled BP). Sodium intake >1,500 mg/day did not alter the risk for cognitive decline in hypertensive women or women with antihypertensive treatment (P for interaction = 0.96 or 0.97). CONCLUSIONS Women with antihypertensive treatment and uncontrolled BP showed highest risk estimates for developing cognitive decline compared to non-hypertensive women. Sodium intake did not modify the risk for cognitive decline in women with hypertension or receiving antihypertensive medication. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials. gov. Unique identifier: NCT00685009 and NCT00745056.
Pin1 promotes GR transactivation by enhancing recruitment to target genes

The glucocorticoid receptor (GR) is a ligand activated transcription factor, serving to regulate both energy metabolism and immune functions. Factors that influence cellular sensitivity to glucocorticoids (GC) are therefore of great interest. The N-terminal of the GR contains numerous potential proline-directed phosphorylation sites, some of which can regulate GR transactivation. Unrestricted proline isomerisation can be inhibited by adjacent serine phosphorylation and requires a prolyl isomerise, Pin1. Pin1 therefore determines the functional outcome of proline-directed kinases acting on the GR, as cis/trans isomers are distinct pools with different interacting proteins. We show that Pin1 mediates GR transactivation, but not GR trans-repression. Two N-terminal GR serines, S203 and S211, are targets for Pin1 potentiation of GR transactivation, establishing a direct link between Pin1 and the GR. We also demonstrate GC-activated co-recruitment of GR and Pin1 to the GILZ gene promoter. The Pin1 effect required both its WW and catalytic domains, and GR recruitment to its GRE was Pin1-dependent. Therefore, Pin1 is a selective regulator of GR transactivation, acting through N-terminal phospho-serine residues to regulate GR recruitment to its target sites in the genome. As Pin1 is dysregulated in disease states, this interaction may contribute to altered GC action in inflammatory conditions.
Current Challenges and Future Perspectives for Applying Biologically Synthesized Magnetic Nanoparticles for Human Health Benefit

In modern science, nanoparticles are considered the next-generation tools of biotechnology. Among the diverse qualities of nanoparticles, the interest of the scientific community in magnetic nanoparticles has always been eminent because of the possibility of manipulating these structures by a magnetic field. Magnetic iron oxide nanoparticles are one of the most relevant tools for biotechnology, and these are usually synthesized by chemical methods. A recent and environmentally friendly method to produce biocompatible magnetic nanoparticles is achieved by the growth of magnetotactic bacteria in large scale. Many advantages of using the biologically synthesized nanoparticles have already been showed, including their higher efficiency on drug delivery and on killing tumors by hyperthermia. Therefore, new proposals for the treatment of human diseases using biologically synthesized nanoparticles are growing in the last few years. In the meantime, discussion about the necessary steps to enable the use of these nanoparticles in health treatments is relatively near to the ground. Here we emphasized future challenges to the use of magnetic nanoparticles in biomedicine and proposed alternative tests to complement research dedicated to the evaluation of new biomedical applications on this subject.
On the Roots of σ‐Polynomials

Given a graph G of order n, the σ‐polynomial of G is the generating function σ(G,x)=∑aixi where ai is the number of partitions of the vertex set of G into i nonempty independent sets. Such polynomials arise in a natural way from chromatic polynomials. Brenti (Trans Am Math Soc 332 (1992), 729–756) proved that σ‐polynomials of graphs with chromatic number at least n−2 had all real roots, and conjectured the same held for chromatic number n−3 . We affirm this conjecture.
Use of electronic results reporting to diagnose and monitor AKI in hospitalized patients.

BACKGROUND AND OBJECTIVES Many patients with AKI are cared for by non-nephrologists. This can result in variable standards of care that contribute to poor outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS To improve AKI recognition, a real-time, hospital-wide, electronic reporting system was designed based on current Acute Kidney Injury Network criteria. This system allowed prospective data collection on AKI incidence and outcomes such as mortality rate, length of hospital stay, and renal recovery. The setting was a 1139-bed teaching hospital with a tertiary referral nephrology unit. RESULTS An electronic reporting system was successfully introduced into clinical practice (false positive rate, 1.7%; false negative rate, 0.2%). The results showed that there were 3202 AKI episodes in 2619 patients during the 9-month study period (5.4% of hospital admissions). The in-hospital mortality rate was 23.8% and increased with more severe AKI (16.1% for stage 1 AKI versus 36.1% for stage 3) (P<0.001). More severe AKI was associated with longer length of hospital stay for stage 1 (8 days; interquartile range, 13) versus 11 days for stage 3 (interquartile range, 16) (P<0.001) and reduced chance of renal recovery (80.0% in stage 1 AKI versus 58.8% in stage 3) (P<0.001). Utility of the Acute Kidney Injury Network criteria was reduced in those with pre-existing CKD. CONCLUSIONS AKI is common in hospitalized patients and is associated with very poor outcomes. The successful implementation of electronic alert systems to aid early recognition of AKI across all acute specialties is one strategy that may help raise standards of care.
Current and emerging “at-site” pain medications: a review

The myriad pain pathophysiology has intrigued and challenged humanity for centuries. In this regard, the traditional pain therapies such as opioids and nonsteroidal anti-inflammatory drugs have been highly successful in treating acute and chronic pain. However, their drawback includes adverse events such as psychotropic effects, addiction potential, and gastrointestinal toxicities, to mention a few. These factors combined with the likelihood of an increase in chronic pain conditions due to an aging population calls for the development of novel mechanism-based or “site-specific” agents to target novel pain pathways. In this regard, rapid progress has been made in understanding the molecular mechanisms of novel pain targets such as cannabinoid receptors, fatty acid hydrolase, voltage-gated and ligand-gated ion channels such as P2 receptors, transient receptor potential channels and glial cell modulators. Accordingly, preclinical studies indicate that the site-specific/selective agents exhibit sufficient efficacy and reduced side effects such as lack of psychotropic effects indicating their clinical potential. This review provides a brief summary of some “at-site” pain targets and their role in the pain pathophysiology, and describes the efforts in developing some small molecules as novel pain therapeutics.
Proofs that yield nothing but their validity and a methodology of cryptographic protocol design

In this paper we demonstrate the generality and wide applicability of zero-knowledge proofs, a notion introduced by Goldwasser, Micali and Rackoff. These are probabilistic and interactive proofs that, for the members x of a language L, efficiently demonstrate membership in the language without conveying any additional knowledge. So far, zero-knowledge proofs were known only for some number theoretic languages in NP ∩ Co-NP.
Should we evaluate and treat sperm DNA fragmentation?

Purpose of review The clinical utility of sperm DNA fragmentation tests needs to be revisited in light of increasing evidence of detrimental effect of sperm DNA damage on reproductive outcomes. Recent findings Current evidence supports the association between high sperm DNA fragmentation and poor outcomes with regards to natural conception and intrauterine insemination. The relationship between high sperm DNA fragmentation and impaired outcomes after in-vitro fertilization and intracytoplasmic sperm injection are more equivocal. However, recent studies indicate that poor sperm chromatin content is associated with an increased risk of early pregnancy loss after in-vitro fertilization and intracytoplasmic sperm injection. Several strategies are proposed to alleviate sperm DNA fragmentation and/or select sperm with higher quality chromatin content for assisted reproductive techniques. The intake of oral antioxidants, varicocele repair, use of recurrent ejaculations alone or combined with micromanipulation-based sperm selection techniques, and the use of testicular sperm for intracytoplasmic sperm injection have been attempted with promising results. Summary Sperm DNA fragmentation tests provide clinically relevant information for natural conception and artificial reproduction independent of those derived from conventional semen parameters. The increasing knowledge of paternal factors on pregnancy outcome and the improvement in treatment strategies should prompt routine evaluation of sperm DNA fragmentation in infertile couples.
Automated Image Analysis for Quantitative Fluorescence In Situ Hybridization with Environmental Samples

ABSTRACT When fluorescence in situ hybridization (FISH) analyses are performed with complex environmental samples, difficulties related to the presence of microbial cell aggregates and nonuniform background fluorescence are often encountered. The objective of this study was to develop a robust and automated quantitative FISH method for complex environmental samples, such as manure and soil. The method and duration of sample dispersion were optimized to reduce the interference of cell aggregates. An automated image analysis program that detects cells from 4′,6′-diamidino-2-phenylindole (DAPI) micrographs and extracts the maximum and mean fluorescence intensities for each cell from corresponding FISH images was developed with the software Visilog. Intensity thresholds were not consistent even for duplicate analyses, so alternative ways of classifying signals were investigated. In the resulting method, the intensity data were divided into clusters using fuzzy c-means clustering, and the resulting clusters were classified as target (positive) or nontarget (negative). A manual quality control confirmed this classification. With this method, 50.4, 72.1, and 64.9% of the cells in two swine manure samples and one soil sample, respectively, were positive as determined with a 16S rRNA-targeted bacterial probe (S-D-Bact-0338-a-A-18). Manual counting resulted in corresponding values of 52.3, 70.6, and 61.5%, respectively. In two swine manure samples and one soil sample 21.6, 12.3, and 2.5% of the cells were positive with an archaeal probe (S-D-Arch-0915-a-A-20), respectively. Manual counting resulted in corresponding values of 22.4, 14.0, and 2.9%, respectively. This automated method should facilitate quantitative analysis of FISH images for a variety of complex environmental samples.
Nuclear Calcium Buffering Capacity Shapes Neuronal Architecture*

Background: Calcium-binding proteins regulate calcium dynamics and downstream signaling events. Results: Increasing the calcium buffering capacity of the nucleus alters the expression of genes that regulate neuronal architecture. Conclusion: The nuclear calcium buffering capacity is an important determinant of neuronal morphology. Significance: Nuclear calcium buffers represent a new target for modulating gene expression and neuronal structure. Calcium-binding proteins (CaBPs) such as parvalbumin are part of the cellular calcium buffering system that determines intracellular calcium diffusion and influences the spatiotemporal dynamics of calcium signals. In neurons, CaBPs are primarily localized to the cytosol and function, for example, in nerve terminals in short-term synaptic plasticity. However, CaBPs are also expressed in the cell nucleus, suggesting that they modulate nuclear calcium signals, which are key regulators of neuronal gene expression. Here we show that the calcium buffering capacity of the cell nucleus in mouse hippocampal neurons regulates neuronal architecture by modulating the expression levels of VEGFD and the complement factor C1q-c, two nuclear calcium-regulated genes that control dendrite geometry and spine density, respectively. Increasing the levels of nuclear calcium buffers by means of expression of a nuclearly targeted form of parvalbumin fused to mCherry (PV.NLS-mC) led to a reduction in VEGFD expression and, as a result, to a decrease in total dendritic length and complexity. In contrast, mRNA levels of the synapse pruning factor C1q-c were increased in neurons expressing PV.NLS-mC, causing a reduction in the density and size of dendritic spines. Our results establish a close link between nuclear calcium buffering capacity and the transcription of genes that determine neuronal structure. They suggest that the development of cognitive deficits observed in neurological conditions associated with CaBP deregulation may reflect the loss of necessary structural features of dendrites and spines.
Protein microarray technology

Following the completion of the human genome sequencing project, well-established DNA microarrays and sophisticated bioinformatic platforms now allow scientists to take a global view of biological systems. The different physiological states of cells correlates with different cellular protein expression and with differences in protein function–known as the cellular proteome. The interactions between a cell and its environment are influenced by several parameters in parallel (e.g., cell signaling molecules, cell–cell and cell–matrix interactions). Cellular processes controlling and defining the physiological state of a cell regulate messenger RNA (mRNA) and protein expression, control protein modification and localization and therefore regulate protein function (FIGURE 1) [1]. Nowadays, several different technologies are applied to analyze the complex and highly dynamic protein content of biological systems. None of these technologies have the potential to deal with the whole complexity and the huge dynamic range (107) of protein expression in cells [2]. The most widely used separation technology for the simultaneous examination of large numbers of proteins is 2D polyacrylamide gel electrophoresis (PAGE), which suffers from low sample throughput, a small dynamic detection range and severe difficulties in the analysis of hydrophobic, small and very basic or acidic proteins. Multidimensional chromatography approaches (e.g., multidimensional protein identification technology) and different affinity capture chromatographic methods (isotope-coded affinity tagging, metal chelates) are used as alternatives to 2D-PAGE for the separation of analytes and reduction of complexity prior to mass spectrometry-based protein identification [3,4]. But despite these very impressive developments in proteome analysis technologies, there is still an urgent need for alternative tools that allow a global view into the proteome. Microarray technology has the potential to monitor complex intracellular gene and protein expression and to simultaneously study the interaction between proteins and a large number of potential interaction partners (FIGURE 1).
An investigation into the effects of substrate properties on the mechanics of corneal epithelial cells

Cells respond to mechanical changes in their extracellular environment, as reflected by various cell behaviours and observed through changes in the tissue biomechanics. Types of cell behaviour that are regulated by mechanical cues in the microenvironment of the cell are cell spreading, migration, proliferation and differentiation. Cell migration is a key part of many biological processes including corneal wound repair. Changes in the biomechanical properties of the cornea can be induced by refractive and therapeutic treatments and also by diseases of the eye or other illnesses. A Rabbit Corneal Epithelial (RCE) cell line was used to study cell mechanics and cell migration. Polydimethylsiloxane (PDMS), a biocompatible silicone elastomer, was used as a substrate to culture RCE cells. In order to promote cell attachment and growth, the hydrophilicity of the PDMS surface was increased by treating it with oxygen-rich cold atmospheric pressure plasma, which was confirmed by surface characterisation techniques. Cell attachment and growth studies over time comparing plasma and non-plasma treated PDMS showed an increase in RCE cell growth and area coverage on plasma treated PDMS. [Continues. ]
Multivariate Realised Kernels: Consistent Positive Semi-Definite Estimators of the Covariation of Equity Prices with Noise and Non-Synchronous Trading

We propose a multivariate realised kernel to estimate the ex-post covariation of log-prices. We show this new consistent estimator is guaranteed to be positive semi-definite and is robust to measurement noise of certain types and can also handle non-synchronous trading. It is the first estimator which has these three properties which are all essential for empirical work in this area. We derive the large sample asymptotics of this estimator and assess its accuracy using a Monte Carlo study. We implement the estimator on some US equity data, comparing our results to previous work which has used returns measured over 5 or 10 minutes intervals. We show the new estimator is substantially more precise.
Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus–infected patients

Boceprevir is a hepatitis C virus (HCV) nonstructural protein (NS) 3/4A protease inhibitor that is currently being evaluated in combination with peginterferon alfa‐2b and ribavirin in phase 3 studies. The clinical resistance profile of boceprevir is not characterized in detail so far. The NS3 protease domain of viral RNA was cloned from HCV genotype 1–infected patients (n = 22). A mean number of 47 clones were sequenced before, at the end, and after treatment with 400 mg boceprevir twice or three times daily for 14 days for genotypic, phenotypic, and viral fitness analysis. At the end of treatment, a wild‐type an NS3 protease sequence was observed with a mean frequency of 85.9%. In the remaining isolates, five previously observed resistance mutations (V36M/A, T54A/S, R155K/T, A156S, V170A) and one mutation (V55A) with unknown resistance to boceprevir were detected either alone or in combination. Phenotypic analysis in the HCV replicon assay showed low (V36G, T54S, R155L; 3.8‐ to 5.5‐fold 50% inhibitory concentration [IC50]), medium (V55A, R155K, V170A, T54A, A156S; 6.8‐ to 17.7‐fold IC50) and high level (A156T; >120‐fold IC50) resistance to boceprevir. The overall frequency of resistant mutations and the level of resistance increased with greater declines in mean maximum HCV RNA levels. Two weeks after the end of treatment, the frequency of resistant variants declined and the number of wild‐type isolates increased to 95.5%. With the exception of V36 and V170 variants all resistant mutations declined by more than 50%. Mathematical modeling revealed impaired replicative fitness for all single mutations, whereas for combined mutations a relative increase of replication efficiency was suggested. Conclusion: During boceprevir monotherapy, resistance mutations at six positions within the NS3 protease were detected by way of clonal sequence analysis. All mutations are associated with reduced replicative fitness estimated by mathematical modeling and show cross‐resistance to telaprevir. (HEPATOLOGY 2009.)
Fabrication of Superhydrophobic AA5052 Aluminum Alloy Surface with Improved Corrosion Resistance and Self Cleaning Property

The development of a self-cleaning and corrosion resistant superhydrophobic coating for aluminum alloy surfaces that is durable in aggressive conditions has attracted great interest in materials science. In the present study, a superphydrophobic film was fabricated on an AA5052 aluminum alloy surface by the electrodeposition of Ni–Co alloy coating, followed by modification with 6-(N-allyl-1,1,2,2-tetrahydro-perfluorodecyl) amino-1,3,5-triazine-2,4-dithiol monosodium (AF17N). The surface morphology and characteristics of the composite coatings were investigated by means of scanning electron microscopy (SEM), energy dispersive X-ray spectrum (EDS), atomic force microscope (AFM) and contact angle (CA). The corrosion resistance of the coatings was assessed by electrochemical tests. The results showed that the surface exhibited excellent superhydrophobicity and self-cleaning performance with a contact angle maintained at 160° after exposed to the atmosphere for 240 days. Moreover, the superhydrophobic coatings significantly improved the corrosion resistant performance of AA5052 aluminum alloy substrate in 3.5 wt. % NaCl solution.
Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia

Severe congenital neutropenia (SCN) is a genetically heterogeneous syndrome associated with mutations of ELANE (ELA2), HAX1, GFI1, WAS, CSF3R or G6PC3. We investigated the prevalence of mutations of ELANE in a cohort of 162 SCN patients for whom blood or bone marrow samples were submitted to the North American Severe Chronic Neutropenia Tissue Repository. Mutations of ELANE were found in 90 of 162 patients (55·6%). Subsequently, we conducted an analysis of a subset of 73 of these cases utilising a high throughput sequencing approach to determine the prevalence of other mutations associated with SCN. Among the 73 patients, mutations of ELANE were detected in 28. In the remaining 45 patients with wild type ELANE alleles, five patients had mutations: GFI1 (1), SBDS (1), WAS (1) and G6PC3 (2); no mutations of HAX1 were detected. In approximately 40% of our cases, the genetic basis of SCN remains unknown. These data suggest that for genetic diagnosis of SCN, ELANE genotyping should first be performed. In patients without ELANE mutations, other known SCN‐associated gene mutations will be found rarely and genotyping can be guided by the clinical features of each patient.