Our understanding of the mechanisms underlying HLA associations with inflammatory arthritis continues to evolve. Disease associations have been refined, and interactions of HLA genotype with other ...genes and environmental risk factors in determining disease risk have been identified. This Review provides basic information on the genetics and molecular function of HLA molecules, as well as general features of HLA associations with disease. Evidence is discussed regarding the various peptide-dependent and peptide-independent mechanisms by which HLA alleles might contribute to the pathogenesis of three types of inflammatory arthritis: rheumatoid arthritis, spondyloarthritis and systemic juvenile idiopathic arthritis. Also discussed are HLA allelic associations that shed light on the genetic heterogeneity of inflammatory arthritides and on the relationships between adult and paediatric forms of arthritis. Clinical implications range from improved diagnosis and outcome prediction to the possibility of using HLA associations in developing personalized strategies for the treatment and prevention of these diseases.
Among persons with type 2 diabetes (t2d), the development of glucose intolerance involves dysfunction in several organs and tissues, including the muscle, liver, pancreas, kidney, gastrointestinal ...tract, adipose tissue, and brain. individuals with t2d typically have a number of comorbidities, including hypertension, hyperlipidemia, and being overweight or obese, and are, consequently, at high cardiovascular risk. guidelines recommend a comprehensive care strategy that includes treatment of diabetes-related complications and comorbidities beyond those related to hyperglycemia. use of glucose-lowering therapies with complementary activities that address multiple facets of the disease may improve long-term outcomes for patients with t2d. two recent drug classes developed for use in t2d, glucagon-like peptide-1 receptor agonists (glp-1ras) and sodium glucose cotransporter 2 (sglt2) inhibitors, have been shown in clinical trials to have beneficial effects on glycemic control, body weight, cardiovascular risk factors, and (for liraglutide, semaglutide, and empagliflozin) cardiovascular outcomes, while having an acceptable safety profile. between them, these drug classes directly or indirectly affect many of the organs and tissues involved in the pathogenesis of t2d, and their beneficial effects on glycemic- and cardiovascular-related parameters are likely to be complementary and potentially additive. in the largest clinical trial of a glp-1ra and an sglt2 inhibitor in combination (duration-8), patients with t2d (n = 685) who received exenatide plus dapagliflozin added to their treatment regimen for 28 weeks had significantly greater reductions from baseline in glycated hemoglobin, body weight, and systolic blood pressure compared with patients who received either drug as monotherapy. this review summarizes the complementary aspects of these drug classes and presents the available data among patients receiving dual therapy with a glp-1ra and an sglt2 inhibitor.
Gold nanoparticles (AuNPs) bound with biomolecules have emerged as suitable biosensors exploiting unique surface chemistries and optical properties. Many efforts have focused on antibody ...bioconjugation to AuNPs resulting in a sensitive bioconjugate to detect specific types of bacteria. Unfortunately, bacteria thrive under various harsh environments, and an understanding of bioconjugate stability is needed. Here, we show a method for optimizing Listeria monocytogenes polyclonal antibodies bioconjugation mechanisms to AuNPs via covalent binding at different pH values, from 2 to 11, and 2-(N-morpholino)ethanesulfonic acid (MES), 3-(N-morpholino)propanesulfonic acid, NaOH, HCl conditions. By fitting Lorentz curves to the amide I and II regions, we analyze the stability of the antibody secondary structure. This shows an increase in the apparent breakdown of the antibody secondary structure during bioconjugation as pH decreases from 7.9 to 2. We find variable adsorption efficiency, measured as the percentage of antibody adsorbed to the AuNP surface, from 17 to 27% as pH increases from 2 to 6 before decreasing to 8 and 13% at pH 7.9 and 11, respectively. Transmission electron microscopy (TEM) analysis reveals discrepancies between size and morphological changes due to the corona layer assembly from antibody binding to single nanoparticles versus aggregation or cluster self-assembly into large aggregates. The corona layer formation size increases from 3.9 to 5.1 nm from pH 2 to 6, at pH 7.9, there is incomplete corona formation, whereas at pH 11, there is a corona layer formed of 6.4 nm. These results indicate that the covalent binding process was more efficient at lower pH values; however, aggregation and deactivation of the antibodies were observed. We demonstrate that optimum bioconjugation condition was determined at pH 6 and MES buffer-type by indicators of covalent bonding and stability of the antibody secondary structure using Fourier transform-infrared, the morphological characteristics and corona layer formation using TEM, and low wavelength shifts of ultraviolet–visible after bioconjugation.
In recent years, modeling gully erosion susceptibility has become an increasingly popular approach for assessing the impact of different land degradation factors. However, different forms of human ...influence have so far not been identified in order to form an independent model. We investigate the spatial relation between gully erosion and distance to settlements and footpaths, as typical areas of human interaction, with the natural environment in rural African areas. Gullies are common features in the Ethiopian Highlands, where they often hinder agricultural productivity. Within a catchment in the north Ethiopian Highlands, 16 environmental and human-related variables are mapped and categorized. The resulting susceptibility to gully erosion is predicted by applying the Random Forest (RF) machine learning algorithm. Human-related and environmental factors are used to generate independent susceptibility models and form an additional inclusive model. The resulting models are compared and evaluated by applying a change detection technique. All models predict the locations of most gullies, while 28% of gully locations are exclusively predicted using human-related factors.
Settlement crises in ancient cultures of Western Asia are commonly thought to be caused by climatic events such as severe droughts. However, the insufficient climate proxy situation in this region ...challenges the inference of clear relationships between climate and settlement dynamics. We investigate the Holocene climatic changes on the Varamin Plain in the context of the climatic history of Western Central Asia by using a transient comprehensive Earth System Model simulation (8 ka BP to pre-industrial), a high-resolution regional snapshot simulation and a synthesis of pollen-based climate reconstructions. In line with the reconstructions, the models reveal only slightly varying mean climatic conditions on the Varamin Plain but indicate substantial changes in seasonality during the Holocene. Increased precipitation during spring, combined with lower temperature and potentially stronger snow accumulation on the upstream Alborz mountains may have led to an increased water supply on the alluvial fan during the vegetation period and thus to more favourable conditions for agricultural production during the Mid-Holocene compared to modern times. According to the model, dry periods on the Central Iranian Plateau are related to particularly weak Westerly winds, fostering the subsidence in the mid-troposphere and hampering precipitation over the region. The model reveals that dry periods have spatially heterogenous manifestations, thus explaining why they do not appear in all proxy records in the wider study region. In fact, the climatic signal may depend on local environmental conditions. The interaction of the topography with the atmospheric circulation leads to additional spatial heterogeneity. Although our results provide several indications for a connection between climate and settlement dynamics, the small overall changes in moisture call into question whether climate is the main driver for settlement discontinuities on the Central Iranian Plateau. To shed further light on this issue, more high-resolution long-term proxy records are needed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hypophosphatasia (HPP) is an inherited disease resulting from loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase. The presentation and severity of the ...disease are highly variable, ranging from perinatal onset with high mortality rates to adult identification with low mortality rates and symptoms ranging from minimal to severe. Moderate forms of HPP typically manifest during middle age and are often undiagnosed. The objective of this study was to determine the occurrence and burden of HPP in an ambulatory care endocrinology practice.
Potential subjects were identified with a computerized text search of patient electronic medical records. Search terms included serum alkaline phosphatase (ALP) levels of ≤40 U/L. Records of patients with at least 2 low ALP levels were reviewed manually to identify potential patients with a history consistent with hypophosphatasia.
In total, 315 patients with ALP levels ≤40 U/L were identified from an estimated 20 000 patient records. Fifty-six patients with a single low level were excluded from further review. The remaining 259 patients were reviewed, 10 of whom had histories consistent with HPP. None of the identified 10 patients was currently being treated or had previously been treated for HPP. Information about these patients was shared with their respective providers, along with the recommendation to proceed with further evaluation to confirm the diagnosis of HPP.
Hypophosphatasia is an uncommon condition with variable presentation, often resulting in a missed diagnosis. Surveillance of practices by identifying patients with low ALP levels is a rational screening approach to identifying potential patients with HPP.
This work offers a facile fabrication method for lignin nanocomposites through the assembly of kraft lignin onto magnetic nanoparticles (Fe3O4) based on pH-driven precipitation, without needing ...organic solvents or lignin functionalization. Kraft lignin@Fe3O4 multicore nanocomposites fabrication proceeded using a simple, pH-driven precipitation technique. An alkaline solution for kraft lignin (pH 12) was rapidly injected into an aqueous-based Fe3O4 nanoparticle colloidal suspension (pH 7) under constant mixing conditions, allowing the fabrication of lignin magnetic nanocomposites. The effects of increasing lignin to initial Fe3O4 mass content (g/g), increasing in ratio from 1:1 to 20:1, are discussed with a complete chemical, structural, and morphological characterization. Results showed that nanocomposites fabricated above 5:1 lignin:Fe3O4 had the highest lignin coverage and content (>20%), possessed superparamagnetic properties (Ms ≈ 45,000 A·m2/kg2); had a negative surface charge (−30 mV), and formed multicore nanostructures (DH ≈ 150 nm). The multicore lignin@Fe3O4 nanocomposites allowed rapid magnetically induced separations from suspension. After 5 min exposure to a rare-earth neodymium magnet (1.27 mm × 1.27 mm × 5.08 mm), lignin@Fe3O4 nanocomposites exhibited a maximum methylene blue removal efficiency of 74.1% ± 7.1%. These nanocomposites have potential in magnetically induced separations to remove organic dyes, heavy metals, or other lignin adsorbates.
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•Kraft lignin@Fe3O4 nanocomposites were prepared via a pH-driven aqueous-based method.•A multicore structure was obtained with Fe3O4 nanoclusters and lignin shells.•Above a 5:1 lignin:Fe3O4 mass ratio, nanocomposite properties remain unchanged.•Methylene blue was adsorbed and magnetically separated with a low strength magnet.
Transient global amnesia (TGA) is a clinical syndrome characterized by the sudden onset of an extraordinarily large reduction of anterograde and a somewhat milder reduction of retrograde episodic ...long-term memory. Additionally, executive functions are described as diminished. Although it is suggested that various factors, such as migraine, focal ischemia, venous flow abnormalities, and epileptic phenomena, are involved in the pathophysiology and differential diagnosis of TGA, the factors triggering the emergence of these lesions are still elusive. Recent data suggest that the vulnerability of CA1 neurons to metabolic stress plays a pivotal part in the pathophysiological cascade, leading to an impairment of hippocampal function during TGA. In this review, we discuss clinical aspects, new imaging findings, and recent clinical-epidemiological data with regard to the phenotype, functional anatomy, and putative cellular mechanisms of TGA.
Summary
Aims
Patients with advanced type 2 diabetes (T2D) and high glycated haemoglobin (HbA1c) values can be difficult to treat because of their severe metabolic disease. This pooled analysis ...examined the treatment effects of exenatide twice daily (BID), exenatide once weekly (QW) and insulin in patients with high baseline HbA1c (≥10.0%).
Methods
This post hoc analysis used pooled data from 12 and 8 randomised controlled trials of exenatide BID and exenatide QW, respectively. Patients with T2D who completed at least 24 weeks of treatment with exenatide BID, exenatide QW or insulin (insulin glargine, insulin detemir or insulin aspart) were categorised by baseline HbA1c. Patients with HbA1c ≥10.0% were included in the analysis.
Results
Both exenatide and insulin reduced HbA1c (mean ± SE reduction: −2.0% ± 0.2% exenatide and −2.1% ± 0.2% insulin in the exenatide BID studies, and −2.6% ± 0.1% exenatide and −2.1% ± 0.2% insulin in the exenatide QW studies; all P < .001). Body weight decreased with exenatide and increased with insulin. Systolic blood pressure decreased with exenatide QW. Insulin dose increased over the course of treatment. The most common adverse events with exenatide were gastrointestinal. Insulin was associated with some hypoglycaemia risk. Hypoglycaemia events occurred infrequently with exenatide when given without sulphonylureas.
Conclusions
For patients with high HbA1c, treatment with exenatide or insulin both improved glycaemic control. Given the associated weight loss and low risk of hypoglycaemia, exenatide may be a suitable alternative to treatment with insulin in certain patients with T2D and high HbA1c.
Two-dimensional (2D) transition metal dichalcogenides (TMDCs) exhibit compelling dimension-dependent exciton-dominated optical behavior influenced by thickness and lateral quantum confinement ...effects. Thickness quantum confinement effects have been observed; however, experimental optical property assessment of nanoscale lateral dimension monolayer TMDCs is lacking. Here, we employ ex situ spectroscopic ellipsometry to evaluate laterally coalescing monolayer metalorganic chemical vapor deposited MoS2. A multisample analysis is used to constrain Bruggeman and Maxwell–Garnett effective medium approximations and the effective dielectric functions are derived for laterally coalesced and uncoalesced MoS2 films (∼10–94% surface coverage for ∼10–140 nm lateral grain sizes). This analysis demonstrates the ability to probe MoS2 optical exciton behavior at growth-relevant grain sizes in relation to chemical vapor nucleation density, ripening, and lateral growth conditions. Our analysis is pertinent toward expected in situ epitaxial 2D TMDC film growth metrology to enable the facile development of monolayer films with targeted process-dependent optical properties.
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