Covalent binding of bioligands to atomic force microscope (AFM) tips converts them into monomolecular biosensors by which cognate receptors can be localized on the sample surface and fine details of ...ligand−receptor interaction can be studied. Tethering of the bioligand to the AFM tip via a ∼6 nm long, flexible poly(ethylene glycol) linker (PEG) allows the bioligand to freely reorient and to rapidly “scan” a large surface area while the tip is at or near the sample surface. In the standard coupling scheme, amino groups are first generated on the AFM tip. In the second step, these amino groups react with the amino-reactive ends of heterobifunctional PEG linkers. In the third step, the 2-pyridyl-S-S groups on the free ends of the PEG chains react with protein thiol groups to give stable disulfide bonds. In the present study, this standard coupling scheme has been critically examined, using biotinylated IgG with free thiols as the bioligand. AFM tips with PEG-tethered biotin-IgG were specifically recognized by avidin molecules that had been adsorbed to mica surfaces. The unbinding force distribution showed three maxima that reflected simultaneous unbinding of 1, 2, or 3 IgG-linked biotin residues from the avidin monolayer. The coupling scheme was well-reproduced on amino-functionalized silicon nitride chips, and the number of covalently bound biotin-IgG per μm2 was estimated by the amount of specifically bound ExtrAvidin−peroxidase conjugate. Coupling was evidently via disulfide bonds, since only biotin-IgG with free thiol groups was bound to the chips. The mechanism of protein thiol coupling to 2-pyridyl-S-S-PEG linkers on AFM tips was further examined by staging the coupling step in bulk solution and monitoring turnover by release of 2-pyridyl-SH which tautomerizes to 2-thiopyridone and absorbs light at 343 nm. These experiments predicted 103-fold slower rates for the disulfide coupling step than actually observed on AFM tips and silicon nitride chips. The discrepancy was reconciled by assuming 103-fold enrichment of protein on AFM tips via preadsorption, as is known to occur on comparable inorganic surfaces.
In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In ...phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 × 10−10), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 × 10−26) and 18q21 (rs4939827; OR = 1.2; P = 7.8 × 10−28). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.
Purpose: Residential care/assisted living describes diverse facilities providing non–nursing home care to a heterogeneous group of primarily elderly residents. This article derives typologies of ...assisted living based on theoretically and practically grounded evidence.Design and Methods: We obtained data from the Collaborative Studies of Long-Term Care, which examined 193 assisted living facilities in four states: Florida, Maryland, New Jersey, and North Carolina. By using mixture modeling, we derived typologies in five different ways, based on: structure; process; resident case-mix; structure and process; and structure, process, and resident case-mix. Results: Although configurations of typologies varied as a function of criterion variables used, common themes emerged from different cluster solutions. A typology based on resident case-mix yielded a five-cluster solution, whereas a typology based on structure, process, and resident case-mix resulted in six distinct clusters. Medicaid case-mix/psychiatric illness and high resident impairment were two clusters identified by both strategies. Implications: Because of the wide variation in structure, residents, and services within assisted living facilities, typologies such as those described here may be useful in clinical practice, research, and policy. To the extent that public payment defines its own cluster, the potential for inequities in care merits careful attention.
Current trends in population aging affect both recipients and providers of informal family caregiving, as the pool of family caregivers is shrinking while demand is increasing. Epidemiological ...research has not yet examined the implications of these trends for burdens experienced by aging family caregivers. Method Cross-sectional community surveys in 20 countries asked 13 892 respondents aged 50+ years about the objective (time, financial) and subjective (distress, embarrassment) burdens they experience in providing care to first-degree relatives with 12 broadly defined serious physical and mental conditions. Differential burden was examined by country income category, kinship status and type of condition.
Among the 26.9-42.5% respondents in high-, upper-middle-, and low-/lower-middle-income countries reporting serious relative health conditions, 35.7-42.5% reported burden. Of those, 25.2-29.0% spent time and 13.5-19.4% money, while 24.4-30.6% felt distress and 6.4-21.7% embarrassment. Mean caregiving hours per week in those giving any time were 16.6-23.6 (169.9-205.8 h/week per 100 people aged 50+ years). Burden in low-/lower-middle-income countries was 2- to 3-fold higher than in higher-income countries, with any financial burden averaging 14.3% of median family income in high-, 17.7% in upper-middle-, and 39.8% in low-/lower-middle-income countries. Higher burden was reported by women than men and for conditions of spouses and children than parents or siblings.
Uncompensated family caregiving is an important societal asset that offsets rising formal healthcare costs. However, the substantial burdens experienced by aging caregivers across multiple family health conditions and geographic regions threaten the continued integrity of their caregiving capacity. Initiatives supporting older family caregivers are consequently needed, especially in low-/lower-middle-income countries.
Automated surface inspection is an important task in many manufacturing industries and often requires machine learning driven solutions. Supervised approaches, however, can be challenging, since it ...is often difficult to obtain large amounts of labeled training data. In this work, we instead perform one-class unsupervised learning on fault-free samples by training a deep convolutional neural network to complete images whose center regions are cut out. Since the network is trained exclusively on fault-free data, it completes the image patches with a fault-free version of the missing image region. The pixel-wise reconstruction error within the cut out region is an anomaly image which can be used for anomaly detection. Results on surface images of decorated plastic parts demonstrate that this approach is suitable for detection of visible anomalies and moreover surpasses all other tested methods.
Adenosine levels increase at seizure foci as part of a postulated endogenous negative feedback mechanism that controls seizure activity through activation of A1 adenosine receptors. Agents that ...amplify this site- and event-specific surge of adenosine could provide antiseizure activity similar to that of adenosine receptor agonists but with fewer dose-limiting side effects. Inhibitors of adenosine kinase (AK) were examined because AK is normally the primary route of adenosine metabolism. The AK inhibitors 5'-amino-5'-deoxyadenosine, 5-iodotubercidin, and 5'-deoxy-5-iodotubercidin inhibited maximal electroshock (MES) seizures in rats. Several structural classes of novel AK inhibitors were identified and shown to exhibit similar activity, including a prototype inhibitor, 4-(N-phenylamino)-5-phenyl-7-(5'-deoxyribofuranosyl)pyrrolo2, 3-dpyrimidine (GP683; MES ED50 = 1.1 mg/kg). AK inhibitors also reduced epileptiform discharges induced by removal of Mg2+ in a rat neocortical preparation. Overall, inhibitors of adenosine deaminase or of adenosine transport were less effective. The antiseizure activities of GP683 in the in vivo and in vitro preparations were reversed by the adenosine receptor antagonists theophylline and 8-(p-sulfophenyl)theophylline. GP683 showed little or no hypotension or bradycardia and minimal hypothermic effect at anticonvulsant doses. This improved side effect profile contrasts markedly with the profound hypotension, bradycardia, and hypothermia and greater inhibition of motor function observed with the adenosine receptor agonist N6-cyclopentyladenosine and opens the way to clinical evaluation of AK inhibitors as a novel, adenosine-based approach to anticonvulsant therapy.
This paper is concerned with the problem of anomaly detection on surfaces that show periodic decoration patterns as shown at car interior components for example. The decoration of the surface is ...allowed to show a smooth deformation that can vary from one sample to another. As a consequence, every sample is unique in its appearance. The task is to robustly distinguish between the regular decoration and possibly occurring surface defects. The proposed algorithm is based on the computation of a unique virtual golden sample that exactly matches the inspected part except from any defects. Through the virtual golden sample an anomaly image is computed that can be used for final defect detection and evaluation. The novel algorithm has been successfully tested for different types of periodic decorations patterns.
We report a 27-week, 850 g infant with severe Streptococcus group B sepsis and life-threatening hyperkalemia due to progressive anuria. On the fourth day of life, after he failed treatment with ...diuretics, salbutamol, insulin, calcium gluconate and sodium bicarbonate, he was treated with sorbitol-free Kayexalate enemas. Potassium level slowly decreased from 9.2 mmol/l to normal level along with a recovery of normal urine output. On the 11th day of life, clinical and radiological signs of a perforated necrotizing enterocolitis (NEC) occurred and the patient required surgical intestinal resection. Histologic examination of the ileum specimen revealed areas of necrosis with fibrosis and giant cell reaction to a nonpolarizable material consistent with sodium polystyrene sulfonate. Usually, Kayexalate is suspended in hyperosmolar sorbitol solutions and the elevated osmolarity seems to be responsible for hemorrhagic colitis, transmural necrosis and definitely NEC. Our case report shows that Kayexalate per se, and not necessarily suspended in sorbitol, can lead to gastrointestinal tract complications and NEC in preterm infants.
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