Growth modes of nanoparticle superlattice thin films

We report about the fabrication and characterization of iron oxide nanoparticle thin film superlattices. The formation into different film morphologies is controlled by tuning the particle plus solvent-to-substrate interaction. It turns out that the wetting vs. dewetting properties of the solvent before the self-assembly process during solvent evaporation plays a major role to determine the resulting film morphology. In addition to layerwise growth also three-dimensional mesocrystalline growth is evidenced. The understanding of the mechanisms ruling nanoparticle self-assembly represents an important step toward the fabrication of novel materials with tailored optical, magnetic or electrical transport properties

Higher risk of intracranial aneurysms and subarachnoid haemorrhage in siblings of families with intracranial aneurysms

Introduction: First-degree relatives of patients with familial aneurysmal subarachnoid hemorrhage have an increased risk of unruptured intracranial aneurysms and aneurysmal subarachnoid hemorrhage. We assessed whether the type of kinship of first-degree relatives of aneurysmal subarachnoid hemorrhage patients influences this risk. Patients and methods: We used all available data from the prospectively collected database of families consulting our outpatient clinic between 1994-2016. We constructed pedigrees for all families with ≥2 first-degree relatives with aneurysmal subarachnoid hemorrhage or unruptured intracranial aneurysms. The proband was defined as the first family member with aneurysmal subarachnoid hemorrhage who sought medical attention. We compared both the proportion of aneurysmal subarachnoid hemorrhage and unruptured intracranial aneurysms in proband's first-degree relatives by calculating relative risks (RR) with children as the reference. Results: We studied 154 families with 1,105 first-degree relatives of whom 146 had aneurysmalsubarachnoid hemorrhage. Unruptured intracranial aneurysms were identified in 63 (19%) of the 326 screened relatives. Siblings had a higher risk of aneurysmal subarachnoid hemorrhage (RR:1.62, 95% CI:1.12–2.38) and parents a lower risk (RR:0.44, 95% CI:0.24–0.81) than children. Siblings also had a higher risk of unruptured intracranial aneurysms (RR:2.28, 95% CI:1.23–4.07, age-adjusted RR:2.04, 95% CI:1.07–3.92) than children. Conclusion: Siblings of patients with aneurysmal subarachnoid hemorrhage have a significanthigher risk of both unruptured intracranial aneurysms and aneurysmal subarachnoid hemorrhage and parents have a lower risk of aneurysmal subarachnoid hemorrhage than children. Discussion: Type of kinship is a relevant factor to consider in risk prediction and screening advice in families with familial aneurysmal subarachnoid hemorrhage

Від коваріацій до каузальності. Відкриття структур залежностей у даних

Проаналізовано сучасну методологію виводу каузальних моделей та структур систем імовірнісних залежностей із статистичних даних пасивних спостережень. Висвітлено можливості, проблеми, застереження та обмеження методів індуктивної ідентифікації каузальних відношень в апараті марковських властивостей та баєсових мереж. Виділено кілька ступенів каузальних моделей згідно з рівнем їх обґрунтованості та адекватності джерелу даних. Сформульовано статистичний паттерн, який зводить обґрунтування висновку про каузальний характер зв’язку двох змінних до тестування набору статистичних фактів (не)залежності.Проанализирована современная методология вывода каузальных моделей и структур систем вероятностных зависимостей из статистических данных пассивных наблюдений. Освещены возможности, проблемы, оговорки и ограничения методов индуктивной идентификации каузальных отношений в аппарате марковских свойств и байесовых сетей. Выделены несколько ступеней каузальных моделей согласно уровню их обоснованности и адекватности источнику данных. Сформулирован статистический паттерн, который сводит обоснование вывода о каузальном характере связи двух переменных к тестированию набора статистических фактов (не)зависимости.The current methodology of output casual models and structures of systems of probabilistic dependencies of stafistical data of passive observation is analysed. The problems, features, traps and limitations of the methods of the inductive identification of casual relation in the unit of marcov properties and bayesias nets are highlighted. Several stages of casual models according to the level of their validity and adequacy of the data source are emphasized. The statistical pattern, which brings the justification of a finding about casual nature of the connections between two variables to the test of a set of statistical facts of (in)dependency is formulated

Absence of Consistent Sex Differences in Outcomes From Symptomatic Carotid Endarterectomy and Stenting Randomized Trials.

BACKGROUND AND PURPOSE: CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported a higher periprocedural risk for any stroke, death, or myocardial infarction for women randomized to carotid artery stenting (CAS) compared with women randomized to carotid endarterectomy (CEA). No difference in risk by treatment was detected for women relative to men in the 4-year primary outcome. We aimed to conduct a pooled analysis among symptomatic patients in large randomized trials to provide more precise estimates of sex differences in the CAS-to-CEA risk for any stroke or death during the 120-day periprocedural period and ipsilateral stroke thereafter. METHODS: Data from the Carotid Stenosis Trialists' Collaboration included outcomes from symptomatic patients in EVA-3S (Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis), SPACE (Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients), ICSS (International Carotid Stenting Study), and CREST. The primary outcome was any stroke or death within 120 days after randomization and ipsilateral stroke thereafter. Event rates and relative risks were estimated using Poisson regression; effect modification by sex was assessed with a sex-by-treatment-by-trial interaction term, with significant interaction defined a priori as P≤0.10. RESULTS: Over a median 2.7 years of follow-up, 433 outcomes occurred in 3317 men and 1437 women. The CAS-to-CEA relative risk of the primary outcome was significantly lower for women compared with men in 1 trial, nominally lower in another, and nominally higher in the other two. The sex-by-treatment-by-trial interaction term was significant (P=0.065), indicating heterogeneity among trials. Contributors to this heterogeneity are primarily differences in periprocedural period. When the trials are nevertheless pooled, there were no significant sex differences in risk in any follow-up period. CONCLUSIONS: There were significant differences between trials in the magnitude of sex differences in treatment effect (CAS-to-CEA relative risk), indicating pooling data from these trials to estimate sex differences might not be valid. Whether sex is acting as an effect modifier of the CAS-to-CEA treatment effect in symptomatic patients remains uncertain. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00190398 (EVA-3S) and NCT00004732 (CREST). URL: https://www.isrctn.com; Unique identifier: ISRCTN57874028 (SPACE) and ISRCTN25337470 (ICSS)

Prediction Models for Clinical Outcome After a Carotid Revascularization Procedure.

Background and Purpose- Prediction models may help physicians to stratify patients with high and low risk for periprocedural complications or long-term stroke risk after carotid artery stenting or carotid endarterectomy. We aimed to evaluate external performance of previously published prediction models for short- and long-term outcome after carotid revascularization in patients with symptomatic carotid artery stenosis. Methods- From a literature review, we selected all prediction models that used only readily available patient characteristics known before procedure initiation. Follow-up data from 2184 carotid artery stenting and 2261 carotid endarterectomy patients from 4 randomized trials (EVA-3S [Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis], SPACE [Stent-Protected Angioplasty Versus Carotid Endarterectomy], ICSS [International Carotid Stenting Study], and CREST [Carotid Revascularization Endarterectomy Versus Stenting Trial]) were used to validate 23 short-term outcome models to estimate stroke or death risk ≤30 days after the procedure and the original outcome measure for which the model was developed. Additionally, we validated 7 long-term outcome models for the original outcome measure. Predictive performance of the models was assessed with C statistics and calibration plots. Results- Stroke or death ≤30 days after the procedure occurred in 158 (7.2%) patients after carotid artery stenting and in 84 (3.7%) patients after carotid endarterectomy. Most models for short-term outcome after carotid artery stenting (n=4) or carotid endarterectomy (n=19) had poor discriminative performance (C statistics ranging from 0.49-0.64) and poor calibration with small absolute risk differences between the lowest and highest risk groups and overestimation of risk in the highest risk groups. Long-term outcome models (n=7) had a slightly better performance with C statistics ranging from 0.59 to 0.67 and reasonable calibration. Conclusions- Current models did not reliably predict outcome after carotid revascularization in a trial population of patients with symptomatic carotid stenosis. In particular, prediction of short-term outcome seemed to be difficult. Further external validation of existing prediction models or development of new prediction models is needed before such models can be used to support treatment decisions in individual patients

Thermodynamic Additivity of Sequence Variations: An Algorithm for Creating High Affinity Peptides Without Large Libraries or Structural Information

BACKGROUND: There is a significant need for affinity reagents with high target affinity/specificity that can be developed rapidly and inexpensively. Existing affinity reagent development approaches, including protein mutagenesis, directed evolution, and fragment-based design utilize large libraries and/or require structural information thereby adding time and expense. Until now, no systematic approach to affinity reagent development existed that could produce nanomolar affinity from small chemically synthesized peptide libraries without the aid of structural information. METHODOLOGY/PRINCIPAL FINDINGS: Based on the principle of additivity, we have developed an algorithm for generating high affinity peptide ligands. In this algorithm, point-variations in a lead sequence are screened and combined in a systematic manner to achieve additive binding energies. To demonstrate this approach, low-affinity lead peptides for multiple protein targets were identified from sparse random sequence space and optimized to high affinity in just two chemical steps. In one example, a TNF-α binding peptide with K(d) = 90 nM and high target specificity was generated. The changes in binding energy associated with each variation were generally additive upon combining variations, validating the basis of the algorithm. Interestingly, cooperativity between point-variations was not observed, and in a few specific cases, combinations were less than energetically additive. CONCLUSIONS/SIGNIFICANCE: By using this additivity algorithm, peptide ligands with high affinity for protein targets were generated. With this algorithm, one of the highest affinity TNF-α binding peptides reported to date was produced. Most importantly, high affinity was achieved from small, chemically-synthesized libraries without the need for structural information at any time during the process. This is significantly different than protein mutagenesis, directed evolution, or fragment-based design approaches, which rely on large libraries and/or structural guidance. With this algorithm, high affinity/specificity peptide ligands can be developed rapidly, inexpensively, and in an entirely chemical manner

Discovery of High-Affinity Protein Binding Ligands – Backwards

BACKGROUND: There is a pressing need for high-affinity protein binding ligands for all proteins in the human and other proteomes. Numerous groups are working to develop protein binding ligands but most approaches develop ligands using the same strategy in which a large library of structured ligands is screened against a protein target to identify a high-affinity ligand for the target. While this methodology generates high-affinity ligands for the target, it is generally an iterative process that can be difficult to adapt for the generation of ligands for large numbers of proteins. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a class of peptide-based protein ligands, called synbodies, which allow this process to be run backwards--i.e. make a synbody and then screen it against a library of proteins to discover the target. By screening a synbody against an array of 8,000 human proteins, we can identify which protein in the library binds the synbody with high affinity. We used this method to develop a high-affinity synbody that specifically binds AKT1 with a K(d)<5 nM. It was found that the peptides that compose the synbody bind AKT1 with low micromolar affinity, implying that the affinity and specificity is a product of the bivalent interaction of the synbody with AKT1. We developed a synbody for another protein, ABL1 using the same method. CONCLUSIONS/SIGNIFICANCE: This method delivered a high-affinity ligand for a target protein in a single discovery step. This is in contrast to other techniques that require subsequent rounds of mutational improvement to yield nanomolar ligands. As this technique is easily scalable, we believe that it could be possible to develop ligands to all the proteins in any proteome using this approach

Differential Scanning Fluorimetry provides high throughput data on silk protein transitions

Here we present a set of measurements using Differential Scanning Fluorimetry (DSF) as an inexpensive, high throughput screening method to investigate the folding of silk protein molecules as they abandon their first native melt conformation, dehydrate and denature into their final solid filament conformation. Our first data and analyses comparing silks from spiders, mulberry and wild silkworms as well as reconstituted ‘silk’ fibroin show that DSF can provide valuable insights into details of silk denaturation processes that might be active during spinning. We conclude that this technique and technology offers a powerful and novel tool to analyse silk protein transitions in detail by allowing many changes to the silk solutions to be tested rapidly with microliter scale sample sizes. Such transition mechanisms will lead to important generic insights into the folding patterns not only of silks but also of other fibrous protein (bio)polymers

Kidney cancer mortality in Spain: geographic patterns and possible hypotheses

<p>Abstract</p> <p>Background</p> <p>Since the second half of the 1990s, kidney cancer mortality has tended to stabilize and decline in many European countries, due to the decrease in the prevalence of smokers. Nevertheless, incidence of kidney cancer is rising across the sexes in some of these countries, a trend which may possibly reflect the fact that improvements in diagnostic techniques are being outweighed by the increased prevalence of some of this tumor's risk factors. This study sought to: examine the geographic pattern of kidney cancer mortality in Spain; suggest possible hypotheses that would help explain these patterns; and enhance existing knowledge about the large proportion of kidney tumors whose cause remains unknown.</p> <p>Methods</p> <p>Smoothed municipal relative risks (RRs) for kidney cancer mortality were calculated in men and women, using the conditional autoregressive model proposed by Besag, York and Molliè. Maps were plotted depicting smoothed relative risk estimates, and the distribution of the posterior probability of RR>1 by sex.</p> <p>Results</p> <p>Municipal maps displayed a marked geographic pattern, with excess mortality in both sexes, mainly in towns along the Bay of Biscay, including areas of Asturias, the Basque Country and, to a lesser extent, Cantabria. Among women, the geographic pattern was strikingly singular, not in evidence for any other tumors, and marked by excess risk in towns situated in the Salamanca area and Extremaduran Autonomous Region. This difference would lead one to postulate the existence of different exposures of environmental origin in the various regions.</p> <p>Conclusion</p> <p>The reasons for this pattern of distribution are not clear, and it would thus be of interest if the effect of industrial emissions on this disease could be studied. The excess mortality observed among women in towns situated in areas with a high degree of natural radiation could reflect the influence of exposures which derive from the geologic composition of the terrain and then become manifest through the agency of drinking water.</p