Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical ...trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD.
A complete contextual marketing platform including an indoor positioning system (IPS) for smartphones is proposed and evaluated to later be deployed in large infrastructures, such as malls. To this ...end, we design and implement a novel methodology based on location-as-a-service (LAAS), comprising all the required phases of IPS generation: mall digital map creation, the tools/procedures for offline calibration fingerprint acquisition, the location algorithm, the smartphone app acquiring the fingerprint data, and a validation procedure. To select an appropriate fingerprint location algorithm, a comparison among K-nearest neighbors (KNN), support vector machine (SVM), and Freeloc is accomplished by employing a set of different smartphones in two malls and assessing different occupancy levels. We demonstrate that our solution can be quickly deployed at shop level accuracy in any new location, resulting in a robust and scalable proposal.
Purpose
The aims were to compare the 5-year outcomes of duodenal switch (DS) and single-anastomosis duodenal switch (SADI-S) in terms of weight loss; remission of comorbidities; nutritional status ...short- and long-term complications; postoperative mortality; and need for revisional surgery.
Materials and Methods
Multicenter prospective observational study of all consecutive patients undergoing DS or SADI-S in three high-volume hospitals.
Results
A total of 87 patients were included in the study, 43 submitted to DS and 44 to SADI-S, with similar basal characteristics, nutritional parameters, and BMI (52.9 kg/m
2
DS vs. 52.5 kg/m
2
SADI-S). Operative time was 152 min (± 32.6) in DS vs. 116 min (± 21.9) in SADI-S (
p
= 0.043). Short-term complications were similar for DS and SADI-S, both overall (11.8% vs. 11.6%), and ranged as Clavien-Dindo > II (4.5% vs. 4.7%), with no mortality. At 5 years, DS and SADI-S results were as follows: BMI 30.6 vs. 33.3 kg/m
2
(
p
= 0.023); %EWL 80.5% vs. 68.6% (
p
= 0.006); and %TWL 42.1 vs. 36.0 (
p
= 0.006). Comorbidity remission rates for DS and SADI-S were as follows: for diabetes, 92.8% vs. 85.7% (n.s.); for hypertension, 95.2% vs. 85.1% (n.s.); for sleep apnea, 75% vs. 73.3% (n.s.); and for dyslipidemia, 76.4% vs. 73.3% (n.s.). DS showed lower levels of vitamin B
12
, iron, vitamin E, and zinc than SADI-S (
p
= < 0.005). In the long term, there were 4 surgical reinterventions (due to 1 internal hernia in the DS group and 1 internal hernia and 2 biliary refluxes in the SADI-S group) with no cases of persistent diarrhea or malnutrition.
Conclusion
Both DS and SADI-S allowed good weight control and resolution of comorbidities. DS achieved a greater weight loss compared to SADI-S, at the expense of longer operative time and lower vitamin and mineral levels.
Graphical abstract
This review focuses on the purinergic ionotropic receptor P2X7 (P2X7R) as a potential target for developing drugs that delay the onset and/or disease progression in patients with amyotrophic lateral ...sclerosis (ALS). Description of clinical and genetic ALS features is followed by an analysis of advantages and drawbacks of transgenic mouse models of disease based on mutations in a bunch of proteins, particularly SOD1, TDP43, FUS and C9orf72. Though of limited value, these models are however critical to study the proof-of-concept of new compounds, before reaching clinical trials. The authors also provide a description of ALS pathogenesis including protein aggregation, calcium-dependent excitotoxicity, dysfunction of calcium-binding proteins, ultrastructural mitochondrial alterations, disruption of mitochondrial calcium handling and overproduction of reactive oxygen species. Understanding disease pathogenic pathways may ease the identification of new drug targets. Subsequently, neuroinflammation linked with P2X7Rs in ALS pathogenesis is described in order to understand the rationale of placing the use of P2X7R antagonists as a new therapeutic pharmacological approach to ALS. This is the basis for the hypothesis that a P2X7R blocker could mitigate the neuroinflammatory state, indirectly leading to neuroprotection and higher motoneuron survival in ALS patients.
A novel accurate and useful approximation of the well-known Beckmann distribution is presented here, which is used to model generalized pointing errors in the context of free-space optical (FSO) ...communication systems. We derive an approximate closed-form probability density function (PDF) for the composite gamma-gamma (GG) atmospheric turbulence with the pointing error model using the proposed approximation of the Beckmann distribution, which is valid for most practical terrestrial FSO links. This approximation takes into account the effect of the beam width, different jitters for the elevation and the horizontal displacement and the simultaneous effect of nonzero boresight errors for each axis at the receiver plane. Additionally, the proposed approximation allows us to delimit two different FSO scenarios. The first of them is when atmospheric turbulence is the dominant effect in relation to generalized pointing errors, and the second one when generalized pointing error is the dominant effect in relation to atmospheric turbulence. The second FSO scenario has not been studied in-depth by the research community. Moreover, the accuracy of the method is measured both visually and quantitatively using curve-fitting metrics. Simulation results are further included to confirm the analytical results.
Aims
The aim of this study was to evaluate the effect of the Mediterranean diet (MedDiet) on the incidence of heart failure (HF), a pre‐specified secondary outcome in the PREDIMED (PREvención con ...DIeta MEDiterránea) primary nutrition‐intervention prevention trial.
Methods and results
Participants at high risk of cardiovascular disease were randomly assigned to one of three diets: MedDiet supplemented with extra‐virgin olive oil (EVOO), MedDiet supplemented with nuts, or a low‐fat control diet. Incident HF was ascertained by a Committee for Adjudication of events blinded to group allocation. Among 7403 participants without prevalent HF followed for a median of 4.8 years, we observed 29 new HF cases in the MedDiet with EVOO group, 33 in the MedDiet with nuts group, and 32 in the control group. No significant association with HF incidence was found for the MedDiet with EVOO and MedDiet with nuts, compared with the control group hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.41–1.13, and HR 0.92; 95% CI 0.56–1.49, respectively.
Conclusion
In this sample of adults at high cardiovascular risk, the MedDiet did not result in lower HF incidence. However, this pre‐specified secondary analysis may have been underpowered to provide valid conclusions. Further randomized controlled trials with HF as a primary outcome are needed to better assess the effect of the MedDiet on HF risk.
Trial registration: ISRCTN35739639.
Exclusive breastfeeding is recommended for the first six months of life to promote adequate infant growth and development, and to reduce infant morbidity and mortality. However, whenever some mothers ...are not able to breastfeed their infants, infant formulas mimicking human milk are needed, and the safety and efficacy of each formula should be tested. Here, we report the results of a multicenter, randomized, blinded, controlled clinical trial that aimed to evaluate a novel starting formula on weight gain and body composition of infants up to 6 and 12 months, as well as safety and tolerability. For the intervention period, infants were divided into three groups: group 1 received formula 1 (Nutribén
Innova 1 (Alter Farmacia S.A., Madrid, Spain) or INN (
= 70)), with a lower amount of protein, a lower casein to whey protein ratio by increasing the content of α-lactalbumin, and a double amount of docosahexaenoic acid/arachidonic acid than the standard formula; it also contained a thermally inactivated postbiotic (
subsp.
, BPL1
HT). Group 2 received the standard formula or formula 2 (Nutriben
Natal (Alter Farmacia S.A., Madrid, Spain) or STD (
= 70)) and the third group was exclusively breastfed for exploratory analysis and used as a reference (BFD group (
= 70)). During the study, visits were made at 21 days and 2, 4, 6, and 12 months of age. Weight gain was higher in both formula groups than in the BFD group at 6 and 12 months, whereas no differences were found between STD and INN groups either at 6 or at 12 months. Likewise, body mass index was higher in infants fed the two formulas compared with the BFD group. Regarding body composition, length, head circumference and tricipital/subscapular skinfolds were alike between groups. The INN formula was considered safe as weight gain and body composition were within the normal limits, according to WHO standards. The BFD group exhibited more liquid consistency in the stools compared to both formula groups. All groups showed similar digestive tolerance and infant behavior. However, a higher frequency of gastrointestinal symptoms was reported by the STD formula group (
= 291), followed by the INN formula (
= 282), and the BFD groups (
= 227). There were fewer respiratory, thoracic, and mediastinal disorders among BFD children. Additionally, infants receiving the INN formula experienced significantly fewer general disorders and disturbances than those receiving the STD formula. Indeed, atopic dermatitis, bronchitis, and bronchiolitis were significantly more prevalent among infants who were fed the STD formula compared to those fed the INN formula or breastfed. To evaluate whether there were significant differences between formula treatments, beyond growth parameters, it would seem necessary to examine more precise health biomarkers and to carry out long-term longitudinal studies.
Sustainability‐oriented innovation in services has recently been raising interest among academics and professionals. The present research has a dual objective. The first is to develop a scale that ...captures the notion of sustainability‐oriented innovation in retailing (SOI‐r) from the consumer's perspective. A sequential process is carried out to purge and retain 17 items which synergistically measure SOI‐r. We use quantitative research, adopting an exploratory‐descriptive approach on a total sample of 510 customers of commercial food establishments. The principal axis factor analysis shows six factors: product innovation, marketing innovation, relational innovation, economic sustainability, social sustainability, and environmental sustainability. The second objective is to develop an index using importance‐performance map analysis, which allows analysis of the level of development of the six dimensions identified in SOI‐r and areas for their improvement. The results are compared across food retail formats (hypermarkets, supermarkets, and discount stores) and recommendations are made at a strategic level.
Chemical descriptors encode the physicochemical and structural properties of small molecules, and they are at the core of chemoinformatics. The broad release of bioactivity data has prompted enriched ...representations of compounds, reaching beyond chemical structures and capturing their known biological properties. Unfortunately, bioactivity descriptors are not available for most small molecules, which limits their applicability to a few thousand well characterized compounds. Here we present a collection of deep neural networks able to infer bioactivity signatures for any compound of interest, even when little or no experimental information is available for them. Our signaturizers relate to bioactivities of 25 different types (including target profiles, cellular response and clinical outcomes) and can be used as drop-in replacements for chemical descriptors in day-to-day chemoinformatics tasks. Indeed, we illustrate how inferred bioactivity signatures are useful to navigate the chemical space in a biologically relevant manner, unveiling higher-order organization in natural product collections, and to enrich mostly uncharacterized chemical libraries for activity against the drug-orphan target Snail1. Moreover, we implement a battery of signature-activity relationship (SigAR) models and show a substantial improvement in performance, with respect to chemistry-based classifiers, across a series of biophysics and physiology activity prediction benchmarks.
Display omitted
•Catalyst efficiency in reactivity controlled compression ignition combustion.•High emission leads to high oxidation inhibition at low temperature.•High hydrocarbons emission affects ...the sizing requirements due to adsorption.•High dependence of pollutants light-off on particular operating conditions.•Increase of pollutants light-off with respect to conventional Diesel combustion.
Reactivity controlled compression ignition is a promising combustion strategy due to the combination of excellent thermal efficiency with ultra-low nitrogen oxides and particulate matter raw emissions. However, very high levels of unburned hydrocarbons and carbon monoxide emissions are found. It limits the reactivity controlled compression ignition use at very low loads and presents an additional challenge for the diesel oxidation catalyst. The low exhaust temperature and high carbon monoxide and hydrocarbon concentration can penalise the catalyst conversion efficiency. The objective of this work is to evaluate the response of an automotive diesel oxidation catalyst when used for reactivity controlled compression ignition combustion combining experimental and modelling approaches. For this purpose, dedicated tests have been done using diesel-gasoline as fuel combination in a single-cylinder engine. This way, the catalyst conversion efficiency has been determined within a wide operating range covering hydrocarbon adsorption conditions and the pollutants abatement dependence on the mass flow and temperature. The experimental results in the full-size catalyst has been analysed by modelling. A lumped diesel oxidation catalyst model has been applied to extend the results to multi-cylinder engine conditions and to determine the light-off curves for both carbon monoxide and hydrocarbons. These tests evidence the penalty in light-off temperature due to high pollutants mass fraction, which promotes inhibition limitations to the reaction rate.
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