Aggregation Response Research Articles

A note on stock market response to elections in the post-communist countries of the European Union

ABSTRACT We examine the stock market response to parliamentary elections in post-communist countries of the European Union. We document that the long-term market response to an election is −200 basis points (bps). The response is symmetric across the ideology of the winner party. Moreover, we show that aggregate responses are driven by elections with policy uncertainty due to the transition of power across ideologies. The long-term market response to right (left) victories after left (right) governments is −500 bps (−600bps).

How do climate warming affect soil aggregate stability and aggregate-associated phosphorus storage under natural restoration?

The responses of soil aggregation and aggregate-associated phosphorus (P) fractions under natural restoration to climate warming remain unclear. Here, we conducted an eight-year mesocosm experiment wherein farmland soil from a colder site was transplanted to a warmer site to simulate climate warming and established continuous soybean cultivation and natural restoration treatments at each site. We investigated soil aggregate stability and the associated P fractions and soil properties under two land-use systems in a warming climate. Our results revealed that natural restoration significantly increased macroaggregates and macroaggregate-associated NaHCO3-Pi, NaOH-Po, and TP, but warming impeded the increases of these P fractions without changing soil aggregation. Although TP within microaggregates and the silt and clay fractions remained consistent across treatments, warming resulted in higher NaHCO3-Pi concentrations in both fractions and lower NaHCO3-Po and NaOH-Po within microaggregates in restored land. Bacterial community and alkaline phosphatase activity may be responsible for organic P mineralization within microaggregates. The enrichment of NaHCO3-Pi in smaller-sized aggregates and non-aggregate particles with warming likely increased the risk for P loss. Fungal and bacterial phospholipid fatty acid explained the most variation in the P fractions within macroaggregates and microaggregates, respectively, suggesting that biological processes are involved in determining P distribution. Our study indicates that the distribution of P fractions in differently sized aggregates during natural restoration can be significantly influenced by warming and highlights that incorporating the responses of soil microorganisms and enzymes will improve our understanding of the P cycling in a warming climate.

Divalent magnesium restores cytoskeletal storage lesions in cold-stored platelet concentrates

Cold storage of platelet concentrates (PC) has become attractive due to the reduced risk of bacterial proliferation, but in vivo circulation time of cold-stored platelets is reduced. Ca2+ release from storage organelles and higher activity of Ca2+ pumps at temperatures < 15 °C triggers cytoskeleton changes. This is suppressed by Mg2+ addition, avoiding a shift in Ca2+ hemostasis and cytoskeletal alterations. We report on the impact of 2–10 mM Mg2+ on cytoskeleton alterations of platelets from PC stored at room temperature (RT) or 4 °C in additive solution (PAS), 30% plasma. Deformation of platelets was assessed by real-time deformability cytometry (RT-DC), a method for biomechanical cell characterization. Deformation was strongly affected by storage at 4 °C and preserved by Mg2+ addition ≥ 4 mM Mg2+ (mean ± SD of median deformation 4 °C vs. 4 °C + 10 mM Mg2+ 0.073 ± 0.021 vs. 0.118 ± 0.023, p < 0.01; n = 6, day 7). These results were confirmed by immunofluorescence microscopy, showing that Mg2+ ≥ 4 mM prevents 4 °C storage induced cytoskeletal structure lesion. Standard in vitro platelet function tests showed minor differences between RT and cold-stored platelets. Hypotonic shock response was not significantly different between RT stored (56.38 ± 29.36%) and cold-stored platelets with (55.22 ± 11.16%) or without magnesium (45.65 ± 11.59%; p = 0.042, all n = 6, day 1). CD62P expression and platelet aggregation response were similar between RT and 4 °C stored platelets, with minor changes in the presence of higher Mg2+ concentrations. In conclusion, increasing Mg2+ up to 10 mM in PAS counteracts 4 °C storage lesions in platelets, maintains platelet cytoskeletal integrity and biomechanical properties comparable to RT stored platelets.

Stiffness and damping properties of railway ballast aggregate considering influence of degradation of aggregate and incorporation of crumb rubber

Impact loads over ballasted railway tracks can accelerate ballast aggregate degradation and deformation. The incorporation of energy-absorbing materials is a practical method to improve the stiffness and damping characteristics of granular layer and diminish aggregate degradation. This study investigated the dynamic responses of ballast aggregates subjected to the drop-weight impact loading test to further illuminate the effect of loading conditions and crumb rubber (CR) incorporation on the stiffness and damping coefficients of ballast material. Experimental measurements were combined with the analytical approach to link the aggregate degradation level to energy evolution and characterize the relationship between the induced impact load and the dynamic properties of granular material. The results demonstrated that the damping properties of ballast material decreased as the number of loading steps increased, which is mainly attributed to further aggregate degradation. The experimental-analytical analysis corroborated lower stiffness and higher damping coefficient for CR-reinforced mixtures. Smaller CR particles led to greater energy dissipation. A linear relationship was also found between the breakage level of aggregates and the energy induced due to friction development between particles and individual aggregate breakage.

Graph convolutional network-based aggregated demand response baseline load estimation

Accurate aggregated baseline load (ABL) estimation is very important for the demand response (DR) compensation settlement between system operators and DR aggregators. Current ABL estimation methods totally ignore the spatial correlation between load patterns of different customers, which will lead to large errors when the load pattern on the DR event day fluctuates largely compared with that in historical days. To this end, this paper proposes a Graph Convolutional Network (GCN)-based ABL estimation method to improve the estimation accuracy. The basic idea is to enhance the estimator's ability to capture load uncertainty by sharing load fluctuation information between different customers. The proposed method contains three main steps: First, all customers are grouped into different clusters by the K-means algorithm according to their historical typical load patterns (TLPs). Second, these clusters are transformed into an undirected graph based on an adjacency matrix reflecting the spatial correlations, which are constructed according to the difference between the TLPs in different clusters. Third, the ABL estimation is transformed into a node regression problem of the graph. Case studies on a real load dataset verify the effectiveness and superiority of the proposed method.

A pilot clinical study to Evaluate Liraglutide-mediated Anti-platelet activity in patients with type-2 Diabetes (ELAID study)

BackgroundLiraglutide is an effective treatment for the management of type 2 diabetes mellitus (T2DM). In addition to glycemic control and potential cardioprotective effects, recent studies suggest a possible role for liraglutide in the inhibition of platelet reactivity, further attenuating atherothrombotic risk in patients with T2DM. We evaluated the in-vivo antiplatelet effect of liraglutide in T2DM patients without macrovascular disease or concurrent anti-platelet therapy. MethodsA double-blind, placebo-controlled pilot study of 16 T2DM patients, 51–69 y/o, (mean age 60.4 y/o, 63.0% male) randomised to receive liraglutide (1.8 mg/day) or placebo (saline) for 6 months was conducted. Platelet aggregation studies at baseline and after initiation of the study intervention: days 1, 7, and 14 and months 1, 3 and 6 were performed. ResultsLiraglutide (n = 7) and placebo (n = 9) treated patients demonstrated normal platelet aggregation responses although transient and significant attenuation in maximum slope of platelet aggregation in response to collagen (p ≤ 0.05), arachidonic acid (p ≤ 0.05) and ADP (p ≤ 0.02) was observed in liraglutide compared to placebo treated patients in the first week. ConclusionsIn this pilot study of patients with T2DM liraglutide treatment was associated with a significant, early and transient decrease in maximum slope of platelet aggregation. The clinical significance of this effect is currently unknown and may warrant further investigation.Clinical Trial Registration Number: UTN 1111-1181-9567.

Regional blood acidification inhibits coagulation during extracorporeal carbon dioxide removal (ECCO2 R).

Consumption of platelets and coagulation factors during extracorporeal carbon dioxide removal (ECCO2 R) increases bleeding complications and associated mortality. Regional infusion of lactic acid enhances ECCO2 R by shifting the chemical equilibrium from bicarbonate to carbon dioxide. Our goal was to test if regional blood acidification during ECCO2 R inhibits platelet function and coagulation. An ECCO2 R system containing a hemofilter circulated blood at 0.25L/min in eight healthy ewes (Ovis aries) for 36h. Three of the sheep received ECCO2 R with no recirculation compared to five sheep that received ECCO2 R plus 12h of regional blood acidification via the hemofilter, placed upstream from the oxygenator, into which 4.4 M lactic acid was infused. Blood gases, platelet count and function, thromboelastography, coagulation-factor activity, and von Willebrand factor activity (vWF:Ag) were measured at baseline, at start of lactic acid infusion, and after 36h of extracorporeal circulation. Twelve hours of regional acid infusion significantly inhibited platelet aggregation response to adenosine diphosphate; vWF; and platelet expression of P-selectin compared to control. It also significantly reduced consumption of fibrinogen and of coagulation factors V, VII, IX, compared to control. Regional acidification reduces platelet activation and vitamin-K-dependent coagulation-factor consumption during ECCO2 R. This is the first report of a simple method that may enhance effective anticoagulation for ECCO2 R.

Dissecting platelet proteomics to understand the pathophysiology of immune thrombocytopenia: studies in mouse models

AbstractImmune thrombocytopenia (ITP) is an autoimmune disease characterized by enhanced platelet clearance and defective platelet production. Diagnosis by exclusion and trial-and-error treatment strategies is common practice, and despite the advancement in treatment options, many patients remain refractory. Although the existence of different pathophysiological entities is acknowledged, we are still far from stratifying and understanding ITP. To investigate, we sought to dissect the platelet proteome dynamics in so-called passive and active preclinical ITP mouse models, with which we propose to phenocopy respectively acute/newly diagnosed and persistent/chronic stages of ITP in humans. We obtained the platelet proteome at the thrombocytopenic stage and after platelet count recovery (reached naturally or by IVIg-treatment, depending on the model). Although most of the proteomic alterations were common to both ITP models, there were model-specific protein dynamics that accompanied and explained alterations in platelet aggregation responses, as measured in the passive ITP model. The expression dynamics observed in Syk may explain, extrapolated to humans and pending validation, the increased bleeding tendency of patients with ITP when treated with fostamatinib as third or later– as opposed to second line of treatment. We propose that the platelet proteome may give diagnostic and prognostic insights into ITP and that such studies should be pursued in humans.

Remarkable difference of phospholipid molecular chirality in regulating PrP aggregation and cell responses

Prion diseases are fatal neurodegenerative diseases that can cause severe dementia. The misfolding and accumulation of the prion peptide (PrP)106–126 is crucial, and this process is closely relevant to biological membranes. However, how PrP106–126 aggregation is affected by the molecular chirality of phospholipid membrane is unknown. Thus, in this study, a pair of l- and d-aspartic acid (Asp)-modified 1,2-dipalmitoyl-sn‑glycero-3-phosphoethanolamine (DPPE) were synthesized to construct chiral liposomes. We discover that l-Asp-DPPE liposomes strongly inhibit the oligomerization and amyloidogenesis of PrP106–126, whether acting on monomers or oligomers, which rescues cytotoxicity induced by PrP106–126. By comparison, d-Asp-DPPE liposomes inhibit peptide oligomerization only at a high concentration and cannot prevent amyloidogenesis when acting on oligomers, which lead to pronounced cytotoxicity. Apoptosis experiment, dynamic change of intracellular Ca2+ (iCa2+) and Ca2+ release from endoplasmic reticulum (ER), reactive oxygen species (ROS) production, adsorption dynamics and affinity tests, and fluorescent imaging clearly disclose that molecular chirality of the liposomes dominates conformational transition of PrP106–126 from random coil to β-sheet, binding and adsorption of the monomers and oligomers, and subsequent fibrillation process, resulting in distinct inhibition effect in Ca2+ overload and release, ROS production and cell apoptosis. This work is the first to report that interfacial molecular chirality is a potentially crucial influence on the fibrillation process of PrP106–126 and its cell responses, whereas the convergence of chiral amino acids and liposomes can be considered potential inhibitors in prion diseases.

Impact of Tropical Cyclones on Pelagic Sargassum

AbstractThe strong proliferation of holopelagic Sargassum in the Tropical Atlantic from 2011, raises many questions on the environmental factors controlling their growth and decay at interannual, seasonal, and intraseasonal scales. In this work, we specifically investigate the response of the Sargassum aggregations to high wind events such as those found in Tropical Cyclones (TCs). The evolution of Sargassum coverage obtained from MODIS observations in the north tropical Atlantic Ocean (from 0 to 30°N and from 0 to 100°W) was analyzed under 86 historical paths of TCs and tropical storms from 2011 to 2020 that crossed Sargassum aggregations. Our results show on average a 40% drop in Sargassum coverage under TC trajectories, which can exceed 60% for the most intense TCs. We associate this drop with a sinking of Sargassum toward the deep ocean. Our estimates suggest that TCs contribute to the seasonal decay of Sargassum biomass from August to November.

Platelet number and function alterations in preclinical models of sterile inflammation and sepsis patients: implications in the pathophysiology and treatment of inflammation

Platelets are the blood cells in charge of maintaining the body hemostasis, recognising the damaged vessel wall, and providing the appropriate cellular surface for the coagulation cascade to act locally. Additionally, platelets are active immunomodulators. At the crossroads of hemostasis and inflammation, platelets may exert either beneficial actions or participate in pathological manifestations, and have been associated with the prothrombotic nature of multi-organ failure in systemic inflammation. Platelet number alterations have been reported in septis, and platelet transfusions are given to thrombocytopenic patients. However, the risk to develop transfusion related acute lung injury (TRALI) is higher in sepsis patients. In this manuscript we show that platelets produced during inflammation in preclinical mouse models of sterile inflammation display lower aggregation capacity when stimulating certain receptors, while responses through other receptors remain intact, and we name them “inflammation-conditioned” platelets. In a cohort of sepsis patients, we observed, as previously reported, alterations in the number of platelets and platelet hyperreactivity. Furthermore, we identified a receptor-wise platelet aggregation response disbalance in these patients, although not similar to platelets from preclinical models of sterile inflammation. Interestingly, we generated evidence supporting the notion that platelet aggregation capacity disbalance was partially triggered by plasma components from sepsis patients. Our findings have implications in the indication of platelet transfusions in sepsis patients: Are fully functional platelets suitable for transfusion in sepsis patients? Current Clinical Trials (RESCUE) will answer whether platelet production stimulation with thrombopoietin receptor agonists (TPO-RAs) could be a substitute of platelet transfusions.

Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation.

AimsAdverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Circadian nuclear receptor Rev-erbα is an essential and negative component of the circadian clock. To date, the expression profile and biological function of Rev-erbα in platelets have never been reported.Methods and resultsHere, we report the presence and functions of circadian nuclear receptor Rev-erbα in human and mouse platelets. Both human and mouse platelet Rev-erbα showed a circadian rhythm that positively correlated with platelet aggregation. Global Rev-erbα knockout and platelet-specific Rev-erbα knockout mice exhibited defective in haemostasis as assessed by prolonged tail-bleeding times. Rev-erbα deletion also reduced ferric chloride-induced carotid arterial occlusive thrombosis, prevented collagen/epinephrine-induced pulmonary thromboembolism, and protected against microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. In vitro thrombus formation assessed by CD41-labelled platelet fluorescence intensity was significantly reduced in Rev-erbα knockout mouse blood. Platelets from Rev-erbα knockout mice exhibited impaired agonist-induced aggregation responses, integrin αIIbβ3 activation, and α-granule release. Consistently, pharmacological inhibition of Rev-erbα by specific antagonists decreased platelet activation markers in both mouse and human platelets. Mechanistically, mass spectrometry and co-immunoprecipitation analyses revealed that Rev-erbα potentiated platelet activation via oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway.ConclusionWe provided the first evidence that circadian protein Rev-erbα is functionally expressed in platelets and potentiates platelet activation and thrombus formation. Rev-erbα may serve as a novel therapeutic target for managing thrombosis-based cardiovascular disease.Key questionAdverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Whether circadian nuclear receptor Rev-erba is present in platelets and regulates platelet function remains unknown.Key findingWe provide the first evidence that Rev-erba is functionally expressed in platelets and acts as a positive regulator of platelet activation/thrombus formation through the oligophrenin-1-mediated RhoA/ERM signalling pathway.Take home messageOur observations highlight the importance of circadian clock machinery in platelet physiology and support the notion that Rev-erba may serve as a novel therapeutic target for managing thrombosis-based cardiovascular diseases.

Enzyme-free colorimetric nanosensor for the rapid detection of lactic acid in food quality analysis

Lactic acid is an essential organic chemical in food, clinical, chemical, and bioprocessing industries. We are reporting for the first time, a rapid and facile enzyme-free colorimetric sensor for the detection of lactic acid (LA) in food samples using nitrophenol ( p -NP) added copper nanoparticles (CuNPs). The responses of p -NP (5 mmol/L) to lactic acid in the presence of CuNPs were reported by analysing the UV-VIS absorption spectra in an aqueous solution. CuNPs were synthesized by the chemical reduction method and were identified to be in the Cubic phase using XRD analysis. The sample characterization studies were performed using the SEM, UV for obtaining good optical and selective lactic acid-sensing properties. The sensing mechanism is due to the aggregation responses of CuNPs conjugated p -NP in the presence of lactic acid as seen in the UV-VIS absorption spectra shift studied in an aqueous solution. The absorption spectrum of p -NP exhibited one intense band at 402 nm in the presence of CuNPs. Although the addition of lactic acid may cause π –π* transitions led to a hypsochromic shift (blue shift) with a subtle decrease in the wavelength from 402 to 315 nm, the solution underwent from being colored (greenish-yellow) to colorless. The stoichiometric ratio of a binding event is explained using Job's plot. The naked eye colorimetric response of the sensor-enabled detection limit of lactic acid to 0.33 mM. The sensor studies were compared with standard LC-MS/MS revealing a good recovery (95%) in food samples. This method is facile and alternate to the current high-cost techniques and enzymatic sensors. Schematic illustration of colorimetric sensor- CuNPs assisted catalytic reduction of p -nitrophenol (colored) to p -aminophenol (colorless) with the exposure of lactic acid. • Nonenzymatic colorimetric nanosensor for lactic acid detection. • The visual detection of trace amounts of lactic acid as low as 0.33 mM. • Sensor is based on the catalytic activity of copper nanoparticles. • Application of developed sensor for real time food sample analysis.

Formation of mixed paragenesis diamonds during multistage growth – Constraints from in situ δ13C–δ15N–[N] analyses of Koidu diamonds

Inclusion-bearing diamonds from the Koidu kimberlite complex, Sierra Leone (West African Craton) were analyzed in situ for carbon and nitrogen isotope compositions, nitrogen concentrations and nitrogen aggregation states. In a suite of 105 diamonds, 78% contain eclogitic mineral inclusions, 17% contain peridotitic mineral inclusions, and 5% − an unusually high proportion − contain co-occurring eclogitic and peridotitic mineral inclusions indicating a mixed paragenesis. Major and trace element compositions of mineral inclusions from two mixed paragenesis diamonds (one with omphacite + Mg-chromite, the other with eclogitic garnet + forsteritic olivine) were determined. The presence of positive Eu anomalies in centrally located omphacite and eclogitic garnet inclusions indicates derivation from subducted protoliths, formed as igneous cumulates in lower oceanic crust. Mg-chromite (Cr# 85.5; Mg# 65.2) and olivine (Mg# 94.5) inclusions, located in outer portions of the mixed paragenesis diamonds, have compositions indicative of derivation from strongly depleted cratonic peridotites. Given that the olivine Mg# of 94.5 is the highest reported to date for the West African Craton, the eclogitic and peridotitic inclusions in these mixed paragenesis diamonds cannot have precipitated during infiltration of peridotitic substrates by eclogite-derived fluids, as the consequent fluid-rock interaction should lead to Mg# lower than that for the original peridotitic diamond substrate. The different origins of eclogitic and peridotitic inclusions could be explained by physical transport of their host diamonds from eclogitic into peridotitic substrates, possibly along high-strain shear zones, before renewed diamond growth.Based on the δ13C–δ15N systematics of the entire inclusion-bearing diamond suite from Koidu, three major compositional clusters are identified. Cluster 1 (eclogitic diamond cores; δ13C = –33.2 to −14.4‰ and δ15N = −5.3 to +10.1‰) bears the isotopic signature of recycled crustal material (± a mantle component). Cluster 2 (peridotitic diamonds and including the core of a diamond containing omphacite + Mg-chromite; δ13C = −6.0 to −1.1‰ and δ15N = −4.2 to +9.7‰) likely involves mixing of carbon and nitrogen from subducted and mantle sources. Cluster 3 (rims of eclogitic diamonds and including the eclogitic garnet + olivine included diamond and the rim of the omphacite + Mg-chromite included diamond; δ13C = −7.8 to −3.6‰ and δ15N = −7.9 to −2.1‰) matches convecting mantle-derived fluids/melts. The distinct isotopic signatures of the three diamond clusters, together with differences in nitrogen aggregation and cathodoluminescence response between diamond cores and rims, suggest episodic diamond growth during multiple fluid/melt pulses.

Proteome Analysis of Urinary Biomarkers in a Bovine IRBP-Induced Uveitis Rat Model via Data-Independent Acquisition and Parallel Reaction Monitoring Proteomics.

Uveitis, a group of intraocular inflammatory diseases, is one of the major causes of severe visual impairment among the working-age population. This study aimed to screen potential urinary biomarkers for uveitis based on proteome analysis. An experimental autoimmune uveitis (EAU) rat model induced by bovine interphotoreceptor retinoid-binding protein (IRBP) was used to mimic uveitis. In discovery phase, a total of 704 urinary proteins were identified via data-independent acquisition (DIA) proteomic technique, of which 76 were significantly changed (34, 36, and 37 on days 5, 8, and 12, respectively, after bovine IRBP immunization). Gene Ontology annotation of the differential proteins indicates that acute-phase response, innate immune response, neutrophil aggregation, and chronic inflammatory response were significantly enriched. Protein-protein interaction network indicates that these differential urinary proteins were biologically connected in EAU, as a group. In validation phase, 17 proteins having human orthologs were verified as the potential markers associated with uveitis by parallel reaction monitoring (PRM) targeted quantitative analysis. Twelve differential proteins changed even when there were no clinical manifestations or histopathological ocular damage. These 12 proteins are potential biomarkers for early diagnosis of uveitis to prevent the development of visual impairment. Five differential proteins changed at three time-points and showed progressive changes as the uveitis progressed, and another five differential proteins changed only on day 12 when EAU severity peaked. These 10 proteins may serve as potential biomarkers for prognostic evaluation of uveitis. Our findings revealed that the urinary proteome could sensitively reflect dynamic pathophysiological changes in EAU, and represent the first step towards the application of urinary protein biomarkers for uveitis.

Biomechanics of the anterior cruciate ligament under simulated molecular degradation.

Injuries to the knee anterior cruciate ligament (ACL) are common, with a known but poorly understood association with intrinsic and extrinsic risk factors. Some of these factors are enzymatically or mechanically mediated, creating acute focal injuries that may cause significant ligament damage. Understanding the relationship between the basic molecular structure and external loading of the ACL requires a hierarchical connection between the two levels. In the present study, a multi-domain frame was developed connecting the molecular dynamics of the collagen networks to the continuum mechanics of the ACL. The model was used to elucidate the effect of the two possible collagen degradation mechanisms on the aggregate ACL behaviour. Results indicated that collagen content and ACL stiffness were reduced significantly, regardless of the degradation mechanism. Furthermore, the volumetric degradation at the molecular level had a devastating effect on the mechanical behaviour of the ACL when it was compared with the superficial degradation. ACL damage initiation and propagation were clearly influenced by collagen degradation. To summarise, the new insights provided by the predicted results revealed the significance of the collagen network structural integrity to the aggregate mechanical response of the ACL and, hence, underlined the biomechanical factors that may help develop an engineering-based approach towards improving the therapeutic intervention for ACL pathologies.

Modeling cyclic behavior of unbound aggregates using two-surface plasticity theory

Various empirical rutting models have been proposed to predict the permanent deformation of aggregate base/subbase layers in pavements. Nevertheless, an analytical model is required for large-scale finite element simulation of the pavement structure. A two-surface plasticity theory is used to predict the long-term cyclic behavior and provide path-dependent material responses of aggregates. The deviatoric stresses for each aggregate were determined based on the shear stress ratio and the shear strength properties at source and engineering gradations. The proposed rutting model was optimized and validated via repeated load triaxial tests using 11 aggregates. The numerical results demonstrate that the proposed model accurately describes aggregates with low-level permanent strain and thus enables the yield surface, long-term shear strain, and path-dependent resilient modulus to be assessed. Overall, the proposed physics-based modeling approach can help understand and predict the deformation behavior of aggregates subjected to moving-wheel loads.

Dysfunction of the blood–brain barrier in Alzheimer's disease: Evidence from human studies

The pathological processes leading to synapse loss, neuronal loss, brain atrophy and gliosis in Alzheimer's disease (AD) and their relation to vascular disease and immunological changes are yet to be fully explored. Amyloid-β (Aβ) aggregation, vascular damage and altered immune response interact at the blood-brain barrier (BBB), affecting the brain endothelium and fuelling neurodegeneration. The aim of the present systematic literature review was to critically appraise and to summarise the published evidence on the clinical correlations and pathophysiological concepts of BBB damage in AD, focusing on human data. The PubMed, Cochrane, Medline and Embase databases were searched for original research articles, systematic reviews and meta-analyses, published in English language from 01/2000 to 07/2021, using the keywords Alzheimer*, amyloid-β or β-amyloid or abeta and BBB. This review shows that specific changes of intercellular structures, reduced expression of transendothelial carriers, induction of vasoactive mediators and activation of both astroglia and monocytes/macrophages characterise BBB damage in human AD and AD models. BBB dysfunction on magnetic resonance imaging takes place early in the disease course in AD-specific brain regions. The toxic effects of Aβ and apolipoprotein E (ApoE) are likely to induce a non-cerebral-amyloid-angiopathy-related degeneration of endothelial cells, independently of cerebrovascular disease; however, some of the observed structural changes may just arise with age. Small vessel disease, ApoE, loss of pericytes, proinflammatory signalling and cerebral amyloid angiopathy enhance BBB damage. Novel therapeutic approaches for AD, including magnetic resonance-guided focused ultrasound, aim to open the BBB, potentially leading to an improved drainage of Aβ along perivascular channels and increased elimination from the brain. In vitro treatments with ApoE-modifying agents yielded promising effects on modulating BBB function. Reducing cardiovascular risk factors represents one of the most promising interventions for dementia prevention at present. However, further research is needed to elucidate the connection of BBB damage and tau pathology, the role of proinflammatory mediators in draining macromolecules and cells from the cerebral parenchyma, including their contribution to cerebral amyloid angiopathy. Improved insight into these pathomechanisms may allow to shed light on the role of Aβ deposition as a primary versus a secondary event in the complex pathogenesis of AD.

High fitness areas drive the aggregation of the sea urchin Mesocentrotus nudus.

Sea urchin aggregation is a common phenomenon in coastlines. However, it remains controversial whether sea urchins form resource aggregations or behavioral aggregations in a non-spawning season. To clarify, we studied the aggregative responses to food and predators in the sea urchin Mesocentrotus nudus when high fitness areas (HFAs) were scarce versus sufficient. By taking the occupied area of each sea urchin (test diameter + spines = 4.5 cm) as a square (4.5 cm × 4.5 cm), we set scarce HFAs for the sea urchins in Experiment 1 (the squares of HFAs: the area occupied by experimental sea urchins = 1:1) and sufficient HFAs for the sea urchins in Experiment 2 (the squares of HFAs: the area occupied by experimental sea urchins = 2:1). If M. nudus form resource aggregations, they would aggregate passively under the scarce HFAs conditions, but not in the sufficient HFAs conditions. Conversely, if M. nudus form behavioral aggregation, aggregation would occur in both scarce and sufficient HFAs. The present results showed that in the scarce HFAs, M. nudus in the food and predator groups were significantly closer to the food and further from predators, and had significantly more aggregated numbers in HFAs than those in the control group. Sea urchins did not aggregate in response to food or predators under the sufficient HFAs, although significantly more sea urchins of the experimental group was found in HFAs than that of the control group. Sea urchins (at least M. nudus) form resource aggregations that are driven by the scarce HFAs. This provides valuable information into the mechanisms of the aggregation of sea urchins.

General Equilibrium Effects of Cash Transfers: Experimental Evidence From Kenya

How large economic stimuli generate individual and aggregate responses is a central question in economics, but has not been studied experimentally. We provided one‐time cash transfers of about USD 1000 to over 10,500 poor households across 653 randomized villages in rural Kenya. The implied fiscal shock was over 15 percent of local GDP. We find large impacts on consumption and assets for recipients. Importantly, we document large positive spillovers on non‐recipient households and firms, and minimal price inflation. We estimate a local transfer multiplier of 2.5. We interpret welfare implications through the lens of a simple household optimization framework.