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Background: The organization of a sports event can be analyzed from the perspective of its impact on the participants, organizers and community. University championships have a sustainable character, with several tournaments being planned over time, receiving increased interest from all stakeholders. Methods: This research aimed to describe aspects regarding the organization and planning of sports events, the academic and professional profiles of student-athletes and the implications of their participation in championships. We used two research methods: one based on geography, and another based on a sociological survey of 139 dual-career students participating in the national university championship of men’s football and women’s volleyball organized by the University of Oradea (Romania). Results: The research results show that academic studies provide professional competencies, while participation in sports events contributes to students’ personal and professional development. The results highlight that dual-career students are more prone to develop their sports careers; therefore, participation in these types of events represents a milestone in their careers. Conclusions: Our study can be considered when organizing these types of sports events and can provide directions for the development of sustainable strategies and programs to support students with dual careers.

Introduction: Surface sputtering by solar wind (SW) ion irradiation is an important process for understanding the surface and exosphere of airless celestial bodies such as the Moon, Mercury, and asteroids. In addition to SW ion induced sputtering, processes such as photon and electron stimulated desorption and impact vaporization, can also contribute to the exosphere formation around airless bodies. A better understanding of relative contributions of these processes is needed to interpret ground-based and spacecraft observations of the exosphere. Our focus here is on SW ion induced sputtering. Laboratory simulations are both complex and expensive. Hence, theoretical sputtering models are used to study the incoming ions, impacted surface, and sputtered atoms. The most common sputtering models, such as TRIM and SDTrimSP, use the binary collision approximation (BCA) and predict the yield and energy distribution of sputtered atoms, along with the depth of deposition and damage, all as a function of the incoming ion type, impact energy, and impact angle. Within SDTrimSP there are several inputs that have been applied differently in previous SW sputtering simulations1,2,3. These parameters can influence the simulated behavior of both the target and sputtered atoms. Laboratory data is often readily available for comparison with ion sputtering simulations from monatomic or simple oxide targets, and simulations can closely match experimental sputtering yields over a broad energy range. Comparatively, little work has been done to determine how the simulation parameters should be chosen for more complex targets relevant to planetary surface analogs. It is therefore of great interest to understand how sensitive sputtering behavior is to these inputs and what parameter choices best approximate SW sputtering. We have conducted a detailed sensitivity study into SDTrimSP parameters to produce a best-practice for simulating SW impacts onto the lunar surface. These results can be used to establish a more consistent methodology for simulations of SW induced sputtering. Methods: First, we consider the sensitivity of the SDTrimSP simulated SW sputtering behavior to several user input parameters. In all cases we simulated the effect of H or a combination of H and He onto an anorthite (CaAl2Si2O8) surface. Within SDTrimSP we considered the role of the O surface binding energy (SBE), ISBV (the method of dealing with SBEs for compounds), static vs. dynamic simulations, impact energy approximations, incidence energy approximations, and the elemental composition of the SW. For all parameters we quantified their effect on the overall sputtering yield, elemental composition of the sputtering yield, elemental surface concentration, damage production, and energy distribution of sputtered atoms. Based on these sensitivity results we recommend a best-practice for simulating SW sputtering using SDTrimSP. Results: The predicted sputtering behavior was shown to be highly dependent on several of the SDTrimSP parameters considered. For example, previous SW simulation studies have used O SBEs between 1 and 6.5 eV, based on recommended values, fitting to experiment, and monomatomic sublimation energies. For all cases considered, the O SBE had a significant affect on the overall and elemental yield. Furthermore, dynamic simulations, which allow for the surface to change as a function of fluence, better represent the surface evolution during SW impacts. The effect of the O SBE can also be seen in the surface composition as a function of fluence (Fig 1). For an O SBE of 1 eV, strong preferential sputtering of O is observed, and the surface composition fraction is reduced from 0.6 to 0.3 at a fluence of 200 x 1016 atoms/cm2. In contrast, there is almost no reduction in O surface composition for an SBE of 6.5 eV. This large depletion in surface O at an SBE of 1 eV has not been observed in previous irradiation experiments of silicates4,5,6. Therefore, O SBEs of 1 eV are likely not representative of what would be seen for materials relevant to planetary science. Varying the ion incidence angle also significantly affected the sputtering behavior. Impacts normal to the surface are often used to simulate a flat surface and can more easily be compared to experimental data. However, the surface of the Moon and Mercury consists largely of approximately spherical weathered grains. As a result, incoming SW ions are impacting the surface at many different relative angles. When oblique incidence angles are simulated the elemental and overall yields increase in all cases. For both cases there was also an increase in the peak of the damage distribution along with a reduction in depth at this peak. Accounting for the He component in the SW leads to a 20% increase the elemental sputtering yields and and a 20% increase in the damage produced within the substrate (Fig 2). Therefore, while He makes up only 4% of the SW it accounts for over 20% of the sputtering behavior. When comparing the H and H + He options the proportion of O in the yield stays consistent. This suggests that a factor could be used to account for the He contributions. In summary, while SDTrimSP represents a valuable tool to better understand the effect, the results are highly dependent on many user-specific parameters. This study directly quantifies these sensitivities on the SW-induced sputtering behavior and concludes with the following best-practice recommendation for SDTrimSP simulations of SW sputtering: 1 keV/amu impacts (96% H, 4% He) to approximate SW composition Dynamic simulations to allow for the behavior to evolve as a function of fluence Cosine distribution of impact angles onto the surface to approximate spherical grains Incorporation of mineral specific SBEs where possible References: 1. Mutzke, A., et al. (2019) “IPP-report 2019-02” 2. Szabo, P. S., et al. (2018) doi: 10.1016/j.icarus.2018.05.028 3. Schaible, M. J., et al. (2017) doi: 10.1002/2017JE005359 4. Dukes, C.A., et al. (1999) doi: 10.1029/98JE02820 5. Dukes, C.A., et al. (2015) doi: 10.1016/j.icarus.2014.11.032 6. Laczniak, D.L., et al. (2021) doi: 10.1016/j.icarus.2021.114479 Fig 1. Surface composition as a function of fluence for and O SBE of 1 eV (A) and 6.5 eV (B) Fig 2. Count of vacancies as a function of depth for different SW compositions using a cosine distribution of the impact flux vs impact angle

Introduction: Electrons emitted from the lunar surface include photoelectrons, cold secondary electrons, and backscattered electrons, all of which contribute to the surface-charging environment. Among these electron populations, secondary electrons have been well characterized by previous studies but not so much for the other two populations that make up the high-energy tail. Recently, we reported of oxygen Auger electron observations at the Moon by the ARTEMIS (Acceleration, Reconnection, Turbulence, and Electrodynamics of the Moon's Interaction with the Sun) spacecraft, which provides a unique feature to identify photoelectrons emitted from the lunar surface. This Auger feature allows for the creation of empirical templates for photoelectrons and backscattered electrons to disentangle these two populations and examine their characteristics separately. Methodology: By utilizing the Auger electron feature, we identify cases that are separately dominated by either photoelectrons or pure backscattered electrons and then create energy spectral templates for each population, when the Moon is immersed in the solar wind. With such templates, we then fit the total measured electron spectrum from the lunar surface as observed by ARTEMIS from mid-2012 to the end of 2020 and determine the relative contributions of the two populations. Results: For photoelectrons, we find that (1) Auger electron fluxes are correlated with solar X-ray photon fluxes as expected; and, (2) there is a dawn-dusk asymmetry in Auger electron fluxes, caused by a selection bias as downward electrons are mainly halo electron on the dusk side, lower in flux than strahl electrons on the dawn side. For backscattered electrons, we find the backscattering ratio (the flux ratio of backscattered electrons and downward electrons at the same energy) varies geographically due to different proportions of surface backscattered electrons and non-adiabatic magnetic scattering by crustal magnetic fields. In addition, for surface backscattering, the backscattering ratio decreases with increasing energies, ranging from

Over the last decade, social media (SM) has dramatically influenced the tourism sector, and information exchange via SM platforms may affect tourists’ intentions to revisit a tourist destination. In the present study, we investigated the impact of content shared on SM on tourists’ intentions to revisit Saudi Arabia as a neighboring destination to Qatar during the period of a mega-event (Football World Cup). We also assessed the potential mediation effects of the perceived values and trust in local tourism services on such a relationship. A structured survey was distributed to football fans who came to visit Saudi Arabia (n = 300), and a partial least squares structural equation model was constructed to validate this study’s model. Results showed that SM content did not significantly impact the revisit intentions directly. SM content was a significant antecedent predictor of the perceived trust, and the perceived trust predicted future intentions to revisit Saudi Arabia. Therefore, the perceived trust in tourism services was a significant mediator of tourism SM’s effects on tourists’ intentions. However, the mediation path of the perceived value was not statistically significant. Tourism marketers had to ensure that they appropriately convey engaging content that focuses on supporting the trust in a destination, particularly during the periods of mega-events.

The heritage woven objects could be analyzed for defects hidden to the naked eye using non-invasive and non-destructive ultrasonography techniques. Ultrasonography is able to offer information about altered areas, such as gasps, interruptions, discontinuances, narrowed areas, fiber breaks, different densities of the material, defects caused by natural or anthropic factors: improper storage and exposure conditions, the presence of microorganisms and traces of their activity, mechanical causes etc. By recycling of the cotton fibers from other decrepit materials, which are not directly usable, the recondition and rendition of the national and world cultural heritage of these refurbished objects would be accomplished. The impact on the environment is diminished compared to the case when new cotton fibers are created.

The present paper offers a theoretical insight regarding the quality of life and health state of people with mental deficiency. Research results regarding the link between physical activity and quality of life of people with mental disorders are discussed. Literature review outlined that physical activity generates major benefits for people with mental deficiency. Conclusions point out the need to implement physical activities that can be performed by people with mental deficiency to increase their quality of life. Public and private stakeholders should cooperate in order to develop specific strategies and policies, as well as adapted programs for people with mental deficiency to maintain their health status and quality of life at a decent level.

Background: Despite the importance of sports injury prevention in youth, no broad scale approaches that work in real-life situations with significant positive effects exist. Main reasons for this are poor uptake and maintenance of current sports injury prevention exercises. Objective: In order to improve uptake of sports injury prevention routines, this project set out to: 1. identify the specifics of current injury prevention programs within 6 European countries, and 2: to establish wishes and needs regarding injury prevention of the end-users (sport coaches, physical educators and youth) within 6 European countries. Design: Semi-structured interviews and focus group sessions. Setting: Youth sports teams and physical education (PE) classes. Patients (or Participants): Interviews and focus group sessions were performed within 6 participating countries (Belgium, Denmark, Lithuania, Romania, The Netherlands, United Kingdom). National stakeholders were interviewed to identify injury prevention programs. The program owners of the identified programs were then individually interviewed. The focus group sessions were organized with youth basketball and soccer players and PE pupils. Separate focus group sessions were organized for basketball/soccer coaches and physical educators. Interventions (or Assessment of Risk Factors): This qualitative study provided input for the development of a freely available ICT based platform with video material of routines designed to prevent sports injuries in youth. Main Outcome Measurements: Overview of country specific results of interviews and focus groups. Results: This study will describe the current availability of national injury prevention programs within 6 European countries. The results of the focus group sessions will establish the differences in beliefs regarding injury prevention in 6 European countries regarding injury prevention. Conclusions: In the coming year, the Move Healthy project will use the qualitative results of this study to develop a freely available ICT based platform with video material of routines developed to prevent sports injuries in youth.

INTRODUCTION: Sorting a huge stream of waste accurately within a short period can be done with the support of digitalization, particularly Artificial Intelligence, instead of traditional methods. The overlap of Artificial Intelligence and Circular Economy can flourish many services in the environmental technology domain, in particular smart e-waste recycling, resulting in enabling circular smart cities.OBJECTIVES: We analyse the growing need for automated e-waste recycling as an essential requirement to cope with the fast-growing e-waste stream and we shed the light on the impact of Artificial Intelligence in supporting the recycling process through smart classification of devices, where the smartphone is our case study.METHODS: Our study applies transfer learning as a special technique of Artificial Intelligence by fine-tuning the output layers of AlexNet as a pre-trained model and perform the implementation on a small-size dataset that contains 12 classes from 6 smartphone brands.RESULTS: We evaluate the performance of our model by tuning the learning rate, choosing the best optimizer, and augmenting the original dataset to avoid overfitting. We found that the optimizer of Stochastic Gradient Descent with Momentum and 3 𝑒𝑒−4 as a learning rate brings almost 98% model accuracy with generalization.CONCLUSION: Our study supports automated e-waste recycling in decreasing the error-rate of e-waste sorting and investigates the advantages of applying transfer learning as the best scenario to overcome the rising challenges.

Atmosphere-free celestial bodies are constantly irradiated by solar wind or magnetospheric ions. In the case of Mercury, the intrinsic magnetic field, although weak, leads to localized plasma precipitation around the magnetospheric cusps and nightside precipitation below the magnetotail [1, 2, 3]. The material ejected by the impacting ions (sputtering) thereby contributes to the exosphere and magnetosphere surrounding Mercury [4, 5, 6]. Magnetospheric ions originate from ionization of exospheric atoms or ions directly sputtered from the surface. Those can become part of the magnetospheric plasma, and have trajectories that lead them back to Mercury’s surface [7, 8]. We explored different scenarios of the sputtering of Mercury’s surface with a strong focus on dynamic surface alteration and sputtering. This includes time varying inputs from varying solar wind conditions as well as contributions of secondary ions originating from Mercury’s exosphere and magnetosphere. We rely on the dynamic sputter model SDTrimSP [9] and compare the simulation results with more simplistic TRIM [10] simulations as well as recent laboratory results of solar wind ion sputtering on Mercury analogues [11, 12, 13]. [1] Winslow, R.M., et al. (2017). J. Geophys.Res.-Space, 122(5), 4960–4975. [2] Winslow, R.M., et al. (2014). Geophys. Res. Lett., 41(13), 4463–4470. [3] Schmidt, C.A. (2013). J. Geophys.Res.-Space, 118(7), 4564–4571. [4] Killen, R.M., & Ip, W. H. (1999). Rev. Geophys., 37(3), 361–406. [5] Raines, J.M., et al. (2016). Plasma Sources of Solar System Magnetospheres (pp. 91–144). Springer. [6] Wurz, P., et al., (2019). J. Geophys. Res., 124, 2603–2612. [7] Yagi, M., et al. (2017). J. Geophys.Res.-Space, 122(11), 10,990-11,002. [8] Delcourt, D.C., et al. (2003). Ann. Geophys., 21(8), 1723–1736. [9] Mutzke, A., et al. (2019). SDTrimSP Version 6.00. Max-Planck-Institut für Plasmaphysik. [10] Ziegler, J.F., et al. (2010). Nucl. Instrum. Methods Phys. Res. B, 268, 1818–1823. [11] Jäggi, N., et al. (2021). Icarus, 365, 114492. [12] Biber H., et al. (2020). Nucl. Instrum. Methods Phys. Res. B, 480, 10. [13] Szabo, P.S., et al. (2018). Icarus, 314, 98–105.

In this paper, we present how Artificial Intelligence (AI) could support automated smartphone recycling, hence, act as an enabler for Circular Smart Cities (CSC), where the Smart City paradigm could be linked to the Circular Economy (CE), which is a leading concept of the sustainable economy. While business and society strive to gain benefits from automation, the ongoing rapid digitalization, in turn, accelerates the mass production of Waste Electric and Electronic Equipment (WEEE), often called E-Waste. Therefore, E-Waste is the fastest growing waste stream in the world and comes up with several negative environmental and social impacts. In our research, we show an AI technique (particularly, Transfer Learning) that could become an enabler for the CSC and the CE in general and supporter of automated recycling, specifically. However, research on this topic is emerging only recently, and practical applications are lacking even more. For instance, object recognition has extensive research, whereas smartphone classification nevertheless has rare attention. Our main contribution is a Transfer Learning (TL) approach based on visual-feature extraction to classify smartphones; as a result, it supports automated smartphone recycling independently of brands and even without any ex-ante information about product designs. Our findings show that the main advantages of using TL, are reducing the size of the training-set, computation time, and significant enhancements without designing a completely new network from scratch. This may ease the automated recycling of smartphones as well as other E-Waste, hence, contribute to the development of the CE and CSC.

Monitoring the indoor microclimate in old buildings of cultural heritage and significance is a practice of great importance because of the importance of their identity for local communities and national consciousness. Most aged heritage buildings, especially those made of wood, develop an indoor microclimate conducive to the development of microorganisms. This study aims to analyze one wooden church dating back to the 1710s in Romania from the microclimatic perspective, i.e., temperature and relative humidity and the fungal load of the air and surfaces. One further aim was to determine if the internal microclimate of the monument is favorable for the health of parishioners and visitors, as well as for the integrity of the church itself. The research methodology involved monitoring of the microclimate for a period of nine weeks (November 2020–January 2021) and evaluating the fungal load in indoor air as well as on the surfaces. The results show a very high contamination of air and surfaces (&gt, 2000 CFU/m3). In terms of fungal contamination, Aspergillus spp. (two different species), Alternaria spp., Cladosporium spp., Mucor spp., Penicillium spp. (two different species) and Trichopyton spp. were the genera of fungi identified in the indoor wooden church air and Aspergillus spp., Cladosporium spp., Penicillium spp. (two different species) and Botrytis spp. on the surfaces (church walls and iconostasis). The results obtained reveal that the internal microclimate not only imposes a potential risk factor for the parishioners and visitors, but also for the preservation of the wooden church as a historical monument, which is facing a crisis of biodeterioration of its artwork.

Bacterial biofilms, especially those associated with implanted medical devices, are difficult to eradicate. Curli amyloid fibers are important components of the biofilms formed by the Enterobacteriaceae family. Here, we show that a human monoclonal antibody with pan-amyloid-binding activity (mAb 3H3) can disrupt biofilms formed by Salmonella enterica serovar Typhimurium in vitro and in vivo. The antibody disrupts the biofilm structure, enhancing biofilm eradication by antibiotics and immune cells. In mice, 3H3 injections allow antibiotic-mediated clearance of catheter-associated S. Typhimurium biofilms. Thus, monoclonal antibodies that bind a pan-amyloid epitope have potential to prevent or eradicate bacterial biofilms., Curli amyloid fibers are important components of bacterial biofilms formed by E. coli and Salmonella. Here, Tursi et al. show that a human monoclonal antibody with pan-amyloid binding activity can disrupt biofilms formed by Salmonella Typhimurium in vitro and in vivo.

Background Mental health leadership is a critical component of patient access to care. More specifically, the ability of mental health professionals to articulate the needs of patients, formulate strategies and engage meaningfully at the appropriate level in pursuit of resources. This is not a skill set routinely taught to mental health professionals. Methods A public–private mental health leadership initiative, emanating from a patient access to care programme, was developed with the aim of building leadership capacity within the South African public mental health sector. The express aim was to equip health care professionals with the requisite skills to more effectively advocate for their patients. The initiative involved participants from various sites within South Africa. Inclusion was based on the proposal of an ongoing “project”, i.e. a clinician-initiated service development with a multidisciplinary focus. The projects were varied in nature but all involved identification of and a plan for addressing an aspect of the participants’ daily professional work which negatively impacted on patient care due to unmet needs. Six such projects were included and involved 15 participants, comprising personnel from psychiatry, psychology, occupational therapy and nursing. Each project group was formally mentored as part of the initiative, with mentors being senior professionals with expertise in psychiatry, public health and nursing. The programme design thus provided a unique practical dimension in which skills and learnings were applied to the projects with numerous and diverse outcomes. Results Benefits were noted by participants but extended beyond the individuals to the health institutions in which they worked and the patients that they served. Participants acquired both the skills and the confidence which enabled them to sustain the changes that they themselves had initiated in their institutions. The initiative gave impetus to the inclusion of public mental health as part of the curriculum for specialist training. Conclusions Despite the significant adverse social and economic costs of mental illness, psychiatric and related services receive a low level of priority within the health care system. Ensuring that mental health receives the recognition and the resources it deserves requires that mental health care professionals become effective advocates through mental health leadership.

Objective:We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia.Methods:In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants.Results:No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo.Conclusions:Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo.Clinicaltrials.gov identifier:NCT00818662.Classification of evidence:This study provides Class II evidence that IVIg infusions performed every 2 weeks do not improve cognition or function at 18 months in patients with mild to moderate AD.

Background: Recent studies have implicated specific assembly subtypes of β-amyloid (Aβ) peptide, specifically soluble oligomers (soAβ) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Aβ assemblies is thought to be essential for any attempt at stabilizing brain function and slowing cognitive decline in Alzheimer disease. IV immunoglobulin (IVIg) therapies have been shown to contain naturally occurring polyclonal antibodies that recognize conformational neoepitopes of soluble or insoluble Aβ assemblies including soAβ. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Aβ antibodies to the clinical bioactivity of IVIg has been lacking. Methods: Five-month-old female Dutch APP E693Q mice were treated for 3 months with neat IVIg or with IVIg that had been affinity-depleted over immobilized Aβ conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAβ levels using standard anti-soAβ antibodies. Results: We provide evidence that NU4-type soAβ (NU4-soAβ) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Aβ plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAβ and A11-soAβ but not OC-type fibrillar Aβ oligomers. Conclusions: We propose that targeting of specific soAβ assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Aβ antibody drugs.

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aβ42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

The human IgG repertoire contains endogenous antibodies against beta amyloid (Aβ) that may be relevant to the pathogenesis and treatment of Alzheimer's disease. There have been widely disparate estimates of the levels of these antibodies in human plasma. We identify factors that have contributed to these disparities and describe improved methods for measuring anti-Aβ antibodies in blood. These methods include isolating immunoglobulin by thiophilic chromatography and using chaotropic salts to dislodge weakly bound antibodies without significantly reducing the binding of specific anti-Aβ antibodies. Using these methods, we show that human blood contains polyvalent IgG antibodies that bind to Aβ with relatively low avidity and specificity, as well as IgG antibodies that bind to linear and conformational epitopes on amyloid monomers and aggregates with moderate to high avidity.

Summary Aging is accompanied by a reduction in the generation of B lymphocytes leading to impaired immune responses. In this study, we have investigated whether the decline in B lymphopoiesis is due to age-related defects in the hematopoietic stem cell compartment. The ability of hematopoietic stem cells from old mice to generate B cells, as measured in vitro, is decreased 2–5-fold, while myeloid potential remains unchanged. This age-related decrease in B-cell potential is more marked in common lymphoid progenitors (CLP) and was associated with reduced expression of the B-lineage specifying factors, EBF and Pax5. Notably, retrovirus-mediated expression of EBF complemented the age-related loss of B-cell potential in CLP isolated from old mice. Furthermore, transduction of CLP from old mice with a constitutively active form of STAT5 restored both EBF and Pax5 expression and increased B-cell potential. These results are consistent with a mechanism, whereby reduced expression of EBF with age decreases the frequency with which multipotent hematopoietic progenitors commit to a B-cell fate, without altering their potential to generate myeloid cells.

Immunoglobulins (Igs) that bind amyloid beta peptide (Abeta) are under clinical trials for immunotherapy of Alzheimer disease (AD). We have identified IgMs and recombinant Ig fragments that hydrolyze Abeta. Hydrolysis of peripheral Abeta by the IgMs may induce increased Abeta release from the brain. The catalytic IgMs are increased in AD patients, presumably reflecting a protective autoimmune response. Reduced Abeta aggregation and neurotoxicity attributable to the catalytic function were evident. These findings provide a foundation for development of catalytic Igs for AD immunotherapy.

We describe IgM class human autoantibodies that hydrolyze amyloid beta peptide 1-40 (Abeta40). A monoclonal IgM from a patient with Waldenström's macroglobulinemia hydrolyzed Abeta40 at the Lys-28-Gly-29 bond and Lys-16-Ala-17 bonds. The catalytic activity was inhibited stoichiometrically by an electrophilic serine protease inhibitor. Treatment with the catalytic IgM blocked the aggregation and toxicity of Abeta40 in neuronal cell cultures. IgMs purified from the sera of patients with Alzheimer disease (AD) hydrolyzed Abeta40 at rates superior to IgMs from age-matched humans without dementia. IgMs from non-elderly humans expressed the least catalytic activity. The reaction rate was sufficient to afford appreciable degradation at physiological Abeta and IgM concentrations found in peripheral circulation. Increased Abeta concentrations in the AD brain are thought to induce neurodegenerative effects. Peripheral administration of Abeta binding antibodies has been suggested as a potential treatment of AD. Our results suggest that catalytic IgM autoantibodies can help clear Abeta, and they open the possibility of using catalytic Abs for AD immunotherapy.

Semicarbazide sensitive amine oxidase (SSAO) metabolizes oxidative deamination of primary aromatic and aliphatic amines. The final products of its catalysis, ammonia, hydrogen peroxide (H2O2) and the corresponding aldehyde, may contribute to diseases involving vascular degeneration. SSAO is selectively expressed in blood vessels in the brain, but is also present in blood plasma. We have previously reported that membrane-bound SSAO is overexpressed in the cerebrovascular tissue of Alzheimer's disease (AD) patients. The aim of the present work is to study whether the circulating SSAO is also altered in this neurodegenerative disease. SSAO activity was determined in plasma of control cases (n = 23) and patients suffering sporadic Alzheimer dementia, distributed according to the Global Deterioration Scale (GDS): mild (n = 33), moderate (n = 14), moderate-severe (n = 15) and severe dementia (n = 19). Results show a clear increase of plasma SSAO activity (p0.001) in moderate-severe and severe AD patients, with patient age being an independent correlative factor. However, plasma SSAO activity was not altered in AD patients with mild or moderate dementia compared to controls. beta-Amyloid (Abeta) (40-42) immunoreactivity in plasma samples was also determined, and no correlation was observed between Abeta 40-42 levels and the severity of the dementia or the plasma SSAO activity. Our results suggest that an increase in circulating SSAO activity could contribute to oxidative stress and vascular damage in advanced Alzheimer's disease.

In this review, the case is made that amyloid-beta peptide in the brain of patients with Alzheimer's disease is a primary cause of the disease and that immunotherapy directed against this peptide has the potential to halt and/or reverse disease progression. This supposition is supported by the capacity of anti-beta-amyloid peptide antibodies to prevent or reverse the disease in mouse models of Alzheimer's disease. Furthermore, preliminary results obtained in a small number of patients with Alzheimer's disease are consistent with the observations made in the mouse model of this disease. We review the relationship between the immune system, amyloid-beta peptide, and Alzheimer's disease and the progress made in applying immunotherapy to patients with Alzheimer's disease.

B-cell clonal expansions (BCE) in young mice are transient, detectable for less than 4 weeks. In contrast, BCE in old mice persist more than 2 months. The greater persistence of BCE in old mice does not appear to be due to the age of the host as the survival of phenyloxazolone chicken serum albumin-induced BCE in most old mice was shorter than in young mice. This raises the possibility that persistent BCE seen in old mice develop over time from transient BCE present earlier in life. To test this hypothesis, young C57BL/6 mice were immunized with hen egg lysozyme (HEL) during the first year of life. By 28 months of age, the majority of these mice had developed a benign, persistent BCE associated with a HEL-specific serum mIg. We also investigated whether benign, persistent BCE, present in 18-month-old mice, can evolve into B-cell lymphomas. We observed that four of eight C57BL/6 mice that survived to 29 months of age had developed diffuse large cell lymphomas. In three of these mice, this diagnosis was made by microscopic analysis of the lymphoid organs. In one mouse, a macroscopic lymphoma was present that permitted us to demonstrate that the IgH mRNA CDR3 length and sequence in the malignant lymphoma was derived from a persistent BCE present 11 months earlier. Together these observations are consistent with the hypothesis that stepwise accumulation of genetic alterations combined with Darwinian selection underlies the evolution of B cells from transient BCE in young mice into persistent BCE, serum mIg, and B-cell lymphomas observed in older mice.

There are fewer bone marrow Pre-B cells in old compared to young mice. We have demonstrated both decreased rearrangement of the V to DJ IgH gene segments and low levels of VH germline transcripts in Pro-B cells, the precursors of Pre-B cells, from old compared to young mice. However, there was no difference in the level of RAG-mRNA in purified Pro-B cells from old and young mice. Consistent with the prior reports that fewer bone marrow emigrants enter the peripheral B cell populations of old than young mice, we identified fewer transitional B cells in the blood, as well as the spleen, of old than young mice. Association of impaired IgH rearrangement with a decreased number of transitional B cells in old mice was supported by finding that the percentage and number of transitional B cells expressing rearranged IgH and IgL transgenes, which do not require rearrangement of their endogenous IgH gene segments, were comparable in old and young mice. In contrast, the percentage and number of transitional B cells in these Ig-transgenic mice, which escaped allelic exclusion and have rearranged endogenous IgH gene segments, showed an age-associated decline similar to that seen in wild type mice. These data are consistent with the view that impaired V to DJ rearrangement contributes to the decreased levels of bone marrow Pre-B cells as well as the decreased levels of transitional B cells in the periphery.

Aging is associated with a decreased production of B cells by the bone marrow and an increased life-span of peripheral B cells. To determine whether the decreased bone marrow B cell production is linked to the increased life-span of B cells in old mice, B cell regeneration following lymphopenia was studied in young and old mice. The rate of bone marrow pre-B cell and of splenic B cell regeneration is slower in irradiated, old compared to irradiated, young recipients of young, congeneic bone marrow. This finding reflects an age-associated defect in the bone marrow microenvironment. As the bone marrow is the only source of a diverse population of B cells, we measured the diversity of the splenic B cell repertoire regenerated following drug-induced lymphopenia in old and young mice. The heterogeneity of mRNA size from IgH complementarity determining region 3 (CDR3) was more restricted in splenic B cells from old compared to young mice providing additional evidence for an age-associated impairment in B cell production by the bone marrow.

Relative diversity and representation of peripheral T cells bearing different TCR Vβ families are remarkably tightly regulated between birth and advanced adulthood. By contrast, individual elderly humans and C3H.SW and B10.BR aged mice display drastic disruption in such regulation. It was suggested that the alterations in the murine aged T cell compartment were due to age-related clonal T cell expansions (TCE). Here, we studied the kinetics of homeostatic dysregulation of T cell populations in aged C57BL/6 (B6) mice. Using mAb staining, we show that the percentages of αβ+CD8+ or CD4+ T cells bearing different TCRVβ elements remain virtually constant in mice up to 12 mo of age. In 22-mo-old mice, however, there is a dramatic disturbance of this pattern owing to the emergence of CD8+ TCE. Expanded T cells did not show any obvious bias in Vβ usage and were derived in all cases examined thus far from a single clone. TCE appeared later in life, compared with B cell clonal expansions. However, and in contrast to those detected in humans, TCE were frequently unstable disappearing within 2–4 mo, with other TCE appearing within the same time frame. Additional studies carried on thymic T cells, thymectomized mice, and young T transferred cells into Rag1−/− mice suggest that the clonal expansions occur in the periphery and that their onset is accelerated by decreased thymic output and/or function(s).

The steady-state level of both RAG-1 and RAG-2 mRNA, the number of Pre-B cells, and the number of Pre-B cells expressing RAG-2 protein decrease in the bone marrow of old mice. These differences appear to be due, at least in part, to increased apoptosis of bone marrow Pre-B cells. To determine whether the age-associated increase in apoptosis reflects the impaired expression of the Pre-B cell receptor required for the survival of Pre-B cells, we examined the recombination of D to J and V to DJ in bone marrow from young and old mice. Both D to J recombination, which occurs early in the Pro-B cell stage of development, and V to DJ, which occurs just prior to the transition to the Pre-B cell stage, are diminished with age. These findings support the view that immunoglobulin recombination may impair the expression of the Pre-B cell receptor and may contribute to the increased rate of apoptosis of Pre-B cells in the bone marrow of old mice.

In tumor transplantation models in mice, cytotoxic T lymphocytes (CTLs) are typically the primary effector cells. CTLs recognize major histocompatibility complex (MHC) class I–associated peptides expressed by tumors, leading to tumor rejection. Peptides presented by cancer cells can originate from viral proteins, normal self-proteins regulated during differentiation, or altered proteins derived from genetic alterations. However, many tumor peptides recognized by CTLs are poor immunogens, unable to induce activation and differentiation of effector CTLs. We used MHC binding motifs and the knowledge of class I:peptide:TCR structure to design heteroclitic CTL vaccines that exploit the expression of poorly immunogenic tumor peptides. The in vivo potency of this approach was demonstrated using viral and self-(differentiation) antigens as models. First, a synthetic variant of a viral antigen was expressed as a tumor antigen, and heteroclitic immunization with peptides and DNA was used to protect against tumor challenge and elicit regression of 3-d tumors. Second, a peptide from a relevant self-antigen of the tyrosinase family expressed by melanoma cells was used to design a heteroclitic peptide vaccine that successfully induced tumor protection. These results establish the in vivo applicability of heteroclitic immunization against tumors, including immunity to poorly immunogenic self-proteins.

A significant increase in the utilization of the VH gene families VH11 and Q52 was observed in LPS-stimulated splenic B lymphocytes from aged mice compared to young mice. VH gene usage was assayed by in situ DNA/RNA hybridization using VH family-specific and kappa chain probes. The observed age-dependent differences appear to reflect the preferential use of VH11 and Q52 VH gene use by the CD5 + B lymphocyte subset whose numbers in the spleen increase with age. The increased use of VH11 by splenic cells from old mice is associated with clonal expansions of splenic CD5 + B lymphocytes.

Cells proliferating from human atherosclerotic lesions are resistant to the antiproliferative effect of TGF-beta1, a key factor in wound repair. DNA from human atherosclerotic and restenotic lesions was used to test the hypothesis that microsatellite instability leads to specific loss of the Type II receptor for TGF-beta1 (TbetaR-II), causing acquired resistance to TGF-beta1. High fidelity PCR and restriction analysis was adapted to analyze deletions in an A10 microsatellite within TbetaR-II. DNA from lesions, and cells grown from lesions, showed acquired 1 and 2 bp deletions in TbetaR-II, while microsatellites in the hMSH3 and hMSH6 genes, and hypermutable regions of p53 were unaffected. Sequencing confirmed that these deletions occurred principally in the replication error-prone A10 microsatellite region, though nonmicrosatellite mutations were observed. The mutations could be identified within specific patches of the lesion, while the surrounding tissue, or unaffected arteries, exhibited the wild-type genotype. This microsatellite deletion causes frameshift loss of receptor function, and thus, resistance to the antiproliferative and apoptotic effects of TGF-beta1. We propose that microsatellite instability in TbetaR-II disables growth inhibitory pathways, allowing monoclonal selection of a disease-prone cell type within some vascular lesions.