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Spanning 464.24 km2, Pokhara Metropolitan City is Nepal’s largest city by area. With over 400 000 residents, it is also Nepal’s second most populous city. This research investigated a biometeorological system present within Pokhara Metropolitan City concerning air pollution, meteorological conditions, and health. Different aspects of this system are more or less influential in various regions of the city, and understanding these relationships can assist with future health interventions for limiting exposure to pollutants. This research was completed using datasets published in government records and scientific literature, showcasing what can be accomplished with open-source data. Key findings were a positive correlation between air pollution levels and chronic obstructive pulmonary disease (COPD) hospital admissions to Pokhara’s Western Regional Hospital and a negative correlation between meteorological measurements and hospital admissions. These findings aligned with the general body of literature on risk factors for COPD hospitalizations. Multivariate regressions yielded better predictions for hospital admissions using both mean low and high temperatures as opposed to using one temperature variable, which implied both daily low and high temperatures are related to hospital admissions. Results also revealed air pollution levels for pollutants ≤ 10 and > 2.5 μm were better predictors of hospital admissions than air pollutants sized 2.5 μm and below. Findings prompted questions about the relationships between different pollutant sizes and their correlations to COPD hospitalizations. Findings also yielded questions about health interventions and Pokhara’s built environment, which may be investigated in future research.

On November 21, 2022, Dr. Ryan Prox, Adjunct Professor in the School of Criminology at Simon Fraser University, presented on Data & Infrastructure Security: The Risk of AI Enabled Cyber Attacks and Quantum Hacking. The presentation was followed by a question-and-answer period with questions from the audience and CASIS Vancouver executives. The key points discussed were the evolution of data and infrastructure security, the increasing interconnectedness of critical infrastructure, and the need to increase resilience in the face of revolutionary technological advancements. Received: 2023-01-23Revised: 2023-01-27

On October 20, 2022, Dr. Ryan Prox, S/Constable-in-Charge of the Crime Analytics Advisory & Developmental Unit at the Vancouver Police Department and Adjunct Professor at Simon Fraser University, presented on Algorithmic Technology: Fueling AI in an Ethical & Transparent Way at the October Digital Roundtable event hosted by the Canadian Association for Security and Intelligence Studies (CASIS)-Vancouver. The key points discussed were algorithmic technology and its implementation within police services; governance, accountability, and public perceptions of AI; and mitigating risk when implementing AI. The presentation was followed by a question-and-answer period with questions from the audience and CASIS-Vancouver executives.

Abstract Even after the 150th anniversary of sexual selection theory, the drivers and mechanisms of female sexual selection remain poorly studied. To understand demographic circumstances favoring female-female competition, trade-offs with kin selection and interactions with male reproductive strategies, we investigated female evictions in redfronted lemurs (Eulemur rufifrons). Based on 24 years of demographic data of known individuals, we show that female redfronted lemurs target close female kin for forcible, permanent, and presumably lethal eviction, even though groups contain multiple unrelated males whose voluntary emigration actually mitigated the probability of future female evictions. Female eviction and male emigration were predicted by group size, but male emigration was primarily driven by a proportional increase of male rivals. Female evictions were more likely than male emigrations when there were more juvenile females in a group, but the identity of evicted females was not predicted by any intrinsic traits. While birth rates were reduced by the number of juvenile females, they were higher when there were more adult females in a group and in years with more rainfall. Early infant survival was reduced with increasing numbers of juvenile females, but variation in female lifetime reproductive success was not related to any of the predictors examined here. Thus, there seems to be a limit on female group size in this lemur species. More generally, our study demonstrates a balanced interplay between female reproductive competition, competition over group membership between both sexes, and kin selection, contributing new insights into the causes and consequences of female competition in animal societies. Significance statement The evolutionary causes of female competition in vertebrate societies remain poorly known. Evictions represent an extreme form of female competition because even close kin are evicted when same-sized unrelated males are theoretically also available as victims. We studied drivers and consequences of evictions in redfronted lemurs (Eulemur rufifrons) using 24 years of demographic data from multiple groups. We show that while voluntary male emigration mitigates the probability of future female evictions, females nonetheless appear to accept the fitness costs of evicting female kin. While group size seems to be the main driver of departures by either sex, the number of juvenile females present in groups is the key variable triggering eviction events as well as physiological responses that could be interpreted as female reproductive restraint. Our study therefore revealed that competition does trump cooperation under some circumstances in the intricate interplay between sexual selection and kin selection on females.

We replicate the study of Gurung et al. (2017): “Dressing ‘in code’: Clothing rules, propriety, and perceptions.

International audience; The causes and consequences of being in a particular dominance position have been illuminated in various animal species, and new methods to assess dominance relationships and to describe the structure of dominance hierarchies have been developed in recent years. Most research has focused on same-sex relationships, however, so that intersexual dominance relationships and hierarchies including both sexes have remained much less studied. In particular, different methods continue to be employed to rank males and females along a dominance hierarchy, and sex biases in dominance are still widely regarded as simple byproducts of sexual size dimorphism. However, males and females regularly compete over similar resources when living in the same group, and sexual conflict takes a variety of forms across Frontiers in Ecology and Evolution 01 frontiersin.org Kappeler et al. 10.3389/fevo.2022.918773 societies. These processes affect the fitness of both sexes, and are mitigated by intersexual hierarchies. In this study, we draw on data from free-ranging populations of nine species of mammals that vary in the degree to which members of one sex dominate members of the other sex to explore the consequences of using different criteria and procedures for describing intraand intersexual dominance relationships in these societies. Our analyses confirmed a continuum in patterns of intersexual dominance, from strictly male-dominated species to strictly female-dominated species. All indices of the degree of female dominance were well correlated with each other. The rank order among same-sex individuals was highly correlated between the intra-and intersexual hierarchies, and such correlation was not affected by the degree of female dominance. The relative prevalence of aggression and submission was sensitive to variation in the degree of female dominance across species, with more submissive signals and fewer aggressive acts being used in societies where female dominance prevails. Thus, this study provides important insights and key methodological tools to study intersexual dominance relationships in mammals.

The relationship between age and reproductive performance is highly variable across species. Humans and some cetaceans exhibit an extreme form of reproductive senescence in that female reproduction ceases years or even decades before average life expectancy is reached. However, neither the existence of reproductive senescence in some taxa nor its absence in others is fully understood. Comparative data from other long-lived mammals may contribute to a more comprehensive understanding of the evolution of menopause, but data from wild primates, in particular, are scarce. We therefore investigated age-related female reproductive performance in two wild sympatric populations of Malagasy primates: Verreaux’s sifakas (Propithecus verreauxi) and redfronted lemurs (Eulemur rufifrons), which have a maximal longevity of more than 20 years. Based on 25 years of long-term demographic data, we extracted information on reproductive output of 38 female Verreaux’s sifakas and 42 female redfronted lemurs. We modeled variation in female reproductive performance and interbirth intervals as a function of age, the number of adult females within a group to account for female competition, and rainfall as a proxy for annual variation in food availability. We also compared our results for these two species with data on captive populations of the same two genera that are buffered from fluctuations in environmental variables. Our analyses disclosed statistical evidence for reproductive senescence in three out of four populations (captive Coquerel’s sifakas, wild redfronted lemurs, and captive red lemurs) but not for wild Verreaux’s sifakas. Compared to wild populations, reproductive senescence was therefore not less pronounced in captive animals, even though the latter are buffered from environmental adversities. In wild redfronted lemurs, mothers were more likely to give birth in years with more rainfall, but neither the number of co-resident females, nor annual rainfall did predict variation in the probability of giving birth in wild Verreaux’s sifakas. Thus, our study contributes valuable comparative information on reproductive senescence in a basal group of primates, and offers insights into the modulating effects of environmental, social and phylogenetic factors on patterns and dynamics of age-specific female reproduction.

Social relationships can have important fitness consequences. Although there is increasing evidence that social relationships carry over across contexts, few studies have investigated whether relationships formed early in life are carried over to adulthood. For example, juveniles of monogamous species go through a major life history stage transition, pair formation, during which the pair bond becomes a central unit of the social organization. At present, it remains unclear whether pair members retain their early life relationships after pair formation. We investigated whether same-sex associations formed early in life carry over into adulthood and whether carryover was dependent on season, in a monogamous species. We also investigated the role of familiarity, genetic relatedness and aggression on the perseverance of social associations. We studied the social structure before and after pair formation in captive barnacle geese, Branta leucopsis, a highly social, long-lived, monogamous species. We constructed association networks of groups of geese before pair formation, during the subsequent breeding season and in the following wintering season. Next, we studied how these associations carried over during seasonal changes. We found that early life associations in females were lost during the breeding season but resurfaced during the subsequent wintering season. In males, the early life associations persisted across both seasons. Association persistence was not mediated by genetic relatedness or familiarity. The high level of aggressiveness of males, but not females, in the breeding season suggests that males may have played a key role in shaping both their own social environment and that of their partners. We show that early life social relationships can be maintained well into later life. Such relationships can be sustained even if they are temporarily disrupted, for example due to reproductive behaviour. Our findings therefore highlight that the early life social environment can have lifelong consequences for individuals’ social environment.

Abstract It has long been recognized that the patterning of social interactions within a group can give rise to a social structure that holds very different places for different individuals. Such within-group variation in sociality correlates with fitness proxies in fish, birds, and mammals. Broader integration of this research has been hampered by the lack of agreement on how to integrate information from a plethora of dyadic interactions into individual-level metrics. As a step towards standardization, we collected comparative data on affinitive and affiliative interactions from multiple groups each of five species of primates to assess whether the same aspects of sociality are measured by different metrics and indices. We calculated 16 different sociality metrics used in previous research and thought to represent three different sociality concepts. We assessed covariation of metrics within groups and then summarized covariation patterns across all 15 study groups, which varied in size from 5 to 41 adults. With some methodological and conceptual caveats, we found that the number of weak ties individuals formed within their groups represented a dimension of sociality that was largely independent from the overall number of ties as well as from the number and strength of the strong ties they formed. Metrics quantifying indirect connectedness exhibited strong covariation with strong tie metrics and thus failed to capture a third aspect of sociality. Future research linking affiliation and affinity to fitness or other individual level outcomes should quantify inter-individual variation in three aspects: the overall number of ties, the number of weak ties, and the number or strength of strong ties individuals form, after taking into account effects of social network density. Significance statement In recent years, long-term studies of individually known animals have revealed strong correlations between individual social bonds and social integration, on the one hand, and reproductive success and survival on the other hand, suggesting strong natural selection on affiliative and affinitive behavior within groups. It proved difficult to generalize from these studies because they all measured sociality in slightly different ways. Analyzing covariation between 16 previously used metrics identified only three rather independent dimensions of variation. Thus, different studies have tapped into the same biological phenomenon. How individuals are weakly connected within their group needs further attention.

Mammalian societies represent many different types of social systems. While some aspects of social systems have been extensively studied, there is little consensus on how to conceptualize social organization across species. Here, we present a framework describing eight dimensions of social organization to capture its diversity across mammalian societies. The framework uses simple information that is clearly separated from the three other aspects of social systems: social structure, care system, and mating system. By applying our framework across 208 species of all mammalian taxa, we find a rich multidimensional landscape of social organization. Correlation analysis reveals that the dimensions have relatively high independence, suggesting that social systems are able to evolve different aspects of social behavior without being tied to particular traits. Applying a clustering algorithm allows us to identify the relative importance of key dimensions on patterns of social organization. Finally, mapping mating system onto these clusters shows that social organization represents a distinct aspect of social systems. In the future, this framework will aid reporting on important aspects of natural history in species and facilitate comparative analyses, which ultimately will provide the ability to generate new insights into the primary drivers of social patterns and evolution of sociality., Social organization is an aspect of animal social systems that has not been conceptualized yet and is often reduced to group size. This framework describes eight central dimensions of social organization to capture its diversity across mammalian societies. By applying our framework across 208 species of all mammalian taxa, we find a rich multidimensional landscape of social organization.

Broad applications of electropolymerized conducting polymers (CPs) often prefer thinner soft electrodes to comply with downscaling of the fabrication resolution. However, high conductivity of existing CP films vanishes as thickness decreases to the nanoscale (i.e., below 100 nm), with an unclear mechanism so far. In this study, with an unprecedented family of polypyrrole (PPy) nanofilms that can be easily transferred in a fast and contamination-free manner, we are able to trace the initial development of electrical conductance along with chains' arrangement starting from the very early electrochemical deposition. Our results evidence that the classical nodular polymeric aggregation fundamentally accounts for the persistent losses of interchain connectivity and macroscopic conductivity at a limited thickness. Surprisingly, this seemingly disadvantageous structure can be altered into a large conjugated network to robustly restore the conductivity back to over 80 S cm-1 even below 100 nm, while the controllable formation, growth, and collapse of such networks radically vary the conductivity over a range of 3 orders of magnitude (0.8-129 S cm-1). These observations depict the first physical picture detailing how the long-range conductivity builds up in a growing conjugated network, which opens a route to fast synthesis and diverse applications of such highly conductive CP nanofilms.

One-dimensional zinc oxide (ZnO) nanostructure arrays show unique semiconducting, piezoelectric, and wetting properties, and how they interact with cells is critical for their biomedical applications. In this work, we prepare ZnO nanorod arrays (ZnO NRAs) and study their interactions with neonatal rat cardiomyocytes either as a substrate or patch. We find that ZnO NRAs can (1) inhibit cell adhesion and spreading as a substrate and (2) selectively kill underneath cells as a patch. We further identify surface nanomorphology as the dominant factor responsible for the inhibitory effect. These discoveries suggest potential application of ZnO NRAs as a cell inhibitory biointerface.

// Tillmann Bedau 1 , Neele Schumacher 1 , Florian Peters 1 , Johannes Prox 1 , Philipp Arnold 2 , Tomas Koudelka 3 , Ole Helm 4 , Frederike Schmidt 1 , Bjorn Rabe 1 , Marlene Jentzsch 5 , Philip Rosenstiel 5 , Susanne Sebens 4 , Andreas Tholey 3 , Stefan Rose-John 1 and Christoph Becker-Pauly 1 1 Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany 2 Anatomical Institute, University of Kiel, 24118 Kiel, Germany 3 Institute of Experimental Medicine, University of Kiel, 24118 Kiel, Germany 4 Institute for Experimental Tumor Research, University of Kiel, 24118 Kiel, Germany 5 Institute of Clinical Molecular Biology, University of Kiel, 24118 Kiel, Germany Correspondence to: Christoph Becker-Pauly, email: cbeckerpauly@biochem.uni-kiel.de Keywords: CD99, meprin β, proteolytic shedding, lung cancer, inflammation Received: January 18, 2017 Accepted: June 17, 2017 Published: July 04, 2017 ABSTRACT Transendothelial cell migration (TEM) is crucial for inflammation and metastasis. The adhesion molecule CD99 was shown to be important for correct immune cell extravasation and is highly expressed on certain cancer cells. Recently, we demonstrated that ectodomain shedding of CD99 by the metalloprotease meprin β promotes TEM in vitro . In this study, we employed an acute inflammation model (air pouch/carrageenan) and found significantly less infiltrated cells in meprin β knock-out animals validating the previously observed pro-inflammatory activity. To further analyze the impact of meprin β on CD99 shedding with regard to cell adhesion and proliferation we characterized two lung cancer associated CD99 variants (D92H, D92Y), carrying point mutations at the main cleavage site. Interestingly, ectodomain shedding of these variants by meprin β was still detectable. However the cleavage site shifted to adjacent positions. Nevertheless, expression of CD99 variants D92H and D92Y revealed partial misfolding and proteasomal degradation. A previously observed influence of CD99 on Src activation and increased proliferation could not be confirmed in this study, independent of wild-type CD99 or the variants D92H and D92Y. However, we identified meprin β as a potent inducer of Src phosphorylation. Importantly, we found significantly increased cell migration when expressing the cancer-associated CD99 variant D92H compared to the wild-type protein.

Mammalian societies represent many different types of social systems. While some aspects of social systems have been extensively studied, there is little consensus on how to conceptualize social organization across species. Here, we present a framework describing eight dimensions of social organization to capture its diversity across mammalian societies. The framework uses simple information that is clearly separated from the three other aspects of social systems: social structure, care system, and mating system. By applying our framework across 208 species of all mammalian taxa, we find a rich multidimensional landscape of social organization. Correlation analysis reveals that the dimensions have relatively high independence, suggesting that social systems are able to evolve different aspects of social behavior without being tied to particular traits. Applying a clustering algorithm allows us to identify the relative importance of key dimensions on patterns of social organization. Finally, mapping mating system onto these clusters shows that social organization represents a distinct aspect of social systems. In the future, this framework will aid reporting on important aspects of natural history in species and facilitate comparative analyses, which ultimately will provide the ability to generate new insights into the primary drivers of social patterns and evolution of sociality. published

Social relationships can have important fitness consequences. Although there is increasing evidence that social relationships carry over across contexts, few studies have investigated whether relationships formed early in life are carried over to adulthood. For example, juveniles of monogamous species go through a major life-history stage transition—pair formation—during which the pair bond becomes a central unit of the social organization. At present, it remains unclear if pair members retain their early-life relationships after pair formation. We investigated whether same-sex associations formed early in life carry over into adulthood and whether carry-over was dependent on season, in a monogamous species. Moreover, we investigated the role of familiarity, genetic relatedness and aggression on the perseverance of social associations. We studied the social structure before and after pair formation in captive barnacle geese (Branta leucopsis), a highly social, long-lived, monogamous species. We constructed association networks of groups of geese before pair formation, during the subsequent breeding season, and in the following wintering season. Next, we studied how these associations carried over during seasonal changes. We found that early-life associations in females were lost during the breeding season, but resurfaced during the subsequent wintering season. In males, the early-life associations persisted across both seasons. Association persistence was not mediated by genetic relatedness or familiarity. The high level of aggressiveness of males, but not females, in the breeding season suggests that males may have played a key role in shaping both their own social environment and that of their partners. We show that early-life social relationships can be maintained well into later life. Such relationships can be sustained even if they are temporarily disrupted, for example due to reproductive behaviour. Our findings therefore highlight that the early-life social environment can have life-long consequences on individuals’ social environment.

1. The social decisions that individuals make—who to interact with and how frequently—gives rise to social structure. The resulting social structure then determines how individuals interact with their surroundings—resources and risks, pathogens and predators, competitors and cooperators. 2. However, despite intensive research on (i) how individuals make social decisions and (ii) how social structure shapes social processes (e.g. cooperation, competition and conflict), there are still few studies linking these two perspectives. These perspectives represent two halves of a feedback loop: individual behaviour scales up to define the social environment, and this environment, in turn, feeds back by shaping the selective agents that drive individual behaviour. 3. We first review well-established research areas that have captured both elements of this feedback loop—host-pathogen dynamics and cultural transmission. We then highlight areas where social structure is well studied but the two perspectives remain largely disconnected. Finally, we synthesise existing research on 14 distinct research topics to identify new prospects where the interplay between social structure and social processes are likely to be important but remain largely unexplored. 4. Our review shows that the inherent links between individuals’ traits, their social decisions, social structure, and social evolution, warrant more consideration. By mapping the existing and missing connections among many research areas, our review highlights where explicitly considering social structure and the individual-to-society feedbacks can reveal new dimensions to old questions in ecology and evolution.

Objective Therapeutic intervention for Parkinson's disease (PD) via deep brain stimulation (DBS) represents the current paradigm for managing the advanced stages of the disease in patients when treatment with pharmaceuticals becomes inadequate. Although DBS is the prevailing therapy in these cases, the overall effectiveness and reliability of DBS can be diminished over time due to hardware complications and biocompatibility issues with the electronic implants. To achieve a lifetime solution, we envision that the next generation of neural implants will be entirely "biological" and "autologous", both physically and functionally. Thus, in this study, we set forth toward developing a biological brain pacemaker (BBP) for treating PD. Our focus is to investigate engineering strategies for creating a multicellular biological circuit that integrates innate biological design and function while incorporating principles of neuromodulation to create a biological mechanism for delivering high-frequency stimulation with cellular specificity. Approach We engineer a 3D multicellular circuit design built entirely from biological and biocompatible components using established tissue engineering protocols to demonstrate the feasibility of creating a living neural implant. Furthermore, using 2D co-culture systems, we investigate the physiologically relevant parameters that would be necessary to further develop a therapeutic benefit of high frequency stimulation with cellular specificity within our construct design. Main results Our results demonstrate the feasibility of fabricating a 3D multicellular circuit device in an implantable form. Furthermore, we show we can organize cellular materials to create potential functional connections in normal physiological conditions, thus laying down the foundation of designing a high-frequency pacing system for selective and controlled therapeutic neurostimulation. Significance The findings from this study may lead to the future development of autologous living neural implants that both circumvent the issues inherent in electronic neural implants and form more biocompatible devices with lifelong robustness to repair and restore motor functions, with the ultimate benefit for patients with PD.

Community Policing (CP), which refers to communities’ participation in police actions, is an evolving topic having a potential impact on reducing crime and creating safer communities. The next generation of community policing (NGCP) is helping to transform CP into a more robust and active participatory process than what has been previously witnessed. There is a connection between the multilayered complexity of CP that is being fuelled in this engagement through the current global digital revolution, exponentially growing big data, and advancement in technology. In the global scene, NGCP is received differently given the cultural, societal, legal, privacy and security aspects in specific continents, countries, regions, cities and even neighbourhoods. This chapter aims at introducing challenges of NGCP at a global stage and offer options for moving forward. To do this, the chapter sets the scene of NGCP in Europe and North America (with focus on Canada). The role of digitalization, big data in predictive policing and digital community policing are also discussed. In particular, the chapter tries to leverage predictive policing from a community engagement perspective that effectively addresses and promotes the seamless collaboration between police and communities. The “Block Watch” programme in Vancouver Police Department (VPD) and European Neighbourhood Watch Association (EUNWA) in Europe are introduced in the chapter as vital role models in the NGCP. The role of technologies and the interdependency on making the right technological choices with the goal of advancing NGCP and then incorporating human interactivity are explored, specifically, by examining, on the one hand, how the Vancouver Police Department (VPD) has operationalized predictive policing to integrate into the community engagement perspective and, on the other hand, by studying the successful case of Burgernet across all of The Netherlands. European research and innovation project INSPEC2T is also presented as solution for NGCP with contributions from around the globe.

The meprin β metalloproteinase is an important enzyme in extracellular matrix turnover, inflammation, and neurodegeneration in humans and mice. Previous studies showed a diminished cleavage of certain meprin β substrates in the presence of calcium, although the mechanism was not clear. With the help of a specific fluorogenic peptide assay and the human amyloid precursor protein as substrate, we demonstrated that the influence of calcium is most likely a direct effect on human meprin β itself. Analyzing the crystal structures of pro- and mature meprin β helped to identify a cluster of negatively charged amino acids forming a potential calcium binding site. Mutation of 2 of these residues (D204A and D245A) led to severe differences in proteolytic activity and cellular localization of meprin β. D245A was almost completely inactive and largely stored into intracellular vesicles, indicating severe misfolding of the protein. Astonishingly, D204A was not transported to the cell surface, but exhibited strong β-secretase activity, resulting in massive accumulation of Aβ-peptides. This could be explained by constitutive maturation of this meprin β mutant already in the early secretory pathway. We hypothesize that lacking D204 abrogates the capability of binding calcium in the catalytic domain, an important step for proper folding of the propeptide and subsequent inhibition of the protease. This is supported by the inhibition constant of calcium for meprin β (inhibitory constant 50 = 11 mM), which resembles the physiologic concentrations found in the endoplasmic reticulum. For instance, it was shown for amyotrophic lateral sclerosis that a loss of calcium in the endoplasmic reticulum leads to the misfolding of calcium-dependent proteins, which might also be relevant for proper function of meprin β.

Objective Implantable neurotechnologies have revolutionized neuromodulatory medicine for treating the dysfunction of diseased neural circuitry. However, challenges with biocompatibility and lack of full control over neural network communication and function limits the potential to create more stable and robust neuromodulation devices. Thus, we propose a platform technology of implantable and programmable cellular systems, namely Integrated Biocircuits, which use only cells as the functional components of the device. Approach We envision the foundational principles for this concept begins with novel in vitro platforms used for the study and reconstruction of cellular circuitry. Additionally, recent advancements in organoid and 3D culture systems account for microenvironment factors of cytoarchitecture to construct multicellular circuits as they are normally formed in the brain. We explore the current state of the art of these platforms to provide knowledge of their advancements in circuit fabrication and identify the current biological principles that could be applied in designing integrated biocircuit devices. Main results We have highlighted the exemplary methodologies and techniques of in vitro circuit fabrication and propose the integration of selected controllable parameters, which would be required in creating suitable biodevices. Significance We provide our perspective and propose new insights into the future of neuromodulaion devices within the scope of living cellular systems that can be applied in designing more reliable and biocompatible stimulation-based neuroprosthetics.

Since May 2014 a new ISO Standard on Guidance for the extension of Material Flow Cost Accounting (MFCA) into the Supply Chain is in preparation. The contribution will elaborate on the challenges and benefits of this extension for the participating supply chain partners. As Material Flow Cost Accounting and Life Cycle Engineering are based on a similar demand on information about Material and Energy Flows along the Supply Chain, respectively along the life Cycle, synergies and differences between the two approaches will be discussed. As far as available guidance for successful collaboration in the supply chain will be given.

[nicht vorhanden / not available], Germania : Anzeiger der Römisch-Germanischen Kommission des Deutschen Archäologischen Instituts, Bd. 23, Nr. 4 (1939)

Zinc oxide (ZnO) nanowires have been widely studied for their applications in electronics, optics, and catalysts. Their semiconducting, piezoelectric, fluorescent, and antibacterial properties have also attracted broad interest in their biomedical applications. Thus, it is imperative to evaluate the biosafety of ZnO nanowires and their biological effects. In this study, the cellular level biological effects of ZnO nanowire arrays are specifically tested on three types of excitable cells, including NG108-15 neuronal cell line, HL-1 cardiac muscle cell line, and neonatal rat cardiomyocytes. Vertically aligned and densely packed ZnO nanowire arrays are synthesized using a solution-based method and used as a substrate for cell culture. The metabolism levels of all three types of cells cultured on ZnO nanowire arrays are studied using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays of a full factorial design. Under the studied settings, the results show statistically significant inhibitory effects of ZnO nanowire arrays on the metabolism of NG108-15 and HL-1 cells in comparison to gold, glass, and polystyrene substrates, and on the metabolism of cardiomyocytes in comparison to gold substrate.

Proteolytic and amyloidogenic processing of amyloid precursor protein (APP) by β- and γ-secretases are pathological hallmarks of Alzheimer’s disease (AD). These proteolytic activities lead to release of the amyloid-β pep­tides believed to cause neurological pathol­ogy and be linked to pathological progres­sion in AD. Due to its capability to cleave APP within the toxic peptide sequence, the metalloproteinase ADAM10 (“a disintegrin and me­talloprotease”) is a known antagonist of the disease-causing pathway. ADAM10 also plays a major role in the ectodomain shedding of a number of important cell surface proteins. In addition, ADAM10 is involved in the proteolytic activation cascade of the Notch receptor, which is of crucial function in develop­mental processes. The study of ADAM10-deficient mice also revealed that ADAM10 regulates synaptic function and synaptogenesis. Pharmacological activation of ADAM10 is postulated to represent a valuable strategy for prevention of AD. However, due to the multiple roles of ADAM10 in the brain, it will be challenging to find a suitable therapeutic window.

Zusammenfassung Als ein auslösender Faktor der Alzheimer-Erkrankung wird die „pathologische“, amy­loidogene Prozessierung des Amyloiden Vorläuferproteins (APP) betrachtet, welches proteolytisch durch die b-Sekretase und anschließend durch den γ-Sekretasekomplex prozessiert wird. Dies führt zur Freisetzung des Amyloiden b-Peptides, welches neu­rotoxisch ist und teilweise ursächlich für die Erkrankung gemacht wird. Aufgrund der Fähigkeit, APP innerhalb der toxischen Peptidsequenz zu schneiden, wird der Metalloproteinase ADAM10 als Gegenspieler dieses krankheitsauslösenden Weges be­sondere Bedeutung zugeschrieben. ADAM10 ist auch bei der membrannahen Spaltung der extrazellulären Domänen einer Reihe wichtiger Zelladhäsionsproteine und bei der aktivierenden Proteolyse des bei Entwicklungsprozessen bedeutenden Notch-Rezeptors beteiligt. Untersuchungen an ADAM10-defizienten Mäusen zeigten auch eine Rolle der Protease bei der korrekten Bildung und Funktion von Synapsen. Eine pharmakolo­gische Aktivierung von ADAM10 wird als therapeutisches Ziel für die Prävention von Morbus Alzheimer diskutiert. Aufgrund der mannigfaltigen Aufgaben von ADAM10 im Gehirn wird es dabei wichtig sein, ein geeignetes therapeutisches Fenster zu finden.

The protease web is a synonym for highly regulated molecular networks comprising enzymes, substrates, inhibitors, and other regulatory proteins. Latest high-throughput methods provided huge data sets, revealing an amazing complexity of proteolytic systems important for health and disease. Based on our previous studies, we discuss major problems and questions that have to be solved to gain precise insight into the regulation of the protease web and its impact on pathophysiological conditions. The goal is a combination of different proteomic approaches that help to investigate specific protease function at a glance. Exemplarily, the characterization of the metalloproteases meprin α and meprin β by proteomic identification of cleavage sites and terminal amine isotopic labeling of substrates demonstrates the power of MS-based techniques. Meprins are rather orphan proteases and could not be assigned to precise biological functions until recently. Proteomics helped to identify meprin α and meprin β being important for collagen assembly and deposition in skin, which makes them potential therapeutic targets in fibrotic conditions. Additionally, identification of the cleavage site specificity provides the basis for the development of activity-based probes and small compound inhibitors, important for the regulation of meprin activity and subsequent treatment of associated diseases.

Adult hematopoiesis requires tightly regulated cell–cell interactions between hematopoietic cells and the bone marrow stromal microenvironment. We addressed the question if the ectodomain sheddase ADAM10 is essential to regulate adult hematopoiesis. Induced ADAM10 deletion in hematopoietic cells resulted in morphological and histological abnormalities that resemble an unclassified myeloproliferative disorder (MPD). The MPD was characterized by an expansion of granulocytic subpopulations and their infiltration of peripheral hematopoietic tissues, the development of hepatosplenomegaly with extramedullary erythropoiesis, lymphnodepathy and death of the mice around 20 weeks after induction. ADAM10 expression analysis during the different stages of the MPD revealed that non-targeted hematopoietic cells repopulated the immune system of the ADAM10-deficient mice. Examination of mice with a myeloid- or epidermis-specific deletion of ADAM10 and bone marrow transplantation (BMT) experiments indicated that the development of the MPD can be triggered by non-cell autonomous effects. We found that plasma levels of clinical markers for MPD such as G-CSF, TIMP-1 and IL-16 were significantly elevated in ADAM10-deficient mice. Our findings indicate that a tightly controlled ADAM10 expression is needed to balance hematopoietic cell-fate decisions in adult mice.

The cellular prion protein (PrP(C)) plays important roles in neurodegenerative diseases. First, it is the well-established substrate for the conformational conversion into its pathogenic isoform (PrP(Sc)) giving rise to progressive and fatal prion diseases. Moreover, several recent reports highlight important roles of PrP(C) in other neurodegenerative conditions such as Alzheimer's disease. Since PrP(C) is subject to proteolytic processing, here we discuss the two main cleavage events under physiological conditions, α-cleavage and shedding. We focus on how these cleavages and the resulting fragments may impact prion diseases as well as other neurodegenerative proteinopathies. Finally, we discuss the recently identified sheddase of PrP(C), namely the metalloprotease ADAM10, with regard to therapeutic potential against neurodegenerative diseases.

The adhesion molecule CD99 is essential for the transendothelial migration of leukocytes. In this study, we used biochemical and cellular assays to show that CD99 undergoes ectodomain shedding by the metalloprotease meprin β and subsequent intramembrane proteolysis by γ-secretase. The cleavage site in CD99 was identified by mass spectrometry within an acidic region highly conserved through different vertebrate species. This finding fits perfectly to the unique cleavage specificity of meprin β with a strong preference for aspartate residues and suggests coevolution of protease and substrate. We hypothesized that limited CD99 cleavage by meprin β would alter cellular transendothelial migration (TEM) behavior in tissue remodeling processes, such as inflammation and cancer. Indeed, meprin β induced cell migration of Lewis lung carcinoma cells in an in vitro TEM assay. Accordingly, deficiency of meprin β in Mep1b-/- mice resulted in significantly increased CD99 protein levels in the lung. Therefore, meprin β could serve as a therapeutic target, given that in a proof-of-concept approach we showed accumulation of CD99 protein in lungs of meprin β inhibitor-treated mice.-Bedau, T., Peters, F., Prox, J., Arnold, P., Schmidt, F., Finkernagel, M., Kollmann, S., Wichert, R., Otte, A., Ohler, A., Stirnberg, M., Lucius, R., Koudelka, T., Tholey, A., Biasin, V., Pietrzik, C. U., Kwapiszewska, G., Becker-Pauly, C. Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration.

In Consequential Life Cycle Assessment (CLCA), the system boundaries are defined to include the activities that change as a consequence of a small change in the demand for the studied products. To understand the potential consequences of a decision that involves the substitution of one product with another, the differences between the alternative product systems are modeled. But in order to be regarded as alternatives, the product systems have to have the same output, fulfil the same performance requirements, i.e., have the same functional unit. This chapter presents a step-wise process for a practitioner to follow in assessing alternative product systems in a consequential LCA approach. The process consists of five basic steps: Step 1 – describing the product by its properties; Step 2 – identifying market boundaries; Step 3 – identifying product alternatives; Step 4 – defining the functional unit; and Step 5 – determining reference flows for alternatives. The chapter concludes with sections on considering differences in price and time consumption (i.e. rebound effects) as well as the effects on the overall productivity of society.

Hepatocellular carcinoma is associated with a high rate of intra-hepatic invasion that carries a poor prognosis. Meprin alpha (Mep1A) is a secreted metalloproteinase with many substrates relevant to cancer invasion. We found that Mep1A was a target of Reptin, a protein that is oncogenic in HCC. We studied Mep1A regulation by Reptin, its role in HCC, and whether it mediates Reptin oncogenic effects. MepA and Reptin expression was measured in human HCC by qRT-PCR and in cultured cells by PCR, western blot and enzymatic activity measurements. Cell growth was assessed by counting and MTS assay. Cell migration was measured in Boyden chambers and wound healing assays, and cell invasion in Boyden chambers. Silencing Reptin decreased Mep1A expression and activity, without affecting meprin β. Mep1A, but not meprin β, was overexpressed in a series of 242 human HCC (2.04 fold, p < 0.0001), and a high expression correlated with a poor prognosis. Mep1A and Reptin expressions were positively correlated (r = 0.39, p < 0.0001). Silencing Mep1A had little effect on cell proliferation, but decreased cell migration and invasion of HuH7 and Hep3B cells. Conversely, overexpression of Mep1A or addition of recombinant Mep1A increased migration and invasion. Finally, overexpression of Mep1A restored a normal cell migration in cells where Reptin was depleted. Mep1A is overexpressed in most HCC and induces HCC cell migration and invasion. Mep1A expression is regulated by Reptin, and Mep1A mediates Reptin-induced migration. Overall, we suggest that Mep1A may be a useful target in HCC.

The paper takes a position on enhancing existing development environments to support awareness of developer affect. To realize this, the environment needs to implicitly interface with biometric devices such as an eye tracker. Such development environments can help the developer detect when they need to take a break or when they need help. Besides helping the developer, researchers can also make use of such environments to study developer behavior in a realistic setting thereby improving tool support for emotional awareness as well as other software tasks.

Meprin β is a dimeric type I transmembrane protein and acts as an ectodomain sheddase at the cell surface. It was shown that meprin β cleaves the amyloid precursor protein (APP), thereby releasing neurotoxic amyloid β peptides and implicating a role of meprin β in Alzheimer’s disease. In order to identify non-proteolytic regulators of meprin β, we performed a split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library. In this screen we identified tetraspanin 8 (TSPAN8) as interaction partner for meprin β. Since several members of the tetraspanin family were described to interact with metalloproteases thereby affecting their localization and/or activity, we hypothesized similar functions of TSPAN8 in the regulation of meprin β. We employed cell biological methods to confirm direct binding of TSPAN8 to meprin β. Surprisingly, we did not observe an effect of TSPAN8 on the catalytic activity of meprin β nor on the specific cleavage of its substrate APP. However, both proteins were identified being present in tetraspanin-enriched microdomains. Therefore we hypothesize that TSPAN8 might be important for the orchestration of meprin β at the cell surface with impact on certain proteolytic processes that have to be further identified.

A disintegrin and metalloproteinase10 (ADAM10) has been implicated as a major sheddase responsible for the ectodomain shedding of a number of important surface molecules including the amyloid precursor protein and cadherins. Despite a well-documented role of ADAM10 in health and disease, little is known about the regulation of this protease. To address this issue we conducted a split-ubiquitin yeast two-hybrid screen to identify membrane proteins that interact with ADAM10. The yeast experiments and co-immunoprecipitation studies in mammalian cell lines revealed tetraspanin15 (TSPAN15) to specifically associate with ADAM10. Overexpression of TSPAN15 or RNAi-mediated knockdown of TSPAN15 led to significant changes in the maturation process and surface expression of ADAM10. Expression of an endoplasmic reticulum (ER) retention mutant of TSPAN15 demonstrated an interaction with ADAM10 already in the ER. Pulse-chase experiments confirmed that TSPAN15 accelerates the ER-exit of the ADAM10-TSPAN15 complex and stabilizes the active form of ADAM10 at the cell surface. Importantly, TSPAN15 also showed the ability to mediate the regulation of ADAM10 protease activity exemplified by an increased shedding of N-cadherin and the amyloid precursor protein. In conclusion, our data show that TSPAN15 is a central modulator of ADAM10-mediated ectodomain shedding. Therapeutic manipulation of its expression levels may be an additional approach to specifically regulate the activity of the amyloid precursor protein alpha-secretase ADAM10.

Background and Objectives: The objective of the present study was to obtain information about the prevalence of addiction disorders in ADHD patients in a German study population, to compare the prevalence of addiction disorders in ADHD patients to that in the normal population according to the German Epidemiological Addiction Survey, and to determine which drugs are consumed most by ADHD patients. Participants: The sample consisted of 61 patients (average age 35.11 ± 9.33 years) from our ADHD consultation who were consecutively included in our study over a period of 12 months. Measurements: We diagnosed ADHD according to DSM-IV-R and by assessing the WURS-k, CAARS and BROWN ADD scales. For diagnosing addiction we conducted the EuropASI, the IDCL, the QOD and the FTNA. For differential diagnosis we assessed the SCL-K. Results: About half of our study population of ADHD patients were diagnosed with a dependence disorder (50.8%, n = 31). Twenty one dot three percent (n = 13) were suffering from an alcohol dependence, 13.1% (n = 8) from a substance use disorder (SUD) and 18% (n = 11) from a combination of both addictions. The drug consumed most commonly by ADHD patients was cannabis. Alcohol and substance abuse commenced significantly earlier in patients with ADHD than in patients with addiction disorders without comorbid ADHD. Conclusions: Our data show that the risk of developing a dependence disorder is elevated in ADHD patients. Clinicians should bear in mind that the characteristics of a dependence in ADHD patients are clinically more pronounced and that an addiction in ADHD patients starts earlier than usually expected.

High-field asymmetric-waveform ion mobility spectrometry (FAIMS) is a rapidly growing gas-phase separation technique with a wide variety of applications. The geometry of the FAIMS cell influences ion transmission and resolution. Commercial FAIMS systems employ planar or cylindrical cell geometries. A spherical or hemispherical FAIMS cell would allow ions to travel equal path lengths through the FAIMS device while minimizing diffusional losses, improving ion resolution without sacrificing ion transmission. Here we detail the development of a novel hemispherical FAIMS cell and demonstrate the separation of a mixture of trinitrotoluene (TNT) and 3,4-dinitrotoluene (3,4-DNT). The resolution between TNT and 3,4-DNT using the hemispherical FAIMS cell is improved over that achieved with a commercial cylindrical cell while maintaining equivalent ion transmission. The novel hemispherical FAIMS cell provides improved resolution and resolving powers when compared to a commercially available cell.

The influence was examined of representative bifunctional catalysts on racemization in peptide syntheses via aminolysis of cyanomethyl, p-nitrophenyl, thiophenyl, and vinyl esters. Three different tests were used, based on gravimetric, polarimetric, and gas-liquid chromatographic analysis, respectively. 1,2,4-Triazole, which was investigated most extensively, did not cause racemization in any of the couplings. Imidazole, which has also been recommended for acceleration of peptide syntheses, led to racemization in several cases. The structure of N-acyl derivatives of 1,2,3- and 1,2,4-triazole was determined by proton resonance measurements.

Nectin-1 is known to undergo ectodomain shedding by alpha-secretase and subsequent proteolytic processing by gamma-secretase. How secretase-mediated cleavage of nectin-1 is regulated in neuronal cells and how nectin-1 cleavage affects synaptic adhesion is poorly understood. We have investigated alpha-and gamma-secretase-mediated processing of nectin-1 in primary cortical neurons and identified which protease acts as a alpha-secretase. We report here that NMDA receptor activation, but not stimulation of AMPA or metabotropic glutamate receptors, resulted in robust alpha- and gamma-secretase cleavage of nectin-1 in mature cortical neurons. Cleavage of nectin-1 required influx of Ca(2+) through the NMDA receptor, and activation of calmodulin, but was not dependent on calcium/calmodulin-dependent protein kinase II (CaMKII) activation. We found that ADAM10 is the major secretase responsible for nectin-1 ectodomain cleavage in neurons and the brain. These observations suggest that alpha- and gamma-secretase processing of nectin-1 is a Ca(2+)/calmodulin-regulated event that occurs under conditions of activity-dependent synaptic plasticity and ADAM10 and gamma-secretase are responsible for these cleavage events.

The metalloproteinase and major amyloid precursor protein (APP) α-secretase candidate ADAM10 is responsible for the shedding of proteins important for brain development, such as cadherins, ephrins, and Notch receptors.Adam10−/−mice die at embryonic day 9.5, due to major defects in development of somites and vasculogenesis. To investigate the function of ADAM10 in brain, we generatedAdam10conditional knock-out (cKO) mice using a Nestin-Cre promotor, limiting ADAM10 inactivation to neural progenitor cells (NPCs) and NPC-derived neurons and glial cells. The cKO mice die perinatally with a disrupted neocortex and a severely reduced ganglionic eminence, due to precocious neuronal differentiation resulting in an early depletion of progenitor cells. Premature neuronal differentiation is associated with aberrant neuronal migration and a disorganized laminar architecture in the neocortex. Neurospheres derived fromAdam10cKO mice have a disrupted sphere organization and segregated more neurons at the expense of astrocytes. We found that Notch-1 processing was affected, leading to downregulation of several Notch-regulated genes inAdam10cKO brains, in accordance with the central role of ADAM10 in this signaling pathway and explaining the neurogenic phenotype. Finally, we found that α-secretase-mediated processing of APP was largely reduced in these neurons, demonstrating that ADAM10 represents the most important APP α-secretase in brain. Our study reveals that ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including APP.

Among children with relapsed or refractory neuroblastoma, the prognosis is poor and novel therapeutic strategies are needed to improve long-term survival. As with other solid tumors, high vascular density within neuroblastoma is associated with advanced disease, and therapeutic regimens directed against the tumor vasculature may provide clinical benefit. The receptor tyrosine kinase RET is widely expressed in neuroblastoma and is known to activate key signal transduction pathways involved in tumor cell survival and progression including Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt. We investigated the effect of dual targeting of tumor cells and tumor endothelium with ZD6474, a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor 2, epidermal growth factor receptor, and RET. ZD6474 inhibited the phosphorylation of RET in neuroblastoma cells and had a direct effect on tumor cell viability in seven neuroblastoma cell lines. In a human neuroblastoma xenograft model, ZD6474 inhibited tumor growth by 85% compared with treatment with vehicle alone. In contrast, no significant inhibition of tumor growth was observed after treatment with bevacizumab, an antihuman VEGF monoclonal antibody, or the epidermal growth factor receptor inhibitor erlotinib, either alone or in combination. Immunohistochemical analysis showed that ZD6474 treatment led to an increase in endothelial cell apoptosis along with inhibition of VEGF receptor-2 activation on tumor endothelium. In conclusion, dual targeting of tumor cells, potentially through RET inhibition, and tumor vasculature with ZD6474 leads to potent antitumor effects. This approach merits further investigation for patients with neuroblastoma. [Mol Cancer Ther 2008;7(2):418–24]

Background The metalloprotease meprin β cleaves the Alzheimer’s Disease (AD) relevant amyloid precursor protein (APP) as a β-secretase reminiscent of BACE-1, however, predominantly generating N-terminally truncated Aβ2-x variants. Results Herein, we observed increased endogenous sAPPα levels in the brains of meprin β knock-out (ko) mice compared to wild-type controls. We further analyzed the cellular interaction of APP and meprin β and found that cleavage of APP by meprin β occurs prior to endocytosis. The N-terminally truncated Aβ2-40 variant shows increased aggregation propensity compared to Aβ1-40 and acts even as a seed for Aβ1-40 aggregation. Additionally, we observed that different APP mutants affect the catalytic properties of meprin β and that, interestingly, meprin β is unable to generate N-terminally truncated Aβ peptides from Swedish mutant APP (APPswe). Conclusion Concluding, we propose that meprin β may be involved in the generation of N-terminally truncated Aβ2-x peptides of APP, but acts independently from BACE-1. Electronic supplementary material The online version of this article (doi:10.1186/s13024-016-0084-5) contains supplementary material, which is available to authorized users.