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Cancer is one of the leading causes of death worldwide [183], with lung tumors being the most frequent cause of cancer deaths in men as well as one of the most common cancers diagnosed in woman [40]. As symptoms often arise in advanced stages, an early diagnosis is especially important to ensure the best and earliest possible treatment. In order to achieve this, Computed Tomography (CT) scans are frequently used for tumor detection and diagnosis. We will present examples of publicly available CT image data of lung cancer patients and discuss possible methods to realize an automatic system for automated cancer diagnosis. We will also look at the recent SPIE-AAPM Lung CT Challenge [10] data set in detail and describe possible methods and challenges for image segmentation and classification based on this data set.
Das Kernanliegen des Datenschutzes ist es, natürliche Personen vor nachteiligen Effekten der Speicherung und Verarbeitung der sie betreffenden Daten zu schützen. Aber viele Personen scheinen gar nicht geschützt werden zu wollen. Im Gegenteil, viele Endanwender willigen “freiwillig“ – bewusst oder unbewusst – in eine umfassende Verarbeitung ihrer personenbezogenen Daten ein. Warum tun Menschen dies? Es werden verschiedene Ursachen diskutiert (beispielsweise in [79]), hierzu gehören Uninformiertheit, mangelnde Sensibilität, das Gefühl der Hilflosigkeit, mangelnde Zahlungsbereitschaft und mangelnde Alternativen. Auch wenn dies in Einzelfällen zutrifft, so gibt es oft sehr wohl datenschutzfreundliche Alternativen. Beispielsweise existiert zu WhatsApp (als Instant Messaging App) die Alternative Threema. Threema gilt als EU-DS-GVO-konform und funktional durchaus mit WhatsApp vergleichbar [62]. Allerdings ist inzwischen die aktuelle Netzwerkgröße ein entscheidendes Auswahlkriterium: Im Januar 2018 hatte Threema 4,5 Millionen Nutzer [172], WhatsApp dagegen 1,5 Milliarden [171]. Dies ist ein Indiz dafür, dass WhatsApp sich quasi zum De-facto-Standard entwickelt hat und es für die einzelne Person nur schwer möglich ist, viele andere “zum Wechsel auf ein anderes Produkt zu bewegen. [. . . ] Bei Diensten mit Nutzerzahlen im Milliardenbereich kann von ’Freiwilligkeit’ nur noch bedingt gesprochen werden.“ [9]
The gasotransmitter hydrogen sulphide decreases Na⁺ transport across pulmonary epithelial cells
(2012)
BACKGROUND AND PURPOSE The transepithelial absorption of Na(+) in the lungs is crucial for the maintenance of the volume and composition of epithelial lining fluid. The regulation of Na(+) transport is essential, because hypo- or hyperabsorption of Na(+) is associated with lung diseases such as pulmonary oedema or cystic fibrosis. This study investigated the effects of the gaseous signalling molecule hydrogen sulphide (H(2) S) on Na(+) absorption across pulmonary epithelial cells. EXPERIMENTAL APPROACH Ion transport processes were electrophysiologically assessed in Ussing chambers on H441 cells grown on permeable supports at air/liquid interface and on native tracheal preparations of pigs and mice. The effects of H(2)S were further investigated on Na(+) channels expressed in Xenopus oocytes and Na(+) /K(+)-ATPase activity in vitro. Membrane abundance of Na(+) /K(+)-ATPase was determined by surface biotinylation and Western blot. Cellular ATP concentrations were measured colorimetrically, and cytosolic Ca(2+) concentrations were measured with Fura-2. KEY RESULTS H(2)S rapidly and reversibly inhibited Na(+) transport in all the models employed. H(2)S had no effect on Na(+) channels, whereas it decreased Na(+) /K(+)-ATPase currents. H(2)S did not affect the membrane abundance of Na(+) /K(+)-ATPase, its metabolic or calcium-dependent regulation, or its direct activity. However, H(2)S inhibited basolateral calcium-dependent K(+) channels, which consequently decreased Na(+) absorption by H441 monolayers. CONCLUSIONS AND IMPLICATIONS H(2) S impairs pulmonary transepithelial Na(+) absorption, mainly by inhibiting basolateral Ca(2+)-dependent K(+) channels. These data suggest that the H(2)S signalling system might represent a novel pharmacological target for modifying pulmonary transepithelial Na(+) transport.
The vectorial transport of Na+ across epithelia is crucial for the maintenance of Na+ and water homeostasis in organs such as the kidneys, lung, or intestine. Dysregulated Na+ transport processes are associated with various human diseases such as hypertension, the salt-wasting syndrome pseudohypoaldosteronism type 1, pulmonary edema, cystic fibrosis, or intestinal disorders, which indicate that a precise regulation of epithelial Na+ transport is essential. Novel regulatory signaling molecules are gasotransmitters. There are currently three known gasotransmitters: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). These molecules are endogenously produced in mammalian cells by specific enzymes and have been shown to regulate various physiological processes. There is a growing body of evidence which indicates that gasotransmitters may also regulate Na+ transport across epithelia. This review will summarize the available data concerning NO, CO, and H2S dependent regulation of epithelial Na+ transport processes and will discuss whether or not these mediators can be considered as true physiological regulators of epithelial Na+ transport biology.
More than 25 years ago, it was a big surprise for physiologists that nitric oxide (NO) was identified as the endothelium derived relaxing factor which is responsible for endothelium-induced smooth muscle relaxation (Ignarro et al., 1987). Until then, small gaseous molecules were simply regarded as byproducts of cellular metabolism which were unlikely to be of any physiological relevance. The discovery that NO was synthesized by specific enzymes (NO-synthases), upon stimulation by specific, physiologically relevant stimuli (e.g., acetylcholine stimulation of endothelial cells), as well as the fact that it acted on specific cellular targets (e.g., soluble guanylate cyclase), set the course for numerous studies which investigated the physiological roles of gaseous signaling molecules—in other words, gasotransmitters (Wang, 2002).
The development of pulmonary edema can be considered as a combination of alveolar flooding via increased fluid filtration, impaired alveolar-capillary barrier integrity, and disturbed resolution due to decreased alveolar fluid clearance. An important mechanism regulating alveolar fluid clearance is sodium transport across the alveolar epithelium. Transepithelial sodium transport is largely dependent on the activity of sodium channels in alveolar epithelial cells. This paper describes how sodium channels contribute to alveolar fluid clearance under physiological conditions and how deregulation of sodium channel activity might contribute to the pathogenesis of lung diseases associated with pulmonary edema. Furthermore, sodium channels as putative molecular targets for the treatment of pulmonary edema are discussed.
Carbon Monoxide Rapidly Impairs Alveolar Fluid Clearance by Inhibiting Epithelial Sodium Channels
(2009)
Carbon monoxide (CO) is currently being evaluated as a therapeutic modality in the treatment of patients with acute lung injury and acute respiratory distress syndrome. No study has assessed the effects of CO on transepithelial ion transport and alveolar fluid reabsorption, two key aspects of alveolocapillary barrier function that are perturbed in acute lung injury/acute respiratory distress syndrome. Both CO gas (250 ppm) and CO donated by the CO donor, CO-releasing molecule (CORM)-3 (100 mu M in epithelial lining fluid), applied to healthy, isolated, ventilated, and perfused rabbit lungs, significantly blocked Na-22(+) clearance from the alveolar compartment, and blocked alveolar fluid reabsorption after fluid challenge. Apical application of two CO donors, CORM-3 or CORM-A1 (100 mu M), irreversibly inhibited amiloride-sensitive short-circuit currents in H441 human bronchiolar epithelial cells and primary rat alveolar type II cells by up to 40%. Using a nystatin permabilization approach, the CO effect was localized to amiloride-sensitive channels on the apical surface. This effect was abolished by hemoglobin, a scavenger of CO, and was not observed when inactive forms of CO donors were employed. The effects of CO were not blocked by 8-bromoguanosine-3',5'-cyclic guanosine monophosphate, soluble guanylate cyclase inhibitors (methylene blue and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), or inhibitors of trafficking events (phalloidin oleate, MG-132, and brefeldin A), but the amiloride affinity of H441 cells was reduced after CO exposure. These data indicate that CO rapidly inhibits sodium absorption across the airway epithelium by cyclic guanosine monophosphate-and trafficking-independent mechanisms, which may rely on critical histidine residues in amiloride-sensitive channels or associated regulatory proteins on the apical surface of lung epithelial cells.
Nitric oxide (NO) is an important regulator of Na+ reabsorption by pulmonary epithelial cells and therefore of alveolar fluid clearance. The mechanisms by which NO affects epithelial ion transport are poorly understood and vary from model to model. In this study, the effects of NO on sodium reabsorption by H441 cell monolayers were studied in an Ussing chamber. Two NO donors, (Z)-1-[N-(3-aminopropyl)-N-(n-propyl) amino]diazen-1-ium-1,2-diolate and diethylammonium(Z)-1-(N, N-diethylamino) diazen-1-ium-1,2-diolate, rapidly, reversibly, and dose-dependently reduced amiloride-sensitive, short-circuit currents across H441 cell monolayers. This effect was neutralized by the NO scavenger hemoglobin and was not observed with inactive NO donors. The effects of NO were not blocked by 8-bromoguanosine-3',5'-cyclic monophosphate or by soluble guanylate cyclase inhibitors (methylene blue and 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one) and were therefore independent of soluble guanylate cyclase signaling. NO targeted apical, highly selective, amiloride-sensitive Na+ channels in basolaterally permeabilized H441 cell monolayers. NO had no effect on the activity of the human epithelial sodium channel heterologously expressed in Xenopus oocytes. NO decreased Na+/K+-ATPase activity in apically permeabilized H441 cell monolayers. The inhibition of Na+/K+-ATPase activity by NO was reversed by mercury and was mimicked by N-ethylmaleimide, which are agents that reverse and mimic, respectively, the reaction of NO with thiol groups. Consistent with these data, S-NO groups were detected on the Na+/K+-ATPase a subunit in response to NO-donor application, using a biotin-switch approach coupled to a Western blot. These data demonstrate that, in the H441 cell model, NO impairs Na+ reabsorption by interfering with the activity of highly selective Na+ channels and the Na+/K+-ATPase.
RELA haploinsufficiency is a recently described autoinflammatory condition presenting with intermittent fevers and mucocutaneous ulcerations. The RELA gene encodes the p65 protein, one of five NF-κB family transcription factors. As RELA is an essential regulator of mucosal homeostasis, haploinsufficiency leads to decreased NF-κB signaling which promotes TNF-driven mucosal apoptosis with impaired epithelial recovery. Thus far, only eight cases have been reported in the literature. Here, we report four families with three novel and one previously described pathogenic variant in RELA. These four families included 23 affected individuals for which genetic testing was available in 16. Almost half of these patients had been previously diagnosed with more common rheumatologic entities (such as Behcet's Disease; BD) prior to the discovery of their pathogenic RELA variants. The most common clinical features were orogenital ulcers, rash, joint inflammation, and fever. The least common were conjunctivitis and recurrent infections. Clinical variability was remarkable even among familial cases, and incomplete penetrance was observed. Patients in our series were treated with a variety of medications, and benefit was observed with glucocorticoids, colchicine, and TNF inhibitors. Altogether, our work adds to the current literature and doubles the number of reported cases with RELA-Associated Inflammatory Disease (RAID). It reaffirms the central importance of the NF-κB pathway in immunity and inflammation, as well as the important regulatory role of RELA in mucosal homeostasis. RELA associated inflammatory disease should be considered in all patients with BD, particularly those with early onset and/or with a strong family history.
IT-Governance, Prüfung & Revision mal agil gedacht! Herausforderungen und Notwendigkeit eines Perspektivwechsels für IT-Governance, Prüfung & Revision viele Fallbeispiele zeigen die praktische Umsetzbarkeit auf Agilität und der Einsatz agiler Methoden sind heute nicht mehr nur auf IT-Projekte begrenzt, sondern prägen zunehmend ganze Organisationen. Dieses Buch zeigt auf, wie sich IT-Governance, Prüfung & Revision erfolgreich dem durch Agilität ausgelösten Wandel stellen können und wie sich der Umgang mit den Kernthemen Risiko & Unsicherheit verändert. Zum einen werden Ansätze für eine agile IT-Governance und eine agile Prüfung & Revision beschrieben, indem sie sich agile Werte und Vorgehensweisen zu eigen machen. Zum anderen werden IT-Governance, Prüfung & Revision befähigt, agile Projekte angemessen steuern und wirksam prüfen zu können.
The invention relates to compounds that include peptide and peptidomimetics that inhibit estrogen receptor dependent cell proliferation. The compounds of the invention are useful for treating cell proliferative disorders or physiological conditions characterized by undesirable or unwanted estrogen induced cell proliferation, including breast cancer.
This study presents the findings of a quantitative study on the use of Open Educational Resources (OER) and Open Educational Practices (OEP) in Higher Education and Adult Learning Institutions. The study is based on the results of an online survey targeted at four educational roles: educational policy makers; institutional policy makers/managers; educational professionals; and learners. The report encompasses five chapters and four annexes. Chapter I presents the survey and Chapter II discloses the main research questions and models. Chapter III characterises the universe of respondents. Chapter IV advances with a detailed survey analysis including an overview of key statistical data. Finally, Chapter V provides an exploratory in-depth analysis of some key issues: representations, attitudes and uses of OEP. The table of contents and the complete list of diagrams and tables can be found at the end of the report.
The human MPV17-related mitochondrial DNA depletion syndrome is an inherited autosomal recessive disease caused by mutations in the inner mitochondrial membrane protein MPV17. Although more than 30 MPV17 gene mutations were shown to be associated with mitochondrial DNA depletion syndrome, the function of MPV17 is still unknown. Mice deficient in Mpv17 show signs of premature aging. In the present study, we used electrophysiological measurements with recombinant MPV17 to reveal that this protein forms a non-selective channel with a pore diameter of 1.8 nm and located the channel's selectivity filter. The channel was weakly cation-selective and showed several subconductance states. Voltage-dependent gating of the channel was regulated by redox conditions and pH and was affected also in mutants mimicking a phosphorylated state. Likewise, the mitochondrial membrane potential (Δψm) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17−/− mice. However, despite the elevated Δψm, the Mpv17-deficient mitochondria showed signs of accelerated fission. Together, these observations uncover the role of MPV17 as a Δψm-modulating channel that apparently contributes to mitochondrial homeostasis under different conditions.
In der vorliegenden Arbeit werden Verfahren vorgestellt, die geeignet sind, Modelle des menschlichen kardiovaskulären Systems an individuelle Kreislaufreaktionen anzupassen. Allgemeine Kreislaufmodelle des menschlichen kardiovaskulären Systems sind in der Regel nichtlineare Differentialgleichungssysteme, für die es keine effizienten Optimierungsverfahren gibt. Durch die Einschränkung auf relevante Aspekte (bzgl. der Individualisierungsaufgabe) wird ein solches Modell auf Modelle einfacherer Struktur projiziert, die eine Approximation durch Funktionsapproximatoren erlauben, für welche wiederum effiziente Optimierungsalgorithmen existieren. In Abhängigkeit von der Struktur der Individualisierungsaufgabe kommt zusätzlich ein modifiziertes BFGS-Verfahren zum Einsatz, das Approximationen solcher Modellaspekte verwendet um die Konvergenz der Modellindividualisierung zu verbessern.
Theoretische Informatik
(2002)
Eine anschauliche Einführung in die klassischen Themenbereiche der Theoretischen Informatik für Studierende der Informatik im Haupt- und Nebenfach. Die Autoren wählen einen Ansatz, der durch zahlreiche ausgearbeitete Beispiele auch LeserInnen mit nur elementaren Mathematikkenntnissen den Zugang zu Berechenbarkeit, Komplexitätstheorie und formalen Sprachen ermöglicht. Die mathematischen Konzepte werden sowohl formal eingeführt als auch informell erläutert und durch grafische Darstellungen veranschaulicht. Das Buch umfasst den Lehrstoff einführender Vorlesungen in die Theoretische Informatik und bietet zahlreiche Übungsaufgaben zu jedem Kapitel an. (Verlagsangaben)
We present a model checking algorithm for ∀CTL (and full CTL) which uses an iterative abstraction refinement strategy.
It terminates at least for all transition systems M that have a finite simulation or bisimulation quotient. In contrast to other abstraction refinement algorithms, we always work with abstract models whose sizes depend only on the length of the formula θ (but not on the size of the system, which might be infinite).
Zusatzstoffe im Obstbau
(2003)
The nutrient element calcium
(2009)
Evolutionary conservation of the antimicrobial function of mucus: a first defence against infection
(2018)
Mucus layers often provide a unique and multi-functional hydrogel interface between the epithelial cells of organisms and their external environment. Mucus has exceptional properties including elasticity, changeable rheology and an ability to self-repair by reannealing, and is therefore an ideal medium for trapping and immobilising pathogens and serving as a barrier to microbial infection. The ability to produce a functional surface mucosa was an important evolutionary step, which evolved first in the Cnidaria, which includes corals, and the Ctenophora. This allowed the exclusion of non-commensal microbes and the subsequent development of the mucus-lined digestive cavity seen in higher metazoans. The fundamental architecture of the constituent glycoprotein mucins is also evolutionarily conserved. Although an understanding of the biochemical interactions between bacteria and the mucus layer are important to the goal of developing new antimicrobial strategies, they remain relatively poorly understood. This review summarises the physicochemical properties and evolutionary importance of mucus, which make it so successful in the prevention of bacterial infection. In addition, the strategies developed by bacteria to counteract the mucus layer are also explored.
The formulation of transport network problems is represented as a translation between two domain specific languages: from a network description language, used by network simulation community, to a problem description language, understood by generic non-linear solvers. A universal algorithm for this translation is developed, an estimation of its computational complexity given, and an efficient application of the algorithm demonstrated on a number of realistic examples. Typically, for a large gas transport network with about 10K elements the translation and solution of non-linear system together require less than 1 sec on the common hardware. The translation procedure incorporates several preprocessing filters, in particular, topological cleaning filters, which accelerate the solution procedure by factor 8.
The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort's experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.
Neues Lizenzmanagement
(2016)
Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100'000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.
A way of combining a relatively new sensor-technology, that is optical analog VLSI devices, with a standard digital omni-directional vision system is investigated. The sensor used is a neuromorphic analog VLSI sensor that estimates the global visual image motion. The sensor provides two analog output voltages that represent the components of the global optical flow vector. The readout is guided by an omni-directional mirror that maps the location of the ball and directs the robot to align its position so that a sensor-actuator module that includes the analog VLSI optical flow sensor can be activated. The purpose of the sensor-actuator module is to operate with a higher update rate than the standard vision system and thus increase the reactivity of the robot for very specific situations. This paper will demonstrate an application example where the robot is a goalkeeper with the task of defending the goal during a penalty kick.
Filling the Pipe
(1995)
An Information on Demand teleservice that was developed at the German National Research Center for Information Technology (GMD) provides remote access to multimedia information consisting of audio, video, and text [jonas et al. 94]. It uses a bidirectional narrowband message link between the end user and the service provider, and a unidirectional broadband data link from the service provider to the end user. Since the IoD teleservice is used across a satellite connection (among others), it turned out to be necessary to implement an access protocol that is optimized for the access of real-time multimedia data across a long-delay high-bandwidth link, a long fat pipe [jacobsen et al. 92]. This paper introduces the MediaService Protocol (MSP) and describes a prototype implementation (version 0.6).
Molybdenum cofactor deficiency (MoCD) is a rare inherited metabolic disorder characterized by severe and progressive neurological damage mainly caused by the loss of sulfite oxidase activity. Elevated urinary levels of sulfite, thiosulfate, and S-sulfocysteine (SSC) are hallmarks in the diagnosis of MoCD and sulfite oxidase deficiency (SOD). Recently, a first successful treatment of a human MoCD type A patient based on a substitution therapy with the molybdenum cofactor precursor cPMP has been reported, resulting in nearly complete normalization of MoCD biomarkers. Knowing the rapid progression of the disease symptoms in nontreated patients, an early diagnosis of MoCD as well as a sensitive method to monitor daily changes in SSC levels, a key marker of sulfite toxicity, is crucial for treatment outcome. Here, we describe a fast and sensitive method for the analysis of SSC in human urine samples using high performance liquid chromatography (HPLC). The analysis is based on precolumn derivatization with O-phthaldialdehyde (OPA) and separation on a C18 reverse phase column coupled to UV detection. The method was extended to human serum analysis and no interference with endogenous amino acids was found. Finally, SSC values from 45 pediatric urine, 75 adult urine, and 24 serum samples from control individuals as well as MoCD patients are reported. Our method represents a cost-effective technique for routine diagnosis of MoCD and SOD, and can be used also to monitor treatment efficiency in those sulfite toxicity disorders on a daily basis.
Social protection refers to the entire system of protective measures that assist individuals, households, and communities to better manage risks and economic shocks and that provide support to the critically vulnerable. Among the major risks covered are illness, accident, death, unemployment, or old age. Social protection includes public as well as private approaches.