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Artificial kidney; Chronic kidney disease; Xenotransplantation Ronyó artificial; Malaltia renal crònica; Xenotrasplantament Riñón artificial; Enfermedad renal crónica; Xenotrasplante Chronic kidney disease (CKD) will become the fifth global case of death by 2040. Its largest impact is on premature mortality but the number of persons with kidney failure requiring renal replacement therapy (RRT) is also increasing dramatically. Current RRT is suboptimal due to the shortage of kidney donors and dismal outcomes associated with both hemodialysis and peritoneal dialysis. Kidney care needs a revolution. In this review, we provide an update on emerging knowledge and technologies that will allow an earlier diagnosis of CKD, addressing the current so-called blind spot (e.g. imaging and biomarkers), and improve renal replacement therapies (wearable artificial kidneys, xenotransplantation, stem cell-derived therapies, bioengineered and bio-artificial kidneys). Research by A.O. is supported by IS/Fondos FEDER (PI18/01 366, PI19/00 588, PI19/00 815, DTS18/00 032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00 064) and PERSTIGAN AC18/00 071, ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM, Instituto de Salud Carlos III (ISCIII) RICORS program to RICORS2040 (RD21/0005/0001) and SPACKDc PMP21/00 109, FEDER funds. RD16/0009.

Leukocytes, the leading players of immune system, are involved in innate and adaptive immune responses. Leukocyte adhesion to endothelial cells during transmigration or to antigen presenting cells during T cell activation, requires integrin activation through a process termed inside-out integrin signaling. In hematopoietic cells, Rap1 and its downstream effector RIAM (Rap1-interacting adaptor molecule) form a cornerstone for inside-out integrin activation. The Rap1/RIAM pathway is involved in signal integration for activation, actin remodeling and cytoskeletal reorganization in T cells, as well as in myeloid cell differentiation and function. RIAM is instrumental for phagocytosis, a process requiring particle recognition, cytoskeletal remodeling and membrane protrusion for engulfment and digestion. In the present review, we discuss the structural and molecular properties of RIAM and the recent discoveries regarding the functional role of the Rap1/RIAM module in hematopoietic cells.

Son zamanlarda önemi hızla artan nesnelerin internetin için siber saldırıların da önemi hızla artmaktadır. Nesnelerin internetine, ağ katmanında yapılacak saldırılar veri kay- bına ve bölünmesine yol açabilmektedir. Siber saldırılar içerisinde yönledirme saldırıları, nesnelerin internetinin yapısı ve kaynak kısıtları sebebiyle, savunmasını hayli zordur. Bu sebeple nesnelerin internetine yönelik saldırıları tespit edecek bir yönteme ihtiyaç vardır. Nesnelerin internetini izlemek ve analiz etmek, kötücül saldırıları öngörmek, beklenmeyen durumlara ayak uydurmak, önlemler almak, hassas verileri korumak ve kayıpları azalt- mak için hayati önem arz etmektedir. Biz, derin öğrenme tabanlı bir güvenlik sistemi sunuyoruz. Derin öğrenme çalışmalarının en önemli kısıtlarından biri olan veri seti ek- sikliğini gidermek için Cooja simülatörü ile ürettiğimiz ve hazırladığımız veri setini de çalışmamızın ek ürünü olarak sunuyoruz. Veri setimiz 1000'e varan düğümlü kablosuz sensör ağlarını içeriyor. Bunun yanı sıra, ölçeklendirilebilir derin öğrenme tabanlı yön- lendirme atak tespit modelleri ile nesnelerin interneti için sağlam bir güvenlik sunuyoruz. Cyber threats are a showstopper for Internet of Things (IoT) which has recently gained popularity. Network layer attacks on IoT can cause significant disruptions and loss of information. Among such attacks, routing attacks are especially hard to defend against because of the ad-hoc nature of IoT systems and resource constraints of IoT devices. Hence a an efficient approach for detecting and predicting IoT attacks is needed. For the security of IoT, detecting malicious attacks is vital to avoid of unintended consequences such as lack of availability, integrity and confidentiality. For secure IoT needs a system that is able to robust detection against routing attacks. We propose a deep-learning based for continuous security monitoring analysis for IoT. Application of deep learning for cyber-security in IoT requires the availability of substantial IoT attack data, however the lack of IoT attack data is an important issue. In our study, the Cooja IoT simulator has been utilized for generation of high-fidelity attack data, within IoT networks ranging from up to 1000 nodes. We propose a highly scalable, deep-learning based attack detection methodology for detection of IoT routing attacks with high accuracy and precision. 97

Integrin-mediated adhesion of lymphocytes to antigen presenting cells (APCs) links innate and adaptive immunity and is mandatory for the initiation of T cell immune responses. Control of lymphocyte adhesion to antigen-presenting cells (APC) is accomplished through the regulation of the principle adhesion molecule on the lymphocyte surface, lymphocyte functional antigen 1 (LFA-1), which binds to intercellular adhesion molecule 1 (ICAM-1) on the surface of APCs. Integrins also play crucial roles in cell migration to different immunological compartments such as the tumor microenvironment but also to targets of tissue and organ damage in autoimmune diseases and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. For these reasons, understanding the mechanisms implicated in LFA-1 activation and their functional implications is a subject of intense investigation. To mediate its adhesive function, LFA-1 must be activated via a process referred to as inside-out signaling, which results in conformation changes of the receptor that extends the ectodomains of the α and β chains leading to a high affinity state. Among the few signaling molecules that have been implicated in this process in hematopoietic cells are the small GTPase Rap1 and its downstream effector RIAM. RIAM is a multidomain protein that includes a talin binding region, two coiled-coiled regions, a small N-terminus proline-rich region, sequential Ras association (RA) and pleckstrin homology (PH) domains, and a large C-terminus proline-rich region, via which interacts with Ena/VASP family proteins and profilin and is recruited to the sites of actin turnover. Through its C-terminus RIAM also interacts with the SH3-domain of PLC-γ1.The RA and PH domains of RIAM function as an integral unit and as a proximity detector since both are required for translocation of RIAM to the plasma membrane. The RA domain of RIAM has specificity for Rap1-GTP whereas the PH domain binds to the PLC-γ1 substrate PI(4,5)P2. Upon interaction with Rap1-GTP, RIAM recruits talin to the LFA-1 β chain leading to its conformational change to the high-affinity state. Previously, we determined that Rap1-GTP induces expression of CD103 (integrin αE),which pairs with integrin beta 7 to form the complete heterodimer, integrin αEβ7. The chief ligand for αEβ7is E-cadherin, an adhesion molecule found on epithelial cells, important for T cell homing to intestinal sites. Moreover, expression of αEβ7(CD103) in T cells confers immunosuppressive and regulatory activity even in the absence of Foxp3. In the present study, we sought to investigate the role of Rap1-RIAM axis in the expression of integrins αEβ7(CD103) and α4β7, both responsible for T cell migration and homing to intestinal compartments, including Peyer's Patches, lamina propria and intestinal epithelium. We generated transgenic mice expressing constitutively active Rap1-GTP in T cells (Rap1-Tg) and mice with T cell-specific deletion of RIAM (RIAMf/fCD4cre). Rap1-Tg mice exhibited an increase of Teff-memory cell fractions, enhanced Treg cell differentiation and elevated expression of αEβ7(CD103), but significant reduction of total T cells in secondary lymphoid organs including Peyer's Patches, spleen and peripheric lymph nodes. These effects of Rap1-GTP were mediated by RIAM because these findings were reversed when RIAM was deleted in Rap1-Tg/RIAMf/fCD4cre mice. Consistent with a mandatory role of RIAM in these outcomes, RIAMf/fCD4cre mice displayed defective αEβ7(CD103) expression, particularly in the CD8+ T cell compartment, which inversely correlated with the expression of α4β7 resulting in > 2-fold increase of the CD8+ α4β7+ T cell fraction in secondary lymphoid organs. Rap1-Tg mice also exhibited enhanced Teff-memory, Th17 and T follicular helper (Tfh) cell differentiation in secondary lymphoid organs including Peyer's Patches, under steady-state conditions. In contrast to Treg differentiation, RIAM deletion in Rap1-Tg mice did not reduce Th17 and Tfh cells suggesting that RIAM plays a role in fate commitment processes of selective T helper cell subsets. Because αEβ7(CD103) and α4β7 guide T lymphocyte homing in the gut whereas the plasticity and reciprocal regulation of the Th17/Treg axis within gut-associated lymphoid tissues guard intestinal inflammation, our results suggest a selective role of the Rap1-RIAM pathway in gut-related immune pathologies. Disclosures No relevant conflicts of interest to declare.

The immune system contains a lot of humoral and cellular components and defends the human body. But in the case of chronic HBV infection, it becomes ineffective. HBV is a hepatotropic virus infecting 350 million people around the World chronically. HBV can be transmitted through sexual intercourse, blood transfusion and prenatally. After viral entry into the hepatocytes, the virus uncoats itself in the nuclear area and tries to escape from the immune system. This escape may occur only in the 4% of the cases which ends up with chronic HBV infection. In the first 6-8 weeks of the infection, a very weak innate immune response may be detected. In the following 12 weeks, delayed and poor adaptive immune response is mounted due to the weak innate immune response. As it’s known, the immune response against viruses is T cell-mediated. T cells defend against HBV by removing infected hepatocytes. This process changes the micro-environment of the liver determining which class of immune response should be mounted. The micro-environment and the tissue components educate dentritic cells to activate T-helper (Th) cells stimulating and recruiting proper immune cells controlling the proper immune-class. Two types of immune classes have been accounted for in this hypothesis: Th1, which is recruited in viral and bacterial infections and Th2 recruited basically in parasitic infections. The changes in the micro-environment of liver and some components of the HBV such as HBeAg may affect the immune class and even convert it from Th1 to Th2 in the case of HBV infection. The question in this hypothesis is whether the class switching (Th1 → Th2) may play role in chronicity of HBV and ineffectiveness of the adaptive immune response mounted against virus. In the light of this information, here we hypothesize that chronic HBV infection may be eradicated and prevented by keeping the liver micro-environment intact inducing Th1 immune-class and novel treatments as wells as new diagnosis methods for chronic HBV infections can be developed based on Th1 → Th2 immune class switching.

The incidence of immune disorders such as autoimmunity and hypersensitivity reactions has been increasing in industrialized countries recently . Although some hypotheses based on epidemiological studies have been proposed to evaluate this increase among the immune disorder cases such as “Hygiene Hypothesis”, the underlying mechanism is not clear yet. It has been well studied that impairments in immune repertoire, total diversity among the antigenic receptors such as B cell receptor, T cell receptor and antibodies, may be causative factors of several immune disorders. Although genetic aspects of these immune disorders are well established, elucidating the responsible mutations in the genes encoding the molecules having key role in the formation of immune repertoire, we still lack knowledge on what kind of environmental factors take role in the pathogenesis of these diseases. Establishment of the diversity of immune repertoire depends on the recruitment of V(D)J re-arrangement which is basically Non-Homologous End Joining (NHEJ), one of the DNA repair mechanisms, mediated pathway. Circadian rhythm which DNA repair mechanisms may have effects on V(D)J recombination through NHEJ pathway especially in the early stages of life when immune repertoire is formed. The proteins recruited in the circadian regulation of the cells and regulation of DNA repair mechanisms such as Per1, Cry1, Parp-1 ve Tim are candidate molecules which may regulate V(D)J rearrangement. We suggested in our hypothesis that a novel molecular pathways linking circadian rhythm to immune system functioning and environmental factors disrupting circadian rhythm may have potential role in the pathogenesis of several immune disorders through epigenetic control of V(D)J recombination.

Chronic kidney disease (CKD) will become the fifth global case of death by 2040. Its largest impact is on premature mortality but the number of persons with kidney failure requiring renal replacement therapy (RRT) is also increasing dramatically. Current RRT is suboptimal due to the shortage of kidney donors and dismal outcomes associated with both hemodialysis and peritoneal dialysis. Kidney care needs a revolution. In this review, we provide an update on emerging knowledge and technologies that will allow an earlier diagnosis of CKD, addressing the current so-called blind spot (e.g. imaging and biomarkers), and improve renal replacement therapies (wearable artificial kidneys, xenotransplantation, stem cell-derived therapies, bioengineered and bio-artificial kidneys)., Research by A.O. is supported by IS/Fondos FEDER (PI18/01 366, PI19/00 588, PI19/00 815, DTS18/00 032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00 064) and PERSTIGAN AC18/00 071, ISCIII-RETIC REDinREN RD016/0009), Sociedad Espanola de Nefrologia, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM, Instituto de Salud Carlos III (ISCIII) RICORS program to RICORS2040 (RD21/0005/0001) and SPACKDc PMP21/00 109, FEDER funds. RD16/0009.