Renal alterations in Pou3f3L423P mutant mice

Mammalian nephrogenesis is a complex process that involves the precise timely and spatially coordinated interaction of a plethora of signaling molecules. During terminal nephron segmentation, POU3F3 (aka BRN1), a POU domain class 3 transcription factor, plays a critical role in the differentiation of the distal tubule, in particular the thick ascending limb of the loop of Henle (TAL). In knock-out mice, deficiency of POU3F3 leads to underdevelopment of the TAL, lack of differentiation of TAL and macula densa cells, and perinatal death due to renal failure. Pou3f3L423P mutant mice were established in the phenotype-driven Munich ENU Mouse Mutagenesis Project within a special screen for increased plasma urea levels to detect novel mouse models for kidney diseases. These mice carry a recessive point mutation in the highly conserved homeodomain of POU3F3. In contrast to Pou3f3 knock-out mice, homozygous Pou3f3L423P mutants are viable and fertile. The present study used functional, as well as qualitative and quantitative morphological analyses to characterize the renal phenotype of juvenile (12 days) and aged (60 weeks) homo- and heterozygous Pou3f3L423P mutant mice and age-matched wildtype littermates of both sexes. In both age groups, homozygous mutants vs. control mice displayed significantly smaller kidney volumes, decreased nephron numbers and smaller mean glomerular volumes. Besides, the absolute TAL volumes and the volume densities of TAL in the kidney were significantly reduced in Pou3f3L423P mutants. There were no histologically or ultrastructurally detectable lesions of TAL or glomerular cells. Aged homozygous mutants displayed increased serum urea concentrations and reduced specific urine gravity, but no evidence of glomerular dysfunction. These results confirm the important function of POU3F3 during nephron patterning, especially in development of the TAL. Furthermore they provide strong evidence that POU3F3 is also involved in the regulation of nephron induction, nephron endowment, and nephron size in the murine kidney, while the mutation is not associated with a distinct pattern of morphological glomerular lesions. The detailed characterization of the renal morphology of Pou3f3L423P mutants provided the basis for further analyses of POU3F3 actions, and showed that Pou3f3L423P mutant mice represent a valuable research model for nephrological studies examining the role of congenital low nephron numbers in kidney disease development and progression

Renal alterations in Pou3f3L423P mutant mice

Mammalian nephrogenesis is a complex process that involves the precise timely and spatially coordinated interaction of a plethora of signaling molecules. During terminal nephron segmentation, POU3F3 (aka BRN1), a POU domain class 3 transcription factor, plays a critical role in the differentiation of the distal tubule, in particular the thick ascending limb of the loop of Henle (TAL). In knock-out mice, deficiency of POU3F3 leads to underdevelopment of the TAL, lack of differentiation of TAL and macula densa cells, and perinatal death due to renal failure. Pou3f3L423P mutant mice were established in the phenotype-driven Munich ENU Mouse Mutagenesis Project within a special screen for increased plasma urea levels to detect novel mouse models for kidney diseases. These mice carry a recessive point mutation in the highly conserved homeodomain of POU3F3. In contrast to Pou3f3 knock-out mice, homozygous Pou3f3L423P mutants are viable and fertile. The present study used functional, as well as qualitative and quantitative morphological analyses to characterize the renal phenotype of juvenile (12 days) and aged (60 weeks) homo- and heterozygous Pou3f3L423P mutant mice and age-matched wildtype littermates of both sexes. In both age groups, homozygous mutants vs. control mice displayed significantly smaller kidney volumes, decreased nephron numbers and smaller mean glomerular volumes. Besides, the absolute TAL volumes and the volume densities of TAL in the kidney were significantly reduced in Pou3f3L423P mutants. There were no histologically or ultrastructurally detectable lesions of TAL or glomerular cells. Aged homozygous mutants displayed increased serum urea concentrations and reduced specific urine gravity, but no evidence of glomerular dysfunction. These results confirm the important function of POU3F3 during nephron patterning, especially in development of the TAL. Furthermore they provide strong evidence that POU3F3 is also involved in the regulation of nephron induction, nephron endowment, and nephron size in the murine kidney, while the mutation is not associated with a distinct pattern of morphological glomerular lesions. The detailed characterization of the renal morphology of Pou3f3L423P mutants provided the basis for further analyses of POU3F3 actions, and showed that Pou3f3L423P mutant mice represent a valuable research model for nephrological studies examining the role of congenital low nephron numbers in kidney disease development and progression

With or Without Blockchain? Towards a Decentralized, SSI-based eRoaming Architecture

Fragmentation and limited accessibility of charging infrastructure impede the adoption of electric vehicles. To improve the availability of charging infrastructure independent of providers, eRoaming offers a promising solution. Yet, current eRoaming systems are typically centralized, which raises concerns of market power concentration. While the use of blockchain technology can obviate such concerns, it comes with significant privacy challenges. To address these challenges, we explore a combination of blockchain with self-sovereign identity. Specifically, we apply a design science research approach, which helps us to identify requirements, derive a conceptual architecture, and deduce design principles for decentralized eRoaming and beyond. We find that blockchain may best leverage its benefits when it takes a backseat as a public registry for legal entities. Moreover, we find that the use of self-sovereign identities could improve compliance with privacy regulations, but they should not be overused

FreqFed: A Frequency Analysis-Based Approach for Mitigating Poisoning Attacks in Federated Learning

Federated learning (FL) is a collaborative learning paradigm allowing multiple clients to jointly train a model without sharing their training data. However, FL is susceptible to poisoning attacks, in which the adversary injects manipulated model updates into the federated model aggregation process to corrupt or destroy predictions (untargeted poisoning) or implant hidden functionalities (targeted poisoning or backdoors). Existing defenses against poisoning attacks in FL have several limitations, such as relying on specific assumptions about attack types and strategies or data distributions or not sufficiently robust against advanced injection techniques and strategies and simultaneously maintaining the utility of the aggregated model. To address the deficiencies of existing defenses, we take a generic and completely different approach to detect poisoning (targeted and untargeted) attacks. We present FreqFed, a novel aggregation mechanism that transforms the model updates (i.e., weights) into the frequency domain, where we can identify the core frequency components that inherit sufficient information about weights. This allows us to effectively filter out malicious updates during local training on the clients, regardless of attack types, strategies, and clients' data distributions. We extensively evaluate the efficiency and effectiveness of FreqFed in different application domains, including image classification, word prediction, IoT intrusion detection, and speech recognition. We demonstrate that FreqFed can mitigate poisoning attacks effectively with a negligible impact on the utility of the aggregated model.Comment: To appear in the Network and Distributed System Security (NDSS) Symposium 2024. 16 pages, 8 figures, 12 tables, 1 algorithm, 3 equation

CrowdGuard: Federated Backdoor Detection in Federated Learning

Federated Learning (FL) is a promising approach enabling multiple clients to train Deep Neural Networks (DNNs) collaboratively without sharing their local training data. However, FL is susceptible to backdoor (or targeted poisoning) attacks. These attacks are initiated by malicious clients who seek to compromise the learning process by introducing specific behaviors into the learned model that can be triggered by carefully crafted inputs. Existing FL safeguards have various limitations: They are restricted to specific data distributions or reduce the global model accuracy due to excluding benign models or adding noise, are vulnerable to adaptive defense-aware adversaries, or require the server to access local models, allowing data inference attacks. This paper presents a novel defense mechanism, CrowdGuard, that effectively mitigates backdoor attacks in FL and overcomes the deficiencies of existing techniques. It leverages clients' feedback on individual models, analyzes the behavior of neurons in hidden layers, and eliminates poisoned models through an iterative pruning scheme. CrowdGuard employs a server-located stacked clustering scheme to enhance its resilience to rogue client feedback. The evaluation results demonstrate that CrowdGuard achieves a 100% True-Positive-Rate and True-Negative-Rate across various scenarios, including IID and non-IID data distributions. Additionally, CrowdGuard withstands adaptive adversaries while preserving the original performance of protected models. To ensure confidentiality, CrowdGuard uses a secure and privacy-preserving architecture leveraging Trusted Execution Environments (TEEs) on both client and server sides.Comment: To appear in the Network and Distributed System Security (NDSS) Symposium 2024. Phillip Rieger and Torsten Krau{\ss} contributed equally to this contribution. 19 pages, 8 figures, 5 tables, 4 algorithms, 5 equation

MANAGING FASHIONABLE ORGANIZING VISIONS: EVIDENCE FROM THE EUROPEAN BLOCKCHAIN SERVICES INFRASTRUCTURE

Grand visions for organizational transformation increasingly build on fashionable information technologies. Organizational leaders may be tempted to adopt these visions due the high degree of legitimacy and mobilization they afford. However, their fashionable nature makes adoption risky. In this paper, we explore how organizations can manage this risk and successfully navigate the adoption of fashionable organizing visions. Specifically, we track how over the last five years the European Blockchain Partnership adopted a self-sovereign identity organizing vision based on blockchain. We find that successful adoption requires dynamic coupling and decoupling between vision and IT – both on a discursive and the material levels. Moreover, it requires effective management of ‘sensegiving’ and ‘sensebreaking’ by the innovation community

How Organizations Sustain and Navigate Between (De)centralization Equilibria: A Process Model

Finding the ‘right’ balance between centralization and decentralization in organizational processes, governance, and IT can be difficult. To navigate this tension field, organizations need to find (de)centralization equilibria that are often dynamic and depend on organizational strategy and context. However, little is known about how organizations should respond once an old equilibrium is punctuated or breaks down. In this paper, we thus conduct an inductive multiple-case study to investigate how organizations sustain and transition between (de)centralization equilibria. We synthesize our insights into a process model that paints the transition as an iterative recalibration process subject to centralization and decentralization tensions. Often, this process will require local and temporary compromises. Our work contributes a much-needed process perspective to the IS literature on (de)centralization

Bacterial urinary tract infection and subclinical bacteriuria in dogs receiving antineoplastic chemotherapy

Background: Immunosuppressive treatment with glucocorticoids and cyclosporine increases the risk for positive urine cultures (PUCs) in dogs. Objective: To investigate the prevalence and incidence of PUC in dogs diagnosed with cancer and treated with antineoplastic chemotherapy while distinguishing between subclinical bacteriuria (SB) and urinary tract infection (UTI). Animals: Forty-six client-owned dogs with nonurogenital cancer treated with anti- neoplastic chemotherapy. Methods: Prospective observational longitudinal clinical study. Dogs in which a urine culture was performed before the start of and at least once during antineoplastic chemotherapy were included. A McNemar's test was used to investigate if the preva- lence of PUC increased during antineoplastic chemotherapy. Positive urine cultures were categorized into SB and UTI and multiple PUCs from the same dog and cate- gory were grouped together as 1 episode of PUC. Results: Urine culture was positive in 21/185 urine samples in 8/46 dogs. Antineo- plastic chemotherapy did not influence the prevalence of PUC (P = 1.00), which was 11% (5/46 dogs; 95% confidence interval: 5-23%) before the start of and 13% (6/46 dogs; 95% confidence interval: 6-26%) during antineoplastic chemotherapy. Eight dogs had 10 episodes of PUC; 7/10 episodes were classified as SB, and in 3/10 epi- sodes UTI (chronic prostatitis, prostatic abscess, and emphysematous cystitis) was diagnosed. Escherichia coli was the most common pathogen, isolated in 9/10 episodes. Conclusions and Clinical Importance: We did not find evidence that antineoplastic chemotherapy is a major predisposing factor for the development of PUC. Most dogs with PUC had SB

Missense Mutation of POU Domain Class 3 Transcription Factor 3 in Pou3f3(L423P) Mice Causes Reduced Nephron Number and Impaired Development of the Thick Ascending Limb of the Loop of Henle

During nephrogenesis, POU domain class 3 transcription factor 3 (POU3F3 aka BRN1) is critically involved in development of distinct nephron segments, including the thick ascending limb of the loop of Henle (TAL). Deficiency of POU3F3 in knock-out mice leads to underdevelopment of the TAL, lack of differentiation of TAL cells, and perinatal death due to renal failure. Pou3f3(L423P) mutant mice, which were established in the Munich ENU Mouse Mutagenesis Project, carry a recessive point mutation in the homeobox domain of POU3F3. Homozygous Pou3f3(L423P) mutants are viable and fertile. The present study used functional, as well as qualitative and quantitative morphological analyses to characterize the renal phenotype of juvenile (12 days) and aged (60 weeks) homo-and heterozygous Pou3f3(L423P) mutant mice and age-matched wild-type controls. In both age groups, homozygous mutants vs. control mice displayed significantly smaller kidney volumes, decreased nephron numbers and mean glomerular volumes, smaller TAL volumes, as well as lower volume densities of the TAL in the kidney. No histological or ultrastructural lesions of TAL cells or glomerular cells were observed in homozygous mutant mice. Aged homozygous mutants displayed increased serum urea concentrations and reduced specific urine gravity, but no evidence of glomerular dysfunction. These results confirm the role of POU3F3 in development and function of the TAL and provide new evidence for its involvement in regulation of the nephron number in the kidney. Therefore, Pou3f3(L423P) mutant mice represent a valuable research model for further analyses of POU3F3 functions, or for nephrological studies examining the role of congenital low nephron numbers