Intercellular adhesion molecule 2 regulates diapedesis hotspots by allowing neutrophil crawling against the direction of flow

Intercellular adhesion molecules (ICAMs) are cell surface proteins that play a crucial role in the body’s immune response and inflammatory processes. ICAM1 and ICAM2 are two ICAM family members expressed on the surface of various cell types, including endothelial cells. They mediate the interaction between immune cells and endothelial cells, which are critical for the trafficking of leukocytes across the blood vessel wall during inflammation. Although ICAM1 plays a prominent role in the leukocyte extravasation cascade, it is less clear if ICAM2 strengthens ICAM1 function or has a separate function in the cascade. With CRISPR–)Cas9 technology, endothelial cells were depleted for ICAM1,ICAM2, or both, and we found that neutrophils favored ICAM1 over ICAM2 to adhere to. However, the absence of only ICAM2 resulted in neutrophils that were unable to find the transmigration hotspot, i.e. the preferred exit site. Moreover, we found that ICAM2 deficiency prevented neutrophils to migrate against the flow. Due to this deficiency, we concluded that ICAM2 helps neutrophils find the preferred exit sites and thereby contributes to efficient leukocyte extravasation

Endothelial junctional membrane protrusions serve as hotspots for neutrophil transmigration

Upon inflammation, leukocytes rapidly transmigrate across the endothelium to enter the inflamed tissue. Evidence accumulates that leukocytes use preferred exit sites, alhough it is not yet clear how these hotspots in the endothelium are defined and how they are recognized by the leukocyte. Using lattice light sheet microscopy, we discovered that leukocytes prefer endothelial membrane protrusions at cell junctions for transmigration. Phenotypically, these junctional membrane protrusions are present in an asymmetric manner, meaning that one endothelial cell shows the protrusion and the adjacent one does not. Consequently, leukocytes cross the junction by migrating underneath the protruding endothelial cell. These protrusions depend on Rac1 activity and by using a photo-activatable Rac1 probe, we could artificially generate local exit-sites for leukocytes. Overall, we have discovered a new mechanism that uses local induced junctional membrane protrusions to facilitate/steer the leukocyte escape/exit from inflamed vessel walls

Disorders of sex development : insights from targeted gene sequencing of a large international patient cohort

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. Results: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46, XY DSD and 48 with 46, XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46, XY DSD. In patients with 46, XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Conclusions: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes

Developing a framework for assessing respiratory sensitization: A workshop report

Respiratory tract sensitization can have significant acute and chronic health implications. While induction of respiratory sensitization is widely recognized for some chemicals, validated standard methods or frameworks for identifying and characterizing the hazard are not available. A workshop on assessment of respiratory sensitization was held to discuss the current state of science for identification and characterization of respiratory sensitizer hazard, identify information facilitating development of validated standard methods and frameworks, and consider the regulatory and practical risk management needs. Participants agreed on a predominant Th2 immunological mechanism and several steps in respiratory sensitization. Some overlapping cellular events in respiratory and skin sensitization are well understood, but full mechanism(s) remain unavailable. Progress on non-animal approaches to skin sensitization testing, ranging from in vitro systems, –omics, in silico profiling, and structural profiling were acknowledged. Addressing both induction and elicitation phases remains challenging. Participants identified lack of a unifying dose metric as increasing the difficulty of interpreting dosimetry across exposures. A number of research needs were identified, including an agreed list of respiratory sensitizers and other asthmagens, distinguishing between adverse effects from immune-mediated versus non immunological mechanisms. A number of themes emerged from the discussion regarding future testing strategies, particularly the need for a tiered framework respiratory sensitizer assessment. These workshop present a basis for moving towards a weight-of-evidence assessment

Autisme et particularités sensorielles : de la rencontre à la prise en charge à travers l’étude de deux cas cliniques

Ce travail a pour intention première de mettre en évidence, à travers la présentation de deux cas cliniques rencontrés dans le cadre de La Consultation Libellule à Lausanne, la complexité des particularités présentes chez une grande partie des enfants diagnostiqués dans le spectre autistique. Il s’agira de décrire la prise en charge dans sa globalité, allant de la rencontre avec l’enfant et ses parents à l’intervention proposée à la famille. Ce travail rend également compte de l’évaluation clinique de l’enfant à travers plusieurs outils comme l’Autism Diagnostic Observation Schedule-2 (ADOS-2) (Rutter, 2002), l’Autism Diagnostic Interview – Revised (ADI-R) (Rutter, 2003) et le Psychoeducational Profile-3 (PEP-3) (Schopler, Lansing, Reichler & Marcus, 2005) ainsi qu’à travers le questionnaire du Profil Sensoriel (Dunn, 1999)..

Anticipating water infrastructure renewal: A framing perspective on organizational learning in public agencies

Water authorities in Western countries are increasingly confronted with waterway renewal. Ageing waterway infrastructures put the reliability of the existing network under pressure. Similarly, they open up the need to anticipate long-term uncertainties to ensure network performance. Aligning organizational practices to this new context can be considered an organizational learning process, which concerns improving current practices as well as reconsidering underlying values. Against the background of public management reforms, we aim to understand the organizational learning process in a case study of the Dutch authority Rijkswaterstaat, which is facing a major waterway renewal challenge. By developing a framing perspective on organizational learning, our analysis theoretically provides more insight into agencies anticipating change and empirically into waterway renewal in practice. Our research demonstrates that waterway renewal is primarily framed from a New Public Management viewpoint in which change is approached rather pragmatically. Accordingly, we observed a refinement of existing practice that protects the agency’s mission. Higher levels of learning were discarded as potentially disruptive to waterway management, leaving more fundamental change untouched. We therefore question to what extent water authorities are capable of fully addressing waterway renewal. Nevertheless, the repositioning process resulted in opportunities for reflecting on dominant frames and introducing new concepts. To better seize such opportunities and thus improve alignment to waterway renewal, water authorities can, in addition to improving existing practices, re-interpret dominant frames and construct a new narrative in which future, long-term uncertainties are acknowledged as inherent conditions for agencies to cope with