Accelerating functional gene discovery in osteoarthritis

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease

Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation

A substantial portion of the regulatory interactions in the higher eukaryotic cell are mediated by simple sequence motifs in the regulatory segments of genes and (pre-)mRNAs, and in the intrinsically disordered regions of proteins. Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms. The ease of motif acquisition simplifies access to basal housekeeping functions, facilitates the co-regulation of multiple biomolecules allowing them to respond in a coordinated manner to changes in the cell state, and supports the integration of multiple signals for combinatorial decision-making. Consequently, motifs are indispensable for temporal, spatial, conditional and basal regulation at the transcriptional, post-transcriptional and post-translational level. In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules. We discuss how co-operativity allows simple static motifs to perform the conditional regulation that underlies decision-making in higher eukaryotic biological systems. We observe that each gene and its products have a unique set of DNA, RNA or protein motifs that encode a regulatory program to define the logical circuitry that guides the life cycle of these biomolecules, from transcription to degradation. Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules

Imaging Findings Of Splenic Emergencies: A Pictorial Review

Abstract Although traumatic injuries are the cause of common splenic emergencies in the emergency room, various nontraumatic conditions may also affect the spleen with possible life-threatening results. In this pictorial review, we present imaging findings of usual and unusual splenic emergencies. It is essential to be familiar with key imaging findings and advantages of different modalities to reach a definitive diagnosis. Teaching points • Delayed splenic rupture is commonly related to subcapsular hematoma., • Subtle haemorrhage is commonly restricted to the site of injury “sentinel clot sign”., • The whorled appearance is the key imaging feature of splenic torsion.PubMedScopu

Ptpn6 inhibits caspase-8-and Ripk3/Mlkl-dependent inflammation

Ptpn6 is a cytoplasmic phosphatase that functions to prevent autoimmune and interleukin-1 (IL-1) receptor-dependent, caspase-1-independent inflammatory disease. Conditional deletion of Ptpn6 in neutrophils (Ptpn6∆PMN) is sufficient to initiate IL-1 receptor-dependent cutaneous inflammatory disease, but the source of IL-1 and the mechanisms behind IL-1 release remain unclear. Here, we investigate the mechanisms controlling IL-1α/β release from neutrophils by inhibiting caspase-8-dependent apoptosis and Ripk1-Ripk3-Mlkl-regulated necroptosis. Loss of Ripk1 accelerated disease onset, whereas combined deletion of caspase-8 and either Ripk3 or Mlkl strongly protected Ptpn6∆PMN mice. Ptpn6∆PMN neutrophils displayed increased p38 mitogen-activated protein kinase-dependent Ripk1-independent IL-1 and tumor necrosis factor production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 mitogen-activated protein kinase activation to control tumor necrosis factor and IL-1α/β expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3-Mlkl-dependent cell death and concomitant IL-1α/β release

Investigating science teachers’ transformations when implementing inquiry-based teaching-learning sequences

In this study we aimed to investigate the most transformed/accepted aspects of scientific inquiry when it is implemented in classroom practice. Thirteen secondary school teachers participated in the study. The teachers were first involved in a professional development (PD) course aimed at familiarizing them with inquiry principles, using seven teaching-learning sequences (TLSs) as training contexts. Then, teachers implemented one TLS in their classrooms for at least 5 h. A knowledge transfer framework, Adaption and Re-Invention Model, was used to investigate teachers’ transfer of TLS in classroom practice. In particular, core and non-core elements of the TLSs were identified: core elements are essential features of inquiry teaching that should not be changed while implementing a TLS since they characterize it in a unique way. Non-core elements concern classroom management and activities timing and can be changed to fit the TLS into the specific educational context. Collected data have been audio/video recordings. Results show that most accepted aspects of inquiry teaching are related to data collection, support to students, activities timing, and homework tasks. Moreover, most teachers acted as resource persons and valued classroom discussions. Overall, our findings may usefully inform PD courses by providing evidence of teachers’ enactment of inquiry in their practice