Murine CASK Is disrupted in a sex-linked cleft palate mouse mutant

A transgenic mouse insertional mutant displayed the phenotype of altered cranial morphology with sex-linked cleft palate. We have cloned the disrupted genomic X-linked locus and report the identification of the mCASK gene. The gene is transcribed to produce two messages of 4.5 and 9.5 kb expressed during development and in adult tissues, particularly the brain. We describe the isolation of two differentially spliced mouse cDNAs from the locus (mCASK-A and mCASK-B). The mCASK-B cDNA probably represents the full-length product of the 4.5-kb transcript. The identical N-termini of the predicted encoded proteins (mCASK-A and -B) are highly homologous to Ca2+/calmodulin-dependent protein kinase II, while the deduced C-terminus of mCASK-B is highly homologous to a family of multidomain proteins containing a guanylate kinase motif, the MAGUK proteins. mCASK-B is a new member of an emerging family of genes in which the encoded proteins combine these domains, termed here, the CAMGUKs, including rat CASK,Caenorhabditis elegans lin-2,andDrosophila caki/camguk.The CAMGUKs are likely to be effectors in signal transduction as regulatory partners of transmembrane molecules, modulated by calcium and nucleotides. The transgene in this mutant mouse line integrated into an intron that bisects the encoded calmodulin-binding domain, a potentially important regulatory domain of the predicted protein, generating hybrid transcripts

Mapping and expression analysis of the human CASK gene

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What public health challenges and unmet medical needs would benefit from interdisciplinary collaboration in the EU? A survey and multi-stakeholder debate

In the past decade, significant European calls for research proposals have supported translational collaborative research on non-communicable and infectious diseases within the biomedical life sciences by bringing together interdisciplinary and multinational consortia. This research has advanced our understanding of disease pathophysiology, marking considerable scientific progress. Yet, it is crucial to retrospectively evaluate these efforts’ societal impact. Research proposals should be thoughtfully designed to ensure that the research findings can be effectively translated into actionable policies. In addition, the choice of scientific methods plays a pivotal role in shaping the societal impact of research discoveries. Understanding the factors responsible for current unmet public health issues and medical needs is crucial for crafting innovative strategies for research policy interventions. A multistakeholder survey and a roundtable helped identify potential needs for consideration in the EU research and policy agenda. Based on survey findings, mental health disorders, metabolic syndrome, cancer, antimicrobial resistance, environmental pollution, and cardiovascular diseases were considered the public health challenges deserving prioritisation. In addition, early diagnosis, primary prevention, the impact of environmental pollution on disease onset and personalised medicine approaches were the most selected unmet medical needs. Survey findings enabled the formulation of some research-policies interventions (RPIs), which were further discussed during a multistakeholder online roundtable. The discussion underscored recent EU-level activities aligned with the survey-derived RPIs and facilitated an exchange of perspectives on public health and biomedical research topics ripe for interdisciplinary collaboration and warranting attention within the EU’s research and policy agenda. Actionable recommendations aimed at facilitating the translation of knowledge into transformative, science-based policies are also provided

Managing the challenge of chemically reactive metabolites in drug development

The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At early stages of drug discovery, iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without compromising pharmacological activity or the need for extensive safety evaluation beyond standard practices. In the future, reactive metabolite evaluation may also be useful during clinical development for improving clinical risk assessment and risk management. Currently, there remains a huge gap in our understanding of the basic mechanisms that underlie chemical stress-mediated adverse reactions in humans. This Review summarizes our views on this complex topic, and includes insights into practices considered by the pharmaceutical industry

Managing the challenge of chemically reactive metabolites in drug development

The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At early stages of drug discovery, iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without compromising pharmacological activity or the need for extensive safety evaluation beyond standard practices. In the future, reactive metabolite evaluation may also be useful during clinical development for improving clinical risk assessment and risk management. Currently, there remains a huge gap in our understanding of the basic mechanisms that underlie chemical stress-mediated adverse reactions in humans. This Review summarizes our views on this complex topic, and includes insights into practices considered by the pharmaceutical industry