110 research outputs found
The sixth international RASopathies symposium: Precision medicine—From promise to practice
The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS‐mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life‐limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion
Role of the Gut Endoderm in Relaying Left-Right Patterning in Mice
Analysis of Sox17 mutant mice reveals that gap junction coupling across the gut endoderm of the embryo transmits the left-right asymmetric signal from the node to the site of asymmetric organogenesis in mice
Fundamental Neutron Physics: a White Paper on Progress and Prospects in the US
Fundamental neutron physics, combining precision measurements and theory,
probes particle physics at short range with reach well beyond the highest
energies probed by the LHC. Significant US efforts are underway that will probe
BSM CP violation with orders of magnitude more sensitivity, provide new data on
the Cabibbo anomaly, more precisely measure the neutron lifetime and decay, and
explore hadronic parity violation. World-leading results from the US
Fundamental Neutron Physics community since the last Long Range Plan, include
the world's most precise measurement of the neutron lifetime from UCN,
the final results on the beta-asymmetry from UCNA and new results on hadronic
parity violation from the NPDGamma and n-He runs at the FNPB (Fundamental
Neutron Physics Beamline), precision measurement of the radiative neutron decay
mode and n-He at NIST. US leadership and discovery potential are ensured
by the development of new high-impact experiments including BL3, Nab, LANL nEDM
and nEDM@SNS. On the theory side, the last few years have seen results for the
neutron EDM from the QCD term, a factor of two reduction in the
uncertainty for inner radiative corrections in beta-decay which impacts CKM
unitarity, and progress on {\it ab initio} calculations of nuclear structure
for medium-mass and heavy nuclei which can eventually improve the connection
between nuclear and nucleon EDMs. In order to maintain this exciting program
and capitalize on past investments while also pursuing new ideas and building
US leadership in new areas, the Fundamental Neutron Physics community has
identified a number of priorities and opportunities for our sub-field covering
the time-frame of the last Long Range Plan (LRP) under development. This white
paper elaborates on these priorities.Comment: arXiv admin note: text overlap with arXiv:2304.0345
A Wnt-Frz/Ror-Dsh Pathway Regulates Neurite Outgrowth in Caenorhabditis elegans
One of the challenges to understand the organization of the nervous system has been to determine how axon guidance molecules govern axon outgrowth. Through an unbiased genetic screen, we identified a conserved Wnt pathway which is crucial for anterior-posterior (A/P) outgrowth of neurites from RME head motor neurons in Caenorhabditis elegans. The pathway is composed of the Wnt ligand CWN-2, the Frizzled receptors CFZ-2 and MIG-1, the co-receptor CAM-1/Ror, and the downstream component Dishevelled/DSH-1. Among these, CWN-2 acts as a local attractive cue for neurite outgrowth, and its activity can be partially substituted with other Wnts, suggesting that spatial distribution plays a role in the functional specificity of Wnts. As a co-receptor, CAM-1 functions cell-autonomously in neurons and, together with CFZ-2 and MIG-1, transmits the Wnt signal to downstream effectors. Yeast two-hybrid screening identified DSH-1 as a binding partner for CAM-1, indicating that CAM-1 could facilitate CWN-2/Wnt signaling by its physical association with DSH-1. Our study reveals an important role of a Wnt-Frz/Ror-Dsh pathway in regulating neurite A/P outgrowth
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The Exocyst Protein Sec10 Interacts with Polycystin-2 and Knockdown Causes PKD-Phenotypes
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by
formation of renal cysts that destroy the kidney. Mutations in PKD1 and PKD2,
encoding polycystins-1 and -2, cause ADPKD. Polycystins are thought to function
in primary cilia, but it is not well understood how these and other proteins are
targeted to cilia. Here, we provide the first genetic and biochemical link
between polycystins and the exocyst, a highly-conserved eight-protein membrane
trafficking complex. We show that knockdown of exocyst component Sec10 yields
cellular phenotypes associated with ADPKD, including loss of flow-generated
calcium increases, hyperproliferation, and abnormal activation of MAPK. Sec10
knockdown in zebrafish phenocopies many aspects of polycystin-2
knockdown—including curly tail up, left-right patterning defects,
glomerular expansion, and MAPK activation—suggesting that the exocyst is
required for pkd2 function in vivo. We observe
a synergistic genetic interaction between zebrafish sec10 and
pkd2 for many of these cilia-related phenotypes.
Importantly, we demonstrate a biochemical interaction between Sec10 and the
ciliary proteins polycystin-2, IFT88, and IFT20 and co-localization of the
exocyst and polycystin-2 at the primary cilium. Our work supports a model in
which the exocyst is required for the ciliary localization of polycystin-2, thus
allowing for polycystin-2 function in cellular processes
Chemical genetics strategies for identification of molecular targets
Chemical genetics is an emerging field that can be used to study the interactions of chemical compounds, including natural products, with proteins. Usually, the identification of molecular targets is the starting point for studying a drug’s mechanism of action and this has been a crucial step in understanding many biological processes. While a great variety of target identification methods have been developed over the last several years, there are still many bioactive compounds whose target proteins have not yet been revealed because no routine protocols can be adopted. This review contains information concerning the most relevant principles of chemical genetics with special emphasis on the different genomic and proteomic approaches used in forward chemical genetics to identify the molecular targets of the bioactive compounds, the advantages and disadvantages of each and a detailed list of successful examples
of molecular targets identified with these approaches
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