Somites are formed from the presomitic mesoderm (PSM) and give rise to the axial skeleton and skeletal muscles. The PSM is dynamic; somites are generated at the anterior end, while the posterior end ...is continually renewed with new cells entering from the tailbud progenitor region. Which genes control the conversion of tailbud progenitors into PSM and how is this process coordinated with cell movement? Using loss- and gain-of-function experiments and heat-shock transgenics we show in zebrafish that the transcription factor Mesogenin 1 (Msgn1), acting with Spadetail (Spt), has a central role. Msgn1 allows progression of the PSM differentiation program by switching off the progenitor maintenance genes ntl, wnt3a, wnt8 and fgf8 in the future PSM cells as they exit from the tailbud, and subsequently induces expression of PSM markers such as tbx24. msgn1 is itself positively regulated by Ntl/Wnt/Fgf, creating a negative-feedback loop that might be crucial to regulate homeostasis of the progenitor population until somitogenesis ends. Msgn1 drives not only the changes in gene expression in the nascent PSM cells but also the movements by which they stream out of the tailbud into the PSM. Loss of Msgn1 reduces the flux of cells out of the tailbud, producing smaller somites and an enlarged tailbud, and, by delaying exhaustion of the progenitor population, results in supernumerary tail somites. Through its combined effects on gene expression and cell movement, Msgn1 (with Spt) plays a key role both in genesis of the paraxial mesoderm and in maintenance of the progenitor population from which it derives.
Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorders (PTLD) are common and potentially fatal complications after allogeneic transplantation with mismatched donors ...and T-cell depletion. Haplo-cord transplantation combines a mismatched UCB graft with third-party cells. Conditioning involves thymoglobulin. EBV reactivation and PTLD were common in initial patients. As of March 2017, we administered a prophylactic dose of rituximab 375 mg/m
2
pre-transplant. Among 147 patients who did not receive rituximab, the cumulative incidence of post-transplant EBV reactivation and of EBV PTLD was 13% and 8%, respectively. Among 51 who received pre-transplant rituximab, the incidences were 2% (p = .0017) and 0% (p = .04), respectively. There was no difference in time to hematopoietic recovery, in the incidence of CMV reactivation, of invasive blood stream infections or of proven or probable invasive fungal infections. Pre-transplant administration of rituximab is an effective and nontoxic intervention that drastically reduces EBV reactivation and PTLD in high-risk patients.
Cell shedding from the intestinal villus is a key element of tissue turnover that is essential to maintain health and homeostasis. However, the signals regulating this process are not well ...understood. We asked whether shedding is controlled by epidermal growth factor receptor (EGFR), an important driver of intestinal growth and differentiation. In 3D ileal enteroid culture and cell culture models (MDCK, IEC-6 and IPEC-J2 cells), extrusion events were suppressed by EGF, as determined by direct counting of released cells or rhodamine-phalloidin labeling of condensed actin rings. Blockade of the MEK-ERK pathway, but not other downstream pathways such as phosphoinositide 3-kinase (PI3K) or protein kinase C (PKC), reversed EGF inhibition of shedding. These effects were not due to a change in cell viability. Furthermore, EGF-driven MAPK signaling inhibited both caspase-independent and -dependent shedding pathways. Similar results were found in vivo, in a novel zebrafish model for intestinal epithelial shedding. Taken together, the data show that EGF suppresses cell shedding in the intestinal epithelium through a selective MAPK-dependent pathway affecting multiple extrusion mechanisms. EGFR signaling might be a therapeutic target for disorders featuring excessive cell turnover, such as inflammatory bowel diseases.
Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of ...patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.
In a recessive ENU mutagenesis screen for embryonic lethality, we identified a mouse pedigree with a missense mutation of SHIP1 (SHIP1el20) leading to an amino acid substitution I641T in the ...inositol-5′-phosphatase domain that represses phosphatidylinositol-3-kinase signaling. Despite detectable expression of functional SHIP1 protein, the phenotype of homozygous SHIP1el20/el20 mice was more severe than gene-targeted SHIP1-null (SHIP1−/−) mice. Compared with age-matched SHIP1−/− mice, 5-week-old SHIP1el20/el20 mice had increased myeloid cells, serum IL-6 levels, marked reductions in lymphoid cells, and died by 7 weeks of age with infiltration of the lungs by activated macrophages. Bone marrow transplantation demonstrated that these defects were hematopoietic-cell-autonomous. We show that the el20 mutation reduces expression in SHIP1el20/el20 macrophages of both SHIP1 and s-SHIP, an isoform of SHIP1 generated by an internal promoter. In contrast, SHIP1−/− macrophages express normal levels of s-SHIP. Compound heterozygous mice (SHIP1−/el20) had the same phenotype as SHIP1−/− mice, thus providing genetic proof that the more severe phenotype of SHIP1el20/el20 mice is probably the result of concomitant loss of SHIP1 and s-SHIP. Our results suggest that s-SHIP synergizes with SHIP1 for suppression of macrophage activation, thus providing the first evidence for a role of s-SHIP in adult hematopoiesis.
Abstract
We present the fifth edition of the TimeTree of Life resource (TToL5), a product of the timetree of life project that aims to synthesize published molecular timetrees and make evolutionary ...knowledge easily accessible to all. Using the TToL5 web portal, users can retrieve published studies and divergence times between species, the timeline of a species’ evolution beginning with the origin of life, and the timetree for a given evolutionary group at the desired taxonomic rank. TToL5 contains divergence time information on 137,306 species, 41% more than the previous edition. The TToL5 web interface is now Americans with Disabilities Act-compliant and mobile-friendly, a result of comprehensive source code refactoring. TToL5 also offers programmatic access to species divergence times and timelines through an application programming interface, which is accessible at timetree.temple.edu/api. TToL5 is publicly available at timetree.org.
High rates of comorbidity, shared risk, and overlapping therapeutic mechanisms have led psychopathology research toward transdiagnostic dimensional investigations of clustered symptoms. One ...influential framework accounts for these transdiagnostic phenomena through a single general factor, sometimes referred to as the p factor, associated with risk for all common forms of mental illness.
We build on previous research identifying unique structural neural correlates of the p factor by conducting a data-driven analysis of connectome-wide intrinsic functional connectivity (n = 605).
We demonstrate that higher p factor scores and associated risk for common mental illness maps onto hyperconnectivity between visual association cortex and both frontoparietal and default mode networks.
These results provide initial evidence that the transdiagnostic risk for common forms of mental illness is associated with patterns of inefficient connectome-wide intrinsic connectivity between visual association cortex and networks supporting executive control and self-referential processes, networks that are often impaired across categorical disorders.
PDF
