A pool of stem cells that arise from the mesoderm during embryogenesis initiates hematopoiesis. However, factors that regulate the expansion of blood stem cells are poorly understood. We show here that cytokine-induced proliferation of primitive human hematopoietic cells could be inhibited with antibodies to hedgehog (Hh). Conversely, Sonic hedgehog (Shh) treatment induced the expansion of pluripotent human hematopoietic repopulating cells detected in immunodeficient mice. Noggin, a specific inhibitor of bone morphogenetic protein 4 (BMP-4), was capable of inhibiting Shh-induced proliferation in a similar manner to anti-Hh; however, anti-Hh had no effect on BMP-4-induced proliferation. Our study shows that Shh functions as a regulator of primitive hematopoietic cells via mechanisms that are dependent on downstream BMP signals.
Despite increased research on the various effects of Corporate Social Responsibility (CSR), the question of whether CSR is worthwhile for firms still remains to be addressed. Prior work suggests that CSR offers firms insurance-like protection against negative publicity due to greater levels of goodwill with various stakeholders. Yet, we still miss an answer to the following question: How effective, if at all, is CSR in insulating firms from scrutiny compared to other important marketing measures, such as customer orientation and service quality orientation? This study develops and empirically tests a theoretical framework that demonstrates the relative impact of CSR on consumer resistance to negative information when confronted with negative information about a firm. The results demonstrate that CSR shields firms from negative information about CSR practices but not information related to firms’ core service offerings. Managerially, the findings demonstrate that CSR may offer less of blanket insurance than assumed in previous research. Furthermore, results indicate that firms with a consumer base of experts should favor a focus on service quality orientation over CSR; conversely, when consumers are novices firms should focus on CSR for greater consumer resistance to negative information.
Traditionally, non-specific chemical conjugations, such as acylation of amines on lysine or alkylation of thiols on cysteines, are widely used; however, they have several shortcomings. First, the lack of site-specificity results in heterogeneous products and irreproducible processes. Second, potential modifications near the complementarity-determining region may reduce binding affinity and specificity. Conversely, site-specific methods produce well-defined and more homogenous antibody conjugates, ensuring developability and clinical applications. Moreover, several recent side-by-side comparisons of site-specific and stochastic methods have demonstrated that site-specific approaches are more likely to achieve their desired properties and functions, such as increased plasma stability, less variability in dose-dependent studies (particularly at low concentrations), enhanced binding efficiency, as well as increased tumor uptake. Herein, we review several standard and practical site-specific bioconjugation methods for native antibodies, i.e., those without recombinant engineering. First, chemo-enzymatic techniques, namely transglutaminase (TGase)-mediated transamidation of a conserved glutamine residue and glycan remodeling of a conserved asparagine N-glycan (GlyCLICK), both in the Fc region. Second, chemical approaches such as selective reduction of disulfides (ThioBridge) and N-terminal amine modifications. Furthermore, we list site-specific antibody–drug conjugates in clinical trials along with the future perspectives of these site-specific methods.
Ret-He can be used as a routine screening test to detect LID in blood donors. This could provide an opportunity to make appropriate and timely interventions like dietary changes or drug supplementation.
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