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Regulation of STAT3 activation is critical for normal and malignant hematopoietic cell proliferation. Here, we have reported that the endogenous transmembrane protein upstream-of-mTORC2 (UT2) negatively regulates activation of STAT3. Specifically, we determined that UT2 interacts directly with GP130 and inhibits phosphorylation of STAT3 on tyrosine 705 ([STAT3.sup.Y705]). This reduces cytokine signaling including IL6 that is implicated in multiple myeloma and other hematopoietic malignancies. Modulation of UT2 resulted in inverse effects on animal survival in myeloma models. Samples from multiple myeloma patients also revealed a decreased copy number of UT2 and decreased expression of UT2 in genomic and transcriptomic analyses, respectively. Together, these studies identify a transmembrane protein that functions to negatively regulate cytokine signaling through GP130 and p[STAT3.sup.Y705] and is molecularly and mechanistically distinct from the suppressors of cytokine signaling (SOCS) family of genes. Moreover, this work provides evidence that perturbations of this activation-dampening molecule participate in hematologic malignancies and may serve as a key determinant of multiple myeloma pathophysiology. UT2 is a negative regulator shared across STAT3 and mTORC2 signaling cascades, functioning as a tumor suppressor in hematologic malignancies driven by those pathways., Introduction We identified UT2 as a transmembrane molecule altered in leukemic cells that emerged from an animal model with modifications in specific BM stromal cells (1). Hypothesizing that the genes [...]

Autoreactive B cells are regulated in the BM during development through mechanisms, including editing of the B cell receptor (BCR), clonal deletion, and anergy. Peripheral B cell tolerance is also important for protection from autoimmune damage, although the mechanisms are less well defined. Here we demonstrated, using a mouse model of SLE-like serology, that during an autoimmune response, RAG was reinduced in antigen-activated early memory or preplasma B cells. Expression of RAG was specific to antigen-reactive B cells, required the function of the IL-7 receptor (IL-7R), and contributed to maintenance of humoral tolerance. We also showed that soluble antigen could diminish a non-autoreactive antibody response through induction of BCR revision. These data suggest that tolerance induction operates in B cells at a postactivation checkpoint and that BCR revision helps regulate autoreactivity generated during an ongoing immune response., Introduction During B lymphocyte development in the BM, immature B cells expressing self-reactive antigen receptors are tolerized by a variety of mechanisms. Prominent among these are clonal deletion, which purges [...]

Azoospermia patients who carry a monogenetic mutation that causes meiotic arrest may have their biological child through genetic correction in spermatogonial stem cells (SSCs). However, such therapy for infertility has not been experimentally investigated yet. In this study, a mouse model with an X-linked testis-expressed 11 (TEX11) mutation (Tex11PM/Y) identified in azoospermia patients exhibited meiotic arrest due to aberrant chromosome segregation. Tex11PM/Y SSCs could be isolated and expanded in vitro normally, and the mutation was corrected by clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated endonuclease 9 (Cas9), leading to the generation of repaired SSC lines. Whole-genome sequencing demonstrated that the mutation rate in repaired SSCs is comparable with that of autonomous mutation in untreated Tex11PM/Y SSCs, and no predicted off-target sites are modified. Repaired SSCs could restore spermatogenesis in infertile males and give rise to fertile offspring at a high efficiency. In summary, our study establishes a paradigm for the treatment of male azoospermia by combining in vitro expansion of SSCs and gene therapy. [ABSTRACT FROM AUTHOR]

Cancer survivors have recovered from a brush with death, but their battle is often not over. The rigors of their initial bout with the disease predispose them to a second [...]

Torenia biniflora is a member of Scrophulariaceae Torenia , and it is an annual flowering plant that widely grows in Chinese subtropical area, such as Guangdong Province and Guangxi Zhuang Autonomous Region. T. biniflora is a wild flower with high great ornamental value. However, in natural growth condition, the reproduction speed of T. Biniflora is slow, proliferation rate is low, and the kinds of flower colour and type are few, therefore, it is unable to meet the diversified need of market. Plant tissue culture technology provides a new way to improve and breed new varieties for ornamental plants. Up to now, a lot of members of Torenia plants have been successfully established in vitro regeration system through tissue culture, such as T. fournieri Linden, T. baillonii Susie Wong and T. concolor Lindl. ,etc. While,tissue culture for T. Biniflora has never been reported. The main objective of this research was to establish in vitro regeneration system of T. Biniflora through tissue culture and study the effects of plant growth substances such as IBA, 6-BA and NAA for clonal multiplication. In this study, we created a reliable protocol for regenerating T. biniflora plants in tissue culture by using leaf explants. The effects of different concentrations and combinations of plant growth substances on adventitious bud induction and growth were studied, and the effects of different ionic strengths of media and concentrations of IBA on rooting were analyzed. According to a series of indices, such as average number of buds, frequency of bud induction, frequency of rooting, average number of root and average length of root, the optimal media for inducing adventitious buds and rooting were screened respectively. The results showed that adventitious bud induction was related with the concentrations and combinations of plant growth regulator, and the optimal medium for buds induction was MS+ 6-BA 0.5 mg • L-1 + NAA 0.2 mg • L-1. The best medium for rooting was 1/2 MS as basal medium with IBA 0.05 mg • L-1. In this study the in vitro plant reproductive system of T. biniflora with high frequence was completely established, and it would provide an important experiment foundation for the research of rapid propagation and genetic transformation for T. biniflora. [ABSTRACT FROM AUTHOR]

Autoreactive B cells are regulated in the BM during development through mechanisms, including editing of the B cell receptor (BCR), clonal deletion, and anergy. Peripheral B cell tolerance is also important for protection from autoimmune damage, although the mechanisms are less well defined. Here we demonstrated, using a mouse model of SLE-like serology, that during an autoimmune response, RAG was reinduced in antigen-activated early memory or preplasma B cells. Expression of RAG was specific to antigen-reactive B cells, required the function of the IL-7 receptor (IL-7R), and contributed to maintenance of humoral tolerance. We also showed that soluble antigen could diminish a non-autoreactive antibody response through induction of BCR revision. These data suggest that tolerance induction operates in B cells at a postactivation checkpoint and that BCR revision helps regulate autoreactivity generated during an ongoing immune response. [ABSTRACT FROM AUTHOR]

Regulation of STAT3 activation is critical for normal and malignant hematopoietic cell proliferation. Here, we have reported that the endogenous transmembrane protein upstream-of-mTORC2 (UT2) negatively regulates activation of STAT3. Specifically, we determined that UT2 interacts directly with GP130 and inhibits phosphorylation of STAT3 on tyrosine 705 (STAT3Y705). This reduces cytokine signaling including IL6 that is implicated in multiple myeloma and other hematopoietic malignancies. Modulation of UT2 resulted in inverse effects on animal survival in myeloma models. Samples from multiple myeloma patients also revealed a decreased copy number of UT2 and decreased expression of UT2 in genomic and transcriptomic analyses, respectively. Together, these studies identify a transmembrane protein that functions to negatively regulate cytokine signaling through GP130 and pSTAT3Y705 and is molecularly and mechanistically distinct from the suppressors of cytokine signaling (SOCS) family of genes. Moreover, this work provides evidence that perturbations of this activation-dampening molecule participate in hematologic malignancies and may serve as a key determinant of multiple myeloma pathophysiology. UT2 is a negative regulator shared across STAT3 and mTORC2 signaling cascades, functioning as a tumor suppressor in hematologic malignancies driven by those pathways. [ABSTRACT FROM AUTHOR]

Non-oxidative glucose metabolism represents a hallmark of cancer. It is now apparent that different cell states among normal stem or progenitor cells have distinct aerobic glycolysis (AG) dependencies. However, malignant cells are markedly more vulnerable to modifications of AG regardless of the differentiation state of their cell of origin.