Inhibition of longevity regulator PAPP-A modulates tissue homeostasis via restraint of mesenchymal stromal cells.

Pregnancy-associated plasma protein-A (PAPP-A) is a secreted metalloprotease that increases insulin-like growth factor (IGF) availability by cleaving IGF-binding proteins. Reduced IGF signaling extends longevity in multiple species, and consistent with this, PAPP-A deletion extends lifespan and healthspan; however, the mechanism remains unclear. To clarify PAPP-A's role, we developed a PAPP-A neutralizing antibody and treated adult mice with it.

Fully Phased Sequence of a Diploid Human Genome Determined from the DNA of a Single Individual.

In recent years, improved sequencing technology and computational tools have made genome assembly more accessible. Many approaches, however, generate either an unphased or only partially resolved representation of a diploid genome, in which polymorphisms are detected but not assigned to one or the other of the homologous chromosomes. Yet chromosomal phase information is invaluable for the understanding of phenotypic trait inheritance in the cases of compound heterozygosity, allele-specific expression or -acting variants.

Alzheimer's Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation.

Damage-associated microglia (DAM) profiles observed in Alzheimer's disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile.

Slashing the timelines: Opting to generate high-titer clonal lines faster via viability-based single cell sorting.

Chinese hamster ovary (CHO) cell line development (CLD) is a long and laborious process, which requires up to 5 - 6 months in order to generate and bank CHO lines capable of stably expressing therapeutic molecules. Additionally, single cell cloning of these production lines is also necessary to confirm clonality of the production lines. Here we introduce the utilization of viability staining dye in combination with flow cytometer to isolate high titer clones from a pool of selected cells and single cell deposit them into the wells of culture plates.

Cutting edge: Self-antigen controls the balance between effector and regulatory T cells in peripheral tissues.

Immune homeostasis in peripheral tissues is achieved by maintaining a balance between pathogenic effector T cells (Teffs) and protective Foxp3(+) regulatory T cells (Tregs). Using a mouse model of an inducible tissue Ag, we demonstrate that Ag persistence is a major determinant of the relative frequencies of Teffs and Tregs. Encounter of transferred naive CD4(+) T cells with transiently expressed tissue Ag leads to generation of cytokine-producing Teffs and peripheral Tregs.

Treating human autoimmunity: current practice and future prospects.

Autoimmune diseases are caused by immune cells attacking the host tissues they are supposed to protect. Recent advances suggest that maintaining a balance of effector and regulatory immune function is critical for avoiding autoimmunity. New therapies, including costimulation blockade, regulatory T cell therapy, antigen-specific immunotherapy, and manipulating the interleukin-2 pathway, attempt to restore this balance.

Response to self antigen imprints regulatory memory in tissues.

Immune homeostasis in tissues is achieved through a delicate balance between pathogenic T-cell responses directed at tissue-specific antigens and the ability of the tissue to inhibit these responses. The mechanisms by which tissues and the immune system communicate to establish and maintain immune homeostasis are currently unknown. Clinical evidence suggests that chronic or repeated exposure to self antigen within tissues leads to an attenuation of pathological autoimmune responses, possibly as a means to mitigate inflammatory damage and preserve function.

Opposing functions of IL-2 and IL-7 in the regulation of immune responses.

Regulation of the magnitude and quality of immune responses is dependent on the integration of multiple signals which typically operate through positive and negative feedback loops. Cytokines that promote or limit T cell expansion and differentiation are often both present in the complex lymphoid environment where antigen-initiated T cell responses take place. The nature and strength of the cytokine signal received by the responding cell, as well as by surrounding regulatory cells, will determine the extent of clonal expansion and the progression towards effector and memory cell differentiation.