Human Frailty, Unbreakable Victims and Asylum

This article analyzes the asylum decisions of immigration agencies and federal appellate courts and demonstrates that the case law driven standard for persecution is out of step with the original meaning of the term, international law standards, and contemporary understanding of how human beings experience physical and mental harm. Medical and psychological evidence establishes that even trauma at the lower end of the spectrum of severity can inflict lasting and debilitating effects on people\u27s health. Yet over the last three decades, virtually no court decisions have decreased the showing of harm needed to establish persecution. To the contrary, courts have generally ratcheted up what is required. Today, most judicial decisions rest on the unwarranted assumption of an unbreakable asylum applicant who must show systematic and escalating physical mistreatment over a sustained period or a single instance of extraordinary harm that results in a scar, disability, or other lasting physical injury. Although mental harm can qualify as persecution, courts rarely find persecution based solely on mental mistreatment. And courts routinely fail to consider the longstanding mental effects of physical trauma. Court decisions on persecution are consistent with troubling studies suggesting people have difficulty empathizing with, and understanding, the situations of others when there is a lack of immediacy, and that decision makers and authority figures are prone to making racialized attributions of pain on the baseless assumption that people of color can withstand more pain than white people. Decision makers should seek to minimize the tendency to downplay the pain of others in asylum adjudications and adopt a human rights approach, which tags the concept of persecution to the violation of a human right and better tracks the prevailing understanding of how humans experience both physical and mental mistreatment, which grows more encompassing over time

Functional Characterization and Localization of the \u3ci\u3eAspergillus nidulan\u3c/i\u3e Formin SEPA

Formins are a family of multidomain scaffold proteins involved in actin-dependent morphogenetic events. In Aspergillus nidulans, the formin SEPA participates in two actin-mediated processes, septum formation and polarized growth. In this study, we use a new null mutant to demonstrate that SEPA is required for the formation of actin rings at septation sites. In addition, we find that a functional SEPA::GFP fusion protein localizes simultaneously to septation sites and hyphal tips, and that SEPA colocalizes with actin at each site. Using live imaging, we show that SEPA localization at septation sites and hyphal tips is dynamic. Notably, at septation sites, SEPA forms a ring that constricts as the septum is deposited. Moreover, we demonstrate that actin filaments are required to maintain the proper localization pattern of SEPA, and that the amino-terminal half of SEPA is sufficient for localization at septation sites and hyphal tips. In contrast, only localization at septation sites is affected by loss of the sepH gene product. We propose that specific morphological cues activate common molecular pathways to direct SEPA localization to the appropriate morphogenetic site

Functional Characterization and Localization of the \u3ci\u3eAspergillus nidulan\u3c/i\u3e Formin SEPA

Formins are a family of multidomain scaffold proteins involved in actin-dependent morphogenetic events. In Aspergillus nidulans, the formin SEPA participates in two actin-mediated processes, septum formation and polarized growth. In this study, we use a new null mutant to demonstrate that SEPA is required for the formation of actin rings at septation sites. In addition, we find that a functional SEPA::GFP fusion protein localizes simultaneously to septation sites and hyphal tips, and that SEPA colocalizes with actin at each site. Using live imaging, we show that SEPA localization at septation sites and hyphal tips is dynamic. Notably, at septation sites, SEPA forms a ring that constricts as the septum is deposited. Moreover, we demonstrate that actin filaments are required to maintain the proper localization pattern of SEPA, and that the amino-terminal half of SEPA is sufficient for localization at septation sites and hyphal tips. In contrast, only localization at septation sites is affected by loss of the sepH gene product. We propose that specific morphological cues activate common molecular pathways to direct SEPA localization to the appropriate morphogenetic site

Hot topics in stem cells and self-renewal: 2010

In many tissues, mammalian aging is associated with a decline in the replicative and functional capacity of somatic stem cells and other self-renewing compartments. Understanding the basis of this decline is a major goal of aging research. In particular, therapeutic approaches to ameliorate or reverse the age-associated loss of stem function could be of use in clinical geriatrics. Such approaches include attempts to protect stem cells from age-promoting damage, to ‘rejuvenate’ stem cells through the use of pharmacologic agents that mitigate aging-induced alterations in signaling, and to replace lost stem cells through regenerative medicine approaches. Some headway has been made in each of these arenas over the last 18 months including advances in the production of donor-specific totipotent stem cells through induced pluripotency (iPS), gains in our understanding of how tumor suppressor signaling is controlled in self-renewing compartments to regulate aging, and further demonstration of extracellular ‘milieu’ factors that perturb stem cell function with age. This period has also been marked by the recent award of the Nobel Prize in Physiology or Medicine for elucidation of telomeres and telomerase, a topic of critical importance to stem cell aging

Tumor suppressor mechanisms in immune aging

The cancer-ageing hypothesis suggests that the activation of some tumor suppressor mechanisms beneficially prevent cancer but also untowardly promote mammalian ageing. Along these lines, activation of tumor suppressor mechanisms that inhibit the cell cycle (e.g. p16INK4a and p53) in response to DNA damage and other age-promoting stimuli have taken center stage in immune-ageing research. Immune cells are intrinsically susceptible to transforming events due to V(D)J recombination, a high rate of cellular turnover and requisite long-term self-renewal. Therefore, the DNA damage response and cell cycle regulation play a clear role in maintaining homeostasis without neoplastic progression. Here we will argue based on recent advances in our understanding of tumor suppressor mechanisms in immune cells, however, that aspects of these same beneficial pathways have the potential to induce intrinsic immune ageing

Cells exhibiting strong p16INK4a promoter activation in vivo display features of senescence

The activation of cellular senescence throughout the lifespan promotes tumor suppression, whereas the persistence of senescent cells contributes to aspects of aging. This theory has been limited, however, by an inability to identify and isolate individual senescent cells within an intact organism. Toward that end, we generated a murine reporter strain by “knocking-in” a fluorochrome, tandem-dimer Tomato (tdTom), into exon 1α of the p16 INK4a locus. We used this allele (p16 tdTom ) for the enumeration, isolation, and characterization of individual p16 INK4a -expressing cells (tdTom + ). The half-life of the knocked-in transcript was shorter than that of the endogenous p16 INK4a mRNA, and therefore reporter expression better correlated with p16 INK4a promoter activation than p16 INK4a transcript abundance. The frequency of tdTom + cells increased with serial passage in cultured murine embryo fibroblasts from p16 tdTom/+ mice. In adult mice, tdTom + cells could be readily detected at low frequency in many tissues, and the frequency of these cells increased with aging. Using an in vivo model of peritoneal inflammation, we compared the phenotype of cells with or without activation of p16 INK4a and found that tdTom + macrophages exhibited some features of senescence, including reduced proliferation, senescence-associated β-galactosidase (SA-β-gal) activation, and increased mRNA expression of a subset of transcripts encoding factors involved in SA-secretory phenotype (SASP). These results indicate that cells harboring activation of the p16 INK4a promoter accumulate with aging and inflammation in vivo, and display characteristics of senescence

The Regulation of INK4/ARF in Cancer and Aging

Loss of the // locus on chromosome 9p21 is among the most frequent cytogenetic events in human cancer. The products of the locus—p15, p16, and ARF—play widespread and independent roles in tumor suppression. Recent data also suggest that expression of p16 induces an age-dependent decrease in the proliferative capacity of certain tissue-specific stem cells and unipotent progenitors. Here, we discuss the regulation and role of p16, ARF, and p15 in cancer and aging