American Indian homicide: A multimethod, multilevel analysis

This study investigates the etiology of American Indian homicide. Its triangulated methodology combined both the quantitative multivariate analyses with indepth interview data from American Indian male homicide offenders. At the national level, a descriptive analysis was performed that compared American Indian, black, and white disaggregated homicide rates. Although black homicide rates are far greater than either American Indian or white rates, American Indian rates are more than double that of the white population. American Indian homicide is more likely to involve knives while both black and white homicide is more likely to involve handguns. However, when handgun and other gun categories are added together, they account for over 40 percent of all homicides regardless of race/ethnicity. Homicide victims are more likely to be acquaintances involved in conflict situations with the offender in all racial/ethnic groups. And although homicide is a predominantly male phenomenon for all groups, both black and American Indian populations have a significantly higher percentage of female perpetrated homicides than the white population. Multiple regression models estimated American Indian homicide at both the state and SMSA levels. Economic deprivation theory was supported at the reservation state level while a subculture of violence theory was supported at the SMSA level. The qualitative analysis of interview data not only supported the same causal forces of economic deprivation and a subculture of violence, but also illuminated other contributing factors as well. Sources of social disorganization culture conflict and alcohol/drug use were also found to play an important role in these offender\u27s lives. This data provided tremendous insight into the nature and extent of the psychological pain that manifests as a result of these structural and cultural conditions. A theoretical model of American Indian Homicide was formulated from the results of both quantitative and qualitative analyses. It includes elements of economic deprivation, a subculture of violence, social disorganization, and culture conflict and perceived powerlessness, with alcohol/drug abuse placed in the model as an intervening variable

Control of mitochondrial physiology and cell death by the Bcl-2 family proteins Bax and Bok.

Neuronal cell death is often triggered by events that involve intracellular increases in Ca(2+). Under resting conditions, the intracellular Ca(2+) concentration is tightly controlled by a number of extrusion and sequestering mechanisms involving the plasma membrane, mitochondria, and ER. These mechanisms act to prevent a disruption of neuronal ion homeostasis. As these processes require ATP, excessive Ca(2+) overloading may cause energy depletion, mitochondrial dysfunction, and may eventually lead to Ca(2+)-dependent cell death. Excessive Ca(2+) entry though glutamate receptors (excitotoxicity) has been implicated in several neurologic and chronic neurodegenerative diseases, including ischemic stroke, epilepsy, and Alzheimer\u27s disease. Recent evidence has revealed that excitotoxic cell death is regulated by the B-cell lymphoma-2 (Bcl-2) family of proteins. Bcl-2 proteins, comprising of both pro-apoptotic and anti-apoptotic members, have been shown to not only mediate the intrinsic apoptosis pathway by controlling mitochondrial outer membrane (MOM) integrity, but to also control neuronal Ca(2+) homeostasis and energetics. In this review, the role of Bcl-2 family proteins in the regulation of apoptosis, their expression in the central nervous system and how they control Ca(2+)-dependent neuronal injury are summarized. We review the current knowledge on Bcl-2 family proteins in the regulation of mitochondrial function and bioenergetics, including the fusion and fission machinery, and their role in Ca(2+) homeostasis regulation at the mitochondria and ER. Specifically, we discuss how the \u27pro-apoptotic\u27 Bcl-2 family proteins, Bax and Bok, physiologically expressed in the nervous system, regulate such \u27non-apoptotic/daytime\u27 functions

Cancer immunotherapy by immunosuppression

We have previously suggested that the stimulatory effect of a weak immune reaction on tumor growth may be necessary for the growth of incipient tumors. In the present paper, we enlarge upon and extend that idea by collecting evidence in the literature bearing upon this new hypothesis that a growing cancer, whether in man or mouse, is throughout its lifespan, probably growing and progressing because of continued immune stimulation by a weak immune reaction. We also suggest that prolonged immunosuppression might interfere with progression and thus be an aid to therapy. While most of the considerable evidence that supports the hypothesis comes from observations of experimental mouse tumors, there is suggestive evidence that human tumors may behave in much the same way, and as far as we can ascertain, there is no present evidence that necessarily refutes the hypothesis

Two different subunits of importin cooperate to recognize nuclear localization signals and bind them to the nuclear envelope

AbstractBackground: Selective protein import into the cell nucleus occurs in two steps: binding to the nuclear envelope, followed by energy-dependent transit through the nuclear pore complex. A 60 kD protein, importin, is essential for the first nuclear import step, and the small G protein Ran/TC4 is essential for the second. We have previously purified the 60 kD importin protein (importin 60) as a single polypeptide.Results We have identified importin 90, a 90 kD second subunit that dissociates from importin 60 during affinity chromatography on nickel (II)–nitrolotriacetic acid–Sepharose, a technique that was originally used to purify importin 60. Partial amino-acid sequencing of Xenopus importin 90 allowed us to clone and sequence its human homologue; the amino-acid sequence of importin 90 is strikingly conserved between the two species. We have also identified a homologous budding yeast sequence from a database entry. Importin 90 potentiates the effects of importin 60 on nuclear protein import, indicating that the importin complex is the physiological unit responsible for import. To assess whether nuclear localization sequences are recognized by cytosolic receptor proteins, a biotin-tagged conjugate of nuclear localization signals linked to bovine serum albumin was allowed to form complexes with cytosolic proteins in Xenopus egg extracts; the complexes were then retrieved with streptavidin–agarose. The pattern of bound proteins was surprisingly simple and showed only two predominant bands: those of the importin complex. We also expressed the human homologue of importin 60, Rch1p, and found that it was able to replace its Xenopus counterpart in a functional assay. We discuss the relationship of importin 60 and importin 90 to other nuclear import factors.Conclusion Importin consists of a 60 and a 90 kD subunit. Together, they constitute a cytosolic receptor for nuclear localization signals that enables import substrates to bind to the nuclear envelope

Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis.

Exposure of rat hippocampal neurons or human D283 medulloblastoma cells to the apoptosis-inducing kinase inhibitor staurosporine induced rapid cytochrome c release from mitochondria and activation of the executioner caspase-3. Measurements of cellular tetramethylrhodamine ethyl ester fluorescence and subsequent simulation of fluorescence changes based on Nernst calculations of fluorescence in the extracellular, cytoplasmic, and mitochondrial compartments revealed that the release of cytochrome c was preceded by mitochondrial hyperpolarization. Overexpression of the anti-apoptotic protein Bcl-xL, but not pharmacological blockade of outward potassium currents, inhibited staurosporine-induced hyperpolarization and apoptosis. Dissipation of mitochondrial potassium and proton gradients by valinomycin or carbonyl cyanide p-trifluoromethoxy-phenylhydrazone also potently inhibited staurosporine-induced hyperpolarization, cytochrome c release, and caspase activation. This effect was not attributable to changes in cellular ATP levels. Prolonged exposure to valinomycin induced significant matrix swelling, and per se also caused release of cytochrome c from mitochondria. In contrast to staurosporine, however, valinomycin-induced cytochrome c release and cell death were not associated with caspase-3 activation and insensitive to Bcl-xL overexpression. Our data suggest two distinct mechanisms for mitochondrial cytochrome c release: (1) active cytochrome c release associated with early mitochondrial hyperpolarization, leading to neuronal apoptosis, and (2) passive cytochrome c release secondary to mitochondrial depolarization and matrix swelling

Calpains are downstream effectors of bax-dependent excitotoxic apoptosis.

Excitotoxicity resulting from excessive Ca(2+) influx through glutamate receptors contributes to neuronal injury after stroke, trauma, and seizures. Increased cytosolic Ca(2+) levels activate a family of calcium-dependent proteases with papain-like activity, the calpains. Here we investigated the role of calpain activation during NMDA-induced excitotoxic injury in embryonic (E16-E18) murine cortical neurons that (1) underwent excitotoxic necrosis, characterized by immediate deregulation of Ca(2+) homeostasis, a persistent depolarization of mitochondrial membrane potential (Δψ(m)), and insensitivity to bax-gene deletion, (2) underwent excitotoxic apoptosis, characterized by recovery of NMDA-induced cytosolic Ca(2+) increases, sensitivity to bax gene deletion, and delayed Δψ(m) depolarization and Ca(2+) deregulation, or (3) that were tolerant to excitotoxic injury. Interestingly, treatment with the calpain inhibitor calpeptin, overexpression of the endogenous calpain inhibitor calpastatin, or gene silencing of calpain protected neurons against excitotoxic apoptosis but did not influence excitotoxic necrosis. Calpeptin failed to exert a protective effect in bax-deficient neurons but protected bid-deficient neurons similarly to wild-type cells. To identify when calpains became activated during excitotoxic apoptosis, we monitored calpain activation dynamics by time-lapse fluorescence microscopy using a calpain-sensitive Förster resonance energy transfer probe. We observed a delayed calpain activation that occurred downstream of mitochondrial engagement and directly preceded neuronal death. In contrast, we could not detect significant calpain activity during excitotoxic necrosis or in neurons that were tolerant to excitotoxic injury. Oxygen/glucose deprivation-induced injury in organotypic hippocampal slice cultures confirmed that calpains were specifically activated during bax-dependent apoptosis and in this setting function as downstream cell-death executioners

Laying the foundations of community engagement in Aboriginal health research: establishing a community reference group and terms of reference in a novel research field

Background Community engagement or community involvement in Aboriginal health research is a process that involves partnering, collaborating and involving Aboriginal and Torres Strait Islander people or potential research participants to empower them to have a say in how research with Aboriginal communities is conducted. In the context of Aboriginal health, this is particularly important so that researchers can respond to the priorities of the community under study and conduct research in a way that is respectful of Aboriginal cultural values and beliefs. One approach to incorporating the principals of community engagement and to ensure cultural oversight and guidance to projects is to engage a community reference group. The aim of this study was to describe the process of establishing an Aboriginal community reference group and terms of reference. The community reference group was established to guide the research activities of a newly formed research collaboration aiming to to develop osteoarthritis care that meets the needs of Aboriginal and Torres Strait Islander people in Australia. Methods Adopting a Participatory Action Research approach, this two-phase study was conducted in Victoria, Australia. In phase one, semi-structured research yarns (a cultural form of conversation used as a data gathering tool) were conducted collaboratively by Aboriginal and non-Aboriginal co-investigators to explore Aboriginal health stakeholder perspectives on establishing a community reference group and terms of reference. In phase two, recommendations in phase one were identified to invite members to participate in the community reference group and to ratify the terms of reference through a focus group. Data were analyzed using a framework analysis approach. Results Thirteen people (eight female, four male) participated in phase one. Participants represented diverse professional backgrounds including physiotherapy, nursing, general practice, health services management, hospital liaison, cultural safety education, health research and the arts. Three themes were identified in phase one; Recruitment and Representation (trust and relationships, in-house call-outs, broad-spectrum expertise and Aboriginal majority); Purpose (community engagement, research steering, knowledge dissemination and advocacy) and; Function and Logistics (frequency and format of meetings, size of group, roles and responsibilities, authority, communication and dissemination). In phase two, six Aboriginal people were invited to become members of the community reference group who recommended changes which were incorporated into the seven domains of the terms of reference. Conclusion The findings of this study are captured in a 10-step framework which describes practical strategies for establishing a community reference group and terms of reference in Aboriginal health research

Understanding the impact and tackling the burden of osteoarthritis for Aboriginal and Torres Strait Islander people

Objective The aim of this study was to understand and describe the lived experience of Aboriginal and Torres Strait Islander people with osteoarthritis. Methods Qualitative study guided by cultural security, which ensures that research is conducted in a way that will not compromise the cultural values, beliefs, and expectations of Aboriginal and Torres Strait Islander people. Participants were purposively sampled through the networks of project staff. Research yarns (a cultural form of conversation used as a data gathering tool) were conducted with 25 Aboriginal and Torres Strait Islander adults with self-reported osteoarthritis in Western Australia and Victoria, Australia. Data were analyzed using a framework approach and presented through composite storytelling (hypothetical stories representing an amalgam of participants’ experiences). Results Two composite stories were constructed to reflect themes relating to beliefs and knowledge, impact, coping, and health care experiences. Common beliefs held by participants were that osteoarthritis is caused by previous physically active lifestyles. Many participants feared for their future, increasing disability and needing a wheelchair. Pain associated with osteoarthritis impacted daily activities, sleep, work, family, and social life and cultural activities. Multidimensional impacts were often experienced within complex health or life circumstances and associated with increased anxiety and depression. Most participants reported negative health care experiences, characterized by poor patient–provider communication. Conclusion Our findings highlight that osteoarthritis is a multidimensional issue for Aboriginal and Torres Strait Islander people that permeates all aspects of life and highlights the need for integrated, multidisciplinary care that is culturally informed and individualized to patient need

Sisyphus Cooling of Electrically Trapped Polyatomic Molecules

The rich internal structure and long-range dipole-dipole interactions establish polar molecules as unique instruments for quantum-controlled applications and fundamental investigations. Their potential fully unfolds at ultracold temperatures, where a plethora of effects is predicted in many-body physics, quantum information science, ultracold chemistry, and physics beyond the standard model. These objectives have inspired the development of a wide range of methods to produce cold molecular ensembles. However, cooling polyatomic molecules to ultracold temperatures has until now seemed intractable. Here we report on the experimental realization of opto-electrical cooling, a paradigm-changing cooling and accumulation method for polar molecules. Its key attribute is the removal of a large fraction of a molecule's kinetic energy in each step of the cooling cycle via a Sisyphus effect, allowing cooling with only few dissipative decay processes. We demonstrate its potential by reducing the temperature of about 10^6 trapped CH_3F molecules by a factor of 13.5, with the phase-space density increased by a factor of 29 or a factor of 70 discounting trap losses. In contrast to other cooling mechanisms, our scheme proceeds in a trap, cools in all three dimensions, and works for a large variety of polar molecules. With no fundamental temperature limit anticipated down to the photon-recoil temperature in the nanokelvin range, our method eliminates the primary hurdle in producing ultracold polyatomic molecules. The low temperatures, large molecule numbers and long trapping times up to 27 s will allow an interaction-dominated regime to be attained, enabling collision studies and investigation of evaporative cooling toward a BEC of polyatomic molecules

Bax regulates neuronal Ca2+ homeostasis

Excessive Ca(2+) entry during glutamate receptor overactivation (\u22excitotoxicity\u22) induces acute or delayed neuronal death. We report here that deficiency in bax exerted broad neuroprotection against excitotoxic injury and oxygen/glucose deprivation in mouse neocortical neuron cultures and reduced infarct size, necrotic injury, and cerebral edema formation after middle cerebral artery occlusion in mice. Neuronal Ca(2+) and mitochondrial membrane potential (Δψm) analysis during excitotoxic injury revealed that bax-deficient neurons showed significantly reduced Ca(2+) transients during the NMDA excitation period and did not exhibit the deregulation of Δψm that was observed in their wild-type (WT) counterparts. Reintroduction of bax or a bax mutant incapable of proapoptotic oligomerization equally restored neuronal Ca(2+) dynamics during NMDA excitation, suggesting that Bax controlled Ca(2+) signaling independently of its role in apoptosis execution. Quantitative confocal imaging of intracellular ATP or mitochondrial Ca(2+) levels using FRET-based sensors indicated that the effects of bax deficiency on Ca(2+) handling were not due to enhanced cellular bioenergetics or increased Ca(2+) uptake into mitochondria. We also observed that mitochondria isolated from WT or bax-deficient cells similarly underwent Ca(2+)-induced permeability transition. However, when Ca(2+) uptake into the sarco/endoplasmic reticulum was blocked with the Ca(2+)-ATPase inhibitor thapsigargin, bax-deficient neurons showed strongly elevated cytosolic Ca(2+) levels during NMDA excitation, suggesting that the ability of Bax to support dynamic ER Ca(2+) handling is critical for cell death signaling during periods of neuronal overexcitation