Critical limb ischemia is a manifestation of peripheral artery disease that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We ...previously discovered 2 overlapping quantitative trait loci in mice,
and
, that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a
variant (Ile81Met) segregates with tissue protection from hind-limb ischemia.
We treated mice with either adeno-associated viruses encoding a control (green fluorescent protein) or 2 BAG3 (Bcl-2-associated athanogene-3) variants, namely Met81 or Ile81, and subjected the mice to hind-limb ischemia.
We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of
(C.B6-
). BALB/c mice treated with adeno-associated virus encoding the BL6 BAG3 variant (Ile81; n=25) displayed reduced limb-tissue necrosis and increased limb tissue perfusion compared with Met81- (n=25) or green fluorescent protein- (n=29) expressing animals. BAG3
, but not BAG3
, improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of adeno-associated virus-BAG3
(n=9), but not BAG3
(n=10) or green fluorescent protein (n=5), improved ischemic limb blood flow and limb muscle histology and restored muscle function (force production). Compared with BAG3
, BAG3
displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux.
Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the setting of ischemia.
We model the governance strategies adopted by suppliers to safeguard relationship-specific investments in asymmetric interorganizational relationships using two dimensions: quasi integration and ...joint decision making. Data from a field study of 211 supplier-retailer relationships support the research model. Domain knowledge specificity arising from relationship-specific intellectual capital investments emerges as the most influential determinant of governance. The results provide preliminary but powerful evidence of the value of intangible assets in interorganizational relationships.
The problem of eliminating the effects of infinite cycles on asynchronous sequential machines is considered in a control theoretic context. The main objective is to develop state feedback controllers ...that stop infinite cycles in an existing asynchronous machine, while controlling the machine to match a prescribed model. Necessary and sufficient conditions for the existence of such controllers are derived in terms of an inequality condition between two numerical matrices. The results include an algorithm for the characterization of all infinite cycles of a given machine as well as an algorithm for the construction of appropriate controllers, whenever they exist.
Neuroinflammation initiated by damage-associated molecular patterns, including high mobility group box 1 protein (HMGB1), has been implicated in adverse neurological outcomes following lethal ...hemorrhagic shock and polytrauma. Emergency preservation and resuscitation (EPR) is a novel method of resuscitation for victims of exsanguinating cardiac arrest, shown in preclinical studies to improve survival with acceptable neurological recovery. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has emerged as a key regulator of metabolic and energy stress response pathways in the brain and a pharmacological target to induce a neuronal pro-survival phenotype. This study aims to examine whether systemic administration of an Annexin-A1 bioactive peptide (ANXA1sp) could resolve neuroinflammation and induce sirtuin-3 regulated cytoprotective pathways in a novel rat model of exsanguinating cardiac arrest and EPR. Adult male rats underwent hemorrhagic shock and ventricular fibrillation, induction of profound hypothermia, followed by resuscitation and rewarming using cardiopulmonary bypass (EPR). Animals randomly received ANXA1sp (3 mg/kg, in divided doses) or vehicle. Neuroinflammation (HMGB1, TNFα, IL-6, and IL-10 levels), cerebral cell death (TUNEL, caspase-3, pro and antiapoptotic protein levels), and neurologic scores were assessed to evaluate the inflammation resolving effects of ANXA1sp following EPR. Furthermore, western blot analysis and immunohistochemistry were used to interrogate the mechanisms involved. Compared to vehicle controls, ANXA1sp effectively reduced expression of cerebral HMGB1, IL-6, and TNFα and increased IL-10 expression, which were associated with improved neurological scores. ANXA1sp reversed EPR-induced increases in expression of proapoptotic protein Bax and reduction in antiapoptotic protein Bcl-2, with a corresponding decrease in cerebral levels of cleaved caspase-3. Furthermore, ANXA1sp induced autophagic flux (increased LC3II and reduced p62 expression) in the brain. Mechanistically, these findings were accompanied by upregulation of the mitochondrial protein deacetylase Sirtuin-3, and its downstream targets FOXO3a and MnSOD in ANXA1sp-treated animals. Our data provide new evidence that engaging pro-resolving pharmacological strategies such as Annexin-A1 biomimetic peptides can effectively attenuate neuroinflammation and enhance the neuroprotective effects of EPR after exsanguinating cardiac arrest.
Offshoring Without Guilt Venkatraman, N Venkat
MIT Sloan management review,
03/2004, Letnik:
45, Številka:
3
Journal Article
Recenzirano
Offshoring, the increasingly common practice among US and European companies of migrating business processes overseas to India, the Philippines, Ireland, China and elsewhere, is often seen as a ...negative phenomenon that suppresses domestic job markets. On the contrary, says the author, offshoring is a critical component of next-generation business design, a dynamic process of continually identifying how to deliver superior value to customers and shareholders. Companies such as General Electric, Intel, J.P. Morgan Chase, Allstate, Prudential, Dell, Cisco and Motorola have all adopted it in some form as they shift their managerial frames of reference toward the requirements of the global-network era. Companies would do well, the author advises, to think rationally - not emotionally - about offshoring's relevant issues: What are their core competencies? What form of governance is optimal? How will work be distributed and integrated? PUBLICATION ABSTRACT
This article explores the stability of the topological structure of the network of alliances between firms in the software sector during considerable shifts in the underlying technology architecture ...during 1990-2001. The software sector exhibits "small world" characteristics and its structure has been remarkably stable during this period. This article also offers lessons for managers to effectively master the challenges of navigating in dynamic networks.
Going beyond the traditional conceptualization of indirect network effects as the number of complements available, this study analyzes how the network positions of platforms and complementors explain ...platform dominance. We use data from the U.S. home video game industry between 2002 and 2006 to test our model of platform dominance. While the impact of degree of links with complementors representing the number of complements is significant, our study also finds that platform dominance is positively influenced by support from a greater breadth of titles by complementors and lesser degree of overlap with other platforms. We also find that ties with high-status complementors influence platform dominance, but this impact decreases with platform age. Our results suggest benefits to refine our conceptualization of indirect network effects from a network perspective. The managerial implications are that each platform provider needs to differentiate its platform by attracting high-status developers and by providing third-party developers with toolkits that encourage them to develop exclusive titles.
Xenon has been proven to be neuroprotective in experimental brain injury. The authors hypothesized that xenon would improve outcome from focal cerebral ischemia with a delayed treatment onset and ...prolonged recovery interval.
Rats were subjected to 70 min temporary focal ischemia. Ninety minutes later, rats were treated with 0, 15, 30, or 45% Xe for 20 h or 0 or 30% Xe for 8, 20, or 44 h. Outcome was measured after 7 days. In another experiment, after ischemia, rats were maintained at 37.5° or 36.0°C for 20 h with or without 30% Xe. Outcome was assessed 28 days later. Finally, mice were subjected to intracerebral hemorrhage with or without 30% Xe for 20 h. Brain water content, hematoma volume, rotarod function, and microglial activation were measured.
Cerebral infarct sizes (mean±SD) for 0, 15, 30, and 45% Xe were 212±27, 176±55, 160±32, and 198±54 mm, respectively (P=0.023). Neurologic scores (median±interquartile range) followed a similar pattern (P=0.002). Infarct size did not vary with treatment duration, but neurologic score improved (P=0.002) at all xenon exposure durations (8, 20, and 44 h). Postischemic treatment with either 30% Xe or subtherapeutic hypothermia (36°C) had no effect on 28-day outcome. Combination of these interventions provided long-term benefit. Xenon improved intracerebral hemorrhage outcome measures.
Xenon improved focal ischemic outcome at 7, but not 28 days postischemia. Xenon combined with subtherapeutic hypothermia produced sustained recovery benefit. Xenon improved intracerebral hemorrhage outcome. Xenon may have potential for clinical stroke therapy under carefully defined conditions.
This paper reports the results of a research study aimed at conceptualizing and developing valid measurements of key dimensions of a strategy construct—termed Strategic Orientation of Business ...Enterprises. This construct is first defined by addressing four theoretical questions of scope; hierarchical level; domain; and intentions versus realizations, and then conceptualized in terms of six dimensions. Subsequently, operational indicators are developed for the six dimensions in terms of managerial perceptions across 200 business units in a field study. An evaluation of the measurement properties within an analysis of covariance structures framework indicated that the operational measures developed here largely satisfy the criteria for unidimensionality, convergent, discriminant, and predictive validity. Implications and lines of extensions are outlined.
This paper seeks to uncover dominant configurations of interorganizational relationships across the United States and Japan in the automotive industry. We integrate relevant theoretical concepts from ...transaction cost economics, organization theory and political economy to develop a conceptual model of interorganizational relationships based on the fit between information processing needs and information processing capabilities. This model is employed to collect data on 447 buyer-supplier relationships in these two countries. We empirically uncover a set of five naturally occurring patterns of interorganizational relationships. These configurations provide rich explanations of the complexity of interorganizational relationships as well as offer differential insights across United States and Japan. We discuss implications for further research pertaining to the logic and development of configurations.
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