Emerging evidence suggests that many proteins may be regulated through cysteine modification, but the extent and functions of this signaling remain largely unclear. The endoplasmic reticulum (ER) ...transmembrane protein IRE-1 maintains ER homeostasis by initiating the unfolded protein response (UPRER). Here we show in C. elegans and human cells that IRE-1 has a distinct redox-regulated function in cytoplasmic homeostasis. Reactive oxygen species (ROS) that are generated at the ER or by mitochondria sulfenylate a cysteine within the IRE-1 kinase activation loop. This inhibits the IRE-1-mediated UPRER and initiates the p38/SKN-1(Nrf2) antioxidant response, thereby increasing stress resistance and lifespan. Many AGC-family kinases (AKT, p70S6K, PKC, ROCK1) seem to be regulated similarly. The data reveal that IRE-1 has an ancient function as a cytoplasmic sentinel that activates p38 and SKN-1(Nrf2) and indicate that cysteine modifications induced by ROS signals can direct proteins to adopt unexpected functions and may coordinate many cellular processes.
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•The ER stress sensor IRE-1 has a distinct function in cytoplasmic homeostasis•Local redox signals block IRE-1 ER signaling by sulfenylating a kinase cysteine•This functional switch initiates the p38/SKN-1(Nrf2) antioxidant response at IRE-1•The IRE-1 paradigm implies broad and versatile functions for signaling at cysteines
We report that the transmembrane endoplasmic reticulum (ER) stress sensor IRE-1 has a redox-regulated cytoplasmic signaling function. Localized ROS sulfenylate an IRE-1 cysteine, inhibiting its ER functions and initiating the antioxidant response. IRE-1 therefore monitors cytoplasmic homeostasis through localized ROS signaling, suggesting that cysteine modifications have broad and diverse regulatory functions.
Recent regional tree die-off events appear to have been triggered by a combination of drought and heat – referred to as ‘global-change-type drought’. To complement experiments focused on resolving ...mechanisms of drought-induced tree mortality, an evaluation of how patterns of tree die-off relate to highly spatially variable precipitation is needed.
Here, we explore precipitation relationships with a die-off event of pinyon pine (Pinus edulis Engelm.) in southwestern North America during the 2002–2003 global-change-type drought. Pinyon die-off and its relationship with precipitation was quantified spatially along a precipitation gradient in north-central New Mexico with standard field plot measurements of die-off combined with canopy cover derived from normalized burn ratio (NBR) from Landsat imagery.
Pinyon die-off patterns revealed threshold responses to precipitation (cumulative 2002– 2003) and vapor pressure deficit (VPD), with little to no mortality (> 10%) above 600mm and below warm season VPD of c. 1.7 kPa. Correction added after online publication 17 June 2013; in the preceding sentence, the word ‘below’ has been inserted.
Our results refine how precipitation patterns within a region influence pinyon die-off, revealing a precipitation and VPD threshold for tree mortality and its uncertainty band where other factors probably come into play – a response type that influences stand demography and landscape heterogeneity and is of general interest, yet has not been documented.
Mucocele‐like lesions of the breast diagnosed on core biopsy are usually excised to exclude the possibility of partial sampling of an invasive mucinous carcinoma. The goal of this study was to ...correlate the pathologic and radiologic features of mucocele‐like lesions to determine if excision is mandatory. Over a 16 year period we identified 32 patients with mucocele‐like lesions diagnosed on 27 (84%) stereotactic and 5 (16%) ultrasound‐guided core biopsies. The indications for core biopsy were: calcifications in 24 (75%), a mass in 7 (22%), and a mass with calcifications in 1 (3%). There were 22 (69%) mucocele‐like lesions without atypia and 10 (31%) with atypical ductal hyperplasia or detached groups of atypical cells. Of the 22 mucocele‐like lesions without atypia, 19 (86%) were excised: 15/19 (79%) were benign, 3/19 (16%) had atypical ductal hyperplasia and 1/19 (5%) had ductal carcinoma in situ. None of the patients with mucocele‐like lesions without atypia were upgraded to invasive carcinoma. The single patient who was upgraded to low‐grade ductal carcinoma in situ had a history of ductal carcinoma in situ in the same breast. Of the 10 patients with mucocele‐like lesions with atypia, 9 (90%) were excised: 5/9 (56%) were benign, 1/9 (11%) had atypical ductal hyperplasia and 3/9 (33%) had invasive carcinoma. Of the patients with mucocele‐like lesions with atypia who were upgraded to invasive carcinoma, one had a BIRADS 5 mass and discordant pathology and one had a history of Hodgkin lymphoma and mantle radiation. There were 24 patients with mucocele‐like lesions with or without atypia who were not upgraded on excision, and none developed breast cancer after a median of 51 months (range 7‐192). These findings indicate that mucocele‐like lesions without atypia are unlikely to be upgraded on excision and are associated with a low risk for the subsequent development of carcinoma.
The reticulon (Rtn) family of proteins are localized primarily to the endoplasmic reticulum (ER) of most cells. The Rtn-4 family, (aka Nogo) consists of 3 splice variants of a common gene called ...Rtn-4A, Rtn-4B, and Rtn-4C. Recently, we identified the Rtn-4B (Nogo-B) protein in endothelial and smooth muscle cells of the vessel wall, and showed that Nogo-B is a regulator of cell migration in vitro and vascular remodeling and angiogenesis in vivo. However, the role of Nogo-B in inflammation is still largely unknown. In the present study, we use 2 models of inflammation to show that endothelial Nogo-B regulates leukocyte transmigration and intercellular adhesion molecule-1 (ICAM-1)–dependent signaling. Mice lacking Nogo-A/B have a marked reduction in neutrophil and monocyte recruitment to sites of inflammation, while Nogo-A/B−/− mice engrafted with wild-type (WT) bone marrow still exhibit impaired inflammation compared with WT mice engrafted with Nogo-A/B−/− bone marrow, arguing for a critical role of host Nogo in this response. Using human leukocytes and endothelial cells, we show mechanistically that the silencing of Nogo-B with small interfering RNA (siRNA) impairs the transmigration of neutrophils and reduces ICAM-1–stimulated phosphorylation of vascular endothelial-cell cadherin (VE-cadherin). Our results reveal a novel role of endothelial Nogo-B in basic immune functions and provide a key link in the molecular network governing endothelial-cell regulation of diapedesis.
PurposeThe purpose of this paper is to address assumptions about the prevalence of change in human resource management (HRM) and organizational change literature, providing evidence from employee ...perceptions across three countries. The results indicate change was commonplace even before the pandemic disruptions of 2020.Design/methodology/approachGiven this study's exploratory, employee perspective, a cross-sectional self-report survey was used. Three survey panel samples were collected in 2017: US (n = 718), Australia (n = 501) and New Zealand (n = 516). Analysis of variance was used to test whether the prevalence of change differed significantly between countries or specific groups of employees. An analysis of comments on change types and emotional response provides further insights.FindingsThe paper provides evidence of the ubiquity of change: 73% of employees are experiencing change at work and 42% perceived it as moderate to massive, with little variation between countries. Employees commonly experience more than one change, with those experiencing large amounts of change reporting predominantly negative emotional impacts.Research limitations/implicationsThe research provides a snapshot across three countries during a prosperous and relatively stable period, providing a point of comparison for the turbulent times we have faced in 2020. Since change can be arduous, the authors recommend that HRM researchers consider change prevalence as a contextual factor, and practitioners heed employee reactions to change, particularly during periods of significant change.Originality/valueIn providing foundational evidence of change ubiquity in contemporary workplaces, this paper enables more accurate discussions regarding change.
Blood vessel formation during ischemia and wound healing requires coordination of the inflammatory response with genes that regulate blood vessel assembly. Here we show that the reticulon family ...member 4B, aka Nogo-B, is upregulated in response to ischemia and is necessary for blood flow recovery secondary to ischemia and wound healing. Mice lacking Nogo-B exhibit reduced arteriogenesis and angiogenesis that are linked to a decrease in macrophage infiltration and inflammatory gene expression in vivo. Bone marrow-derived macrophages isolated from Nogo knock-out mice have reduced spreading and chemotaxis due to impaired Rac activation. Bone marrow reconstitution experiments show that Nogo in myeloid cells is necessary to promote macrophage homing and functional recovery after limb ischemia. Thus, endogenous Nogo coordinates macrophage-mediated inflammation with arteriogenesis, wound healing, and blood flow control.
Nogo-B is a member of the reticulon family of proteins that has been implicated in diverse forms of vascular injury. Although Nogo-B is expressed in renal tissues, its localization and function in ...the kidney have not been examined. Here, we report that Nogo-B is expressed specifically in the epithelial cells of the distal nephron segments in the murine kidney. After unilateral ureteral obstruction (UUO) and ischemia/reperfusion, Nogo-B gene and protein levels increased dramatically in the kidney. This increase was driven in part by injury-induced de novo expression in proximal tubules. Examination of Nogo-B immunostaining in human biopsy specimens from patients with acute tubular necrosis showed similar increases in Nogo-B in cortical tubules. Mice genetically deficient in Nogo-A/B were indistinguishable from wild-type (WT) mice based on histological appearance and serum analyses. After UUO, there was a significant delay in recruitment of macrophages to the kidney in the Nogo-A/B–deficient mice. However, measurements of fibrosis, inflammatory gene expression, and histological damage were not significantly different from WT mice. Thus, Nogo-B is highly expressed in murine kidneys in response to experimental injuries and may serve as a marker of diverse forms of renal injury in tissues from mice and humans. Furthermore, Nogo-B may regulate macrophage recruitment after UUO, although it does not greatly affect the degree of tissue injury or fibrosis in this model.
Nogo-B is a member of the reticulon family of proteins (RTN-4B) that is highly expressed in lung tissue; however, its function remains unknown. We show that mice with Th2-driven lung inflammation ...results in a loss of Nogo expression in airway epithelium and smooth muscle compared with nonallergic mice, a finding which is replicated in severe human asthma. Mice lacking Nogo-A/B (Nogo-KO) display an exaggerated asthma-like phenotype, and epithelial reconstitution of Nogo-B in transgenic mice blunts Th2-mediated lung inflammation. Microarray analysis of lungs from Nogo-KO mice reveals a marked reduction in palate lung and nasal clone (PLUNC) gene expression, and the levels of PLUNC are enhanced in epithelial Nogo-B transgenic mice. Finally, transgenic expression of PLUNC into Nogo-KO mice rescues the enhanced asthmatic-like responsiveness in these KO mice. These data identify Nogo-B as a novel protective gene expressed in lung epithelia, and its expression regulates the levels of the antibacterial antiinflammatory protein PLUNC.
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