The guanylate kinase domain of the beta-subunit of voltage-gated calcium channels suffices to modulate gating

Inactivation of voltage-gated calcium channels is crucial for the spatiotemporal coordination of calcium signals and prevention of toxic calcium buildup. Only one member of the highly conserved family of calcium channel β-subunits—Ca_Vβ—inhibits inactivation. This unique property has been attributed to short variable regions of the protein; however, here we report that this inhibition actually is conferred by a conserved guanylate kinase (GK) domain and, moreover, that this domain alone recapitulates Ca_Vβ-mediated modulation of channel activation. We expressed and refolded the GK domain of Ca_Vβ_2a, the unique variant that inhibits inactivation, and of Ca_Vβ_1b, an isoform that facilitates it. The refolded domains of both Ca_Vβ variants were found to inhibit inactivation of Ca_V2.3 channels expressed in Xenopus laevis oocytes. These findings suggest that the GK domain endows calcium channels with a brake restraining voltage-dependent inactivation, and thus facilitation of inactivation by full-length Ca_Vβ requires additional structural determinants to antagonize the GK effect. We found that Ca_Vβ can switch the inactivation phenotype conferred to Ca_V2.3 from slow to fast after posttranslational modifications during channel biogenesis. Our findings provide a framework within which to understand the modulation of inactivation and a new functional map of Ca_Vβ in which the GK domain regulates channel gating and the other conserved domain (Src homology 3) may couple calcium channels to other signaling pathways.     

Clinical correlation of asbestos bodies in BAL fluid

BACKGROUND: Asbestos bodies (AB) in BAL cells are specific markers of asbestos exposure. METHODS: We retrospectively reviewed BAL cytocentrifuge slides of 30 utility workers with a history of asbestos exposure and 30 normal volunteers. BAL cytocentrifuge slides were blinded and scanned under 40 x light microscope. RESULTS: AB were found more frequently in subjects with a history of asbestos exposure compared to normal volunteers (10 of 30 subjects, 33%, vs 0 of 30 subjects). The mean number of AB seen in the AB-positive group was 2.7 per slide. Demographic data were comparable including age, gender, and smoking. Exposure histories were also similar: duration > 20 years, onset > 30 years ago, and time since last exposure > 7 years. More AB-positive patients reported respiratory symptoms (70% vs 26%, p < 0.05). High-resolution CT scans of AB-positive patients revealed a higher prevalence of parenchymal disease (70% vs 26%, p < 0.05). AB-positive subjects had reduced pulmonary function compared to AB-negative subjects: FVC (86% vs 97% predicted), FEV(1) (77% vs 92% predicted, p < 0.05), and diffusion capacity of the lung for carbon monoxide (76% vs 104% predicted, p < 0.01). CONCLUSION: In individuals with a history of asbestos exposure, the presence of AB in BAL cells is associated with higher prevalence of parenchymal abnormalities, respiratory symptoms, and reduced pulmonary function.     

Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism

Limiting dysfunctional neutrophilic inflammation while preserving effective immunity requires a better understanding of the processes that dictate neutrophil function in the tissues. Quantitative mass-spectrometry identified how inflammatory murine neutrophils regulated expression of cell surface receptors, signal transduction networks, and metabolic machinery to shape neutrophil phenotypes in response to hypoxia. Through the tracing of labeled amino acids into metabolic enzymes, proinflammatory mediators, and granule proteins, we demonstrated that ongoing protein synthesis shapes the neutrophil proteome. To maintain energy supplies in the tissues, neutrophils consumed extracellular proteins to fuel central carbon metabolism. The physiological stresses of hypoxia and hypoglycemia, characteristic of inflamed tissues, promoted this extracellular protein scavenging with activation of the lysosomal compartment, further driving exploitation of the protein-rich inflammatory milieu. This study provides a comprehensive map of neutrophil proteomes, analysis of which has led to the identification of active catabolic and anabolic pathways that enable neutrophils to sustain synthetic and effector functions in the tissues.     

Perception of cancer recurrence risk: More information is better

Objective

Breast cancer is the most common cancer among women worldwide. Given the advances in extending survival, the number of recently diagnosed breast cancer patients and longer-term breast cancer survivors is growing. The goals of this study were to better understand (1) perceptions of provider cancer recurrence risk communication, (2) perceived risk of breast cancer recurrence in cancer patients and survivors, and (3) accuracy of perceived risk.

Methods

A survey was conducted on women with a prior breast cancer (n = 141).

Results

Approximately 40% of women perceived that providers had not talked about their breast cancer recurrence risk; although only 1 person reported not wanting a physician to talk to her about her risk. Women were largely inaccurate in their assessments of risk. Greater worry, living in a rural area, and longer time since diagnosis were associated with greater inaccuracy. Women tended to think about distal recurrence of cancer as often of local recurrence.

Conclusions

Perceived risk of breast cancer recurrence was inaccurate, and patients desired more communication about recurrence risk.

Practice implications

Consistent with findings from other studies, greater efforts are needed to improve the communication of cancer recurrence risk to patients. Attention should be paid to those from rural areas and to distal cancer recurrence in women with a previous history of breast cancer.     

Further specimens of the Asian tiger mosquito Aedes albopictus (Diptera, Culicidae) trapped in southwest Germany

After two previous demonstrations of introductions of the Asian tiger mosquito, Aedes albopictus, into southern Germany in 2007 and 2011, another three specimens were trapped in the city of Freiburg in the Upper Rhine Valley. The females were caught in early September 2011 (n?=?2) and mid-July 2012 (n?=?1). The trap was located at a railway container station where cargo is transferred to trains from trucks predominantly coming from southern Europe where A. albopictus is widely distributed. The reported findings confirm vehicle transport of A. albopictus to be an important and probably frequent mode of importation, and suggest that more regular and intense monitoring for invasive mosquito species in the Upper Rhine Valley should be undertaken in order to detect an establishment and implement adequate control measures in good time.     

The BAFF Receptor Transduces Survival Signals by Co-opting the B Cell Receptor Signaling Pathway

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Highlights? Inducible loss of the Syk tyrosine kinase results in death of follicular B cells ? Syk transduces survival signals from BAFFR to the ERK and PI3 kinase-PDK1 pathways ? BAFFR signaling results in phosphorylation of Igα and Syk ? BAFFR transduces signals via the BCR to activation of Syk