In this task, you are given a passage which has a question and the context. You have to generate an answer to the question based on the information present in the context.

Q: Context: The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial.', 'We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA).', 'We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001).\Question: Are de novo donor-specific HLA antibodies associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation?

A: Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA.
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Q: Context: Strontium ranelate reduces fracture risk in postmenopausal women with osteoporosis. Evidence from non-clinical studies and analyses of bone markers in phase III trials indicate that this is due to an increase in osteoblast formation and a decrease of osteoclastic resorption. The aim of this work was to investigate, in human cells, the mechanisms by which strontium ranelate is able to influence the activities of osteoblasts and osteoclasts.', 'Human primary osteoblasts were used to examine effects of strontium ranelate on replication (thymidine incorporation), differentiation (Runx2 and alkaline phosphatase) and cell survival (cell counts and caspase activity). Osteoprotegerin (OPG) was measured by quantitative reverse transcription PCR (qRT-PCR) and elisa and receptor activator of NFkappaB ligand (RANKL) by qRT-PCR and Western blot. As strontium ranelate has been proposed as an agonist of the calcium-sensing receptor (CaSR), the involvement of CaSR in the effects of strontium ranelate on OPG and RANKL expression, and cell replication was examined using siRNA.', 'Strontium ranelate increased mRNA and protein levels of OPG and suppressed those of RANKL. Strontium ranelate also stimulated osteoblast replication and differentiation and increased cell survival under stress. Knocking down CaSR suppressed strontium ranelate-induced stimulation of OPG mRNA, reduction of RANKL mRNA, and increase in replication, indicating the involvement of CaSR in these responses.\Question: Do osteoblasts play key roles in the mechanisms of action of strontium ranelate?

A: Our results demonstrate that osteoblasts play a key role in the mechanism of action of the anti-fracture agent, strontium ranelate by mediating both its anabolic and anti-resorptive actions, at least in part, via activation of CaSR.
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Q: Context: Declines in skeletal muscle structure and function are found in various clinical populations, but the intramuscular proteolytic pathways that govern declines in these individuals remain relatively poorly understood. The nematode Caenorhabditis elegans has been developed into a model for identifying and understanding these pathways. Recently, it was reported that UNC-105/degenerin channel activation produced muscle protein degradation via an unknown mechanism.', 'Generation of transgenic and double mutant C.elegans, RNAi, and drug treatments were utilized to assess molecular events governing protein degradation. Western blots were used to measure protein content. Cationic dyes and adenosine triphosphate (ATP) production assays were utilized to measure mitochondrial function.', 'unc-105 gain-of-function mutants display aberrant muscle protein degradation and a movement defect; both are reduced in intragenic revertants and in let-2 mutants that gate the hyperactive UNC-105 channel. Degradation is not suppressed by interventions suppressing proteasome-mediated, autophagy-mediated, or calpain-mediated degradation nor by suppressors of degenerin-induced neurodegeneration. Protein degradation, but not the movement defect, is decreased by treatment with caspase inhibitors or RNAi against ced-3 or ced-4. Adult unc-105 muscles display a time-dependent fragmentation of the mitochondrial reticulum that is associated with impaired mitochondrial membrane potential and that correlates with decreased rates of maximal ATP production. Reduced levels of CED-4, which is sufficient to activate CED-3 in vitro, are observed in unc-105 mitochondrial isolations.\Question: Does degenerin channel activation cause caspase-mediated protein degradation and mitochondrial dysfunction in adult C. elegans muscle?

A:
Constitutive cationic influx into muscle appears to cause caspase degradation of cytosolic proteins as the result of mitochondrial dysfunction, which may be relevant to ageing and sarcopenia.
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