Early childhood lung function is a stronger predictor of adolescent lung function in cystic fibrosis than early Pseudomonas aeruginosa infection

Pseudomonas aeruginosa has been suggested as a major determinant of poor pulmonary outcomes in cystic fibrosis (CF), although other factors play a role. Our objective was to investigate the association of early childhood Pseudomonas infection on differences in lung function in adolescence with CF

The Lived Experiences of Students and Faculty of a Christian College who Participated in a Short-term International Mission Trip

Short-term international mission trips (STIMTs) are increasing in popularity. Likewise, educators and health care workers are increasingly concerned with obtaining an understanding that improves culturally competent care. The purpose of this study was to investigate the lived experiences of participants of a Christian college who travelled on a short-term international mission trip (STIMT). One openended inquiry guided the interviews: How would you describe your experience as a participant who travelled on a STIMT? An in-depth, oneon- one interview of participants occurred until data saturation was reached. Colaizzi’s strategy was used to analyze and organize the data. Leininger’s sunrise model was used to guide this study. Themes that emerged from this study included cultural adaptation, relationships, spiritual factors, and personal gain

Inhibition of a Secreted Immune Molecule Interferes With Termite Social Immunity

Social immune behaviors are described in a great variety of insect societies and their role in preventing emerging infectious diseases has become a major topic in insect research. The social immune system consists of multiple layers, ranging from the synthesis of external immune molecules to the coordination of individual behaviors into sophisticated collective defensive tasks. But our understanding of how complex group-level behavioral defenses are orchestrated has remained limited. We sought to address this gap in knowledge by investigating the relationship between the external activity of an important immune effector molecule in termites, Gram negative binding protein 2 (GNBP-2) and collective grooming and cannibalism. We reasoned that as an external enzyme capable of degrading entomopathogenic fungi, GNBP-2 can facilitate the spread of pathogenic molecules in the colony, and thus serve to trigger collective defenses in a manner analogous to pathogen-associated molecular signatures (PAMPs) of the individual immune system. To test whether GNBP-2 could play a role in regulating social immune behavior, we experimentally inhibited its fungicidal activity using the glycomimetic molecule, D-d-gluconolactone (GDL) and recorded collective behavioral responses to an infected nestmate. Contrary to expectations, GNBP-2 inhibition did not influence the rate or intensity of grooming of either control or fungus-infected nestmates. By contrast, we found that the probability of being harmed through defensive cannibalistic behaviors was significantly reduced by the inhibition of GNBP-2. Our findings indicate that the regulation of collective immune behaviors may depend in part on the external secretion of an enzyme originating from the individual immune system, but that other cues are also necessary

Mechanical compression regulates tumor spheroid invasion into a 3D collagen matrix

Uncontrolled growth of tumor cells in confined spaces leads to the accumulation of compressive stress within the tumor. Although the effects of tension within 3D extracellular matrices on tumor growth and invasion are well established, the role of compression in tumor mechanics and invasion is largely unexplored. In this study, we modified a Transwell assay such that it provides constant compressive loads to spheroids embedded within a collagen matrix. We used microscopic imaging to follow the single cell dynamics of the cells within the spheroids, as well as invasion into the 3D extracellular matrices (EMCs). Our experimental results showed that malignant breast tumor (MDA-MB-231) and non-tumorigenic epithelial (MCF10A) spheroids responded differently to a constant compression. Cells within the malignant spheroids became more motile within the spheroids and invaded more into the ECM under compression; whereas cells within non-tumorigenic MCF10A spheroids became less motile within the spheroids and did not display apparent detachment from the spheroids under compression. These findings suggest that compression may play differential roles in healthy and pathogenic epithelial tissues and highlights the importance of tumor mechanics and invasion.Comment: 10 pages, 5 figure and 3 supplementary figure

Osteocytic connexin 43 is not required for the increase in bone mass induced by intermittent PTH administration in male mice

Objective: To investigate whether osteocytic connexin 43 (Cx43) is required for the bone response to intermittent PTH administration, and whether the connexin is involved in maintaining the bone matrix. Methods: Human PTH(1-34) was injected to adult male mice expressing (Cx43fl/fl) or not osteocytic Cx43 (Cx43fl/fl;DMP1-8kb-Cre) daily (100 μg/kg/d) for 14 days. Results: Cx43fl/fl;DMP1-8kb-Cre mice have no difference in body weight and BMD from 1 to 4 months of age. Intermittent PTH administration increased BMD and BV/TV and induced a similar increase in type I collagen, alkaline phosphatase, runx2, osteocalcin, and bone sialoprotein expression in mice from both genotypes. On the other hand, osteocytic deletion of Cx43 did not alter mRNA levels of glycosaminoglycans, proteoglycans, collagens and osteoblast-related genes. In addition, expression of collagens assessed by immunohistochemistry was not affected by deleting osteocytic Cx43. However, PTH administration increased type II collagen only in Cx43fl/fl control mice, whereas hormone increased type I collagen expression only in Cx43fl/fl;DMP1-8kb-Cre mice. Furthermore, PTH increased maturity of collagen fibers in control, but not in Cx43-deficient mice. Conclusion: Expression of Cx43 in osteocytes is dispensable for bone anabolism induced by intermittent PTH administration; but it can modulate, at least in part, the effect of PTH on the bone matrix environment

Dysregulation of metabolic-associated pathways in muscle of breast cancer patients: preclinical evaluation of interleukin-15 targeting fatigue

Background Breast cancer patients report a perception of increased muscle fatigue, which can persist following surgery and standardized therapies. In a clinical experiment, we tested the hypothesis that pathways regulating skeletal muscle fatigue are down-regulated in skeletal muscle of breast cancer patients and that different muscle gene expression patterns exist between breast tumour subtypes. In a preclinical study, we tested the hypothesis that mammary tumour growth in mice induces skeletal muscle fatigue and that overexpression of the cytokine interleukin-15 (IL-15) can attenuate mammary tumourinduced muscle fatigue. Methods Early stage non-metastatic female breast cancer patients (n = 14) and female non-cancer patients (n = 6) provided a muscle biopsy of the pectoralis major muscle during mastectomy, lumpectomy, or breast reconstruction surgeries. The breast cancer patients were diagnosed with either luminal (ER+ /PR+ , n = 6), triple positive (ER+ /PR+ /Her2/neu+ , n = 5), or triple negative (ER/PR/Her2/neu, n = 3) breast tumours and were being treated with curative intent either with neoadjuvant chemotherapy followed by surgery or surgery followed by standard post-operative therapy. Biopsies were used for RNA-sequencing to compare the skeletal muscle gene expression patterns between breast cancer patients and non-cancer patients. The C57BL/6 mouse syngeneic mammary tumour cell line, E0771, was used to induce mammary tumours in immunocompetent mice, and isometric muscle contractile properties and fatigue properties were analysed following 4 weeks of tumour growth. Results RNA-sequencing and subsequent bioinformatics analyses revealed a dysregulation of canonical pathways involved in oxidative phosphorylation, mitochondrial dysfunction, peroxisome proliferator-activated receptor signalling and activation, and IL-15 signalling and production. In a preclinical mouse model of breast cancer, the rate of muscle fatigue was greater in mice exposed to mammary tumour growth for 4 weeks, and this greater muscle fatigue was attenuated in transgenic mice that overexpressed the cytokine IL-15. Conclusions Our data identify novel genes and pathways dysregulated in the muscles of breast cancer patients with early stage non-metastatic disease, with particularly aberrant expression among genes that would predispose these patients to greater muscle fatigue. Furthermore, we demonstrate that IL-15 overexpression can attenuate muscle fatigue associated with mammary tumour growth in a preclinical mouse model of breast cancer. Therefore, we propose that skeletal muscle fatigue is an inherent consequence of breast tumour growth, and this greater fatigue can be targeted therapeutically

Effects of immunization against bone morphogenetic protein-15 and growth differentiation factor-9 on ovarian function in mares

Currently there is no contraceptive vaccine that can cause permanent sterility in mares. This study investigates the effect of vaccination against oocyte-specific growth factors, Bone Morphogenetic Protein 15 (BMP-15) and Growth Differentiation Factor 9 (GDF-9), on ovarian function of mares. It was hypothesized that immunization against these growth factors would prevent ovulation and/or accelerate depletion of the oocyte reserve. For this study, 30 mares were randomly assigned to three groups (n=10/group) and vaccinated with BMP-15 or GDF-9 peptides conjugated to KLH and adjuvant, or a control of phosphate buffered saline and adjuvant. Horses received vaccinations at weeks 0, 6, 12, and 18. Ovarian activity and estrous behavior were evaluated 3 days a week via ultrasonography and interaction with a stallion. The study was initiated on March1, 2016. Upon evaluation of ovulation rate, the GDF-9 group did not have a difference (P=0.66) in ovulation rate when compared to controls (10.8 and 10.0 ovulations, respectively), but the number of ovulations in the BMP-15 group was less (P=0.02; 4.9 ovulations). Average follicle size prior to ovulation was less (P \u3c 0.0001) in both treatment groups compared to controls. Estrous behavior was altered in both the BMP-15 and GDF-9 groups compared to controls after the second vaccination (P=0.05 and 0.03, respectively). Although further research is required to determine the continued effects of vaccination against GDF-9 on ovulation rates, these results indicate that vaccination against BMP-15 and GDF-9 could serve as a contraceptive in wild horse populations

Reversal of loss of bone mass in old mice treated with mefloquine

Aging is accompanied by imbalanced bone remodeling, elevated osteocyte apoptosis, and decreased bone mass and mechanical properties; and improved pharmacologic approaches to counteract bone deterioration with aging are needed. We examined herein the effect of mefloquine, a drug used to treat malaria and systemic lupus erythematosus and shown to ameliorate bone loss in glucocorticoid-treated patients, on bone mass and mechanical properties in young and old mice. Young 3.5-month-old and old 21-month-old female C57BL/6 mice received daily injections of 5 mg/kg/day mefloquine for 14 days. Aging resulted in the expected changes in bone volume and mechanical properties. In old mice mefloquine administration reversed the lower vertebral cancellous bone volume and bone formation; and had modest effects on cortical bone volume, thickness, and moment of inertia. Mefloquine administration did not change the levels of the circulating bone formation markers P1NP or alkaline phosphatase, whereas levels of the resorption marker CTX showed trends towards increase with mefloquine treatment. In addition, and as expected, aging bones exhibited an accumulation of active caspase3-expressing osteocytes and higher expression of apoptosis-related genes compared to young mice, which were not altered by mefloquine administration at either age. In young animals, mefloquine induced higher periosteal bone formation, but lower endocortical bone formation. Further, osteoclast numbers were higher on the endocortical bone surface and circulating CTX levels were increased, in mefloquine- compared to vehicle-treated young mice. Consistent with this, addition of mefloquine to bone marrow cells isolated from young mice led to increased osteoclastic gene expression and a tendency towards increased osteoclast numbers in vitro. Taken together our findings identify the age and bone-site specific skeletal effects of mefloquine. Further, our results highlight a beneficial effect of mefloquine administration on vertebral cancellous bone mass in old animals, raising the possibility of using this pharmacologic inhibitor to preserve skeletal health with aging

Cognition in older adults in Uganda: Correlates, trends over time and association with mortality in prospective population study.

Dementia is an important and growing issue in sub-Saharan Africa, but epidemiological data are lacking. Risk factors may differ from other regions due to high stroke incidence and HIV prevalence. Understanding the epidemiology of cognition in older adults in Africa is crucial for informing public health strategies to improve the lives of people with dementia and their carers. The Wellbeing of Older People Study in Uganda is an open cohort of adults aged 50+ with and without HIV, established in 2009. Detailed socio-demographic and health data have been collected at four waves spanning 10 years, including cognitive assessment using internationally validated WHO-recommended tests: verbal recall, digit span, and verbal fluency. Mortality data was collected until the end of the fourth wave (2019). We examined associations of low baseline cognition scores and changes in cognition score over time using random effects modelling, care needs of people with lower cognition scores, and the relationship between cognition score and mortality. Data were collected on 811 participants. Older age, lower educational attainment, lower socio-economic position, and extremes of BMI were associated with lower cognition scores. Cognition scores declined faster at older ages, but rate of decline was not associated with cardiovascular disease or HIV at baseline. People with lower cognition scores required more assistance with Activities of Daily Living, but mortality rates were similar across the range of cognition scores. The crucial next step will be to investigate types and presentation of clinical dementia in this cohort, so we can better understand the clinical relevance of these findings to inform public health planning

The yeast molecular chaperone, Hsp104, influences transthyretin aggregate formation

Patients with the fatal disorder Transthyretin Amyloidosis (ATTR) experience polyneuropathy through the progressive destruction of peripheral nervous tissue. In these patients, the transthyretin (TTR) protein dissociates from its functional tetrameric structure, misfolds, and aggregates into extracellular amyloid deposits that are associated with disease progression. These aggregates form large fibrillar structures as well as shorter oligomeric aggregates that are suspected to be cytotoxic. Several studies have shown that these extracellular TTR aggregates enter the cell and accumulate intracellularly, which is associated with increased proteostasis response. However, there are limited experimental models to study how proteostasis influences internalized TTR aggregates. Here, we use a humanized yeast system to recapitulate intracellular TTR aggregating protein in vivo. The yeast molecular chaperone Hsp104 is a disaggregase that has been shown to fragment amyloidogenic aggregates associated with certain yeast prions and reduce protein aggregation associated with human neurogenerative diseases. In yeast, we found that TTR forms both SDS-resistant oligomers and SDS-sensitive large molecular weight complexes. In actively dividing cultures, Hsp104 has no impact on oligomeric or large aggregate populations, yet overexpression of Hsp104 is loosely associated with an increase in overall aggregate size. Interestingly, a potentiating mutation in the middle domain of Hsp104 consistently results in an increase in overall TTR aggregate size. These data suggest a novel approach to aggregate management, where the Hsp104 variant shifts aggregate populations away from toxic oligomeric species to more inert larger aggregates. In aged cultures Hsp104 overexpression has no impact on TTR aggregation profiles suggesting that these chaperone approaches to shift aggregate populations are not effective with age, possibly due to proteostasis decline