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Context: Dietary fiber intake may relate to bone health.Objective: To investigate whether dietary fiber intake is associated with bone mineral density (BMD), and the modification effect of genetic variations related to gut microbiota-derived short-chain fatty acids (SCFAs).Design: The associations of dietary fiber intake with estimated BMD derived from heel ultrasound and fractures were assessed in 224 630 and 384 134 participants from the UK Biobank.Setting: UK Biobank.Main Outcome Measures: Estimated BMD derived from heel ultrasound.Results: Higher dietary fiber intake (per standard deviation) was significantly associated with higher heel-BMD (β [standard error] = 0.0047 [0.0003], P = 1.10 × 10-54). Similarly significant associations were observed for all the fiber subtypes including cereal, fruit (dried and raw), and vegetable (cooked and raw) (all P < .05). A positive association was found in both women and men but more marked among men except for dietary fiber in cooked vegetables (all Pinteraction < .05). A protective association was found between dietary fiber intake and hip fracture (hazard ratio, 95% confidence interval: 0.94, 0.89-0.99; P = 3.0 × 10-2). In addition, the association between dietary fiber and heel BMD was modified by genetically determined SCFA propionate production (Pinteraction = 5.1 × 10-3). The protective association between dietary fiber and heel BMD was more pronounced among participants with lower genetically determined propionate production.Conclusions: Our results indicate that greater intakes of total dietary fiber and subtypes from various food sources are associated with higher heel-BMD. Participants with lower genetically determined propionate production may benefit more from taking more dietary fiber. [ABSTRACT FROM AUTHOR]

Background: Data on how respiratory syncytial virus (RSV) genotypes influence disease severity and host immune responses is limited. Here, we characterized the genetic variability of RSV during 5 seasons, and evaluated the role of RSV subtypes, genotypes, and viral loads in disease severity and host transcriptional profiles.Methods: A prospective, observational study was carried out, including a convenience sample of healthy infants hospitalized with RSV bronchiolitis. Nasopharyngeal samples for viral load quantitation, typing, and genotyping, and blood samples for transcriptome analyses were obtained within 24 hours of hospitalization. Multivariate models were constructed to identify virologic and clinical variables predictive of clinical outcomes.Results: We enrolled 253 infants (median age 2.1 [25%-75% interquartile range] months). RSV A infections predominated over RSV B and showed greater genotype variability. RSV A/GA2, A/GA5, and RSV B/BA were the most common genotypes identified. Compared to GA2 or BA, infants with GA5 infections had higher viral loads. GA5 infections were associated with longer hospital stay, and with less activation of interferon and increased overexpression of neutrophil genes.Conclusions: RSV A infections were more frequent than RSV B, and displayed greater variability. GA5 infections were associated with enhanced disease severity and distinct host immune responses. [ABSTRACT FROM AUTHOR]

With aging, there is a decline in cardiac function accompanying increasing risk of arrhythmias. These effects are likely to be mechanistically associated with age-associated changes in calcium regulation within cardiac myocytes. Previous studies suggest that lifelong exercise can potentially reduce age-associated changes in the heart. Although exercise itself is associated with changes in cardiac function, little is known about the interactions of aging and exercise with respect to myocyte calcium regulation. To investigate this, adult (12 months) and old (24 months) C57/Bl6 mice were trained using moderate-intensity treadmill running. In response to 10 weeks' training, comparable cardiac hypertrophic responses were observed, although aging independently associated with additional cardiac hypertrophy. Old animals also showed increased L- and T-type calcium channels, the sodium-calcium exchange, sarcoendoplasmic reticulum calcium ATPase, and collagen (by 50%, 92%, 66%, 88%, and 113% respectively). Short-term exercise training increased D-type and T-type calcium channels in old animals only, whereas an increase in sodium-calcium exchange was seen only in adult animals. Long-term (12 months) training generally opposed the effects of aging. Significant hypertrophy remained in long-term trained old animals, but levels of sarcoendoplasmic reticulum calcium ATPase, sodium-calcium exchange, and collagen were not significantly different from those found in the adult trained animals. [ABSTRACT FROM AUTHOR]

Background: The anti-angiogenic Sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance limits its efficacy. An emerging theory to explain intrinsic resistance to other anti-angiogenic drugs is 'vessel co-option,' ie, the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thus limiting the need for sprouting angiogenesis. Vessel co-option has not been evaluated as a potential mechanism for acquired resistance to anti-angiogenic agents.Methods: To study sorafenib resistance mechanisms, we used an orthotopic human HCC model (n = 4-11 per group), where tumor cells are tagged with a secreted protein biomarker to monitor disease burden and response to therapy. Histopathology, vessel perfusion assessed by contrast-enhanced ultrasound, and miRNA sequencing and quantitative real-time polymerase chain reaction were used to monitor changes in tumor biology.Results: While sorafenib initially inhibited angiogenesis and stabilized tumor growth, no angiogenic 'rebound' effect was observed during development of resistance unless therapy was stopped. Instead, resistant tumors became more locally infiltrative, which facilitated extensive incorporation of liver parenchyma and the co-option of liver-associated vessels. Up to 75% (±10.9%) of total vessels were provided by vessel co-option in resistant tumors relative to 23.3% (±10.3%) in untreated controls. miRNA sequencing implicated pro-invasive signaling and epithelial-to-mesenchymal-like transition during resistance development while functional imaging further supported a shift from angiogenesis to vessel co-option.Conclusions: This is the first documentation of vessel co-option as a mechanism of acquired resistance to anti-angiogenic therapy and could have important implications including the potential therapeutic benefits of targeting vessel co-option in conjunction with vascular endothelial growth factor receptor signaling. [ABSTRACT FROM AUTHOR]

Background: Cryptococcal meningitis remains a significant cause of death among human immunodeficiency virus type 1 (HIV)-infected persons in Africa. We aimed to better understand the pathogenesis and identify immune correlates of mortality, particularly the role of monocyte activation.Methods: A prospective cohort study was conducted in Cape Town, South Africa. Patients with a first episode of cryptococcal meningitis were enrolled, and their immune responses were assessed in unstimulated and stimulated blood specimens, using flow cytometry and cytokine analysis.Results: Sixty participants were enrolled (median CD4(+) T-cell count, 34 cells/µL). Mortality was 23% (14 of 60 participants) at 14 days and 39% (22 of 57) at 12 weeks. Nonsurvivors were more likely to have an altered consciousness and higher cerebrospinal fluid fungal burden at presentation. Principal component analysis identified an immune signature associated with early mortality, characterized by monocyte deactivation (reduced HLA-DR expression and tumor necrosis factor α response to lipopolysaccharide); increased serum interleukin 6, CXCL10, and interleukin 10 levels; increased neutrophil counts; and decreased T-helper cell type 1 responses. This immune signature remained an independent predictor of early mortality after adjustment for consciousness level and fungal burden and was associated with higher serum titers of cryptococcal glucuronoxylomannan.Conclusions: Cryptococcal-related mortality is associated with monocyte deactivation and an antiinflammatory blood immune signature, possibly due to Cryptococcus modulation of the host immune response. Validation in other cohorts is required. [ABSTRACT FROM AUTHOR]

Henipaviruses are zoonotic viruses that can cause severe and acute respiratory diseases and encephalitis in humans. To date, no vaccine or treatments are approved for human use. The presence of neutralizing antibodies is a strong correlate of protection against lethal disease in animals. However, since RNA viruses are prone to high mutation rates, the possibility that these viruses will escape neutralization remains a potential concern. In the present study, we generated neutralization-escape mutants, using 6 different monoclonal antibodies, and studied the effect of these neutralization-escape mutations on in vitro and in vivo fitness. These data provide a mechanism for overcoming neutralization escape by use of cocktails of cross-neutralizing monoclonal antibodies that recognize residues within the glycoprotein that are important for virus replication and virulence. [ABSTRACT FROM AUTHOR]

Decline in mitochondrial DNA (mtDNA) copy number, function, and accumulation of mutations and deletions have been proposed to contribute to age-related physical decline, based on cross sectional studies in genetically unrelated individuals. There is wide variability of mtDNA and functional measurements in many population studies and therefore we assessed mitochondrial function and physical function in 18 families of grandmothers, mothers, and daughters who share the same maternally inherited mtDNA sequence. A significant age-related decline in mtDNA copy number, mitochondrial protein expression, citrate synthase activity, cytochrome c oxidase content, and VO2 peak were observed. Also, a lower abundance of SIRT3, accompanied by an increase in acetylated skeletal muscle proteins, was observed in grandmothers. Muscle tissue-based full sequencing of mtDNA showed greater than 5% change in minor allele frequency over a lifetime in two locations, position 189 and 408 in the noncoding D-loop region but no changes were noted in blood cells mtDNA. The decline in oxidative capacity and muscle function with age in three generations of women who share the same mtDNA sequence are associated with a decline in muscle mtDNA copy number and reduced protein deacetylase activity of SIRT3. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial dysfunction is a prominent hallmark of many sensory neuropathies. The purpose of this study was to assess the influence of mitochondrial DNA sequence variation on peripheral nerve function in the population-based Health, Aging, and Body Composition Study.Methods: We investigated the role of common mitochondrial DNA variation (n = 1,580) and complete mitochondrial DNA sequences (n = 138) on peroneal motor nerve conduction velocity and amplitude, average vibration detection threshold, and monofilament sensitivity.Results: Nominal associations among common mitochondrial DNA variants and haplogroups were identified but were not statistically significant after adjustment for multiple comparisons. Sequence-based approaches were used to identify aggregate variant associations across the 16S rRNA (weighted-sum, p = 2E-05 and variable threshold, p = 9E-06) for nerve conduction velocity. Several of these rare 16S variants occurred at or near sites with earlier disease associations and are also in close proximity to the peptidyl transferase center, which is the catalytic center of the 16S rRNA CONCLUSIONS: These results suggest that sequence variation related to mitochondrial protein synthesis/assembly is associated with peripheral nerve function and may provide insight into targets for intervention or new clinical strategies to preserve nerve function in late life. [ABSTRACT FROM AUTHOR]

Objective. A large number of genes, including several not previously implicated in SLE susceptibility, have recently been identified or confirmed by genome-wide association studies (GWAS). In this study, we sought to replicate some of these results in Finnish SLE patients (n = 275) and control individuals (n = 356).Methods. We genotyped 32 single nucleotide polymorphisms (SNPs) in 12 of the best-supported GWAS-identified SLE genes and loci. We further investigated gene–gene interactions between the loci included in the study.Results. The strongest evidence of association was found at the IRF5-TNPO3 locus, with the most significant P-value being 2.0 × 10−7 and an odds ratio of 1.95 (95% CI 1.51, 2.50). Association between SLE and TNFAIP3, FAM167A-BLK, BANK1 and KIAA1542 was also confirmed, although at a lower significance level and contribution to individual risk. No significant association was found with 1q25.1, PXK, ATG5, ICA1, XKR6, LYN and SCUBE1. Furthermore, no significant gene–gene interactions were detected.Conclusion. Replication of previous GWAS findings across diverse populations is of importance to validate these associations and to get a better understanding of potential genetic heterogeneity between populations in SLE susceptibility. Our results attest the importance of B-cell receptor pathway and IFN signalling in SLE pathogenesis. [ABSTRACT FROM PUBLISHER]

Objectives. To determine whether increased levels of B-cell activating factor (BAFF) in patients with SLE are due to disease activity or genetic variations in the promoter region of the BAFF gene and BAFF gene expression.Methods. The case–control study included 101 SLE patients and 111 healthy controls. Five single nucleotide polymorphisms (SNPs) in the BAFF promoter region were investigated by melting point analysis: c.-2841 (T > C), c.-2704 (T > C), c.-2701 (A > T), c.-871 (C > T) and c.-514 (A > G). BAFF mRNA levels were determined by real-time PCR (BAFF-RQ) and serum BAFF (s-BAFF) levels were measured by ELISA. Independent predictors that might be correlated with increased s-BAFF in SLE patients were analysed by multivariate regression methods.Results. Although s-BAFF levels were increased in SLE patients (1.73 vs 0.98 ng/μl, P < 0.001), no specific BAFF genotype was found to associate with SLE. The different genotypes defined by the investigated SNPs were identified both in SLE patients and healthy controls with similar frequencies. No association was found between BAFF genotype and BAFF-RQ. s-BAFF was independent of other factors, correlated with CRP (β = 0.40, P < 0.001) and physician's visual analogue score (R = 0.21, P = 0.046) and inversely with haemoglobin (β = −0.32, P < 0.001) and IgA (β = −0.33, P = 0.001).Conclusions. Increased s-BAFF levels in SLE patients are associated with the acute-phase responses, CRP and haemoglobin, but probably not dependent on BAFF genotype or expression. This indicates that s-BAFF production occurs at sites of inflammation. [ABSTRACT FROM PUBLISHER]