Affinity maturation refines a naive B-cell response by selecting mutations in antibody variable domains that enhance antigen binding. We describe a B-cell lineage expressing broadly neutralizing ...influenza virus antibodies derived from a subject immunized with the 2007 trivalent vaccine. The lineage comprises three mature antibodies, the unmutated common ancestor, and a common intermediate. Their heavy-chain complementarity determining region inserts into the conserved receptor-binding pocket of influenza HA. We show by analysis of structures, binding kinetics and long time-scale molecular dynamics simulations that antibody evolution in this lineage has rigidified the initially flexible heavy-chain complementarity determining region by two nearly independent pathways and that this preconfiguration accounts for most of the affinity gain. The results advance our understanding of strategies for developing more broadly effective influenza vaccines.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
In recent decades, plantations of exotic species have transformed large tracts of forested landscapes, where they often form a mosaic with the surrounding native forest. Wildfires have also increased ...in frequency and intensity globally, impacting both plantation and native forests and affecting soil organic matter (SOM), including dissolved organic matter (DOM). DOM of soils is considered highly labile and likely sensitive to effects of fire and changes in land use. However, it is unclear how wildfire influences key characteristics of DOM in exotic plantations compared to native forest. In this study, we investigated the impacts of wildfire on chemical properties of DOM in exotic Pinus radiata plantations and adjacent native jarrah (Eucalyptus marginata) forest in southwest Australia. We coupled fluorescence excitation-emission matrix parallel factor analysis (EEM-PARAFAC) and 1H‐NMR with soil nutrient analyses to characterise soil DOM (0–5 cm) from burned and unburned plots of each forest type, four months after the fire. Four fluorescent components (humic-, fulvic-, microbial and protein-like substances) were derived from soil DOM using the PARAFAC model. DOM from burnt forest soils was predominantly of lower molecular weight (E2:E3) and contained a greater microbial-derived component and a lower fulvic component than unburnt forest. As expected, soil pH and labile inorganic P increased in both forest types after fire. By contrast, an increase in the amount of DOC after fire was only recorded in native forest, while δ15N signatures were more enriched in pine plantation soils after fire but not in native forest soils. Differences in impacts of fire on DOC and δ15N between forest types suggest a different response to fire according forest type, even though these differences were not evident above ground. The 1H NMR spectra of DOM revealed all samples were largely dominated by aliphatic structures. However, there were no significant differences in the overall spectra between forest types or between burnt and unburnt forests. Overall, our findings suggest that transformations in soil DOM after fire were affected by feedbacks between forest type and fire (where soils from pine plantations appeared to be more affected by fire).
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•Fire reduced the molecular weight of DOM in both native and exotic forest.•Fire increased microbial-like components in both forest types.•Fire did not increase the aromatic region of 1H NMR or SUVA254 in both forest types.•Differences in soil properties suggested differences in response to fire between forest types.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and Purpose
Patients with irritable bowel syndrome suffer from chronic visceral pain (CVP) and limited analgesic therapeutic options are currently available. We have shown that α‐conotoxin ...Vc1.1 induced activation of GABAB receptors on the peripheral endings of colonic afferents and reduced nociceptive signalling from the viscera. However, the analgesic efficacy of more stable, cyclized versions of Vc1.1 on CVP remains to be determined.
Experimental Approach
Using ex vivo colonic afferent preparations from mice, we determined the inhibitory actions of cyclized Vc1.1 (cVc1.1) and two cVc1.1 analogues on mouse colonic nociceptors in healthy and chronic visceral hypersensitivity (CVH) states. Using whole‐cell patch clamp recordings, we also assessed the inhibitory actions of these peptides on the neuronal excitability of colonic innervating dorsal root ganglion neurons. In vivo, the analgesic efficacy of these analogues was assessed by determining the visceromotor response to colorectal distension in healthy and CVH mice.
Key Results
cVc1.1 and the cVc1.1 analogues, C2H,C8FcVc1.1 and N9WcVc1.1, all caused concentration‐dependent inhibition of colonic nociceptors from healthy mice. Inhibition by these peptides was greater than those evoked by linear Vc1.1 and was substantially greater in colonic nociceptors from CVH mice. cVc1.1 also reduced excitability of colonic dorsal root ganglion neurons, with greater effect in CVH neurons. CVH mice treated with cVc1.1 intra‐colonically displayed reduced pain responses to noxious colorectal distension compared with vehicle‐treated CVH mice.
Conclusions and Implications
Cyclic versions of Vc1.1 evoked significant anti‐nociceptive actions in CVH states, suggesting that they could be novel candidates for treatment of CVP.
Linked Articles
This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Individuals with COPD and preserved ratio impaired spirometry (PRISm) findings in clinical settings have an increased risk of cardiovascular disease (CVD).
Do individuals with mild to moderate or ...worse COPD and PRISm findings in community settings have a higher prevalence and incidence of CVD compared with individuals with normal spirometry findings? Can CVD risk scores be improved when impaired spirometry is added?
The analysis was embedded in the Canadian Cohort Obstructive Lung Disease (CanCOLD). Prevalence of CVD (ischemic heart disease IHD and heart failure HF) and their incidence over 6.3 years were compared between groups with impaired and normal spirometry findings using logistic regression and Cox models, respectively, adjusting for covariables. Discrimination of the pooled cohort equations (PCE) and Framingham risk score (FRS) in predicting CVD were assessed with and without impaired spirometry.
Participants (n = 1,561) included 726 people with normal spirometry findings and 835 people with impaired spirometry findings (COPD Global Initiative for Chronic Obstructive Lung Disease GOLD stage 1 disease, n = 408; GOLD stage ≥ 2, n = 331; PRISm findings, n = 96). Rates of undiagnosed COPD were 84% in GOLD stage 1 and 58% in GOLD stage ≥ 2 groups. Prevalence of CVD (IHD or HF) was significantly higher among individuals with impaired spirometry findings and COPD compared with those with normal spirometry findings, with ORs of 1.66 (95% CI, 1.13-2.43; P = .01∗) (∗ indicates statistical significane with P < .05) and 1.55 (95% CI, 1.04-2.31; P = .033∗), respectively. Prevalence of CVD was significantly higher in participants having PRISm findings and COPD GOLD stage ≥ 2, but not GOLD stage 1. CVD incidence was significantly higher, with hazard ratios of 2.07 (95% CI, 1.10-3.91; P = .024∗) for the impaired spirometry group and 2.09 (95% CI, 1.10-3.98; P = .024∗) for the COPD group compared to individuals with normal spirometry findings. The difference was significantly higher among individuals with COPD GOLD stage ≥ 2, but not GOLD stage 1. The discrimination for predicting CVD was low and limited when impaired spirometry findings were added to either risk score.
Individuals with impaired spirometry findings, especially those with moderate or worse COPD and PRISm findings, have increased comorbid CVD compared with their peers with normal spirometry findings, and having COPD increases the risk of CVD developing.
Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences ...on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h
), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h
for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10
, FOXP1; rs10262462, p = 3.24 × 10
, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h
for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r
= 0.0025; p = 1.8 × 10
). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (r
= 0.70, p = 4.65 × 10
), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.
A 48-year-old man presented to a neurologist with complaints of bilateral hearing loss and tinnitus. The patient was a member of a large family affected by neurofibromatosis type 2 and first noted ...hearing loss 10 years before presentation.
Medical and neurological examination, MRI scan of the brain and spinal cord, pure-tone audiometry, NU-6 monosyllabic word test with phoneme scoring, City University of New York topic-related sentences test, noise/voice test of minimal auditory capability battery.
Progressive neurofibromatosis-type-2-related vestibular schwannomas.
Annual cranial MRI and audiology, surgical resection of right vestibular schwannoma, high-power behind-the-ear hearing aid, erlotinib therapy for progressive left vestibular schwannoma.
Immigration Give Me Your Rich, Your Lucky Lacayo, Richard; Cray, Dan; O''Donnell, Moira M ...
Time (Chicago, Ill.),
10/1991, Volume:
138, Issue:
15
Magazine Article
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Esta Red de cooperación, creada en 2010, constituye una estrategia política eficaz para la consolidación del Sistema de Investigación en el sector salud. Así lo demuestran los avances realizados en ...la creación de nuevas áreas ministeriales, la regulación de aspectos éticos y el registro de la investigación a nivel provincia
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