Domestic chickens activate a piRNA defense against avian leukosis virus

PIWI-interacting RNAs (piRNAs) protect the germ line by targeting transposable elements (TEs) through the base-pair complementarity. We do not know how piRNAs co-evolve with TEs in chickens. Here we reported that all active TEs in the chicken germ line are targeted by piRNAs, and as TEs lose their activity, the corresponding piRNAs erode away. We observed de novo piRNA birth as host responds to a recent retroviral invasion. Avian leukosis virus (ALV) has endogenized prior to chicken domestication, remains infectious, and threatens poultry industry. Domestic fowl produce piRNAs targeting ALV from one ALV provirus that was known to render its host ALV resistant. This proviral locus does not produce piRNAs in undomesticated wild chickens. Our findings uncover rapid piRNA evolution reflecting contemporary TE activity, identify a new piRNA acquisition modality by activating a pre-existing genomic locus, and extend piRNA defense roles to include the period when endogenous retroviruses are still infectious. DOI: http://dx.doi.org/10.7554/eLife.24695.00

The extraordinary evolutionary history of the reticuloendotheliosis viruses

The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events

Conserved presence of G-quadruplex forming sequences in the Long Terminal Repeat Promoter of Lentiviruses

G-quadruplexes (G4s) are secondary structures of nucleic acids that epigenetically regulate cellular processes. In the human immunodeficiency lentivirus 1 (HIV-1), dynamic G4s are located in the unique viral LTR promoter. Folding of HIV-1 LTR G4s inhibits viral transcription; stabilization by G4 ligands intensifies this effect. Cellular proteins modulate viral transcription by inducing/unfolding LTR G4s. We here expanded our investigation on the presence of LTR G4s to all lentiviruses. G4s in the 5'-LTR U3 region were completely conserved in primate lentiviruses. A G4 was also present in a cattle-infecting lentivirus. All other non-primate lentiviruses displayed hints of less stable G4s. In primate lentiviruses, the possibility to fold into G4s was highly conserved among strains. LTR G4 sequences were very similar among phylogenetically related primate viruses, while they increasingly differed in viruses that diverged early from a common ancestor. A strong correlation between primate lentivirus LTR G4s and Sp1/NF\u3baB binding sites was found. All LTR G4s folded: their complexity was assessed by polymerase stop assay. Our data support a role of the lentiviruses 5'-LTR G4 region as control centre of viral transcription, where folding/unfolding of G4s and multiple recruitment of factors based on both sequence and structure may take place

Research into the Health Benefits of Sprint Interval Training Should Focus on Protocols with Fewer and Shorter Sprints

Over the past decade, it has been convincingly shown that regularly performing repeated brief supramaximal cycle sprints (sprint interval training [SIT]) is associated with aerobic adaptations and health benefits similar to or greater than with moderate-intensity continuous training (MICT). SIT is often promoted as a time-efficient exercise strategy, but the most commonly studied SIT protocol (4–6 repeated 30-s Wingate sprints with 4 min recovery, here referred to as ‘classic’ SIT) takes up to approximately 30 min per session. Combined with high associated perceived exertion, this makes classic SIT unsuitable as an alternative/adjunct to current exercise recommendations involving MICT. However, there are no indications that the design of the classic SIT protocol has been based on considerations regarding the lowest number or shortest duration of sprints to optimise time efficiency while retaining the associated health benefits. In recent years, studies have shown that novel SIT protocols with both fewer and shorter sprints are efficacious at improving important risk factors of noncommunicable diseases in sedentary individuals, and provide health benefits that are no worse than those associated with classic SIT. These shorter/easier protocols have the potential to remove many of the common barriers to exercise in the general population. Thus, based on the evidence summarised in this current opinion paper, we propose that there is a need for a fundamental change in focus in SIT research in order to move away from further characterising the classic SIT protocol and towards establishing acceptable and effective protocols that involve minimal sprint durations and repetitions

Seasonal changes and population dynamics of the ctenophore Mnemiopsis leidyi after its first year of invasion in the Kiel Fjord, Western Baltic Sea

We analyzed the seasonal variations of the ctenophore Mnemiopsis leidyi weekly collected since its first record in the western Baltic Sea in October 2006. The distribution pattern together with the seasonal dynamics and population outbreaks in late summer 2007 indicate recent successfully establishment of M. leidyi in this area. Seasonal changes showed two periods of high reproductive activity characterized by a population structure dominated by small size classes, followed by an increase of larger ones. These results further revealed that the bulk of the population remains in deep layers during the periods of low population density, whereas it appeared situated in upper layers during the proliferation of the species. We further emphasized the strength of the population outbreaks, which can reach abundances >10-fold higher in time periods shorter than a week. The predatory impact this species may have in pelagic ecosystems warns on the importance of its recent range of expansion

The relationship between white matter microstructure and self-perceived cognitive decline

Subjective cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer's disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis. Vanderbilt Memory & Aging Project participants with diffusion MRI data and a 45-item measure of SCD were included [n = 236, 137 cognitively unimpaired (CU), 99 with mild cognitive impairment (MCI), 73 ± 7 years, 37% female]. A subset of participants (64 CU, 40 MCI) underwent a fasting lumbar puncture for quantification of cerebrospinal fluid (CSF) amyloid-β(CSF Aβ42), total tau (CSF t-tau), and phosphorylated tau (CSF p-tau). Diffusion MRI data was post-processed using the free-water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive-related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto-parietal tracts using a region of interest approach. General linear modeling related each tract to SCD scores adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE ε4 carrier status, diagnosis, Geriatric Depression Scale scores, hippocampal volume, and total white matter volume. Competitive models were analyzed to determine if white matter microstructural values have a unique role in SCD scores separate from CSF Aβ42. FW-corrected radial diffusivity (RDT) was related to SCD scores in 8 tracts: cingulum bundle, inferior longitudinal fasciculus, as well as inferior frontal gyrus (IFG) pars opercularis, IFG orbitalis, IFG pars triangularis, tapetum, medial frontal gyrus, and middle frontal gyrus transcallosal tracts. While CSF Aβ42 was related to SCD scores in our cohort (Radj2 = 39.03%; β = −0.231; p = 0.020), competitive models revealed that fornix and IFG pars triangularis transcallosal tract RDT contributed unique variance to SCD scores beyond CSF Aβ42 (Radj2 = 44.35% and Radj2 = 43.09%, respectively), with several other tract measures demonstrating nominal significance. All tracts which demonstrated nominal significance (in addition to covariates) were input into a backwards stepwise regression analysis. ILF RDT, fornix RDT, and UF FW were best associated with SCD scores (Radj2 = 46.69%; p = 6.37 × 10-12). Ultimately, we found that medial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD scores independent of early amyloid deposition. Our results highlight the potential importance of abnormal white matter diffusivity as an early contributor to cognitive decline. These results also highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline

Cerebrospinal fluid and plasma neurofilament light relate to abnormal cognition

Introduction Neuroaxonal damage may contribute to cognitive changes preceding clinical dementia. Accessible biomarkers are critical for detecting such damage. Methods Plasma and cerebrospinal fluid (CSF) neurofilament light (NFL) were related to neuropsychological performance among Vanderbilt Memory & Aging Project participants (plasma n = 333, 73 ± 7 years; CSF n = 149, 72 ± 6 years) ranging from normal cognition (NC) to mild cognitive impairment (MCI). Models adjusted for age, sex, race/ethnicity, education, apolipoprotein E ε4 carriership, and Framingham Stroke Risk Profile. Results Plasma NFL was related to all domains (P values ≤ .008) except processing speed (P values ≥ .09). CSF NFL was related to memory and language (P values ≤ .04). Interactions with cognitive diagnosis revealed widespread plasma associations, particularly in MCI participants, which were further supported in head-to-head comparison models. Discussion Plasma and CSF NFL (reflecting neuroaxonal injury) relate to cognition among non-demented older adults albeit with small to medium effects. Plasma NFL shows particular promise as an accessible biomarker with relevance to cognition in MCI

Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences

INTRODUCTION: While Alzheimer’s disease (AD) is divided into severity stages, mild cognitive impairment (MCI) remains a solitary construct despite clinical and prognostic heterogeneity. This study aimed to characterize differences in genetic, cerebrospinal fluid (CSF), neuroimaging, and neuropsychological markers across clinician-derived MCI stages. METHODS: Vanderbilt Memory & Aging Project participants with MCI were categorized into 3 severity subtypes at screening based on neuropsychological assessment, functional assessment, and Clinical Dementia Rating interview, including mild (n = 18, 75 ± 8 years), moderate (n = 89 72 ± 7 years), and severe subtypes (n = 18, 78 ± 8 years). At enrollment, participants underwent neuropsychological testing, 3T brain magnetic resonance imaging (MRI), and optional fasting lumbar puncture to obtain CSF. Neuropsychological testing and MRI were repeated at 18-months, 3-years, and 5-years with a mean follow-up time of 3.3 years. Ordinary least square regressions examined cross-sectional associations between MCI severity and apolipoprotein E (APOE)-ε4 status, CSF biomarkers of amyloid beta (Aβ), phosphorylated tau, total tau, and synaptic dysfunction (neurogranin), baseline neuroimaging biomarkers, and baseline neuropsychological performance. Longitudinal associations between baseline MCI severity and neuroimaging and neuropsychological trajectory were assessed using linear mixed effects models with random intercepts and slopes and a follow-up time interaction. Analyses adjusted for baseline age, sex, race/ethnicity, education, and intracranial volume for MRI models. RESULTS: Stages differed at baseline on APOE-ε4 status (early middle = late), phosphorylated and total tau (early = middle < late; p-values < 0.05), and neurogranin concentrations (early = middle < late; p-values < 0.05). MCI stage related to greater longitudinal cognitive decline, hippocampal atrophy, and inferior lateral ventricle dilation (early < late; p-values < 0.03). DISCUSSION: Clinician staging of MCI severity yielded longitudinal cognitive trajectory and structural neuroimaging differences in regions susceptible to AD neuropathology and neurodegeneration. As expected, participants with more severe MCI symptoms at study entry had greater cognitive decline and gray matter atrophy over time. Differences are likely attributable to baseline differences in amyloidosis, tau, and synaptic dysfunction. MCI staging may provide insight into underlying pathology, prognosis, and therapeutic targets

Evaluation of the ClearVoice Strategy in Adults Using HiResolution Fidelity 120 Sound Processing

ObjectivesThis study aimed to evaluate the benefits of ClearVoice strategy on speech perception in noise and in everyday listening situations in Cantonese-speaking cochlear implant users.MethodsTwelve experienced adult users of the Harmony implant and HiRes 120 sound processing participated in the study. The study employed a prospective within-subjects design wherein speech recognition in adults using HiRes 120 without ClearVoice turned on (control option) was compared to their performance with HiRes 120 with ClearVoice turned on. Each subject was evaluated with two different ClearVoice gain settings: -12 dB (ClearVoice medium) and -18 dB (ClearVoice high) after one-week of use. The Cantonese hearing in noise test and a questionnaire were used as the outcome measures.ResultsSubjects performed significantly better with ClearVoice medium than with control option in noise. No significant difference in performance was noted among the 3 settings in quiet. Most subjects reported high level of satisfaction with ClearVoice in daily listening situations and preferred to keep ClearVoice on.ConclusionClearVoice can help cochlear implant recipients to hear better in noise

Lower Left Ventricular Ejection Fraction Relates to Cerebrospinal Fluid Biomarker Evidence of Neurodegeneration in Older Adults

BACKGROUND: Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer's disease (AD) pathology and neurodegeneration. OBJECTIVE: This study investigates the association between subclinical cardiac dysfunction, measured by left ventricular ejection fraction (LVEF), and cerebrospinal fluid (CSF) biomarkers of AD and neurodegeneration. METHODS: Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n = 152, 72±6 years, 68% male) underwent echocardiogram to quantify LVEF and lumbar puncture to measure CSF levels of amyloid-β42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau). Linear regressions related LVEF to CSF biomarkers, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E ɛ4 status. Secondary models tested an LVEF x cognitive diagnosis interaction and then stratified by diagnosis (normal cognitive (NC), mild cognitive impairment (MCI)). RESULTS: Higher LVEF related to decreased CSF Aβ42 levels (β= -6.50, p = 0.04) reflecting greater cerebral amyloid accumulation, but this counterintuitive result was attenuated after excluding participants with cardiovascular disease and atrial fibrillation (p = 0.07). We observed an interaction between LVEF and cognitive diagnosis on CSF t-tau (p = 0.004) and p-tau levels (p = 0.002), whereas lower LVEF was associated with increased CSF t-tau (β= -9.74, p = 0.01) and p-tau in the NC (β= -1.41, p = 0.003) but not MCI participants (p-values>0.13). CONCLUSIONS: Among cognitively normal older adults, subclinically lower LVEF relates to greater molecular evidence of tau phosphorylation and neurodegeneration. Modest age-related changes in cardiovascular function may have implications for pathophysiological changes in the brain later in life