The understanding that organelles are not floating in the cytosol, but rather held in an organized yet dynamic interplay through membrane contact sites, is altering the way we grasp cell biological ...phenomena. However, we still have not identified the entire repertoire of contact sites, their tethering molecules and functions. To systematically characterize contact sites and their tethering molecules here we employ a proximity detection method based on split fluorophores and discover four potential new yeast contact sites. We then focus on a little-studied yet highly disease-relevant contact, the Peroxisome-Mitochondria (PerMit) proximity, and uncover and characterize two tether proteins: Fzo1 and Pex34. We genetically expand the PerMit contact site and demonstrate a physiological function in β-oxidation of fatty acids. Our work showcases how systematic analysis of contact site machinery and functions can deepen our understanding of these structures in health and disease.
Highlights • We examined effects of intranasal oxytocin on resting-state functional connectivity. • Young and older men and women either self-administered oxytocin or placebo. • Oxytocin increased ...amygdala–mPFC coupling at rest for young women. • No significant modulatory effect of oxytocin in the other age-by-sex subgroups. • Age- and sex-specific neurobiological change impact oxytocin's effect at rest.
The hippocampus is one of the most well studied structures in the human brain. While age-related decline in hippocampal volume is well documented, most of our knowledge about hippocampal ...structure-function relationships was discovered in the context of neurological and neurodegenerative diseases. The relationship between cognitive aging and hippocampal structure in the absence of disease remains relatively understudied. Furthermore, the few studies that have investigated the role of the hippocampus in cognitive aging have produced contradictory results. To address these issues, we assessed 93 older adults from the general community (mean age = 71.9 ± 9.3 years) on the Montreal Cognitive Assessment (MoCA), a brief cognitive screening measure for dementia, and the NIH Toolbox-Cognitive Battery (NIHTB-CB), a computerized neurocognitive battery. High-resolution structural magnetic resonance imaging (MRI) was used to estimate hippocampal volume. Lower MoCA Total (
= 0.01) and NIHTB-CB Fluid Cognition (
< 0.001) scores were associated with decreased hippocampal volume, even while controlling for sex and years of education. Decreased hippocampal volume was significantly associated with decline in multiple NIHTB-CB subdomains, including episodic memory, working memory, processing speed and executive function. This study provides important insight into the multifaceted role of the hippocampus in cognitive aging.
Marked improvements in survival and health outcome for people infected with HIV have occurred since the advent of combination antiretroviral therapy over a decade ago. Yet HIV-associated ...neurocognitive disorders continue to occur with an alarming prevalence. This may reflect the fact that infected people are now living longer with chronic infection. There is mounting evidence that HIV exacerbates age-associated cognitive decline. Many middle-aged HIV-infected people are experiencing cognitive decline similar that to that found among much older adults. An increased prevalence of vascular and metabolic comorbidities has also been observed and is greatest among older adults with HIV. Premature age-associated neurocognitive decline appears to be related to structural and functional brain changes on neuroimaging, and of particular concern is the fact that pathology indicative of neurodegenerative disease has been shown to occur in the brains of HIV-infected people. Yet notable differences also exist between the clinical presentation and brain disturbances occurring with HIV and those occurring in neurodegenerative conditions such as Alzheimer's disease. HIV interacts with the aging brain to affect neurological structure and function. However, whether this interaction directly affects neurodegenerative processes, accelerates normal cognitive aging, or contributes to a worsening of other comorbidities that affect the brain in older adults remains an open question. Evidence for and against each of these possibilities is reviewed.
This study aimed to synthesize existing research on the effects of sleep disturbances on trauma‐focused psychotherapy outcomes in adults with posttraumatic stress disorder (PTSD). A systematic review ...using PubMed, PsycINFO, Embase, Web of Science, and PTSDpubs was performed up to April 2021. Two independent reviewers screened articles for inclusion, performed data extraction, and assessed risk of bias and certainty of the evidence. Narrative synthesis was conducted based on the type of sleep disorder symptom assessed. Sixteen primary studies were included in this review, the majority of which had a high overall risk of bias. Results suggested that sleep disorder symptoms were associated with higher overall PTSD severity across treatment; however, they did not interfere with treatment effectiveness, with the exception of sleep‐disordered breathing. Improvements in insomnia, sleep duration, and sleep quality during treatment were associated with greater treatment gains. Certainty of the evidence ranged from low to very low. These results suggest that it may not be necessary to address sleep disorder symptoms prior to initiating trauma‐focused psychotherapy. Instead, concurrent treatment of sleep‐ and trauma‐related symptoms may be most beneficial. Continued research is needed to clarify the mechanistic relationship between sleep and treatment outcomes and to guide clinical decision‐making.
This systematic review aimed to synthesize existing research on the effects of sleep disturbances on trauma‐focused psychotherapy outcomes in adults with posttraumatic stress disorder (PTSD). Results suggested that sleep disorder symptoms were associated with higher overall PTSD severity across treatment; however, they did not interfere with treatment effectiveness, with the exception of sleep‐disordered breathing.
The neuropeptide oxytocin (OT) has been implicated in a wide range of affiliative processes. OT exerts its functions via OT receptors, which are encoded by the oxytocin receptor gene (OXTR). ...Epigenetic modification of OXTR through the process of DNA methylation has been associated with individual differences in behavioral phenotypes. Specifically, lower levels of OXTR methylation have been linked to better social and affective functioning. However, research on epigenetic mechanisms of OXTR is scarce in non-clinical populations, and even less is known about epigenetic variability across adulthood. The present study assessed methylation levels at OXTR CpG site −934 and plasma OT levels in 22 young (20–31 years, M = 23.6) and 34 older (63–80 years, M = 71.4) participants. Lower levels of OXTR methylation and higher plasma OT levels were associated with less self-reported attachment anxiety in young but not older participants, with largely independent contributions of OXTR methylation and plasma OT levels. In contrast, in the overall sample, lower levels of OXTR methylation were associated with higher self-reported attachment avoidance. Age analysis suggested that these results were largely driven by young adults. Plasma OT levels were unrelated to attachment avoidance. Taken together, these findings support the emerging notion in the literature that epigenetic properties of OXTR, in addition to endogenous OT levels, are related to adult attachment. Further, the age effects observed in the associations between OXTR methylation, plasma OT, and adult attachment emphasize the importance of adopting a developmental perspective when studying properties of the OT system and their relation to affiliative processes. Findings contribute to growing evidence suggesting that epigenetic modification of genes regulating OT pathways and endogenous OT levels are associated with the way people form and maintain intimate social relationships.
•The study assessed associations between OXTR methylation, plasma oxytocin (OT), and attachment in young and older adults.•Lower OXTR methylation and higher OT were associated with less attachment anxiety in young but not older adults.•Contributions of OXTR methylation and OT on attachment were largely independent.•Epigenetic modifications of genes regulating OT pathways and OT levels are associated with affiliative processes.•Findings support importance of adopting a developmental perspective on the OT system in relation to affiliative processes.
Extracellular free water within cerebral white matter tissue has been shown to increase with age and pathology, yet the cognitive consequences of free water in typical aging prior to the development ...of neurodegenerative disease remains unclear. Understanding the contribution of free water to cognitive function in older adults may provide important insight into the neural mechanisms of the cognitive aging process.
A diffusion-weighted MRI measure of extracellular free water as well as a commonly used diffusion MRI metric (fractional anisotropy) along nine bilateral white matter pathways were examined for their relationship with cognitive function assessed by the NIH Toolbox Cognitive Battery in 47 older adults (mean age = 74.4 years, SD = 5.4 years, range = 65–85 years). Probabilistic tractography at the 99th percentile level of probability (Tracts Constrained by Underlying Anatomy; TRACULA) was utilized to produce the pathways on which microstructural characteristics were overlaid and examined for their contribution to cognitive function independent of age, education, and gender.
When examining the 99th percentile probability core white matter pathway derived from TRACULA, poorer fluid cognitive ability was related to higher mean free water values across the angular and cingulum bundles of the cingulate gyrus, as well as the corticospinal tract and the superior longitudinal fasciculus. There was no relationship between cognition and mean FA or free water-adjusted FA across the 99th percentile core white matter pathway. Crystallized cognitive ability was not associated with any of the diffusion measures. When examining cognitive domains comprising the NIH Toolbox Fluid Cognition index relationships with these white matter pathways, mean free water demonstrated strong hemispheric and functional specificity for cognitive performance, whereas mean FA was not related to age or cognition across the 99th percentile pathway.
Extracellular free water within white matter appears to increase with normal aging, and higher values are associated with significantly lower fluid but not crystallized cognitive functions. When using TRACULA to estimate the core of a white matter pathway, a higher degree of free water appears to be highly specific to the pathways associated with memory, working memory, and speeded decision-making performance, whereas no such relationship existed with FA. These data suggest that free water may play an important role in the cognitive aging process, and may serve as a stronger and more specific indicator of early cognitive decline than traditional diffusion MRI measures, such as FA.
Community dwelling older individuals from the North Florida region were examined for health status and a comprehensive neuropsychological battery, including the Montreal Cognitive Assessment (MoCA), ...was performed on each participant. A subpopulation (58 females and 39 males) met the criteria for age (60-89) and no evidence of mild cognitive impairment, with a MoCA score ≥23. Despite the stringent criteria for participation, MoCA scores were negatively correlated within the limited age range. Extracellular microvesicles were isolated from the plasma and samples were found to be positive for the exosome marker CD63, with an enrichment of particles within the size range for exosomes. miRNA was extracted and examined using next generation sequencing with a stringent criterion (average of ≥10 counts per million reads) resulting in 117 miRNA for subsequent analysis. Characterization of expression confirmed pervious work concerning the relative abundance and overall pattern of expression of miRNA in plasma. Correlation analysis indicated that most of the miRNAs (74 miRNAs) were positively correlated with age (
<0.01). Multiple regression was employed to identify the relationship of miRNA expression and MoCA score, accounting for age. MoCA scores were negatively correlated with 13 miRNAs. The pattern of expression for cognition-related miRNA did not match that previously described for Alzheimer's disease. Enrichment analysis was employed to identify miRNA-gene interactions to reveal possible links to brain function.
We consider the problem of approximating a given element f from a Hilbert space $\scr{H}$ by means of greedy algorithms and the application of such procedures to the regression problem in statistical ...learning theory. We improve on the existing theory of convergence rates for both the orthogonal greedy algorithm and the relaxed greedy algorithm, as well as for the forward stepwise projection algorithm. For all these algorithms, we prove convergence results for a variety of function classes and not simply those that are related to the convex hull of the dictionary. We then show how these bounds for convergence rates lead to a new theory for the performance of greedy algorithms in learning. In particular, we build upon the results in IEEE Trans. Inform. Theory 42 (1996) 2118-2132 to construct learning algorithms based on greedy approximations which are universally consistent and provide provable convergence rates for large classes of functions. The use of greedy algorithms in the context of learning is very appealing since it greatly reduces the computational burden when compared with standard model selection using general dictionaries.
Summary Metastatic papillary thyroid carcinoma without an identifiable primary tumor despite extensive microscopic examination of the thyroid gland is a rare but true phenomenon. We retrieved seven ...of such cases and described in details the clinical and pathologic features of these tumors. BRAF V600E immunohistochemistry and Sequenom molecular profile were conducted in selected cases. All patients harbored metastatic disease in the central (n = 3), lateral (n = 3), or both neck compartments (n = 1). The histotype of the metastatic disease was papillary thyroid carcinoma (PTC, n = 5), poorly differentiated thyroid carcinoma (PDTC) in association with a PTC columnar variant (n = 1), and anaplastic thyroid carcinoma (ATC) in association with a PTC tall cell variant (n = 1). Fibrosis was present in the thyroid of five patients. All patients with PTC were alive without evidence of recurrence. The 76-year-old patient with PDTC did not recur and died of unknown causes. Finally, the patient with ATC was alive with distant metastasis at last follow up. The median follow up for this cohort was 2.2 years (range 0.8–17). BRAF V600E was detected in 4 of 6 cases by immunohistochemistry. In conclusion, metastatic nodal disease without identifiable thyroid primary is a rare but real phenomenon of unknown mechanisms. Although most tumors are low grade and well differentiated, aggressive behavior due to poorly differentiated or anaplastic carcinoma can happen. Most cases are BRAFV600E positive thyroid tumors. A papillary carcinoma phenotype is found in all reported cases.
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