Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF ...diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Rhesus macaques as a tractable physiological model of human ageing Chiou, Kenneth L.; Montague, Michael J.; Goldman, Elisabeth A. ...
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
11/2020, Volume:
375, Issue:
1811
Journal Article
Peer reviewed
Open access
Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve ...human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from short-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research owing to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with the model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population.
This article is part of the theme issue ‘Evolution of the primate ageing process’.
The role of the circadian clock in controlling the metabolism of entire trees has seldom been considered. We tested whether the clock influences nocturnal whole-tree water use.
Whole-tree chambers ...allowed the control of environmental variables (temperature, relative humidity). Night-time stomatal conductance (g
s) and sap flow (Q) were monitored in 6- to 8-m-tall Eucalyptus globulus trees during nights when environmental variables were kept constant, and also when conditions varied with time. Artificial neural networks were used to quantify the relative importance of circadian regulation of g
s and Q.
Under a constant environment, g
s and Q declined from 0 to 6 h after dusk, but increased from 6 to 12 h after dusk. While the initial decline could be attributed to multiple processes, the subsequent increase is most consistent with circadian regulation of g
s and Q.
We conclude that endogenous regulation of g
s is an important driver of night-time Q under natural environmental variability. The proportion of nocturnal Q variation associated with circadian regulation (23–56%) was comparable to that attributed to vapor pressure deficit variation (25–58%). This study contributes to our understanding of the linkages between molecular and cellular processes related to circadian regulation, and whole-tree processes related to ecosystem gas exchange in the field.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
In the current study, we used a sample of predominantly African-American women with high rates of trauma exposure (N = 434) to examine psychometric properties of the Personality Inventory for ...DSM-5-Brief Form (PID-5-BF). We compared model fit between a model with five correlated latent factors and a higher-order model in which the five latent factors were used to estimate a single "general pathology" factor. Additionally, we computed estimates of internal consistency and domain interrelations and examined indices of convergent/discriminant validity of the PID-5-BF domains by examining their relations to relevant criterion variables. The expected five-factor structure demonstrated good fit indices in a confirmatory factor analysis, and the more parsimonious, higher-order model was retained. Within this higher-order model, the first-order factors accounted for more variance in the criterion variables than the general pathology factor in most instances. The PID-5-BF domains were highly interrelated (rs = .38 to .66), and convergent/discriminant validity of the domains varied: Negative Affectivity and Detachment generally showed the hypothesized pattern of relations with external criteria, while Antagonism and Disinhibition displayed less consistent and discriminant relations. Results are discussed in terms of the costs and benefits of using brief pathological trait measures in samples characterized by high levels of psychopathology.
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BFBNIB, DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose To examine the anatomy and function of the forearm interosseous membrane by exploring the anatomical insertions of the central band (CB) on the radius and the ulna and by quantifying the ...length of the intact ligament and replacement grafts located at the original CB attachment sites and alternative locations. Methods Eight fresh cadaver forearms were supinated and pronated and the wrist was extended and flexed while the motion between the distal radius and ulna were recorded. The length of the CB was computed for the intact CB as well for several alternative graft orientations and positions. Results The maximum length of the CB did not significantly change among different wrist motions. However, with the wrist in a static neutral position, the CB length was significantly shorter in forearm supination than in neutral. During active forearm rotation when CB replacement grafts were positioned distal or proximal to the original CB site, yet still parallel to it, each had a similar trend to be longer in neutral than in supination. If a graft was more transversely oriented, the computed CB length would be 1.6 mm shorter in supination than in neutral. Conclusions These results support tensioning a CB graft with the forearm in supination if the goal is to maximize graft tension and to maintain the native 22° angle for a CB graft between the radius and ulna. The results also suggest that the CB graft can probably be located slightly distal or slightly proximal to its original attachment sites. Clinical relevance Reconstruction of the interosseous membrane has been hampered by a lack of understanding of its length changes with forearm or wrist motion. These results provide a starting point in helping clinicians understand how to more precisely reconstruct this ligament in an anatomical manner.
Emission excitation cross sections are recorded for collisions between Xe
+ O
and O
+ Xe over a collision energy range of approximately 2 to 900 eV in the center-of-mass (E
) frame. Emissive products ...of the O
+ Xe reaction are examined in the 700-1000 nm optical range and include neutral atomic oxygen emissions and neutral xenon emissions. Atomic emission products of the O
+ Xe collision appear to have measureable cross sections near E
= 14 eV and increase in intensity until about E
= 60 eV where they remain approximately constant for the remainder of the measured collision energies. For the Xe
+ O
collision system, O
charge transfer products are measured through fluorescence of the O
(A-X) and (b-a) manifolds over the 200-850 nm window. Total cross sections for both manifolds do not vary beyond the experimental precision at all measured energies. Vibrational populations are derived from a fitting of the experimental data. The populations are found to deviate from a Franck-Condon distribution at all collision energies and appear to be well-modeled within a multi-channel Landau-Zener framework over the collision energy range measured.
Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal ...brain arterio-venous malformations, shunting arterial blood into the brain’s deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.
•Exome sequencing identifies genetic drivers of vein of Galen malformations (VOGMs)•Mutations in chromatin modifier and Ephrin genes account for ∼30% of VOGM cases•Probands often exhibit vasculo-cutaneous lesions, suggesting a two-hit mechanism•These data implicate impaired arterio-venous specification in VOGM pathogenesis
Vein of Galen malformations (VOGMs) are the most severe neonatal brain arterio-venous malformations. Duran et al. identify de novo chromatin modifier and rare inherited Ephrin signaling mutations in ∼30% of VOGM cases. The data implicate disrupted arterio-venous specification in VOGM pathogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To determine if tumor-specific loss of heterozygosity (LOH) for chromosomes 1p or 16q is associated with a poorer prognosis for children with favorable-histology (FH) Wilms tumor entered on the fifth ...National Wilms Tumor Study (NWTS-5).
Between August 1995 and June 2002, 2,021 previously untreated children with FH or anaplastic Wilms tumor, clear-cell sarcoma of the kidney (CCSK) or malignant rhabdoid tumor of the kidney (RTK), were treated with stage- and histology-specific therapy. Their tumors were assayed for LOH for polymorphic DNA markers on chromosomes 1p and 16q. ResultsLOH for 1p or 16q was rarely observed in CCSK (n = 90) or RTK (n = 22). The relative risk (RR) of relapse for patients with FH stage I to IV tumors with LOH, stratified by stage, was 1.56 for LOH 1p (P = .01) and 1.49 for LOH 16q (P = .01), whereas the RR of death was 1.84 (P = .03) and 1.44 (P = .15), respectively. When the effects of LOH for both regions were considered jointly among patients with stage I to II FH disease, the risks of relapse and death were increased for LOH 1p only (RR = 2.2, P = .02 for relapse; RR = 4.0, P = .02 for death), for LOH 16q only (RR = 1.9, P = .01 and RR = 1.4, P = .60) and for LOH for both regions (RR = 2.9, P = .001 and RR = 4.3, P = .01) in comparison with patients with LOH at neither locus. The risks of relapse and death for patients with stage III to IV FH tumors were increased only with LOH for both regions (RR = 2.4, P = .01 and RR = 2.7, P = .04).
Tumor-specific LOH for both chromosomes 1p and 16q identifies a subset of FH Wilms tumor patients who have a significantly increased risk of relapse and death. LOH for these chromosomal regions can now be used as an independent prognostic factor together with disease stage to target intensity of treatment to risk of treatment failure.
Disrupted sleep is associated with non-suicidal self-injury (NSSI) in young adults, but many specific features of sleep continuity and timing have yet to be examined. Additionally, the psychological ...mechanisms linking sleep to NSSI are unclear. The present study evaluated 14 sleep variables as classifiers of lifetime or recent NSSI and examined potential confounding and mediating factors.
A sample of 885 college students provided measures of sleep continuity (e.g., duration, timing, fragmentation), nightmares, insomnia, and perceived sleep control. Lifetime and past 3-month NSSI were measured using a self-report version of the Columbia Suicide Severity Ratings Scale. Bidirectional stepwise regression identified significant sleep classifiers and subsequent models examined their associations with NSSI after adjusting for covariates and through potential psychological mediators.
Only absolute social jetlag was associated with recent NSSI, even after adjusting for covariates, such that each additional hour difference between weekday and weekend sleep schedules was associated with a 17% greater risk of recent NSSI. Nightmares, weekend sleep efficiency, and perceived sleep control were associated with lifetime NSSI, although only weekend sleep efficiency remained associated after adjusting for covariates. Bootstrap mediations identified negative urgency as a partial mediator for recent and lifetime NSSI, and lack of premeditation and perceived burdensomeness as partial mediators for lifetime NSSI.
The timing and consistency of young adults' sleep schedules may be of greater importance to NSSI among college students than insomnia or insufficient sleep. Future studies of sleep and NSSI should include these measures as potential risk factors.
HIGHLIGHTS
Differences between weekday/weekend sleep timing are linked to recent NSSI.
Negative urgency partially mediates poor sleep on recent and lifetime NSSI.
Sleep shares a multifaceted relationship with NSSI risk in college students.
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BFBNIB, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Puerto Ricans, the second largest Latino group in the continental US, are underrepresented in genomic studies of Alzheimer disease (AD). To increase representation of this group in genomic studies of ...AD, we developed a multisource ascertainment approach to enroll AD patients, and their family members living in Puerto Rico (PR) as part of the Alzheimer's Disease Sequencing Project (ADSP), an international effort to advance broader personalized/precision medicine initiatives for AD across all populations.
The Puerto Rico Alzheimer Disease Initiative (PRADI) multisource ascertainment approach was developed to recruit and enroll Puerto Rican adults aged 50 years and older for a genetic research study of AD, including individuals with cognitive decline (AD, mild cognitive impairment), their similarly, aged family members, and cognitively healthy unrelated individuals age 50 and up. Emphasizing identification and relationship building with key stakeholders, we conducted ascertainment across the island. In addition to reporting on PRADI ascertainment, we detail admixture analysis for our cohort by region, group differences in age of onset, cognitive level by region, and ascertainment source.
We report on 674 individuals who met standard eligibility criteria 282 AD-affected participants (42% of the sample), 115 individuals with mild cognitive impairment (MCI) (17% of the sample), and 277 cognitively healthy individuals (41% of the sample). There are 43 possible multiplex families (10 families with 4 or more AD-affected members and 3 families with 3 AD-affected members). Most individuals in our cohort were ascertained from the Metro, Bayamón, and Caguas health regions. Across health regions, we found differences in ancestral backgrounds, and select clinical traits.
The multisource ascertainment approach used in the PRADI study highlights the importance of enlisting a broad range of community resources and providers. Preliminary results provide important information about our cohort that will be useful as we move forward with ascertainment. We expect that results from the PRADI study will lead to a better understanding of genetic risk for AD among this population.
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