22q11.2 deletion carriers show specific cognitive deficits, and ∼30% of them develop schizophrenia. One of the disrupted genes is ZDHHC8, which encodes for a palmitoyltransferase. We show that ...Zdhhc8-deficient mice have reduced palmitoylation of proteins that regulate axonal growth and branching. Analysis of axonal projections of pyramidal neurons from both Zdhhc8-deficient and Df(16)A(+/-) mice, which model the 22q11.2 deletion, revealed deficits in axonal growth and terminal arborization, which can be prevented by reintroduction of active ZDHHC8 protein. Impaired terminal arborization is accompanied by a reduction in the strength of synaptic connections and altered functional connectivity and working memory. The effect of ZDHHC8 is mediated in part via Cdc42-dependent modulation of Akt/Gsk3β signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3β activity during postnatal brain development. Our findings provide valuable mechanistic insights into the cognitive and psychiatric symptoms associated with a schizophrenia-predisposing mutation.
An estimated 34 million people are living with HIV worldwide (UNAIDS, 2012), with the number of infected persons rising every year. Increases in HIV prevalence have resulted not only from new ...infections, but also from increases in the survival of HIV-infected persons produced by effective anti-retroviral therapies. Augmentation of anti-viral immune responses may be able to further increase the survival of HIV-infected persons. One strategy to augment these responses is to reinvigorate exhausted anti-HIV immune cells present in chronically infected persons. The PD-1-PD-L1 pathway has been implicated in the exhaustion of virus-specific T cells during chronic HIV infection. Inhibition of PD-1 signaling using blocking anti-PD-1 antibodies has been shown to reduce simian immunodeficiency virus (SIV) loads in monkeys. We now show that PD-1 blockade can improve control of HIV replication in vivo in an animal model. BLT (Bone marrow-Liver-Thymus) humanized mice chronically infected with HIV-1 were treated with an anti-PD-1 antibody over a 10-day period. The PD-1 blockade resulted in a very significant 45-fold reduction in HIV viral loads in humanized mice with high CD8(+) T cell expression of PD-1, compared to controls at 4 weeks post-treatment. The anti-PD-1 antibody treatment also resulted in a significant increase in CD8(+) T cells. PD-1 blockade did not affect T cell expression of other inhibitory receptors co-expressed with PD-1, including CD244, CD160 and LAG-3, and did not appear to affect virus-specific humoral immune responses. These data demonstrate that inhibiting PD-1 signaling can reduce HIV viral loads in vivo in the humanized BLT mouse model, suggesting that blockade of the PD-1-PD-L1 pathway may have therapeutic potential in the treatment of patients already infected with the AIDS virus.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cross-frequency coupling supports the organization of brain rhythms and is present during a range of cognitive functions. However, little is known about whether and how long-range cross-frequency ...coupling across distant brain regions subserves working memory. Here we report that theta-slow gamma coupling between the hippocampus and medial prefrontal cortex (mPFC) is augmented in a genetic mouse model of cognitive dysfunction. This increased cross-frequency coupling is observed specifically when the mice successfully perform a spatial working memory task. In wild-type mice, increasing task difficulty by introducing a long delay or by optogenetically interfering with encoding, also increases theta-gamma coupling during correct trials. Finally, epochs of high hippocampal theta-prefrontal slow gamma coupling are associated with increased synchronization of neurons within the mPFC. These findings suggest that enhancement of theta-slow gamma coupling reflects a compensatory mechanism to maintain spatial working memory performance in the setting of increased difficulty.
Aim
To systematically review the evidence on the effectiveness of motor interventions for infants from birth to 2 years with a diagnosis of cerebral palsy or at high risk of it.
Method
Relevant ...literature was identified by searching journal article databases (PubMed, Embase, CINAHL, Cochrane, Web of Knowledge, and PEDro). Selection criteria included infants between the ages of birth and 2 years diagnosed with, or at risk of, cerebral palsy who received early motor intervention.
Results
Thirty‐four studies met the inclusion criteria, including 10 randomized controlled trials. Studies varied in quality, interventions, and participant inclusion criteria. Neurodevelopmental therapy was the most common intervention investigated either as the experimental or control assignment. The two interventions that had a moderate to large effect on motor outcomes (Cohen's effect size>0.7) had the common themes of child‐initiated movement, environment modification/enrichment, and task‐specific training.
Interpretation
The published evidence for early motor intervention is limited by the lack of high‐quality trials. There is some promising evidence that early intervention incorporating child‐initiated movement (based on motor‐learning principles and task specificity), parental education, and environment modification have a positive effect on motor development. Further research is crucial.
What this paper adds
Updated review of early motor intervention studies of infants with cerebral palsy found evidence of efficacy was weak.
Promising approaches involve child‐initiated movement, task specificity, and environmental modification.
This review outlines a conceptual approach to inform research and practice aimed at supporting children whose lives are complicated by impairment and/or chronic medical conditions, and their ...families. ‘Participation’ in meaningful life activities should be an essential intervention goal, to meet the challenges of healthy growth and development, and to provide opportunities to help ensure that young people with impairments reach their full potential across their lifespan. Intervention activities and research can focus on participation as either an independent or dependent variable. The proposed framework and associated hypotheses are applicable to children and young people with a wide variety of conditions, and to their families. In taking a fresh ‘non‐categorical’ perspective to health for children and young people, asking new questions, and exploring issues in innovative ways, we expect to learn lessons and to develop creative solutions that will ultimately benefit children with a wide variety of impairments and challenges, and their families, everywhere.
What this paper adds
An innovative conceptual framework to support participation‐based research and practice.
Recommendations for future participation‐based research.
Aim
To evaluate available evidence examining safety and efficacy of non‐invasive brain stimulation (NIBS) on upper extremity outcomes in children with cerebral palsy (CP).
Method
We electronically ...searched 12 sources up to May 2023 using JBI and Cochrane guidelines. Two reviewers selected articles with predetermined eligibility criteria, conducted data extraction, and assessed risk of bias using the Cochrane Risk of Bias criteria.
Results
Nineteen studies were included: eight using repetitive transcranial magnetic stimulation (rTMS) and 11 using transcranial direct current stimulation (tDCS). Moderate certainty evidence supports the safety of rTMS and tDCS for children with CP. Very low to moderate certainty evidence suggests that rTMS and tDCS result in little to no difference in upper extremity outcomes.
Interpretation
Evidence indicates that NIBS is a safe and feasible intervention to target upper extremity outcomes in children with CP, although it also indicates little to no significant impact on upper extremity outcomes. These findings are discussed in relation to the heterogeneous participants’ characteristics and stimulation parameters. Larger studies of high methodological quality are required to inform future research and protocols for NIBS.
Evidence indicates that non‐invasive brain stimulation (NIBS) is a safe and feasible intervention to target upper extremity outcomes in children with cerebral palsy, though studies to date suggest little to no significant impact on upper extremity outcomes. These findings are discussed in relation to the heterogeneous participant characteristics and stimulation parameters. Larger studies of high methodological quality are required to inform future research and NIBS protocols.
Video Podcast: https://youtu.be/SFQT_‐bhMZ0
Impaired hand function is among the most functionally disabling symptoms of unilateral cerebral palsy. Evidence‐based treatment approaches are generally lacking. However, recent approaches providing ...intensive upper extremity training appear promising. In this review, we first describe two such approaches, constraint‐induced movement therapy (CIMT) and bimanual training (hand–arm bimanual intensive therapy). We then summarize findings across more than 100 participants in our CIMT/bimanual training studies since 1997. We show that (1) at high intensities, CIMT and bimanual training improve dexterity and bimanual upper extremity use; (2) bimanual training may allow direct practice of functionally meaningful goals, and such practice may transfer to unpracticed goals and improve bimanual coordination; (3) 90 hours of CIMT and bimanual training leads to greater improvements than 60 hours of the same treatments; (4) higher doses may be required for bimanual training; (5) increased dosing frequency and shaping may be needed for older children; and (6) combined CIMT/bimanual approaches may be useful, but require sufficient intensity. Together these findings suggest that dosage (treatment amount and frequency), more so than ingredients, may well be the key to successful training protocols, especially for older children. Such rehabilitation efforts should be ‘child‐friendly’, and as least invasive as possible, especially because these approaches may be provided throughout development.
Roadmap on structured light Rubinsztein-Dunlop, Halina; Forbes, Andrew; Berry, M V ...
Journal of optics (2010),
01/2017, Letnik:
19, Številka:
1
Journal Article, Publication
Recenzirano
Odprti dostop
Structured light refers to the generation and application of custom light fields. As the tools and technology to create and detect structured light have evolved, steadily the applications have begun ...to emerge. This roadmap touches on the key fields within structured light from the perspective of experts in those areas, providing insight into the current state and the challenges their respective fields face. Collectively the roadmap outlines the venerable nature of structured light research and the exciting prospects for the future that are yet to be realized.
The Arctic tundra is warming rapidly, yet the exact mechanisms linking warming and observed ecological changes are often unclear. Understanding mechanisms of change requires long-term monitoring of ...multiple ecological parameters. Here, we present the findings of a collaboration between government scientists, local people, park rangers, and academic researchers that provide insights into changes in plant composition, phenology, and growth over 18 yr on Qikiqtaruk-Herschel Island, Canada. Qikiqtaruk is an important focal research site located at the latitudinal tall shrub line in the western Arctic. This unique ecological monitoring program indicates the following findings: (1) nine days per decade advance of spring phenology, (2) a doubling of average plant canopy height per decade, but no directional change in shrub radial growth, and (3) a doubling of shrub and graminoid abundance and a decrease by one-half in bare ground cover per decade. Ecological changes are concurrent with satellite-observed greening and, when integrated, suggest that indirect warming from increased growing season length and active layer depths, rather than warming summer air temperatures alone, could be important drivers of the observed tundra vegetation change. Our results highlight the vital role that long-term and multi-parameter ecological monitoring plays in both the detection and attribution of global change.
PDF
