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"Sheldon, D."
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Quantitative and temporal analysis of autophagy: Differential Response to amino acid and glucose starvation
Autophagy is a highly conserved, intracellular recycling process by which cytoplasmic contents are degraded in the lysosome. This process occurs at a low level constitutively; however, it is induced robustly in response to stressors, in particular, starvation of critical nutrients such as amino acids and glucose. That said, the relative contribution of these inputs is ambiguous, and many starvation medias are poorly defined or devoid of multiple nutrients. Here, we set out to create a quantitative dataset of autophagy across multiple stages in single, living cells, measured under normal growth conditions and during nutrient starvation of amino acids or glucose. We found that autophagy is induced by starvation of amino acids, but not glucose, in U2OS cells, and that MTORC1-mediated ULK1 regulation and autophagy are tightly linked to amino acid levels. While autophagy is engaged immediately during amino acid starvation, a heightened response occurs during a period marked by transcriptional upregulation of autophagy genes during sustained starvation. Finally, we demonstrated that cells immediately return to their initial, low-autophagy state when nutrients are restored, highlighting the dynamic relationship between autophagy and environmental conditions.
Journal Article
SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits
In addition to cognitive impairments, neurodevelopmental disorders often result in sensory processing deficits. However, the biological mechanisms that underlie impaired sensory processing associated with neurodevelopmental disorders are generally understudied and poorly understood. We found that SYNGAP1 haploinsufficiency in humans, which causes a sporadic neurodevelopmental disorder defined by cognitive impairment, autistic features, and epilepsy, also leads to deficits in tactile-related sensory processing. In vivo neurophysiological analysis in Syngap1 mouse models revealed that upper-lamina neurons in somatosensory cortex weakly encode information related to touch. This was caused by reduced synaptic connectivity and impaired intrinsic excitability within upper-lamina somatosensory cortex neurons. These results were unexpected, given that Syngap1 heterozygosity is known to cause circuit hyperexcitability in brain areas more directly linked to cognitive functions. Thus, Syngap1 heterozygosity causes a range of circuit-specific pathologies, including reduced activity within cortical neurons required for touch processing, which may contribute to sensory phenotypes observed in patients.
Journal Article
Professional practice in sport psychology : a review
Sport psychologists working with athletes, teams and sports performers are only as effective as their professional techniques and competencies will allow. This is the first book to offer a detailed and critical appraisal of the conceptual foundations of contemporary professional practice in sport psychology.
Book
Syngap1 promotes cognitive function through regulation of cortical sensorimotor dynamics
Perception, a cognitive construct, emerges through sensorimotor integration (SMI). The genetic mechanisms that shape SMI required for perception are unknown. Here, we demonstrate in mice that expression of the autism/intellectual disability gene,
Syngap1
, in cortical excitatory neurons is required for the formation of somatomotor networks that promote SMI-mediated perception. Cortical
Syngap1
expression was necessary and sufficient for setting tactile sensitivity, sustaining tactile object exploration, and promoting tactile learning. Mice with deficient
Syngap1
expression exhibited impaired neural dynamics induced by exploratory touches within a cortical-thalamic network that promotes attention and perception. Disrupted neuronal dynamics were associated with circuit-specific long-range synaptic connectivity abnormalities. Our data support a model where autonomous
Syngap1
expression in cortical excitatory neurons promotes cognitive abilities through the assembly of long-range circuits that integrate temporally-overlapping sensory and motor signals, a process that promotes perception and attention. These data provide systems-level insights into the robust association between
Syngap1
expression and cognitive ability.
Whether and how highly penetrant NDD (neurodevelopmental disorder) genes such as Syngap1 regulate sensorimotor integration are not fully understood. This study shows that Syngap1 expression in cortical projection neurons promotes cognitive abilities in mice through forming distributed networks that integrate sensory information with motor signals, a dynamic process required for perception and attention.
Journal Article
شراكات المدرسة والأسرة والمجتمع : دليلك للعمل =
كتاب ثري وعملي يشجعك على البدء في بناء شراكة فاعلة بين المدرسة والأسرة والمجتمع ويقدم لك مختلف الأدوات التي تحتاجها لتبدأ ستجد نموذجا مميزا لمساعدة كل مدرسة على بناء خطة العام للشراكة مع الأسر والمجتمع بالتفصيل ستحصل على خطوات تكوين فرق الشراكة في داخل المدرسة ستحصل على نماذج جاهزة للعمل أيضا قوائم بأنشطة هادفة يمكن تنفيذها وأثبتت جدواها عبر دراسات.
BOOK
Correlates of HIV Acquisition in a Cohort of Black Men Who Have Sex with Men in the United States: HIV Prevention Trials Network (HPTN) 061
Black men who have sex with men (MSM) in the United States (US) are affected by HIV at disproportionate rates compared to MSM of other race/ethnicities. Current HIV incidence estimates in this group are needed to appropriately target prevention efforts.
From July 2009 to October 2010, Black MSM reporting unprotected anal intercourse with a man in the past six months were enrolled and followed for one year in six US cities for a feasibility study of a multi-component intervention to reduce HIV infection. HIV incidence based on HIV seroconversion was calculated as number of events/100 person-years. Multivariate proportional hazards modeling with time-dependent covariates was used to identify correlates of HIV acquisition.
Of 1,553 Black MSM enrolled, 1,164 were HIV-uninfected at baseline and included in follow-up. Overall annual HIV incidence was 3.0% (95% confidence interval (CI): 2.0, 4.4%) and 5.9% among men ≤30 years old (95% CI: 3.6, 9.1%). Men ≤30 years old reported significantly higher levels of sexual risk and were more likely to have a sexually transmitted infection diagnosed during follow-up. Younger men also were more likely to not have a usual place for health care, not have visited a health care provider recently, and to have unmet health care needs. In multivariate analysis, age ≤30 years (hazard ratio (HR): 3.4; 95% CI: 1.4, 8.3) and unprotected receptive anal intercourse with HIV-positive or unknown status partners (HR: 4.1; 95% CI: 1.9, 9.1) were significantly associated with HIV acquisition.
In the largest cohort of prospectively-followed Black MSM in the US, HIV incidence was high, particularly among young men. Targeted, tailored and culturally appropriate HIV prevention strategies incorporating behavioral, social and biomedical based interventions are urgently needed to lower these rates.
Journal Article
The Endo-GeneScreen platform identifies drug-like probes that regulate endogenous protein levels within physiological contexts
Traditional phenotypic drug discovery platforms suffer from poor scalability and/or a lack of mechanistic understanding of discovered probes. We address this by creating Endo-
GeneScreen
(
EGS
), a high-throughput platform that identifies small molecules that regulate endogenous protein levels encoded by a preselected target gene within disease-modeling contexts. Two initial
screens
identify >40 validated small molecules that boost endogenous neuronal
Syngap1
levels, a gene that causes a neurodevelopmental disorder when haploinsufficient
. EGS
assays also accelerate preclinical development of drug candidates and facilitate mode-of-action deconvolution studies of orphaned probes. SR-1815 represents a fully validated proof-of-concept candidate from the platform. It is a previously unknown drug-like small molecule multikinase inhibitor that regulates splicing of
Syngap1
transcripts. It restores SynGAP protein abundance to
wildtype
levels and mitigates major cellular consequences of
Syngap1
loss-of-function. Thus, the
EGS
platform promotes identification and development of small molecules that alter the abundance of disease-linked proteins in a translationally-relevant context.
Dysregulated protein levels can cause disease. The authors present a scalable platform capable of identifying small molecules that alter disease-linked target protein levels, and report >40 that increase SynGAP protein abundance, with SR1815 restoring neuronal function in Syngap1 deficient neurons.
Journal Article
A diverse proteome is present and enzymatically active in metabolite extracts
Metabolite extraction is the critical first-step in metabolomics experiments, where it is generally regarded to inactivate and remove proteins. Here, arising from efforts to improve extraction conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This is a ubiquitous feature across several common extraction and sample types. By combining post-resuspension stable isotope addition and enzyme inhibitors, we demonstrate in-extract metabolite interconversions due to residual transaminase activity. We extend these findings with untargeted metabolomics where we observe extensive protein-mediated metabolite changes, including in-extract formation of glutamate dipeptide and depletion of total glutathione. Finally, we present a simple extraction workflow that integrates 3 kDa filtration for protein removal as a superior method for polar metabolomics. In this work, we uncover a previously unrecognized, protein-mediated source of observer effects in metabolomics experiments with broad-reaching implications across all research fields using metabolomics and molecular metabolism.
Metabolite extraction with organic solvents is assumed to remove/denature proteins. Here, the authors uncover a vast landscape of >1,000 proteins in metabolite extracts. These proteins can retain catalytic activity and drive post-extraction metabolite changes, obscuring biological interpretation.
Journal Article