rudyvdbrink/CitationDatabase huggingface dataset:
Transplanted photoreceptor precursors transfer proteins to host photoreceptors by a mechanism of cytoplasmic fusion.
Nature communications, 2016

Photoreceptor transplantation is a potential future treatment for blindness caused by retinal degeneration. Photoreceptor transplantation restores visual responses in end-stage retinal degeneration, but has also been assessed in non-degenerate retinas. In the latter scenario, subretinal transplantation places donor cells beneath an intact host outer nuclear layer (ONL) containing host photoreceptors. Here we show that host cells are labelled with the donor marker through cytoplasmic transfer-94±4.1% of apparently well-integrated donor cells containing both donor and host markers. We detect the occurrence of Cre-Lox recombination between donor and host photoreceptors, and we confirm the findings through FISH analysis of X and Y chromosomes in sex-discordant transplants. We do not find evidence of nuclear fusion of donor and host cells. The artefactual appearance of integrated donor cells in host retinas following transplantation is most commonly due to material transfer from donor cells. Understanding this novel mechanism may provide alternate therapeutic strategies at earlier stages of retinal degeneration.
Rapid molecular evolution of pain insensitivity in multiple African rodents.
Science (New York, N.Y.), 2019

Noxious substances, called algogens, cause pain and are used as defensive weapons by plants and stinging insects. We identified four previously unknown instances of algogen-insensitivity by screening eight African rodent species related to the naked mole-rat with the painful substances capsaicin, acid (hydrogen chloride, pH 3.5), and allyl isothiocyanate (AITC). Using RNA sequencing, we traced the emergence of sequence variants in transduction channels, like transient receptor potential channel TRPA1 and voltage-gated sodium channel Na
Respiratory related control of hypoglossal motoneurons--knowing what we do not know.
Respiratory physiology & neurobiology, 2011

Because tongue position and stiffness help insure that the pharyngeal airspace is sufficiently open during breathing, the respiration-related behavior of the tongue muscles has been studied in detail, particularly during the last two decades. Although eight different muscles act upon the mammal tongue, we know very little about the respiration-related control of the majority of these, and almost nothing about how they work together as a complex electro-mechanical system. Other significant gaps include how hypoglossal motoneuron axons find their appropriate muscle target during development, whether the biophysical properties of hypoglossal motoneurons driving different muscles are the same, and how afferent information from cardiorespiratory reflex systems is transmitted from major brainstem integrating centers to the hypoglossal motoneuron pool. This brief review outlines some of these issues, with the hope that this will spur research in the field, ultimately leading to an improved understanding of the respiration-related control of the mammalian tongue musculature.
GABA actions and ionic plasticity in epilepsy.
Current opinion in neurobiology, 2014

Concepts of epilepsy, based on a simple change in neuronal excitation/inhibition balance, have subsided in face of recent insights into the large diversity and context-dependence of signaling mechanisms at the molecular, cellular and neuronal network level. GABAergic transmission exerts both seizure-suppressing and seizure-promoting actions. These two roles are prone to short-term and long-term alterations, evident both during epileptogenesis and during individual epileptiform events. The driving force of GABAergic currents is controlled by ion-regulatory molecules such as the neuronal K-Cl cotransporter KCC2 and cytosolic carbonic anhydrases. Accumulating evidence suggests that neuronal ion regulation is highly plastic, thereby contributing to the multiple roles ascribed to GABAergic signaling during epileptogenesis and epilepsy.
ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010

Proneurotrophins and mature neurotrophins activate different signaling pathways with distinct effects on their target cells: proneurotrophins can induce apoptotic signaling via p75(NTR), whereas mature neurotrophins activate Trk receptors to influence survival and differentiation. Here, we demonstrate that the PTEN (phosphatase and tensin homolog deleted on chromosome 10) phosphatase represents a novel switch between the survival and apoptotic signaling pathways in rat CNS neurons. Simultaneous activation of p75(NTR) by proNGF and TrkB signaling by BDNF elicited apoptosis despite TrkB phosphorylation. Apoptosis induced by p75(NTR) required suppression of TrkB-induced phosphoinositide-3 kinase signaling, mediated by induction of PTEN, for apoptosis to proceed. Inhibition of PTEN restored the ability of BDNF to phosphorylate Akt and protect cultured basal forebrain neurons from proNGF-induced death. In vivo, inhibition or knockdown of PTEN after pilocarpine-induced seizures protected CNS neurons from p75(NTR)-mediated death, demonstrating that PTEN is a crucial factor mediating the balance between p75(NTR)-induced apoptotic signaling and Trk-mediated survival signaling in brain neurons.
White Matter Microstructural Properties are Related to Inter-Individual Differences in Cognitive Instability after Sleep Deprivation.
Neuroscience, 2017

Several diseases are characterized by cognitive instability, which is amplified in the conditions of sleep deprivation (SD). Cognitive instability in SD can be examined by the number of lapses on the psychomotor vigilance test (PVT), which is considered to be a gold standard in the field. However, the number of PVT lapses widely range according to inter-individual differences, from apparent cognitive resistance to severe cognitive impairment. In this study, tract-based spatial statistical analyses with multiple diffusion tensor imaging-derived characteristics (i.e., fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity) were employed to investigate the relationships between the number of PVT lapses and the diffusion characteristics. A hierarchical linear regression model was then used to assess the contributions of tract-specific FA values in predicting PVT lapses. Finally, dichotomized analysis was used to investigate white matter (WM) differences between resilient and vulnerable groups. Our results showed significant negative correlations between numbers of PVT lapses and FA in multiple WM tracts, with the FA variations in the superior longitudinal fasciculus and splenium of the corpus callosum accounting for nearly 37.5% of individual variability in PVT lapses. In addition, dichotomized analyses indicated that the resilient participants exhibited significantly higher FA values compared with the vulnerable participants. Together, these findings suggest that cognitive instability after SD was closely associated with individual differences in WM integrity.
Cdc42 controls the dilation of the exocytotic fusion pore by regulating membrane tension.
Molecular biology of the cell, 2014

Membrane fusion underlies multiple processes, including exocytosis of hormones and neurotransmitters. Membrane fusion starts with the formation of a narrow fusion pore. Radial expansion of this pore completes the process and allows fast release of secretory compounds, but this step remains poorly understood. Here we show that inhibiting the expression of the small GTPase Cdc42 or preventing its activation with a dominant negative Cdc42 construct in human neuroendocrine cells impaired the release process by compromising fusion pore enlargement. Consequently the mode of vesicle exocytosis was shifted from full-collapse fusion to kiss-and-run. Remarkably, Cdc42-knockdown cells showed reduced membrane tension, and the artificial increase of membrane tension restored fusion pore enlargement. Moreover, inhibiting the motor protein myosin II by blebbistatin decreased membrane tension, as well as fusion pore dilation. We conclude that membrane tension is the driving force for fusion pore dilation and that Cdc42 is a key regulator of this force.
"Community ambassadors" for South Asian elder immigrants: late-life acculturation and the roles of community health workers.
Social science & medicine (1982), 2012

Elder immigrants face multiple barriers to accessing health care and other basic services. The Community Ambassador Program for Seniors (CAPS), based in Fremont, California, trains volunteer "ambassadors" from several ethnic and faith communities to perform information and referral services for elders, particularly immigrants. The purpose of this study is to examine the roles of ambassadors in ecologic context as community health workers (CHWs) for clients undergoing late-life acculturation. Ambassadors from three different communities, all of South Asian heritage, were interviewed using a semi-structured guide. 20 out of 23 ambassadors from these communities participated, from December 2008 to December 2009. Data collection and analysis followed grounded theory methodology. Results are presented as an integrated explanatory model, with three major components: (1) acculturative stress, particularly within elders' families; (2) polygonal relationships, a construct that includes elders, their caregivers, CHWs, and service providers, and builds on the notion of a "geriatric triad" (Adelman, Greene, & Charon, 1987); and (3) role hybridity, a novel explanation for CHWs' social niche. Ambassadors mediated elder clients' acculturation both inside and outside elders' families. As such, ambassadors worked in polygonal relationships with elder clients and elders' children, rather than simply working in dyads with elder clients themselves. In the CAPS context, this polygonal framework integrates intra-familial and extra-familial acculturative dynamics into a single relational model. Within these relationships, CHWs exhibited hybridity of social roles, integrating familial and professional attributes, but fully achieving neither familial nor professional status. Practical implications, including importance of outreach to elders' children, accessibility of social programs, and the consequences of role hybridity as a property of CHW identity and function, are discussed.
Spike Time Synchrony in the Absence of Continuous Oscillations.
Neuron, 2018

Eliav et al., (2018) recently reported hippocampal-entorhinal spiking in bats occurring preferentially at specific phases of nonrhythmic extracellular voltage fluctuations. This disentanglement of phase coding from continuous oscillations raises new questions about the importance of rhythms for neuronal coordination.
Frontotemporal dementia as a comorbidity to idiopathic normal pressure hydrocephalus (iNPH): a short review of literature and an unusual case.
Fluids and barriers of the CNS, 2017

Behavioural variant frontotemporal dementia (bvFTD) and idiopathic normal pressure hydrocephalus (iNPH) are neurodegenerative diseases that can present with similar symptoms. These include decline in executive functions, psychomotor slowness, and behavioural and personality changes. Ventricular enlargement is a key radiological finding in iNPH that may also be present in bvFTD caused by the C9ORF72 expansion mutation. Due to this, bvFTD has been hypothesized as a potential comorbidity to iNPH but bvFTD patients have never been identified in studies focusing in clinical comorbidities with iNPH. Here we describe a patient with the C9ORF72 expansion-associated bvFTD who also showed enlarged ventricles on brain imaging. The main clinical symptoms were severe gait disturbances and psychiatric problems with mild cognitive decline. Cerebrospinal fluid removal increased the patient's walking speed, so a ventriculoperitoneal shunt was placed. After insertion of the shunt, there was a significant improvement in walking speed as well as mild improvement in cognitive function but not in neuropsychiatric symptoms relating to bvFTD. Comorbid iNPH should be considered in bvFTD patients who have enlarged ventricles and severely impaired gait.
Diabetic retinopathy in Tanzania: prevalence and risk factors at entry into a regional screening programme.
Tropical medicine & international health : TM & IH, 2016

The number of adults with diabetes in sub-Saharan Africa (SSA) is expected to almost double by 2035. This study investigated the prevalence of diabetic retinopathy (DR) and its risk factors at entry into a community-based screening programme.
Improving the effectiveness of nutritional information policies: assessment of unconscious pleasure mechanisms involved in food-choice decisions.
Nutrition reviews, 2012

The rise in obesity in many countries has led to the emergence of nutritional information policies that aim to change people's diets. Changing an individual's diet is an ambitious goal, since numerous factors influence a person's food-choice decisions, many of which are made unconsciously. These frequently subconscious processes should not be underestimated in food-choice behavior, as they play a major role in food diet composition. In this review, research in cognitive experimental psychology and neuroscience provides the basis for a critical analysis of the role of pleasure in eating behaviors. An assessment of the main characteristics of nutritional policies is provided, followed by recent findings showing that food choices are guided primarily by automatic emotional processes. Neuroimaging and behavioral studies, which provide new insights into the relationships between emotions and food both in lean persons and in persons with eating disorders, are reported as well. Lastly, the argument is presented that future nutritional policies can be more effective if they associate healthy food with eating pleasure.
Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates.
Science translational medicine, 2018

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.
Neurofilament dot blot assays: novel means of assessing axon viability in culture.
Journal of neuroscience methods, 2011

Axonal structure and integrity are vital to overall neuronal maintenance and action potential propagation. Neurofilaments (NFs) are one of the main cytoskeletal components of axons and phosphorylation of NF subunits regulates speed of NF transport through axons and determines optimal axonal calibre required for signal propagation. Many previous studies of neuroprotective agents have focussed on neuronal viability in models of neurodegenerative disease, without specifically considering axon function as an indicator of neuronal damage. In this study, we have focused on developing novel assays for determining axon viability by measuring levels of neurofilament phosphorylation in cultured cortical neurons. The nitric oxide donor DETANONOate (NO) was used as an inflammatory insult and glial cell line-derived neurotrophic factor (GDNF) and superoxide dismutase (SOD) were tested as potential axonal protective agents. Using 'dot blot' methodologies, we show a decrease in NF phosphorylation in cortical neurons exposed to NO-mediated cell toxicity and an attenuation of NO-mediated changes in NF phosphorylation associated with GDNF and SOD treatment. These results correlated well with immunocytochemical counts. We propose therefore that the dot blot assay is a novel method for assessing axonal integrity in vitro and may play a useful role in the future for testing the effects of agents on axonal viability, providing a reliable and reproducible screening method for potential therapeutics for neurodegenerative diseases.
Bursts of transcranial electrical stimulation increase arousal in a continuous performance test.
Neuropsychologia, 2015

Arousal reflects a state of generalised physiological activation, and its key role in cognition and behaviour has been extensively described. The regulation of arousal is controlled by specific nuclei located in the brainstem that contain widely distributed projections to the cortex and form the arousal systems. In humans, arousal has been commonly studied and modulated through behavioural paradigms, whereas in animals, direct electrical stimulation has been used to confirm the important role of these widely distributed structures. Recent evidence suggests that it might be possible to use transcranial electrical stimulation (tES) to non-invasively induce currents in the brainstem regions of the brain. Therefore, we hypothesise that, using a specific electrode arrangement, it might be possible to employ tES to stimulate subcortical-cortical neuromodulatory networks, inducing modulation of general arousal. The aim of the present study was to determine if it is possible to increase arousal during a discriminative reaction times (RTs) task, through the application of tES, to improve the subjects' performance. We developed 3 experiments: Experiment 1 validated the behavioural task, which was an adapted version of the continuous performance test. Experiment 2 aimed to show the task sensitivity to the level of activation. The results confirmed that the task was sensitive enough to reveal modulations of arousal. In Experiment 3, we applied bursts of tES concurrent with the onset of the relevant stimuli of the task to increase the physiological phasic activation of arousal. The skin conductance response was recorded during the experiment in addition to the RTs. The results showed a reduction of RTs and a concurrent increase in skin conductance during the real stimulation condition, which is consistent with a general increase in arousal. In all, these data support the effectiveness of bursts of tES in modulating arousal.
Understanding and Enhancing Sepsis Survivorship. Priorities for Research and Practice.
American journal of respiratory and critical care medicine, 2019

An estimated 14.1 million patients survive sepsis each year. Many survivors experience poor long-term outcomes, including new or worsened neuropsychological impairment; physical disability; and vulnerability to further health deterioration, including recurrent infection, cardiovascular events, and acute renal failure. However, clinical trials and guidelines have focused on shorter-term survival, so there are few data on promoting longer-term recovery. To address this unmet need, the International Sepsis Forum convened a colloquium in February 2018 titled "Understanding and Enhancing Sepsis Survivorship." The goals were to identify gaps and limitations of current research and shorter- and longer-term priorities for understanding and enhancing sepsis survivorship. Twenty-six experts from eight countries participated. The top short-term priorities identified by nominal group technique culminating in formal voting were to better leverage existing databases for research, develop and disseminate educational resources on postsepsis morbidity, and partner with sepsis survivors to define and achieve research priorities. The top longer-term priorities were to study mechanisms of long-term morbidity through large cohort studies with deep phenotyping, build a harmonized global sepsis registry to facilitate enrollment in cohorts and trials, and complete detailed longitudinal follow-up to characterize the diversity of recovery experiences. This perspective reviews colloquium discussions, the identified priorities, and current initiatives to address them.
Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA.
Pharmacology & therapeutics, 2010

alpha5IA is a triazolophthalazine that selectively attenuates the effects of GABA at GABA(A) receptors containing an alpha5 subunit. It enhances long-term potentiation in an in vitro model of mouse hippocampal synaptic plasticity, gives good in vivo receptor occupancy and improves cognitive performance in normal rats as measured using the delayed-matching-to-place version of the Morris water maze yet, importantly, it is without anxiogenic or proconvulsant liabilities. The hydroxymethyl isoxazole metabolite, which occurs both in vitro and in vivo, has a very low aqueous solubility (0.6microg/mL) that resulted in renal toxicity (crystal formation) at very high doses in preclinical safety and toxicity studies. Although this precluded it from being dosed to humans over prolonged periods of time, alpha5IA is, nevertheless, well tolerated in young and elderly subjects up to a dose of 6mg in multiple-dose studies and gives a plasma EC(50) for alpha5IA occupancy measured using [(11)C]flumazenil PET of 10ng/mL. The compound was evaluated in experimental studies and although in elderly subjects alpha5IA does not improve performance in a paired-associate learning task (a 4-mg dose actually impairs performance), it is able to reverse the ethanol-induced impairment in performance in healthy young normal volunteers. These data demonstrate that in man an alpha5-selective inverse agonist may be effective at increasing performance under certain conditions. Whether or not such a compound has efficacy in conditions associated with cognitive deficits, such as attention-deficit hyperactivity disorder, Alzheimer's disease or schizophrenia remains to be determined.
Cytidine 5'-Diphosphocholine (Citicoline): Evidence for a Neuroprotective Role in Glaucoma.
Nutrients, 2020

Glaucoma, a heterogeneous set of progressively degenerative optic neuropathies characterized by a loss of retinal ganglion cells (RGCs) and typical visual field deficits that can progress to blindness, is a neurodegenerative disease involving both ocular and visual brain structures. Although elevated intraocular pressure (IOP) remains the most important modifiable risk factor of primary open-angle glaucoma (POAG) and is the main therapeutic target in treating glaucoma, other factors that influence the disease course are involved and reaching the optimal IOP target does not stop the progression of glaucoma, as the visual field continues to narrow. In addition to a managed IOP, neuroprotection may be beneficial by slowing the progression of glaucoma and improving the visual defects. Citicoline (cytidine 5'-diphosphocholine) is a naturally occurring endogenous compound that has been investigated as a novel therapeutic agent for the management of glaucoma. Citicoline has demonstrated activity in a range of central neurodegenerative diseases, and experimental evidence suggests a it performs a neuromodulator and neuroprotective role on neuronal cells, including RGCs, associated with improvement in visual function, extension of the visual field and central benefits for the patient. This review aims to critically summarize the current evidence for the neuroprotective properties of citicoline in glaucoma.