rudyvdbrink/CitationDatabase huggingface dataset:
An ALS-linked mutation in TDP-43 disrupts normal protein interactions in the motor neuron response to oxidative stress.
Neurobiology of disease, 2020

TDP-43 pathology is a key feature of amyotrophic lateral sclerosis (ALS), but the mechanisms linking TDP-43 to altered cellular function and neurodegeneration remain unclear. We have recently described a mouse model in which human wild-type or mutant TDP-43 are expressed at low levels and where altered stress granule formation is a robust phenotype of TDP-43
History of the Department of Neurosurgery at Thomas Jefferson University Hospital.
Neurosurgery, 2013

The neurosurgical tradition at Jefferson Medical College began in the 19th century with Samuel Gross. In his textbook entitled A System of Surgery, Gross revealed his knowledge of the disorders of the nervous system at a time when innovations were practically inexistent. Gross' work paved the way for William Williams Keen, "America's first brain surgeon." In 1887, Keen became the first surgeon in the nation to successfully remove a primary brain tumor. In 1893, Keen operated secretly on President Grover Cleveland for removal of an intraoral sarcoma and later served as a consultant to Franklin Roosevelt after he contracted poliomyelitis. The neurosurgery division was established in 1943 by J. Rudolph Jaeger. It was Philip Gordy who created a distinct Department of Neurosurgery in 1969. Jewell L. Osterholm became chairman of the Department of Neurosurgery in 1974. Since 2004, Robert Rosenwasser has served as chairman, and the Department of Neurosurgery at Jefferson has grown to include 26 faculty members. The residency has expanded to include 3 residents per academic year since 2007.
Atypical measures of diffusion at the gray-white matter boundary in autism spectrum disorder in adulthood.
Human brain mapping, 2021

Autism spectrum disorder (ASD) is a highly complex neurodevelopmental condition that is accompanied by neuroanatomical differences on the macroscopic and microscopic level. Findings from histological, genetic, and more recently in vivo neuroimaging studies converge in suggesting that neuroanatomical abnormalities, specifically around the gray-white matter (GWM) boundary, represent a crucial feature of ASD. However, no research has yet characterized the GWM boundary in ASD based on measures of diffusion. Here, we registered diffusion tensor imaging data to the structural T1-weighted images of 92 adults with ASD and 92 matched neurotypical controls in order to examine between-group differences and group-by-sex interactions in fractional anisotropy and mean diffusivity sampled at the GWM boundary, and at different sampling depths within the superficial white and into the gray matter. As hypothesized, we observed atypical diffusion at and around the GWM boundary in ASD, with between-group differences and group-by-sex interactions depending on tissue class and sampling depth. Furthermore, we identified that altered diffusion at the GWM boundary partially (i.e., ~50%) overlapped with atypical gray-white matter tissue contrast in ASD. Our study thus replicates and extends previous work highlighting the GWM boundary as a crucial target of neuropathology in ASD, and guides future work elucidating etiological mechanisms.
Aged rhesus monkeys: Cognitive performance categorizations and preclinical drug testing.
Neuropharmacology, 2021

Rodent models have facilitated major discoveries in neurobiology, however, the low success rate of novel medications in clinical trials have led to questions about their translational value in neuropsychiatric drug development research. For age-related disorders of cognition such as Alzheimer' disease (AD) there is interest in moving beyond transgenic amyloid-β and/or tau-expressing rodent models and focusing more on natural aging and dissociating "healthy" from "pathological" aging to identify new therapeutic targets and treatments. In complex disorders such as AD, it can also be argued that animals with closer neurobiology to humans (e.g., nonhuman primates) should be employed more often particularly in the later phases of drug development. The purpose of the work described here was to evaluate the cognitive capabilities of rhesus monkeys across a wide range of ages in different delayed response tasks, a computerized delayed match to sample (DMTS) task and a manual delayed match to position (DMTP) task. Based on specific performance criteria and comparisons to younger subjects, the older subjects were generally less proficient, however, some performed as well as young subjects, while other aged subjects were markedly impaired. Accordingly, the older subjects could be categorized as aged "cognitively-unimpaired" or aged "cognitively-impaired" with a third group (aged-other) falling in between. Finally, as a proof of principle, we demonstrated using the DMTP task that aged cognitively-impaired monkeys are sensitive to the pro-cognitive effects of a nicotinic acetylcholine receptor (nAChR) partial agonist, encenicline, suggesting that nAChR ligands remain viable as potential treatments for age-related disorders of cognition.
Chicks prefer to peck at insect-like elongated stimuli moving in a direction orthogonal to their longer axis.
Animal cognition, 2009

Spontaneous preferences towards possible prey have been little investigated using targets in motion. Preferences of domestic chicks (Gallus gallus) to peck at video-images of stimuli representing live insects moving along their longer body axis (i.e. "forwards") or along the shorter body axis (i.e. "sideways") were investigated. Chicks presented with both types of stimulus displayed a significant preference for pecking at stimuli moving sideways. This preference was already present on day 1 post-hatching, and it strengthened on day 6 for those chicks that had experienced pecking at live insects. Head angles used to fixate the stimuli prior to pecking were also analysed and were consistent (i.e. 30 degrees -35 degrees and 60 degrees -65 degrees ) with those reported for fixation of non-edible targets (larger stimuli at a distance). In a first control experiment the same video-presented stimuli were used but the insect's legs were removed to reduce flickering. In a second control experiment, paper-printed images of the whole insect were used. In both cases, the sideways direction of movement was clearly preferred. Overall, our data show that chicks have a spontaneous preference to peck at video-images resembling live insects moving along their shorter body axis. Sideways movement may constitute a crucial signal attracting chicks' attention and enhancing predatory responses possibly because of stronger stimulation of motion detectors.
Impaired glymphatic function and clearance of tau in an Alzheimer's disease model.
Brain : a journal of neurology, 2020

The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain in Alzheimer's disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer's disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer's disease, and possibly other neurodegenerative diseases alike.
Targeting increased levels of APP in Down syndrome: Posiphen-mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model.
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2021

Recent clinical trials targeting amyloid beta (Aβ) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis and defining possible links between them may enhance insights into both upstream initiating events and downstream mechanisms, thereby promoting discovery of novel treatments. Evidence that in Down syndrome (DS), a population markedly predisposed to develop early onset AD, increased APP gene dose is necessary for both AD neuropathology and dementia points to normalization of the levels of the amyloid precursor protein (APP) and its products as a route to further define AD pathogenesis and discovering novel treatments.
Vascular and metabolic risk factor differences prior to dementia diagnosis: a multidatabase case-control study using European electronic health records.
BMJ open, 2020

The objective of the study is to compare body mass index (BMI), systolic/diastolic blood pressure (SBP/DBP) and serum total cholesterol levels between dementia cases and controls at multiple time intervals prior to dementia onset, and to test time interval as a modifying factor for these associations.
"Incidence and Clinico-Radiological Correlations of Early Arterial Reocclusion After Successful Thrombectomy in Acute Ischemic Stroke".
Translational stroke research, 2020

About half of acute stroke patients treated with mechanical thrombectomy (MT) do not show clinical improvement despite successful recanalization. Early arterial reocclusion (EAR) may be one of the causes that explain this phenomenon. We aimed to analyze the incidence and clinico-radiological correlations of EAR after successful MT. A consecutive series of patients treated with MT between 2010 and 2018 at a single-center included in a prospective registry was retrospectively reviewed. Specific inclusion criteria for the analysis were (1) successful recanalization after MT and (2) availability of pretreatment CT perfusion and follow-up MRI. EAR was evaluated in the follow-up MR angiography. Adjusted regression models were used to analyze the association of EAR with pretreatment variables, infarct growth, final infarct volume, and clinical outcome at 90 days (ordinal distribution of the modified Rankin Scale scores). Out of 831 MT performed, 218 (26%) patients fulfilled inclusion criteria, from whom 13 (6%) suffered EAR. In multivariate analysis controlled by confounders, EAR was independently associated with poor clinical outcome (aOR = 3.2, 95%CI = 1.16-9.72, p = 0.039), greater final infarct volume (aOR = 3.8, 95%CI = 1.93-7.49, p < 0.001), and increased infarct growth (aOR = 8.5, CI95% = 2.04-34.70, p = 0.003). According to mediation analyses, the association between EAR and poor clinical outcome was mainly explained through its effects on final infarct volume and infarct growth. Additionally, EAR was associated with non-cardioembolic etiology (adjusted Odds Ratio (aOR) = 10.1, 95%CI = 1.25-81.35, p = 0.030) and longer procedural time (aOR = 2.6, 95%CI = 1.31-5.40, p = 0.007). Although uncommon, EAR hampers the benefits of successful recanalization after MT resulting in increased infarct growth and larger final lesions.
Determinants of seeding and spreading of α-synuclein pathology in the brain.
Science advances, 2020

In Parkinson's disease (PD), fibrillar forms of α-synuclein are hypothesized to propagate through synaptically coupled networks, causing Lewy pathology (LP) and neurodegeneration. To more rigorously characterize the determinants of spreading, preformed α-synuclein fibrils were injected into the mouse pedunculopontine nucleus (PPN), a brain region that manifests LP in PD patients and the distribution of developing α-synuclein pathology compared to that ascertained by anterograde and retrograde connectomic mapping. Within the PPN, α-synuclein pathology was cell-specific, being robust in PD-vulnerable cholinergic neurons but not in neighboring noncholinergic neurons. While nearly all neurons projecting to PPN cholinergics manifested α-synuclein pathology, the kinetics, magnitude, and persistence of the propagated pathology were unrelated to the strength of those connections. Thus, neuronal phenotype governs the somatodendritic uptake of pathological α-synuclein, and while the afferent connectome restricts the subsequent spreading of pathology, its magnitude and persistence is not a strict function of the strength of coupling.
Sustained-release buprenorphine induces acute opioid tolerance in the mouse.
European journal of pharmacology, 2020

Sustained-release buprenorphine is widely used in mice with the intention of providing long-lasting analgesia. Statements about duration of therapeutic efficacy are based on persistence of serum buprenorphine levels over a minimum threshold, but behavioral data demonstrating sustained efficacy is not established. Additionally, chronic opioid exposure can induce tolerance and/or hyperalgesia; mice receiving sustained-release buprenorphine have not been evaluated for these effects. This study assessed clinical efficacy and duration of sustained-release buprenorphine in inflammatory, post-operative, and cancer pain; and screened for centrally-mediated opioid-induced hyperalgesia as well as opioid tolerance. At 1-2 mg/kg sustained-release buprenorphine, statistically significant analgesic efficacy occurred only at time points up to 2 h. These animals showed no changes in von Frey thresholds on the contralateral side, i.e. no centrally-mediated opioid hyperalgesia. To establish whether acute onset opioid tolerance resulted from a single sustained-release buprenorphine administration, we used the tail flick assay, exposing mice to sustained-release buprenorphine or saline on Day 1 and buprenorphine on Day 2. We measured duration and efficacy of 1 mg/kg buprenorphine after 1 mg/kg sustained-release buprenorphine, and also quantified a dose-response curve of buprenorphine (0.1-3 mg/kg) after 2 mg/kg sustained-release buprenorphine. Compared to control animals, mice previously exposed to sustained-release buprenorphine showed diminished analgesic response to buprenorphine; the resultant dose-response curve showed decreased efficacy. Pretreatment with naloxone, an opioid receptor antagonist, blocked sustained-release buprenorphine analgesic action. The short duration of antinociception following administration of sustained-release buprenorphine in mice is caused by the rapid development of tolerance.
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.
Brain : a journal of neurology, 2020

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
Muscle Strength and Physical Performance in Patients Without Previous Disabilities Recovering From COVID-19 Pneumonia.
American journal of physical medicine & rehabilitation, 2021

In this cross-sectional study, we evaluated skeletal muscle strength and physical performance (1-min sit-to-stand and short physical performance battery tests), dyspnea, fatigue, and single-breath counting at discharge from a postacute COVID department, in patients recovering from COVID-19 pneumonia who had no locomotor disability before the infection.Quadriceps and biceps were weak in 86% and 73% of the patients, respectively. Maximal voluntary contraction for quadriceps was 18.9 (6.8) kg and for biceps 15.0 (5.5) kg (i.e., 54% and 69% of the predicted normal value, respectively). The number of chair rises in the 1-min sit-to-stand test was 22.1 (7.3 corresponding to 63% of the predicted normal value), whereas the short physical performance battery score was 7.9 (3.3 corresponding to 74% of the predicted normal value). At the end of the 1-min sit-to-stand test, 24% of the patients showed exercise-induced desaturation. The single-breath counting count was 35.4 (12.3) corresponding to 72% that of healthy controls. Mild-to-moderate dyspnea and fatigue were found during activities of daily living (Borg scale score, median value = 0.5 [0-2] and 1 [0-2]) and after the 1-min sit-to-stand (Borg scale score, median value = 3 [2-5] and 1 [0-3]). Significant correlations were observed between muscle strength and physical performance indices (R = 0.31-0.69).The high prevalence of impairment in skeletal muscle strength and physical performance in hospitalized patients recovering from COVID-19 pneumonia without previous locomotor disabilities suggests the need for rehabilitation programs after discharge.
Further investigation of the effects of 5-hydroxytryptamine, 8-OH-DPAT and DOI to mediate contraction and relaxation responses in the intestine and emesis in Suncus murinus.
European journal of pharmacology, 2018

5-HT receptors are implicated in many gastrointestinal disorders. However, the precise role of 5-HT in mediating GI responses in Suncus murnius is still unclear. Therefore in this study, the effects of 5-HT and its agonists were investigated in Suncus. The involvement of 5-HT
Neural substrates of appetitive and aversive prediction error.
Neuroscience and biobehavioral reviews, 2021

Prediction error, defined by the discrepancy between real and expected outcomes, lies at the core of associative learning. Behavioural investigations have provided evidence that prediction error up- and down-regulates associative relationships, and allocates attention to stimuli to enable learning. These behavioural advances have recently been followed by investigations into the neurobiological substrates of prediction error. In the present paper, we review neuroscience data obtained using causal and recording neural methods from a variety of key behavioural designs. We explore the neurobiology of both appetitive (reward) and aversive (fear) prediction error with a focus on the mesolimbic dopamine system, the amygdala, ventrolateral periaqueductal gray, hippocampus, cortex and locus coeruleus noradrenaline. New questions and avenues for research are considered.
A combined cohort analysis of prenatal exposure to phthalate mixtures and childhood asthma.
Environment international, 2020

Previous studies of prenatal phthalate exposure and childhood asthma are inconsistent. These studies typically model phthalates as individual, rather than co-occurring, exposures. We investigated whether prenatal phthalates are associated with childhood wheeze and asthma using a mixtures approach.
Leveraging the effector independent nature of motor imagery when it is paired with physical practice.
Scientific reports, 2020

While considered analogous to physical practice, the nature of imagery-based skill acquisition-specifically whether or not both effector independent and dependent encoding occurs through motor imagery-is not well understood. Here, motor imagery-based training was applied prior to or after physical practice-based training to probe the nature of imagery-based skill acquisition. Three groups of participants (N = 38) engaged in 10 days of training of a dart throwing task: 5 days of motor imagery prior to physical practice (MIP-PP), motor imagery following physical practice (PP-MIP), or physical practice only (PP-PP). Performance-related outcomes were assessed throughout. Brain activity was measured at three time points using fMRI (pre/mid/post-training; MIP-PP and PP-MIP groups). In contrast with physical practice, motor imagery led to changes in global versus specific aspects of the movement. Following 10 days of training, performance was greater when motor imagery preceded physical practice, although remained inferior to performance resulting from physical practice alone. Greater activation of regions that support effector dependent encoding was observed mid-, but not post-training for the PP-MIP group. Findings indicate that changes driven by motor imagery reflect effector independent encoding, providing new information regarding how motor imagery may be leveraged for skill acquisition.
USP15 Deubiquitinates TUT1 Associated with RNA Metabolism and Maintains Cerebellar Homeostasis.
Molecular and cellular biology, 2020

Precise regulation of RNA metabolism is crucial for dynamic gene expression and controlling cellular functions. In the nervous system, defects in RNA metabolism are implicated in the disturbance of brain homeostasis and development. Here, we report that deubiquitinating enzyme, ubiquitin specific peptidase 15 (USP15), deubiquitinates terminal uridylyl transferase 1 (TUT1) and changes global RNA metabolism. We found that the expression of USP15 redistributes TUT1 from the nucleolus to nucleoplasm, resulting in the stabilization of U6 snRNA. We also found that lack of the