rudyvdbrink/CitationDatabase huggingface dataset:
Maternal and offspring methylenetetrahydrofolate-reductase genotypes interact in a mouse model to induce autism spectrum disorder-like behavior.
Genes, brain, and behavior, 2019

Individuals with autism constitute a variable population whose members are spread along the autism spectrum. Subpopulations within that spectrum exhibit other conditions, such as anxiety, intellectual disabilities, hyperactivity and epilepsy, with different severities and co-occurrences. Among the genes associated with the increased risk for autism is the methylenetetrahydrofolate-reductase (MTHFR) 677C>T polymorphism, which impairs one-carbon (C1) metabolic pathway efficiency. The frequency of the MTHFR677TT homozygote is markedly higher among autism patients and their mothers than in the general population. Here, we report on the Mthfr heterozygous knockout (KO) mouse as a rodent model of autism that shows the contributions of maternal and offspring genotypes to the development of autistic-like behaviors. Maternal Mthfr-deficiency was associated with developmental delays in morphogenic features and sensory-motor reflexes in offspring. In the adult male mouse, behaviors representing core autism symptoms, such as repetitive behavior and restricted interest, were affected by maternal genotype while social behaviors were affected by both maternal and offspring genotypes. In females and males, behaviors associated with autism such as memory impairment, social aggression and anxiety were affected by both the maternal and offspring Mthfr genotypes, with sex-dependent differences. Mthfr-deficient male mice with observable impacts on behavior presented a particular laminar disturbance in parvalbumin interneuron density and innervation in superficial and deep layers of the cingulate cortex. This mouse model of autism will help to elucidate the molecular mechanisms that predispose a significant subgroup of autistic patients to abnormal development and to distinguish between the in-utero and autonomous factors involved in autism.
Genetic and epigenetic contributions to the cortical phenotype in mammals.
Brain research bulletin, 2008

One aspect of cortical organization, cortical field size, is variable both within and across species. The observed variability arises from a variety of sources, including genes intrinsic to the neocortex and a number of extrinsic and epigenetic factors. Genes intrinsic to the cortex are directly involved in the development and specification of cortical fields and are regulated from both signaling centers located outside of the neocortex, which secrete diffusible molecules, and the expression of transcription factors within the neocortex. In addition, extrinsic factors such as the type, location and density of sensory receptor arrays and how these receptor arrays are utilized, are also strongly related to cortical field size. Epigenetic factors including the relative activity patterns generated by the different types of physical stimuli in a given environment also contribute to differences in cortical organization, including cortical field size. Since both genetic and epigenetic factors contribute to cortical organization, some aspects of the cortical phenotype evolve, while other aspects of the cortical phenotype persist only if the environment in which an individual develops is relatively stable.
Regulation of the HIV-1 promoter by HIF-1α and Vpr proteins.
Virology journal, 2011

We previously demonstrated the ability of HIV-1 Vpr protein to activate the oxidative stress pathway, thus leading to the induction of the hypoxia inducible factor 1 alpha (HIF-1α). Therefore, we sought to examine the interplay between the two proteins and the impact of HIF-1α activation on HIV-1 transcription. Using transient transfection assays, we identified the optimal concentration of HIF-1α necessary for the activation of the HIV-1 promoter as well as the domain within HIF-1α responsible for this activation. Our findings indicated that activation of the HIV-1 LTR by Vpr is HIF-1α dependent. Furthermore, we showed that both Vpr and HIF-1α activate the HIV-1 promoter through the GC-rich binding domain within the LTR. Taken together, these data shed more light on the mechanisms used by Vpr to activate the HIV-1 promoter and placed HIF-1α as a major participant in this activation.
The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders.
Developmental medicine and child neurology, 2011

A group of disorders with disparate symptomatology, including congenital cerebellar ataxia, retinal blindness, liver fibrosis, polycystic kidney disease, and polydactyly, have recently been united under a single disease mechanism called 'ciliopathies'. The ciliopathies are due to defects of the cellular antenna known as the primary cilium, a microtubule-based extension of cellular membranes found in nearly all cell types. Key among these ciliopathies is Joubert syndrome, displaying ataxia, oculomotor apraxia, and mental retardation* with a pathognomonic 'molar tooth sign' on brain magnetic resonance imaging. The importance of ciliary function in neuronal development has been appreciated only in the last decade with the classification of Joubert syndrome as a ciliopathy. This, together with the identification of many of the clinical features of ciliopathies in individuals with Joubert syndrome and the localization of Joubert syndrome's causative gene products at or near the primary cilium, have defined a new class of neurological disease. Cilia are involved in diverse cellular processes including protein trafficking, photoreception, embryonic axis patterning, and cell cycle regulation. Ciliary dysfunction can affect a single tissue or manifest as multi-organ involvement. Ciliary defects have been described in retinopathies such as retinitis pigmentosa and Leber congenital amaurosis (defects in photoreceptor ciliary protein complexes), renal syndromes with nephronophthisis and cystic dysplastic kidneys, and liver conditions such as fibrosis and biliary cirrhosis. Recognizing the diverse presentations of the ciliopathies and screening strategies following diagnosis is an important part of the treatment plan of children with cilia-related disorders.
Head movement during walking in the cat.
Neuroscience, 2016

Knowledge of how the head moves during locomotion is essential for understanding how locomotion is controlled by sensory systems of the head. We have analyzed head movements of the cat walking along a straight flat pathway in the darkness and light. We found that cats' head left-right translations, and roll and yaw rotations oscillated once per stride, while fore-aft and vertical translations, and pitch rotations oscillated twice. The head reached its highest vertical positions during second half of each forelimb swing, following maxima of the shoulder/trunk by 20-90°. Nose-up rotation followed head upward translation by another 40-90° delay. The peak-to-peak amplitude of vertical translation was ∼1.5cm and amplitude of pitch rotation was ∼3°. Amplitudes of lateral translation and roll rotation were ∼1cm and 1.5-3°, respectively. Overall, cats' heads were neutral in roll and 10-30° nose-down, maintaining horizontal semicircular canals and utriculi within 10° of the earth horizontal. The head longitudinal velocity was 0.5-1m/s, maximal upward and downward linear velocities were ∼0.05 and ∼0.1m/s, respectively, and maximal lateral velocity was ∼0.05m/s. Maximal velocities of head pitch rotation were 20-50°/s. During walking in light, cats stood 0.3-0.5cm taller and held their head 0.5-2cm higher than in darkness. Forward acceleration was 25-100% higher and peak-to-peak amplitude of head pitch oscillations was ∼20°/s larger. We concluded that, during walking, the head of the cat is held actively. Reflexes appear to play only a partial role in determining head movement, and vision might further diminish their role.
SMN deficiency reduces cellular ability to form stress granules, sensitizing cells to stress.
Cellular and molecular neurobiology, 2011

Spinal Muscular Atrophy (SMA) is a neurodegenerative disease that is caused by deletion of the SMN (Survival of Motor Neuron) gene. The SMN protein is essential for cell survival and co-localized with TIA-1/R and G3BP, two characteristic markers of stress granules (SGs). To further study the SMN function in stress granules and in response to stress, we generated stable cell lines with SMN knockdown. Our data indicate that suppression of SMN drastically reduces cellular ability to form stress granules in response to stress treatment. In addition, we show that SMN deficiency sensitizes cells to sodium arsenite and H(2)O(2), two well-known stress inducers, leading to cell death at a much lower concentration of inducers in SMN knockdown cells than in control cells. Interestingly, the cell death is correlated with formation of stress granules, suggesting that involvement of SMN in formation of stress granules may play an important role in cell survival. Furthermore, rescue of SGs formation by overexpression of G3BP can reverse the defective formation of stress granules and results in partial abrogation of cell death against SMN deficiency. We deduce that modulation of stress response may be useful for potential SMN treatment.
CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor.
Developmental cell, 2013

Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.
Biosimilars: opinion of an expert panel in the Middle East.
Current medical research and opinion, 2008

Several biotechnology-derived drugs are reaching the end of their patent lives. As a result, so-called biosimilar products are in development, and a few have already gained approval in Europe and other countries such as the USA. Biosimilars, unlike generic versions of conventional drugs, are not identical to their reference product, and their production is complex and sensitive to even slight changes in the manufacturing and storage process. Therefore, the registration of these products requires more stringent evaluation than that for conventional generics.
Signaling pathways controlling activity-dependent local translation of BDNF and their localization in dendritic arbors.
Journal of cell science, 2016

Brain-derived neurotrophic factor (BDNF) is encoded by multiple mRNA variants whose differential subcellular distribution constitutes a 'spatial code' for local translation of BDNF and selective morphological remodeling of dendrites. Here, we investigated where BDNF translation takes place and what are the signaling pathways involved. Cultured hippocampal neurons treated with KCl showed increased BDNF in the soma, proximal and distal dendrites, even in quaternary branches. This activity-dependent increase of BDNF was abolished by cycloheximide, suggesting local translation, and required activation of glutamate and Trk receptors. Our data showed that BDNF translation was regulated by multiple signaling cascades including RAS-Erk and mTOR pathways, and CaMKII-CPEB1, Aurora-A-CPEB1 and Src-ZBP1 pathways. Aurora-A, CPEB1, ZBP1 (also known as IGF2BP1), eiF4E, S6 (also known as rpS6) were present throughout the dendritic arbor. Neuronal activity increased the levels of Aurora-A, CPEB1 and ZBP1 in distal dendrites whereas those of eiF4E and S6 were unaffected. BDNF-6, the main dendritic BDNF transcript, was translated in the same subcellular domains and in response to the same pathways as total BDNF. In conclusion, we identified the signaling cascades controlling BDNF translation and we describe how the translational machinery localization is modulated in response to electrical activity.
Acute care utilisation towards the end of life and the place of death for patients with serious mental disorders: a register-based cohort study in South London.
Public health, 2021

The aim of the study was to explore acute care utilisation towards end of life by and the place of death for patients with serious mental disorders and to demonstrate any inequalities in end-of-life care faced by this patient group.
Spindle-F-actin interactions in mitotic spindles in an intact vertebrate epithelium.
Molecular biology of the cell, 2019

Mitotic spindles are well known to be assembled from and dependent on microtubules. In contrast, whether actin filaments (F-actin) are required for or are even present in mitotic spindles has long been controversial. Here we have developed improved methods for simultaneously preserving F-actin and microtubules in fixed samples and exploited them to demonstrate that F-actin is indeed associated with mitotic spindles in intact
Fourteen-year trajectories of posttraumatic stress disorder (PTSD) symptoms in UK military personnel, and associated risk factors.
Journal of psychiatric research, 2019

The aim of this study was to examine trajectories of posttraumatic stress disorder (PTSD) symptoms over a 14-year period and the risk factors associated with each trajectory. 1885 UK military personnel provided information at four time points since 2002. The PTSD Check list-Civilian Version (PCL-C) was used at all time points. Growth mixture models (GMM) were estimated to examine whether individuals could be clustered into discrete groups with similar trajectories. Multinomial logistic regressions were carried out to investigate factors associated with class membership. The three-class GMM was the most parsimonious solution. This included 90.2% in the resilient class, 4.1% in the improving class and 5.7% in the deteriorating class. Both the deteriorating and improving classes were associated with childhood adversity (odds ratios (OR) 3.9 (95% CI 2.3, 6.7) and 3.3 (95% CI 2.1, 5.0) respectively) and antisocial behaviour (OR 2.8 (95% CI 1.9, 4.2) and 3.7 (95% CI 2.4, 5.8) respectively), alcohol misuse (OR 3.5 (95% CI 2.4, 5.1) and 3.3 (95% CI 2.1, 5.2) respectively) and longer time since leaving Service in comparison to the resilient group. Those in the youngest group and those in a combat role (OR 0.32, 95% CI 0.19, 0.54) were more likely to belong to the deteriorating class. 10% of the cohort had symptoms of PTSD; of those, up to half were symptomatic for most of the follow-up period. Those whose score improved did not reach the low scores of the resilient group. Younger age and combat role were associated with worse prognosis of PTSD.
Human category learning 2.0.
Annals of the New York Academy of Sciences, 2011

During the 1990s and early 2000s, cognitive neuroscience investigations of human category learning focused on the primary goal of showing that humans have multiple category-learning systems and on the secondary goals of identifying key qualitative properties of each system and of roughly mapping out the neural networks that mediate each system. Many researchers now accept the strength of the evidence supporting multiple systems, and as a result, during the past few years, work has begun on the second generation of research questions-that is, on questions that begin with the assumption that humans have multiple category-learning systems. This article reviews much of this second generation of research. Topics covered include (1) How do the various systems interact? (2) Are there different neural systems for categorization and category representation? (3) How does automaticity develop in each system? and (4) Exactly how does each system learn?
Clinicopathological findings of pediatric NTRK fusion mesenchymal tumors.
Diagnostic pathology, 2020

While ETV6- NTRK3 fusion is common in infantile fibrosarcoma, NTRK1/3 fusion in pediatric tumors is scarce and, consequently, not well known. Herein, we evaluated for the presence of NTRK1/3 fusion in pediatric mesenchymal tumors, clinicopathologically and immunophenotypically.
Mapping the dynamic allocation of temporal attention in musical patterns.
Journal of experimental psychology. Human perception and performance, 2018

Many environmental sounds, such as music or speech, are patterned in time. Dynamic attending theory, and supporting empirical evidence, suggests that a stimulus's temporal structure serves to orient attention to specific moments in time. One instantiation of this theory posits that attention synchronizes to the temporal structure of a stimulus in an oscillatory fashion, with optimal perception at salient time points or oscillation peaks. We examined whether a model consisting of damped linear oscillators succeeds at predicting temporal attention behavior in rhythmic multi-instrumental music. We conducted 3 experiments in which we mapped listeners' perceptual sensitivity by estimating detection thresholds for intensity deviants embedded at multiple time points within a stimulus pattern. We compared participants' thresholds for detecting intensity changes at various time points with the modeled salience prediction at each of those time points. Across all experiments, results showed that the resonator model predicted listener thresholds, such that listeners were more sensitive to probes at time points corresponding to greater model-predicted salience. This effect held for both intensity increment and decrement probes and for metrically simple and complex stimuli. Moreover, the resonator model explained the data better than did predictions based on canonical metric hierarchy or auditory scene density. Our results offer new insight into the temporal orienting of attention in complex auditory scenes using a parsimonious computational model for predicting attentional dynamics. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
Burden of Sexual Dysfunction.
Journal of sex & marital therapy, 2017

Similar to the burden of other diseases, the burden of sexual dysfunction has not been systematically studied. However, there is growing evidence of various burdens (e.g., economic, symptomatic, humanistic) among patients suffering from sexual dysfunctions. The burden of sexual dysfunction has been studied a bit more often in men, namely the burden of erectile dysfunction (ED), premature ejaculation (PE) and testosterone deficiency syndrome (TDS). Erectile dysfunction is frequently associated with chronic conditions such as cardiovascular disease, diabetes, and depression. These conditions could go undiagnosed, and ED could be a marker of those diseases. The only available report from the United Kingdom estimated the total economic burden of ED at £53 million annually in terms of direct costs and lost productivity. The burden of PE includes significant psychological distress: anxiety, depression, lack of sexual confidence, poor self-esteem, impaired quality of life, and interpersonal difficulties. Some suggest that increase in female sexual dysfunction is associated with partner's PE, in addition to significant interpersonal difficulties. The burden of TDS includes depression, sexual dysfunction, mild cognitive impairment, and osteoporosis. One UK estimate of the economic burden of female sexual dysfunctions demonstrated that the average cost per patient was higher than the per annum cost of ED. There are no data on burden of paraphilic disorders. The burden of sexual dysfunctions is underappreciated and not well studied, yet it is significant for both the patients and the society.
A translational view of cells' secretome analysis - from untargeted proteomics to potential circulating biomarkers.
Biochimie, 2018

The identification of circulating biomarkers capable of being used as routine for diagnosis, prognosis, risk stratification and therapeutic monitoring is still the major aim at clinical proteomics. However, the direct search in blood samples or other clinical relevant biofluids is frequently associated with technical limitations that make the biomarker discovery process extremely difficult when using these types of samples. In this sense, the use of different approaches, such as the analysis of cells' secretomes, can be an important and promising complementary method for the identification and pre-selection of potential circulating biomarkers. Therefore, the present review is focused on published works exclusively devoted to the use of cells' secretomes for the identification of new circulating biomarkers. Considering these publications, the translational workflow used to identify potential protein circulating biomarkers from untargeted cells' secretome screenings is presented and discussed in this review. This translational workflow follows a 3-phase pipeline (discovery, verification and validation phase) similar to the "triangular strategy" already applied in biomarker discovery using blood or other clinical samples. For each phase it will be indicated the type of samples, the techniques used to analyze the samples, as well as, the major outcomes and methods used to analyze the data obtained. The examples presented in this review points out the potential of this secretome-based translational pipeline for the identification of new circulating biomarker candidates, with some of the biomarkers pointed out presenting better discriminatory capacity or at least improving the discriminatory capacity of well-established biomarkers. Finally, some of the potential improvements are also identified and discussed in this review, which can increase the visibility and importance of this cells' secretome-based pipeline for the identification of new potential circulating biomarkers.
Overlapping effects of age on associative memory and the anterior hippocampus from middle to older age.
Behavioural brain research, 2017

The anterior hippocampus has been implicated in associative memory, and along with hippocampal volume, this type of memory declines with age. However, few cross-sectional studies include middle-aged samples, making it unclear at what point these age-related changes occur. In addition, although men and women have been shown to differ in associative memory and rates of age-related hippocampal atrophy, sex-differences in aging are rarely studied. To address these issues, we assessed memory for word-pairs, hippocampal volume and activation during encoding and retrieval, across middle-aged (n=39) and older (n=44) participants, specifically in relation to sex. Older adults showed significantly poorer associative memory compared to middle-aged adults, paralleled by smaller anterior hippocampi and less activation during successful retrieval. The age-by-sex interaction observed in memory performance was also mirrored in the volume and activation of the hippocampus, indicating more pronounced age-effects in men as compared to women. These results indicate a specific role of the anterior hippocampus in verbal associative memory and suggest they both decline between middle-age and older age.