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International Journal of... Mar 2021Trauma exposure is prevalent, associated with multiple forms of psychopathology, and thought to alter the neurobiological substrates of threat processing. The late...
Trauma exposure is prevalent, associated with multiple forms of psychopathology, and thought to alter the neurobiological substrates of threat processing. The late positive potential (LPP) is an event-related potential (ERP) that may be a clinically useful probe of the neurobiology of threat processing. Despite evidence that combat-exposed veterans exhibit aberrant threat modulation of the LPP, no studies to date have tested the psychometric properties of the LPP in combat trauma-exposed, symptomatic veterans. The primary aim of the current study was to evaluate the reliability (internal consistency, retest reliability) and convergent validity of LPP modulation by threatening faces and scenes in two common tasks among combat-exposed veterans. Participants included 82 combat-exposed veterans who completed face-matching and emotion regulation tasks during EEG recording at baseline and twelve weeks. Internal consistencies of the early LPP time windows (<1000 ms) were acceptable in both tasks, whereas they were poor in late time windows (>1000 ms). Twelve-week retest reliabilities were fair for the early window LPPs to threatening scenes and fear faces, as well as in the late time window for fear faces. Reliabilities were better for individual condition compared to difference scores. Finally, LPPs modulated by threatening scenes and faces were unrelated. Together, these results suggest that the LPPs to threatening scenes and faces reflect distinct forms of threat processing in combat-exposed veterans, and their reliabilities for the early window indicate potential clinical utility in this population.
Topics: Electroencephalography; Emotions; Humans; Psychometrics; Reproducibility of Results; Stress Disorders, Post-Traumatic; Veterans
PubMed: 33450313
DOI: 10.1016/j.ijpsycho.2021.01.001 -
Neural Plasticity 2018Cerebral palsy (CP) has long been investigated to be associated with a range of motor and cognitive dysfunction. As the two most common CP subtypes, spastic cerebral...
Cerebral palsy (CP) has long been investigated to be associated with a range of motor and cognitive dysfunction. As the two most common CP subtypes, spastic cerebral palsy (SCP) and dyskinetic cerebral palsy (DCP) may share common and distinct elements in their pathophysiology. However, the common and distinct dysfunctional characteristics between SCP and DCP on the brain network level are less known. This study aims to detect the alteration of brain functional connectivity in children with SCP and DCP based on resting-state functional MRI (fMRI). Resting-state networks (RSNs) were established based on the independent component analysis (ICA), and the functional network connectivity (FNC) was performed on the fMRI data from 16 DCP, 18 bilateral SCP, and 18 healthy children. Compared with healthy controls, altered functional connectivity within the cerebellum network, sensorimotor network (SMN), left frontoparietal network (LFPN), and salience network (SN) were found in DCP and SCP groups. Furthermore, the disconnections of the FNC consistently focused on the visual pathway; covariance of the default mode network (DMN) with other networks was observed both in DCP and SCP groups, while the DCP group had a distinct connectivity abnormality in motor pathway and self-referential processing-related connections. Correlations between the functional disconnection and the motor-related clinical measurement in children with CP were also found. These findings indicate functional connectivity impairment and altered integration widely exist in children with CP, suggesting that the abnormal functional connectivity is a pathophysiological mechanism of motor and cognitive dysfunction of CP.
Topics: Adolescent; Brain; Brain Mapping; Cerebral Palsy; Child; Child, Preschool; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Neural Pathways; Signal Processing, Computer-Assisted
PubMed: 30186320
DOI: 10.1155/2018/7058953 -
Progress in Neurobiology Sep 2021As a major eukaryotic cell clearing machinery, autophagy grants cell proteostasis, which is key for neurotransmitter release, synaptic plasticity, and neuronal survival.... (Review)
Review
As a major eukaryotic cell clearing machinery, autophagy grants cell proteostasis, which is key for neurotransmitter release, synaptic plasticity, and neuronal survival. In line with this, besides neuropathological events, autophagy dysfunctions are bound to synaptic alterations that occur in mental disorders, and early on, in neurodegenerative diseases. This is also the case of methamphetamine (METH) abuse, which leads to psychiatric disturbances and neurotoxicity. While consistently altering the autophagy machinery, METH produces behavioral and neurotoxic effects through molecular and biochemical events that can be recapitulated by autophagy blockade. These consist of altered physiological dopamine (DA) release, abnormal stimulation of DA and glutamate receptors, as well as oxidative, excitotoxic, and neuroinflammatory events. Recent molecular insights suggest that METH early impairs the autophagy machinery, though its functional significance remains to be investigated. Here we discuss evidence suggesting that alterations of DA transmission and autophagy are intermingled within a chain of events underlying behavioral alterations and neurodegenerative phenomena produced by METH. Understanding how METH alters the autophagy machinery is expected to provide novel insights into the neurobiology of METH addiction sharing some features with psychiatric disorders and parkinsonism.
Topics: Autophagy; Dopamine; Humans; Methamphetamine; Neurodegenerative Diseases; Neuronal Plasticity; Neurotransmitter Agents
PubMed: 34171442
DOI: 10.1016/j.pneurobio.2021.102112 -
Frontiers in Human Neuroscience 2016Brain architecture can be divided into a cortico-thalamic system and modulatory "subcortical-cerebellar" systems containing key structures such as striatum, medial...
BACKGROUND
Brain architecture can be divided into a cortico-thalamic system and modulatory "subcortical-cerebellar" systems containing key structures such as striatum, medial temporal lobes (MTLs), amygdala, and cerebellum. Subcortical-cerebellar systems are known to be altered in schizophrenia. In particular, intrinsic functional brain connectivity (iFC) between these systems has been consistently demonstrated in patients. While altered connectivity is known for each subcortical-cerebellar system separately, it is unknown whether subcortical-cerebellar systems' connectivity patterns with the cortico-thalamic system are comparably altered across systems, i.e., if separate subcortical-cerebellar systems' connectivity patterns are consistent across patients.
METHODS
To investigate this question, 18 patients with schizophrenia (3 unmedicated, 15 medicated with atypical antipsychotics) and 18 healthy controls were assessed by resting-state functional magnetic resonance imaging (fMRI). Independent component analysis of fMRI data revealed cortical intrinsic brain networks (NWs) with time courses representing proxies for cortico-thalamic system activity. Subcortical-cerebellar systems' activity was represented by fMRI-based time courses of selected regions-of-interest (ROIs; i.e., striatum, MTL, amygdala, cerebellum). Correlation analysis among ROI- and NWs-time courses yielded individual connectivity matrices [i.e., connectivity between NW and ROIs (allROIs-NW, separateROI-NW), only NWs (NWs-NWs), and only ROIs (allROIs-allROIs)] as main outcome measures, which were classified by support-vector-machine-based (SVM) leave-one-out cross-validation. Differences in classification accuracy were statistically evaluated for consistency across subjects and systems.
RESULTS
Correlation matrices based on allROIs-NWs yielded 91% classification accuracy, which was significantly superior to allROIs-allROIs and NWs-NWs (56 and 74%, respectively). Considering separate subcortical-cerebellar systems, cerebellum-NWs and MTL-NWs reached highest accuracy values with 91 and 85%, respectively, while those of striatum-NW and amygdala-NW were significantly lower with about 65% classification accuracy.
CONCLUSION
RESULTS provide initial evidence for differential consistency of altered intrinsic connectivity patterns between subcortical-cerebellar systems and the cortico-thalamic system. Data suggest that differential dysconnectivity patterns between subcortical-cerebellar and cortical systems might reflect different disease states or patient subgroups.
PubMed: 26924973
DOI: 10.3389/fnhum.2016.00055 -
Frontiers in Neuroscience 2022The Notch pathway is fundamental for the generation of neurons during development. We previously reported that adult mice heterozygous for the null allele of the gene...
INTRODUCTION
The Notch pathway is fundamental for the generation of neurons during development. We previously reported that adult mice heterozygous for the null allele of the gene encoding the Delta-like ligand 1 for Notch ( ) have a reduced neuronal density in the substantia nigra pars compacta. The aim of the present work was to evaluate whether this alteration extends to other brain structures and the behavioral consequences of affected subjects.
METHODS
Brains of embryos and mice at different ages were phenotypically compared against their wild type (WT) counterpart. Afterwards, brain histological analyses were performed followed by determinations of neural cell markers in tissue slices. Neurological deficits were diagnosed by applying different behavioral tests to and WT mice.
RESULTS
Brain weight and size of mice was significantly decreased compared with WT littermates (i.e., microcephaly), a phenotype detected early after birth. Interestingly, enlarged ventricles (i.e., hydrocephalus) was a common characteristic of brains of Dll1 haploinsufficient mice since early ages. At the cell level, general cell density and number of neurons in several brain regions, including the cortex and hippocampus, of mice were reduced as compared with those regions of WT mice. Also, fewer neural stem cells were particularly found in the adult dentate gyrus of mice but not in the subventricular zone. High myelination levels detected at early postnatal ages (P7-P24) were an additional penetrant phenotype in mice, observation that was consistent with premature oligodendrocyte differentiation. After applying a set of behavioral tests, mild neurological alterations were detected that caused changes in motor behaviors and a deficit in object categorization.
DISCUSSION
Our observations suggest that Dll1 haploinsufficiency limits Notch signaling during brain development which, on one hand, leads to reduced brain cell density and causes microcephaly and hydrocephalus phenotypes and, on the other, alters the myelination process after birth. The severity of these defects could reach levels that affect normal brain function. Therefore, Dll1 haploinsufficiency is a risk factor that predisposes the brain to develop abnormalities with functional consequences.
PubMed: 36590296
DOI: 10.3389/fnins.2022.951418 -
Dysphagia Feb 2023Dysphagia in People with Parkinson's Disease (PWPD) is expected to occur in most individuals. The manifestation of dysphagia and its salient swallow dysfunction...
Dysphagia in People with Parkinson's Disease (PWPD) is expected to occur in most individuals. The manifestation of dysphagia and its salient swallow dysfunction characteristics leading to decreased airway safety are not well understood. The aim of this study was to quantify dysphagia presentation and severity, examine contributors to airway invasion, and explore gender differences in dysphagia manifestation in PWPD. 60 PWPD in clinical, healthcare settings underwent a Videofluoroscopic Swallow Study (VFSS) after referral for complaints of dysphagia. VFSS records and videos were analyzed to obtain dysphagia diagnosis, Videofluoroscopic Dysphagia Scale (VDS) scores, laryngeal vestibule kinematic timings, and Penetration-Aspiration Scale scores. Frequencies of VDS component and PAS scores were examined. MANOVA and logistic regression analyses were used to identify predictors of penetration and aspiration. Pharyngeal stage dysphagia was prevalent throughout PWPD and presented more frequently than oral stage dysphagia. Pharyngeal residue was a significant predictor for aspiration events. Laryngeal vestibule closure reaction time (LVCrt) and duration time (LVCd) were significant predictors of airway invasion, as were bolus consistency and volume. LVCrt, LVCd, and pharyngeal stage VDS scores were significantly altered in men compared to women in PWPD. A broad clinical sample of PWPD displayed atypical frequencies of airway invasion and frequent atypical scores of oral and pharyngeal stage physiologies. Thicker and smaller bolus consistencies significantly reduced the odds of airway invasion. Men and women presented with significantly different swallow physiology including prolonged LVCrt, LVCd, and more frequent atypical scores of pharyngeal residue and laryngeal elevation.Journal instruction requires a country for affiliations; however, these are missing in affiliation [1, 2]. Please verify if the provided country are correct and amend if necessary.Yes, USA is correct as the provided country.
Topics: Male; Humans; Female; Deglutition Disorders; Parkinson Disease; Sex Factors; Pharynx; Cineradiography; Deglutition; Fluoroscopy
PubMed: 35809095
DOI: 10.1007/s00455-022-10472-y -
Journal of Proteome Research Aug 2022Gastrointestinal (GI) cancers constitute the largest portion of all human cancers, and the most prevalent GI cancers in China are colorectal cancer (CRC), gastric cancer...
Gastrointestinal (GI) cancers constitute the largest portion of all human cancers, and the most prevalent GI cancers in China are colorectal cancer (CRC), gastric cancer (GC), and hepatocellular carcinoma (HCC). Exosomes are nanosized vesicles containing proteins, lipids, glycans, and nucleic acid, which play important roles in the tumor microenvironment and progression. Aberrant glycosylation is closely associated with GI cancers; however, little is known about the glycopattern of the exosomes from GI cancer cells. In this study, glycopatterns of HCC, CRC, and GC cell lines and their exosomes were detected using lectin microarrays. For all exosomes, (GlcNAcβ1-4) and Galβ1-4GlcNAc (DSA) were the most abundant glycans, but αGalNAc and αGal (GSL-II and SBA) were the least. Different cancers had various characteristic glycans in either cells or exosomes. Glycans altered in cell-derived exosomes were not always consistent with the host cells in the same cancer. However, Fucα1-6GlcNAc (core fucose) and Fucα1-3(Galβ1-4)GlcNAc (AAL) were altered consistently in cells and exosomes although they were decreased in HCC and CRC but increased in GC. The study drew the full-scale glycan fingerprint of cells and exosomes related to GI cancer, which may provide useful information for finding specific biomarkers and exploring the underlying mechanism of glycosylation in exosomes.
Topics: Carcinoma, Hepatocellular; Cell Line; Exosomes; Gastrointestinal Neoplasms; Glycoproteins; Humans; Liver Neoplasms; Polysaccharides; Tumor Microenvironment
PubMed: 35786973
DOI: 10.1021/acs.jproteome.2c00159 -
Obesity Reviews : An Official Journal... Oct 2015Alterations in the dopaminergic system have been implicated in both animal and human obesity. However, to date, a comprehensive model on the nature and functional... (Review)
Review
Alterations in the dopaminergic system have been implicated in both animal and human obesity. However, to date, a comprehensive model on the nature and functional relevance of this relationship is missing. In particular, human data remain equivocal in that seemingly inconsistent reports exist of positive, negative or even no relationships between dopamine D2/D3 receptor availability in the striatum and measures of obesity. Further, data on receptor availability have been commonly interpreted as reflecting receptor density, despite the possibility of an alternative interpretation, namely alterations in the basal levels of endogenous dopaminergic tone. Here, we provide a unifying framework that is able to explain the seemingly contradictory findings and offer an alternative and novel perspective on existing data. In particular, we suggest (i) a quadratic relationship between alterations in the dopaminergic system and degree of obesity, and (ii) that the observed alterations are driven by shifts in the balance between general dopaminergic tone and phasic dopaminergic signalling. The proposed model consistently integrates human data on molecular and behavioural characteristics of overweight and obesity. Further, the model provides a mechanistic framework accounting not only for the consistent observation of altered (food) reward-responsivity but also for the differences in reinforcement learning, decision-making behaviour and cognitive performance associated with measures of obesity.
Topics: Corpus Striatum; Dopamine; Dopamine Agonists; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Humans; Membrane Potentials; Neural Pathways; Obesity; Postsynaptic Potential Summation; Receptors, Dopamine D3; Reward
PubMed: 26098597
DOI: 10.1111/obr.12303 -
Journal of Medical Virology Mar 2023Serum hepatitis B virus (HBV) RNA is a new serological indicator reflecting viral replication with good clinical application prospects. This study aimed to clarify the...
Serum hepatitis B virus (HBV) RNA is a new serological indicator reflecting viral replication with good clinical application prospects. This study aimed to clarify the dynamic changes of serum HBV RNA levels and the quasispecies of HBV RNA virus-like particles in nucleos(t)ide analogues (NAs)-experienced chronic hepatitis B (CHB) patients harboring NAs-resistant mutations and their identifiable effects on NAs resistance. We included CHB patients who were on long-term NAs treatment and with HBV DNA rebound. The longitudinally dynamics of serum HBV RNA levels were quantitatively detected, and the quasispecies differences between serum HBV DNA and serum HBV RNA were compared by high-throughput sequencing. The effect of NAs concentration pressure on altering the resistance mutations quasispecies proportion of HBV DNA and HBV RNA in cell supernatant was analyzed in vitro. A total of 447 serum samples from 36 CHB patients treated with NAs were collected. The median follow-up period was 47 months (about 4 years), and the longest follow-up period was 117 months (about 10 years). Our results showed that HBV RNA could reflect virological breakthrough in 23 (64%, 23/36) patients, and serum HBV RNA rebound earlier than HBV DNA in 12 (52%, 12/23) patients. However, serum HBV RNA remained at a consistently high level and did not fluctuate significantly with the HBV DNA rebound in 6 of 36 patients. In addition, serum HBV RNA was not consistently detectable in 7 of the 36 patients, and their serum HBV RNA was undetectable even after HBV DNA had rebounded. The proportion of drug-resistant mutations in HBV DNA was higher than that of HBV RNA by high-throughput sequencing. The results of in vitro experiments showed that the viral strains with drug-resistant mutation in HBV DNA in cell supernatants gradually become the dominant strains with the increase of NAs concentrations. Serum HBV RNA levels can reflect virological breakthrough in most NAs- treated CHB patients, but there are certain limitations. NAs alter the quasispecies composition of serum HBV DNA and serum HBV RNA, resulting in a higher detection rate of drug-resistant mutations in serum HBV DNA than in serum HBV RNA.
Topics: Humans; Hepatitis B virus; DNA, Viral; Antiviral Agents; RNA; Quasispecies; Hepatitis B, Chronic; Mutation
PubMed: 36840474
DOI: 10.1002/jmv.28612 -
ACS Chemical Biology Apr 2021Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development of aggressive cancers....
Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development of aggressive cancers. Mutations in the YEATS domain have been recently reported as a cause of MLLT1 aberrant reader function. However, the structural basis for the reported alterations in affinity for acetylated/acylated histone has remained elusive. Here, we report the crystal structures of both insertion and substitution mutants present in cancer, revealing significant conformational changes of the YEATS-domain loop 8. Structural comparison demonstrates that not only did such alteration alter the binding interface for acetylated/acylated histones, but the sequence alterations in the loop in T1 mutant may enable dimeric assembly consistent with inducing self-association behavior. Nevertheless, we show that also the MLLT1 mutants can be targeted by developed acetyllysine mimetic inhibitors with affinities similarly to wild-type. Our report provides a structural basis for the altered behaviors and a potential strategy for targeting oncogenic MLLT1 mutants.
Topics: Humans; Mutation; Neoplasm Proteins; Nuclear Proteins; Protein Conformation; Transcription Factors
PubMed: 33749253
DOI: 10.1021/acschembio.0c00960