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Behavioral and Brain Functions : BBF Jun 2024An intronic deletion within intron 2 of the DCDC2 gene encompassing the entire READ1 (hereafter, READ1d) has been associated in both children with developmental dyslexia...
BACKGROUND
An intronic deletion within intron 2 of the DCDC2 gene encompassing the entire READ1 (hereafter, READ1d) has been associated in both children with developmental dyslexia (DD) and typical readers (TRs), with interindividual variation in reading performance and motion perception as well as with structural and functional brain alterations. Visual motion perception -- specifically processed by the magnocellular (M) stream -- has been reported to be a solid and reliable endophenotype of DD. Hence, we predicted that READ1d should affect neural activations in brain regions sensitive to M stream demands as reading proficiency changes.
METHODS
We investigated neural activations during two M-eliciting fMRI visual tasks (full-field sinusoidal gratings controlled for spatial and temporal frequencies and luminance contrast, and sensitivity to motion coherence at 6%, 15% and 40% dot coherence levels) in four subject groups: children with DD with/without READ1d, and TRs with/without READ1d.
RESULTS
At the Bonferroni-corrected level of significance, reading skills showed a significant effect in the right polar frontal cortex during the full-field sinusoidal gratings-M task. Regardless of the presence/absence of the READ1d, subjects with poor reading proficiency showed hyperactivation in this region of interest (ROI) compared to subjects with better reading scores. Moreover, a significant interaction was found between READ1d and reading performance in the left frontal opercular area 4 during the 15% coherent motion sensitivity task. Among subjects with poor reading performance, neural activation in this ROI during this specific task was higher for subjects without READ1d than for READ1d carriers. The difference vanished as reading skills increased.
CONCLUSIONS
Our findings showed a READ1d-moderated genetic vulnerability to alterations in neural activation in the ventral attentive and salient networks during the processing of relevant stimuli in subjects with poor reading proficiency.
Topics: Humans; Dyslexia; Male; Child; Female; Magnetic Resonance Imaging; Parietal Lobe; Reading; Motion Perception; Frontal Lobe; Microtubule-Associated Proteins; Brain Mapping; Nerve Net; Photic Stimulation
PubMed: 38926731
DOI: 10.1186/s12993-024-00241-2 -
Scientific Reports Jun 2024The role of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) is debated. We investigated whether the administration of ICS could lower the...
The role of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) is debated. We investigated whether the administration of ICS could lower the mortality risk in patients with COPD. We utilized the Korean National Health Insurance Service-National Sample Cohort database from 2002 to 2019. We included patients who had claim codes for COPD and inhalation respiratory medicine at least twice a year. A time-dependent Cox regression model was employed to estimate the association between ICS usage and survival. The cumulative dose of ICS was classified into three groups, and the mortality risk was compared among these groups. Of 16,463 included patients, there were 4395 (26.7%) deaths during the mean follow-up period of 5.0 years. The time-dependent Cox regression model demonstrated that ICS users had a significantly lower mortality risk compared to non-users (adjusted hazard ratio, 0.89; 95% CI, 0.83-0.94; p < 0.001), particularly among individuals aged ≥ 55 years, women, never smokers, and those with history of asthma or coronary heart disease. Higher cumulative dose groups were associated with a lower mortality risk compared to the lowest cumulative dose group. In conclusion, the administration of ICS seemed to be associated with a lower mortality risk in patients with COPD.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Female; Male; Administration, Inhalation; Middle Aged; Adrenal Cortex Hormones; Aged; Republic of Korea; Cohort Studies; Proportional Hazards Models
PubMed: 38926519
DOI: 10.1038/s41598-024-65763-1 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jun 2024To observe the effects of melatonin on autophagy in cortical neurons of neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore its mechanisms via the...
OBJECTIVES
To observe the effects of melatonin on autophagy in cortical neurons of neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore its mechanisms via the PI3K/AKT signaling pathway, aiming to provide a basis for the clinical application of melatonin.
METHODS
Seven-day-old Sprague-Dawley neonatal rats were randomly divided into a sham operation group, an HIBD group, and a melatonin group (=9 each). The neonatal rat HIBD model was established using the classic Rice-Vannucci method. Neuronal morphology in the neonatal rat cerebral cortex was observed with hematoxylin-eosin staining and Nissl staining. Autophagy-related protein levels of microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 were detected by immunofluorescence staining and Western blot analysis. Phosphorylated phosphoinositide 3-kinase (p-PI3K) and phosphorylated protein kinase B (p-AKT) protein expression levels were measured by immunohistochemistry and Western blot. The correlation between autophagy and the PI3K pathway in the melatonin group and the HIBD group was analyzed using Pearson correlation analysis.
RESULTS
Twenty-four hours post-modeling, neurons in the sham operation group displayed normal size and orderly arrangement. In contrast, neurons in the HIBD group showed swelling and disorderly arrangement, while those in the melatonin group had relatively normal morphology and more orderly arrangement. Nissl bodies were normal in the sham operation group but distorted in the HIBD group; however, they remained relatively intact in the melatonin group. The average fluorescence intensity of LC3 and Beclin-1 was higher in the HIBD group compared to the sham operation group, but was reduced in the melatonin group compared to the HIBD group (<0.05). The number of p-PI3K and p-AKT cells decreased in the HIBD group compared to the sham operation group but increased in the melatonin group compared to the HIBD group (<0.05). LC3 and Beclin-1 protein expression levels were higher, and p-PI3K and p-AKT levels were lower in the HIBD group compared to the sham operation group (<0.05); however, in the melatonin group, LC3 and Beclin-1 levels decreased, and p-PI3K and p-AKT increased compared to the HIBD group (<0.05). The correlation analysis results showed that the difference of the mean fluorescence intensity of LC3 and Beclin-1 protein in the injured cerebral cortex between the melatonin and HIBD groups was negatively correlated with the difference of the number of p-PI3K and p-AKT cells between the two groups (<0.05).
CONCLUSIONS
Melatonin can inhibit excessive autophagy in cortical neurons of neonatal rats with HIBD, thereby alleviating HIBD. This mechanism is associated with the PI3K/AKT pathway.
Topics: Animals; Melatonin; Hypoxia-Ischemia, Brain; Rats, Sprague-Dawley; Rats; Proto-Oncogene Proteins c-akt; Animals, Newborn; Cerebral Cortex; Autophagy; Phosphatidylinositol 3-Kinases; Neurons; Signal Transduction; Male; Female
PubMed: 38926381
DOI: 10.7499/j.issn.1008-8830.2312053 -
Annals of Clinical and Translational... Jun 2024To define tauopathy-associated changes in the human gray and white matter proteome.
OBJECTIVE
To define tauopathy-associated changes in the human gray and white matter proteome.
METHOD
We applied tandem mass tagged labeling and mass spectrometry, consensus, and ratio weighted gene correlation network analysis (WGCNA) to gray and white matter sampled from postmortem human dorsolateral prefrontal cortex. The sampled tissues included control as well as Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal degeneration with tau pathology, and chronic traumatic encephalopathy.
RESULTS
Only eight proteins were unique to gray matter while six were unique to white matter. Comparison of the gray and white matter proteome revealed an enrichment of microglial proteins in the white matter. Consensus WGCNA sorted over 6700 protein isoforms into 46 consensus modules across the gray and white matter proteomic networks. Consensus network modules demonstrated unique and shared disease-associated microglial and endothelial protein changes. Ratio WGCNA sorted over 6500 protein ratios (white:gray) into 33 modules. Modules associated with mitochondrial proteins and processes demonstrated higher white:gray ratios in diseased tissues relative to control, driven by mitochondrial protein downregulation in gray and upregulation in white.
INTERPRETATION
The dataset is a valuable resource for understanding proteomic changes in human tauopathy gray and white matter. The identification of unique and shared disease-associated changes across gray and white matter emphasizes the utility of examining both tissue types. Future studies of microglial, endothelial, and mitochondrial changes in white matter may provide novel insights into tauopathy-associated changes in human brain.
PubMed: 38924699
DOI: 10.1002/acn3.52134 -
Metabolites Jun 2024Acetate is an important metabolite in metabolic fluxes. Its presence in biological entities originates from both exogenous inputs and endogenous metabolism. Because the...
Acetate is an important metabolite in metabolic fluxes. Its presence in biological entities originates from both exogenous inputs and endogenous metabolism. Because the change in blood acetate level has been associated with both beneficial and adverse health outcomes, blood acetate analysis has been used to monitor the systemic status of acetate turnover. The present study examined the use of urinary -acetyltaurine (NAT) as a marker to reflect the hyperacetatemic status of mice from exogenous inputs and endogenous metabolism, including triacetin dosing, ethanol dosing, and streptozotocin-induced diabetes. The results showed that triacetin dosing increased serum acetate and urinary NAT but not other -acetylated amino acids in urine. The co-occurrences of increased serum acetate and elevated urinary NAT were also observed in both ethanol dosing and streptozotocin-induced diabetes. Furthermore, the renal cortex was determined as an active site for NAT synthesis. Overall, urinary NAT behaved as an effective marker of hyperacetatemia in three experimental mouse models, warranting further investigation into its application in humans.
PubMed: 38921457
DOI: 10.3390/metabo14060322 -
Cells Jun 2024Multiple sclerosis (MS) is a clinically heterogeneous disease underpinned by inflammatory, demyelinating and neurodegenerative processes, the extent of which varies...
BACKGROUND
Multiple sclerosis (MS) is a clinically heterogeneous disease underpinned by inflammatory, demyelinating and neurodegenerative processes, the extent of which varies between individuals and over the course of the disease. Recognising the clinicopathological features that most strongly associate with disease outcomes will inform future efforts at patient phenotyping.
AIMS
We used a digital pathology workflow, involving high-resolution image acquisition of immunostained slides and opensource software for quantification, to investigate the relationship between clinical and neuropathological features in an autopsy cohort of progressive MS.
METHODS
Sequential sections of frontal, cingulate and occipital cortex, thalamus, brain stem (pons) and cerebellum including dentate nucleus (n = 35 progressive MS, females = 28, males = 7; age died = 53.5 years; range 38-98 years) were immunostained for myelin (anti-MOG), neurons (anti-HuC/D) and microglia/macrophages (anti-HLA). The extent of demyelination, neurodegeneration, the presence of active and/or chronic active lesions and quantification of brain and leptomeningeal inflammation was captured by digital pathology.
RESULTS
Digital analysis of tissue sections revealed the variable extent of pathology that characterises progressive MS. Microglia/macrophage activation, if found at a higher level in a single block, was typically elevated across all sampled blocks. Compartmentalised (perivascular/leptomeningeal) inflammation was associated with age-related measures of disease severity and an earlier death.
CONCLUSION
Digital pathology identified prognostically important clinicopathological correlations in MS. This methodology can be used to prioritise the principal pathological processes that need to be captured by future MS biomarkers.
Topics: Humans; Middle Aged; Female; Male; Multiple Sclerosis; Aged; Adult; Biomarkers; Aged, 80 and over; Inflammation; Brain; Microglia; Macrophages
PubMed: 38920650
DOI: 10.3390/cells13121020 -
Neurology(R) Neuroimmunology &... Sep 2024To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS).
BACKGROUND AND OBJECTIVES
To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS).
METHODS
CSF levels of osteopontin (OPN) and 66 inflammatory markers were assessed using an immune-assay multiplex technique in 107 patients with RRMS (82 F/25 M, mean age 35.7 ± 11.8 years). All patients underwent regular clinical assessment and yearly 3T MRI scans for 2 years while 39 patients had a 4-year follow-up. White matter lesion number and volume, cortical lesions (CLs) and volume, and global cortical thickness (CTh) were evaluated together with the 'no evidence of disease activity' (NEDA-3) status, defined by no relapses, no disability worsening, and no MRI activity, including CLs.
RESULTS
The random forest algorithm selected OPN, CXCL13, TWEAK, TNF, IL19, sCD30, sTNFR1, IL35, IL16, and sCD163 as significantly associated with changes in global CTh. OPN and CXCL13 were most related to accumulation of atrophy after 2 and 4 years. In a multivariate linear regression model on CSF markers, OPN ( < 0.001), CXCL13 ( = 0.001), and sTNFR1 ( = 0.024) were increased in those patients with accumulating atrophy (adjusted R-squared 0.615). The 10 markers were added in a model that included all clinical, demographic, and MRI variables: OPN ( = 0.002) and IL19 ( = 0.022) levels were confirmed to be significantly increased in patients developing more CTh change over the follow-up (adjusted R-squared 0.619). CXCL13 and OPN also revealed the best association with NEDA-3 after 2 years, with OPN significantly linked to disability accumulation (OR 2.468 [1.46-5.034], = 0.004) at the multivariate logistic regression model.
DISCUSSION
These data confirm and expand our knowledge on the prognostic role of the CSF inflammatory profile in predicting changes in cortical pathology and disease activity in early MS. The data emphasize a crucial role of OPN.
Topics: Humans; Osteopontin; Female; Male; Adult; Multiple Sclerosis, Relapsing-Remitting; Atrophy; Middle Aged; Cerebral Cortex; Magnetic Resonance Imaging; Biomarkers; Follow-Up Studies; Young Adult; Disease Progression
PubMed: 38917380
DOI: 10.1212/NXI.0000000000200265 -
Oxford Open Neuroscience 2024Decision making is a process of selecting a course of action by assessing the worth or value of the potential consequences. Rat Gambling Task (RGT) is a well-established...
Decision making is a process of selecting a course of action by assessing the worth or value of the potential consequences. Rat Gambling Task (RGT) is a well-established behavioral paradigm that allows for assessment of the decision-making performance of rats. Astrocytes are emerging as key players in modulating cognitive functions. Using repeated RGTs with short intersession time intervals (48 h), the current study demonstrates that G pathway activation of astrocytes in the anterior cingulate cortex (ACC) leads to impaired decision-making in consistently good decision-making rats. On the other hand, ACC astrocytic G pathway activation improves decision-making in a subset of rats who are not consistently good decision-makers. Furthermore, we show that astrocytic G activation is associated with an increase in the L-lactate level in the extracellular fluid of the ACC. Together, these results expand our knowledge of the role of astrocytic GPCR signaling in modulating cognitive functions.
PubMed: 38915791
DOI: 10.1093/oons/kvae010 -
BioRxiv : the Preprint Server For... Jun 2024The mammalian cortex is comprised of cells with different morphological, physiological, and molecular properties that can be classified according to shared properties...
The mammalian cortex is comprised of cells with different morphological, physiological, and molecular properties that can be classified according to shared properties into cell types. Defining the contribution of each cell type to the computational and cognitive processes that are guided by the cortex is essential for understanding its function in health and disease. We use transcriptomic and epigenomic cortical cell type taxonomies from mice and humans to define marker genes and enhancers, and to build genetic tools for cortical cell types. Here, we present a large toolkit for selective targeting of cortical populations, including mouse transgenic lines and recombinant adeno-associated virus (AAV) vectors containing genomic enhancers. We report evaluation of fifteen new transgenic driver lines and over 680 different enhancer AAVs covering all major subclasses of cortical cells, with many achieving a high degree of specificity, comparable with existing transgenic lines. We find that the transgenic lines based on marker genes can provide exceptional specificity and completeness of cell type labeling, but frequently require generation of a triple-transgenic cross for best usability/specificity. On the other hand, enhancer AAVs are easy to screen and use, and can be easily modified to express diverse cargo, such as recombinases. However, their use depends on many factors, such as viral titer and route of administration. The tools reported here as well as the scaled process of tool creation provide an unprecedented resource that should enable diverse experimental strategies towards understanding mammalian cortex and brain function.
PubMed: 38915722
DOI: 10.1101/2024.06.10.597244 -
BioRxiv : the Preprint Server For... Jun 2024Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS might...
Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS might protect against a future episode of prolonged pain. The present study aimed to determine i) whether 5 consecutive days of rTMS delivered prior to experimentally-induced prolonged jaw pain could reduce future pain intensity and ii) whether any effects of rTMS on pain were mediated by changes in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from Day 0-4, forty healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. PAF and CME were assessed on Day 0 (before rTMS) and Day 4 (after rTMS). Prolonged pain was induced via intramuscular injection of nerve growth factor (NGF) in the right masseter muscle after the final rTMS session. From Days 5-25, participants completed twice-daily electronic dairies including pain on chewing and yawning (primary outcomes), as well as pain during other activities (e.g. talking), functional limitation in jaw function and muscle soreness (secondary outcomes). Compared to sham, individuals who received active rTMS subsequently experienced lower pain on chewing and yawning. Although active rTMS increased PAF, the effects of rTMS on pain were not mediated by changes in PAF or CME. This study is the first to show that rTMS delivered to pain onset can protect against future pain and associated functional impairment. Thus, rTMS may hold promise as a prophylactic intervention for persistent pain.
PubMed: 38915700
DOI: 10.1101/2024.06.11.598596