bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the causal effects of the gut microbiome on serum lipid levels: A two-sample Mendelian randomization analysis
Authors: Guo Gongjie , Wu Yonglin , Liu Yingjian , Wang Zixian , Xu Guifeng , Wang Xipei , Liang Feiqing , Lai Weihua , Xiao Xiao , Zhu Qian , Zhong Shilong
Published: February 2023

Background

The gut microbiome was reported to be associated with dyslipidemia in previous observational studies. However, whether the composition of the gut microbiome has a causal effect on serum lipid levels remains unclear.

Objective

A two-sample Mendelian randomization (MR) analysis was conducted to investigate the potential causal relationships between gut microbial taxa and serum lipid levels, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and log-transformed triglyceride (TG) levels.

Materials and methods

Summary statistics of genome-wide association studies (GWASs) for the gut microbiome and four blood lipid traits were obtained from public datasets. Five recognized MR methods were applied to assess the causal estimates, among which, the inverse-variance weighted (IVW) regression was used as the primary MR method. A series of sensitivity analyses were performed to test the robustness of the causal estimates.

Results

The combined results from the five MR methods and sensitivity analysis showed 59 suggestive causal associations and four significant causal associations. In particular, genus Terrisporobacter was associated with higher LDL-C (PIVW = 3.01 × 10−6) and TC levels (PIVW = 2.11 × 10−4), phylum Actinobacteria was correlated with higher LDL-C level (PIVW = 4.10 × 10−4), and genus Oscillospira was associated with lower TG level (PIVW = 2.19 × 10−6).

Conclusion

This research may provide novel insights into the causal relationships of the gut microbiome on serum lipid levels and new therapeutic or prevention strategies for dyslipidemia.
The first discovery of Tc1 transposons in yeast
Authors: Chang Jia , Duan Guangyou , Li Wenjing , Yau Tung On , Liu Chang , Cui Jianlin , Xue Huaijun , Bu Wenjun , Hu Yanping , Gao Shan
Published: February 2023

Background

Identification of transposons without close homologs is still a difficult task. IS630/Tc1/mariner transposons, classified into a superfamily, are probably the most widespread DNA transposons in nature. Tc1/mariner transposons have been discovered in animals, plants, and filamentous fungi, however, not in yeast.

Results

In the present study, we report the discovery of two intact Tc1 transposons in yeast and filamentous fungi, respectively. The first one, named Tc1-OP1 (DD40E), represents Tc1 transposons in Ogataea parapolymorpha. The second one, named Tc1-MP1 (DD34E), represents Tc1 transposons in the Rhizopodaceae and Mucoraceae families. As a homolog of Tc1-OP1 and Tc1-MP1, IS630-AB1 (DD34E) was discovered as an IS630 transposon in Acinetobacter spp.

Conclusion

Tc1-OP1 is not only the first reported Tc1 transposon in yeast, but also the first reported nonclassical Tc1 transposon. Tc1-OP1 is the largest of IS630/Tc1/mariner transposons reported to date and significantly different from others. Notably, Tc1-OP1 encodes a serine-rich domain and a transposase, extending the current knowledge of Tc1 transposons. The phylogenetic relationships of Tc1-OP1, Tc1-MP1 and IS630-AB1 indicated that these transposons had evolved from a common ancestor. Tc1-OP1, Tc1-MP1 and IS630-AB1 can be used as reference sequences to facilitate the identification of IS630/Tc1/mariner transposons. More Tc1/mariner transposons will be identified in yeast, following our discovery.
Metabolism-based approaches for autosomal dominant polycystic kidney disease
Authors: Bakaj Ivona , Pocai Alessandro
Published: February 2023

Autosomal Dominant Polycystic Kidney Disease (ADPKD) leads to end stage kidney disease (ESKD) through the development and expansion of multiple cysts throughout the kidney parenchyma. An increase in cyclic adenosine monophosphate (cAMP) plays an important role in generating and maintaining fluid-filled cysts because cAMP activates protein kinase A (PKA) and stimulates epithelial chloride secretion through the cystic fibrosis transmembrane conductance regulator (CFTR). A vasopressin V2 receptor antagonist, Tolvaptan, was recently approved for the treatment of ADPKD patients at high risk of progression. However additional treatments are urgently needed due to the poor tolerability, the unfavorable safety profile, and the high cost of Tolvaptan. In ADPKD kidneys, alterations of multiple metabolic pathways termed metabolic reprogramming has been consistently reported to support the growth of rapidly proliferating cystic cells. Published data suggest that upregulated mTOR and c-Myc repress oxidative metabolism while enhancing glycolytic flux and lactic acid production. mTOR and c-Myc are activated by PKA/MEK/ERK signaling so it is possible that cAMPK/PKA signaling will be upstream regulators of metabolic reprogramming. Novel therapeutics opportunities targeting metabolic reprogramming may avoid or minimize the side effects that are dose limiting in the clinic and improve on the efficacy observed in human ADPKD with Tolvaptan.
Exploration of novel biomarkers in Alzheimer’s disease based on four diagnostic models
Authors: Zou Cuihua , Su Li , Pan Mika , Chen Liechun , Li Hepeng , Zou Chun , Xie Jieqiong , Huang Xiaohua , Lu Mengru , Zou Donghua
Published: February 2023

Background

Despite tremendous progress in diagnosis and prediction of Alzheimer’s disease (AD), the absence of treatments implies the need for further research. In this study, we screened AD biomarkers by comparing expression profiles of AD and control tissue samples and used various models to identify potential biomarkers. We further explored immune cells associated with these biomarkers that are involved in the brain microenvironment.

Methods

By differential expression analysis, we identified differentially expressed genes (DEGs) of four datasets (GSE125583, GSE118553, GSE5281, GSE122063), and common expression direction of genes of four datasets were considered as intersecting DEGs, which were used to perform enrichment analysis. We then screened the intersecting pathways between the pathways identified by enrichment analysis. DEGs in intersecting pathways that had an area under the curve (AUC) > 0.7 constructed random forest, least absolute shrinkage and selection operator (LASSO), logistic regression, and gradient boosting machine models. Subsequently, using receiver operating characteristic curve (ROC) and decision curve analysis (DCA) to select an optimal diagnostic model, we obtained the feature genes. Feature genes that were regulated by differentially expressed miRNAs (AUC > 0.85) were explored further. Furthermore, using single-sample GSEA to calculate infiltration of immune cells in AD patients.

Results

Screened 1855 intersecting DEGs that were involved in RAS and AMPK signaling. The LASSO model performed best among the four models. Thus, it was used as the optimal diagnostic model for ROC and DCA analyses. This obtained eight feature genes, including ATP2B3, BDNF, DVL2, ITGA10, SLC6A12, SMAD4, SST, and TPI1. SLC6A12 is regulated by miR-3176. Finally, the results of ssGSEA indicated dendritic cells and plasmacytoid dendritic cells were highly infiltrated in AD patients.

Conclusion

The LASSO model is the optimal diagnostic model for identifying feature genes as potential AD biomarkers, which can supply new strategies for the treatment of patients with AD.
Variation in maternal sensitivity and the development of memory biases in preschoolers
Authors: Rifkin-Graboi Anne , Tsotsi Stella , Syazwana Nadhrah , Stephenson Mary C. , Sim Lit Wee , Lee Kerry
Published: February 2023

Introduction

Links between maternal sensitivity, hippocampal development, and memory abilities suggests early life insensitive care may shape structures and schemas influencing future decisions and stress management, biasing children to negative information. While it is possible that this pattern of neurodevelopment may have adaptive consequences, for example, preventing children from encountering untoward experience with future adversity, it may also leave some children at risk for the development of internalizing problems.

Methods

Here, in a Two Wave Study, we examine whether insensitive care predicts sub sequentially assessed memory biases for threatening (but not happy) stimuli in preschoolers (n = 49), and if such relations cut across different forms of relational memory, i.e., memory for relations between two “items,” between an “item” and its spatial location, and an “item” and its temporal sequence. In a subset (n = 18) we also examine links between caregiving, memory, and hippocampal subregion volume.

Results

Results indicate no main or interactive influence of gender on relational memory. However, insensitive caregiving predicted the difference between Angry and Happy memory during the Item-Space condition (B = 2.451, se = 0.969, p = 0.014, 95% CI (0.572, 4.340)], as well as memory for Angry (but not Happy) items [B = −2.203, se = 0.551, p < 0.001, 95% CI (−3.264,−1.094)]. Memory for the difference between Angry and Happy stimuli in the Space condition associated with larger right hippocampal body volumes (Rho = 0.639, p = 0.004). No relations were observed with internalizing problems.

Discussion

Results are discussed with reference to developmental stage and in consideration of whether negative biases may serve as an intermediate factor linking early life insensitive care and later socioemotional problems including an increased incidence of internalizing disorders.
Selective inhibition of excitatory synaptic transmission alters the emergent bursting dynamics of in vitro neural networks
Authors: Weir Janelle Shari , Christiansen Nicholas , Sandvig Axel , Sandvig Ioanna
Published: February 2023

Neurons in vitro connect to each other and form neural networks that display emergent electrophysiological activity. This activity begins as spontaneous uncorrelated firing in the early phase of development, and as functional excitatory and inhibitory synapses mature, the activity typically emerges as spontaneous network bursts. Network bursts are events of coordinated global activation among many neurons interspersed with periods of silencing and are important for synaptic plasticity, neural information processing, and network computation. While bursting is the consequence of balanced excitatory-inhibitory (E/I) interactions, the functional mechanisms underlying their evolution from physiological to potentially pathophysiological states, such as decreasing or increasing in synchrony, are still poorly understood. Synaptic activity, especially that related to maturity of E/I synaptic transmission, is known to strongly influence these processes. In this study, we used selective chemogenetic inhibition to target and disrupt excitatory synaptic transmission in in vitro neural networks to study functional response and recovery of spontaneous network bursts over time. We found that over time, inhibition resulted in increases in both network burstiness and synchrony. Our results indicate that the disruption in excitatory synaptic transmission during early network development likely affected inhibitory synaptic maturity which resulted in an overall decrease in network inhibition at later stages. These findings lend support to the importance of E/I balance in maintaining physiological bursting dynamics and, conceivably, information processing capacity in neural networks.
Role of a novel mouse mutant of the Galnt2tm1Lat/tm1Lat gene in otitis media
Authors: Ma Weijun , Li Heng , Hu Juan , Gao Ying , Lv Hui , Zhang Xiaotong , Zhang Qing , Xu Min , Cheng Ying
Published: February 2023

Genetic susceptibility is one of the most important causes of otitis media (OM). Mutant Galnt2 homozygote (Galnt2tm1Lat/tm1Lat) mimics human otitis media in comparable pathology and causes hearing loss. Otitis media is characterized by effusion and dysregulated mucosa proliferation and capillary expansion in the middle ear cavity, which is associated with hearing loss. The mucociliary dysfunction could be seen in the middle ear cavity (MEC) in a patient harboring the disease that develops in severity with age by a scanning electron microscope. Tumor necrosis factor alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1), Muc5ac, and Muc5b upregulate the expression in the middle ear, which correlates with inflammation, craniofacial development, and mucin secretion. The mouse model with a mutation in the Galnt2 (Galnt2tm1Lat/tm1Lat) was explored in this study as a novel model of human otitis media.
New techniques and methods for prevention and treatment of symptomatic traumatic neuroma: A systematic review
Authors: Zhou Liping , Huo Tong , Zhang Wenmin , Han Na , Wen Yongqiang , Zhang Peixun
Published: February 2023

Generally, axons located at the central end of the nerve system will sprout after injury. Once these sprouts cannot reach the distal end of the severed nerve, they will form a traumatic neuroma. Traumatic neuromas bring a series of complex symptoms to patients, such as neuropathic pain, skin abnormalities, skeletal abnormalities, hearing loss, and visceral damage. To date, the most promising and practical clinical treatments are drug induction and surgery, but both have their limitations. Therefore, it will be the mainstream trend to explore new methods to prevent and treat traumatic neuroma by regulating and remodeling the microenvironment of nerve injury. This work first summarized the pathogenesis of traumatic neuroma. Additionally, the standard methods of prevention and treatment on traumatic neuroma were analyzed. We focused on three essential parts of advanced functional biomaterial therapy, stem cell therapy, and human-computer interface therapy to provide the availability and value of preventing and treating a traumatic neuroma. Finally, the revolutionary development of the prevention and treatment on traumatic neuroma has been prospected. How to transform the existing advanced functional materials, stem cells, and artificial intelligence robots into clinical practical technical means as soon as possible for high-quality nerve repair and prevention of neuroma was further discussed.
Sudden unexpected death in epilepsy: Investigation of autopsy-based studies
Authors: Yan Fengping , Zhang Fu , Yan Yanan , Zhang Le , Chen Yuanyuan
Published: February 2023

Epilepsy is a common neurological disorder that is associated with increased morbidity and mortality. Sudden unexpected death in epilepsy (SUDEP) is one of the most common causes for epilepsy-related deaths and its characteristics remain largely unknown, particularly from a forensic autopsy perspective. The present study aimed to investigate the neurological, cardiac, and pulmonary findings for a total of 388 SUDEP decedents, encompassing three cases from our forensic center during 2011–2020 and 385 literature-reported autopsy cases. In the cases mentioned in this study, two of them presented with only mild cardiac abnormalities, such as focal myocarditis and mild coronary atherosclerosis of the left anterior coronary artery. The third one was negative of any pathological findings. After pooling together these SUDEP cases, we found that neurological changes (n = 218 cases, 56.2%) were the most common postmortem findings associated with SUDEP, with cerebral edema/congestion (n = 60 cases, 15.5%) and old traumatic brain injury (n = 58 cases, 14.9%) being the major findings. Interstitial fibrosis, myocyte disarray/hypertrophy, and mild coronary artery atherosclerosis were the most common findings related to primary cardiac pathology, documented in 49 (12.6%), 18 (4.6%), and 15 (3.9%) cases, respectively. Non-specific pulmonary edema was the major finding in the lungs. This is an autopsy-based study that reports the scenario of postmortem findings for SUDEP cases. Our study paves the way for understanding the pathogenesis of SUDEP and the interpretation of death.
Pregnancy-related healthcare utilization among women with multiple sclerosis
Authors: Mainguy Marie , Le Page Emmanuelle , Michel Laure , Leray Emmanuelle
Published: February 2023

Introduction

Many studies have investigated pregnancy in women with multiple sclerosis (MS). However, no study has measured prenatal healthcare utilization in women with MS or adherence to follow-up recommendations to improve antenatal care quality. A better knowledge of the quality of antenatal care in women with MS would help identify and better support women with insufficient follow-up. Our objective was to measure the level of compliance to prenatal care recommendations in women with MS using data from the French National Health Insurance Database.

Methods

This retrospective cohort study included all pregnant women with MS who gave live birth in France between 2010 and 2015. Using the French National Health Insurance Database, follow-up visits with gynecologists, midwives, and general practitioners (GPs) were identified, as well as ultrasound exams and laboratory tests. Based on the Adequacy of Prenatal Care Use and Content and Timing of care in Pregnancy indices, a new tool adapted to the French recommendations was developed to measure and classify the antenatal care trajectory (adequate or inadequate). Explicative factors were identified using multivariate logistic regression models. A random effect was included because women may have had more than one pregnancy during the study period.

Results

In total, 4,804 women with MS (N = 5,448 pregnancies ending in live births) were included. When considering only visits with gynecologists/midwives, 2,277 pregnancies (41.8%) were considered adequate. When adding visits with GP, their number increased to 3,646 (66.9%). Multivariate models showed that multiple pregnancy and higher medical density were associated with better adherence to follow-up recommendations. Conversely, adherence was lower in 25–29-year-old and >40-year-old women, in women with very low income, and agricultural and self-employed workers. No visits, ultrasound exams, and laboratory tests were recorded in 87 pregnancies (1.6%). In 50% of pregnancies, women had at least one visit with a neurologist during the pregnancy, and women restarted disease-modifying therapy (DMT) within 6 months after delivery in 45.9% of pregnancies.

Discussion

Many women consulted their GP during pregnancy. This could be linked to a low density of gynecologists but may also reflect the preferences of women. Our findings can help adapt recommendations and healthcare providers' practices according to the women's profiles.
Improving the brain image resolution of generalized q-sampling MRI revealed by a three-dimensional CNN-based method
Authors: Shin Chun-Yuan , Chao Yi-Ping , Kuo Li-Wei , Chang Yi-Peng Eve , Weng Jun-Cheng
Published: February 2023

Background

Understanding neural connections facilitates the neuroscience and cognitive behavioral research. There are many nerve fiber intersections in the brain that need to be observed, and the size is between 30 and 50 nanometers. Improving image resolution has become an important issue for mapping the neural connections non-invasively. Generalized q-sampling imaging (GQI) was used to reveal the fiber geometry of straight and crossing. In this work, we attempted to achieve super-resolution with a deep learning method on diffusion weighted imaging (DWI).

Materials and methods

A three-dimensional super-resolution convolutional neural network (3D SRCNN) was utilized to achieve super-resolution on DWI. Then, generalized fractional anisotropy (GFA), normalized quantitative anisotropy (NQA), and the isotropic value of the orientation distribution function (ISO) mapping were reconstructed using GQI with super-resolution DWI. We also reconstructed the orientation distribution function (ODF) of brain fibers using GQI.

Results

With the proposed super-resolution method, the reconstructed DWI was closer to the target image than the interpolation method. The peak signal-to-noise ratio (PSNR) and structural similarity index measure (SSIM) were also significantly improved. The diffusion index mapping reconstructed by GQI also had higher performance. The ventricles and white matter regions were much clearer.

Conclusion

This super-resolution method can assist in postprocessing low-resolution images. With SRCNN, high-resolution images can be effectively and accurately generated. The method can clearly reconstruct the intersection structure in the brain connectome and has the potential to accurately describe the fiber geometry on a subvoxel scale.
Differential saccade-pursuit coordination under sleep loss and low-dose alcohol
Authors: Tyson Terence L. , Flynn-Evans Erin E. , Stone Leland S.
Published: February 2023

Introduction

Ocular tracking of a moving object requires tight coordination between smooth pursuit and saccadic eye movements. Normally, pursuit drives gaze velocity to closely match target velocity, with residual position offsets corrected by catch-up saccades. However, how/if common stressors affect this coordination is largely unknown. This study seeks to elucidate the effects of acute and chronic sleep loss, and low-dose alcohol, on saccade-pursuit coordination, as well as that of caffeine.

Methods

We used an ocular tracking paradigm to assess three metrics of tracking (pursuit gain, saccade rate, saccade amplitude) and to compute “ground lost” (from reductions in steady-state pursuit gain) and “ground recouped” (from increases in steady-state saccade rate and/or amplitude). We emphasize that these are measures of relative changes in positional offsets, and not absolute offset from the fovea.

Results

Under low-dose alcohol and acute sleep loss, ground lost was similarly large. However, under the former, it was nearly completely recouped by saccades, whereas under the latter, compensation was at best partial. Under chronic sleep restriction and acute sleep loss with a caffeine countermeasure, the pursuit deficit was dramatically smaller, yet saccadic behavior remained altered from baseline. In particular, saccadic rate remained significantly elevated, despite the fact that ground lost was minimal.

Discussion

This constellation of findings demonstrates differential impacts on saccade-pursuit coordination with low-dose alcohol impacting only pursuit, likely through extrastriate cortical pathways, while acute sleep loss not only disrupts pursuit but also undermines saccadic compensation, likely through midbrain/brainstem pathways. Furthermore, while chronic sleep loss and caffeine-mitigated acute sleep loss show little residual pursuit deficit, consistent with uncompromised cortical visual processing, they nonetheless show an elevated saccade rate, suggesting residual midbrain and/or brainstem impacts.
Fast estimation of adult cerebral blood content and oxygenation with hyperspectral time-resolved near-infrared spectroscopy
Authors: Cohen David Jonathan Fulop , Li Natalie C. , Ioussoufovitch Seva , Diop Mamadou
Published: February 2023

Near-infrared spectroscopy (NIRS) can measure tissue blood content and oxygenation; however, its use for adult neuromonitoring is challenging due to significant contamination from their thick extracerebral layers (ECL; primarily scalp and skull). This report presents a fast method for accurate estimation of adult cerebral blood content and oxygenation from hyperspectral time resolved NIRS (trNIRS) data. A two-phase fitting method, based on a two-layer head model (ECL and brain), was developed. Phase 1 uses spectral constraints to accurately estimate the baseline blood content and oxygenation in both layers, which are then used by Phase 2 to correct for the ECL contamination of the late-arriving photons. The method was validated with in silico data from Monte-Carlo simulations of hyperspectral trNIRS in a realistic model of the adult head obtained from a high-resolution MRI. Phase 1 recovered cerebral blood oxygenation and total hemoglobin with an accuracy of 2.7 ± 2.5 and 2.8 ± 1.8%, respectively, with unknown ECL thickness, and 1.5 ± 1.4 and 1.7 ± 1.1% when the ECL thickness was known. Phase 2 recovered these parameters with an accuracy of 1.5 ± 1.5 and 3.1 ± 0.9%, respectively. Future work will include further validation in tissue-mimicking phantoms with various top layer thicknesses and in a pig model of the adult head before human applications.
Motivation in the metaverse: A dual-process approach to consumer choices in a virtual reality supermarket
Authors: Saffari Farzad , Kakaria Shobhit , Bigné Enrique , Bruni Luis E. , Zarei Sahar , Ramsøy Thomas Z.
Published: February 2023

Introduction

Consumer decision-making processes involve a complex interrelation between perception, emotion, and cognition. Despite a vast and diverse literature, little effort has been invested in investigating the neural mechanism behind such processes.

Methods

In the present work, our interest was to investigate whether asymmetrical activation of the frontal lobe of the brain could help to characterize consumer’s choices. To obtain stronger experimental control, we devised an experiment in a virtual reality retail store, while simultaneously recording participant brain responses using electroencephalogram (EEG). During the virtual store test, participants completed two tasks; first, to choose items from a predefined shopping list, a phase we termed as “planned purchase”. Second, subjects were instructed that they could also choose products that were not on the list, which we labeled as “unplanned purchase.” We assumed that the planned purchases were associated with a stronger cognitive engagement, and the second task was more reliant on immediate emotional responses.

Results

By analyzing the EEG data based on frontal asymmetry measures, we find that frontal asymmetry in the gamma band reflected the distinction between planned and unplanned decisions, where unplanned purchases were accompanied by stronger asymmetry deflections (relative frontal left activity was higher). In addition, frontal asymmetry in the alpha, beta, and gamma ranges illustrate clear differences between choices and no-choices periods during the shopping tasks.

Discussion

These results are discussed in light of the distinction between planned and unplanned purchase in consumer situations, how this is reflected in the relative cognitive and emotional brain responses, and more generally how this can influence research in the emerging area of virtual and augmented shopping.
RNA epitranscriptomics dysregulation: A major determinant for significantly increased risk of ASD pathogenesis
Authors: Beopoulos Athanasios , Géa Manuel , Fasano Alessio , Iris François
Published: February 2023

Autism spectrum disorders (ASDs) are perhaps the most severe, intractable and challenging child psychiatric disorders. They are complex, pervasive and highly heterogeneous and depend on multifactorial neurodevelopmental conditions. Although the pathogenesis of autism remains unclear, it revolves around altered neurodevelopmental patterns and their implications for brain function, although these cannot be specifically linked to symptoms. While these affect neuronal migration and connectivity, little is known about the processes that lead to the disruption of specific laminar excitatory and inhibitory cortical circuits, a key feature of ASD. It is evident that ASD has multiple underlying causes and this multigenic condition has been considered to also dependent on epigenetic effects, although the exact nature of the factors that could be involved remains unclear. However, besides the possibility for differential epigenetic markings directly affecting the relative expression levels of individual genes or groups of genes, there are at least three mRNA epitranscriptomic mechanisms, which function cooperatively and could, in association with both genotypes and environmental conditions, alter spatiotemporal proteins expression patterns during brain development, at both quantitative and qualitative levels, in a tissue-specific, and context-dependent manner. As we have already postulated, sudden changes in environmental conditions, such as those conferred by maternal inflammation/immune activation, influence RNA epitranscriptomic mechanisms, with the combination of these processes altering fetal brain development. Herein, we explore the postulate whereby, in ASD pathogenesis, RNA epitranscriptomics might take precedence over epigenetic modifications. RNA epitranscriptomics affects real-time differential expression of receptor and channel proteins isoforms, playing a prominent role in central nervous system (CNS) development and functions, but also RNAi which, in turn, impact the spatiotemporal expression of receptors, channels and regulatory proteins irrespective of isoforms. Slight dysregulations in few early components of brain development, could, depending upon their extent, snowball into a huge variety of pathological cerebral alterations a few years after birth. This may very well explain the enormous genetic, neuropathological and symptomatic heterogeneities that are systematically associated with ASD and psychiatric disorders at large.
Literature review on the interdisciplinary biomarkers of multi-target and multi-time herbal medicine therapy to modulate peripheral systems in cognitive impairment
Authors: Park Sang-Min , Lee Seung Hyun , Zhao HuiYan , Kim Jeongtae , Jang Jae young , Choi Yujin , Jeong Soyeon , Son Soyeong , Jung Kyungsook , Jang Jung-Hee
Published: February 2023

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease characterized by the deposition of amyloid-beta (Aβ) peptide and neurofibrillary tangles in the brain. The approved drug for AD has certain limitations such as a short period of cognitive improvement effect; moreover, the development of drug for AD therapeutic single target for Aβ clearance in brain ended in failure. Therefore, diagnosis and treatment of AD using a multi-target strategy according to the modulation of the peripheral system, which is not only limited to the brain, is needed. Traditional herbal medicines can be beneficial for AD based on a holistic theory and personalized treatment according to the time-order progression of AD. This literature review aimed to investigate the effectiveness of herbal medicine therapy based on syndrome differentiation, a unique theory of traditional diagnosis based on the holistic system, for multi-target and multi-time treatment of mild cognitive impairment or AD stage. Possible interdisciplinary biomarkers including transcriptomic and neuroimaging studies by herbal medicine therapy for AD were investigated. In addition, the mechanism by which herbal medicines affect the central nervous system in connection with the peripheral system in an animal model of cognitive impairment was reviewed. Herbal medicine may be a promising therapy for the prevention and treatment of AD through a multi-target and multi-time strategy. This review would contribute to the development of interdisciplinary biomarkers and understanding of the mechanisms of action of herbal medicine in AD.
Nerve growth factor promotes differentiation and protects the oligodendrocyte precursor cells from in vitro hypoxia/ischemia
Authors: Baldassarro Vito Antonio , Cescatti Maura , Rocco Maria Luisa , Aloe Luigi , Lorenzini Luca , Giardino Luciana , Calzà Laura
Published: February 2023

Introduction

Nerve growth factor (NGF) is a pleiotropic molecule acting on different cell types in physiological and pathological conditions. However, the effect of NGF on the survival, differentiation and maturation of oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs), the cells responsible for myelin formation, turnover, and repair in the central nervous system (CNS), is still poorly understood and heavily debated.

Methods

Here we used mixed neural stem cell (NSC)-derived OPC/astrocyte cultures to clarify the role of NGF throughout the entire process of OL differentiation and investigate its putative role in OPC protection under pathological conditions.

Results

We first showed that the gene expression of all the neurotrophin receptors (TrkA, TrkB, TrkC, and p75NTR) dynamically changes during the differentiation. However, only TrkA and p75NTR expression depends on T3-differentiation induction, as Ngf gene expression induction and protein secretion in the culture medium. Moreover, in the mixed culture, astrocytes are the main producer of NGF protein, and OPCs express both TrkA and p75NTR. NGF treatment increases the percentage of mature OLs, while NGF blocking by neutralizing antibody and TRKA antagonist impairs OPC differentiation. Moreover, both NGF exposure and astrocyte-conditioned medium protect OPCs exposed to oxygenglucose deprivation (OGD) from cell death and NGF induces an increase of AKT/pAKT levels in OPCs nuclei by TRKA activation.

Discussion

This study demonstrated that NGF is implicated in OPC differentiation, maturation, and protection in the presence of metabolic challenges, also suggesting implications for the treatment of demyelinating lesions and diseases.
Altered frontoparietal activity in acoustic startle priming tasks during reticulospinal tract facilitation: An fNIRS study
Authors: Xia Nan , He Chang , Wei Xiupan , Li Yang-An , Lou Weiwei , Gu Minghui , Chen Zejian , Xu Jiang , Liu Yali , Han Xiaohua , Huang Xiaolin
Published: February 2023

Background

Because it is one of the important pathways for promoting motor recovery after cortical injury, the function of the reticulospinal tract (RST) has received increasing attention in recent years. However, the central regulatory mechanism of RST facilitation and reduction of apparent response time is not well understood.

Objectives

To explore the potential role of RST facilitation in the acoustic startle priming (ASP) paradigm and observe the cortical changes induced by ASP reaching tasks.

Methods

Twenty healthy participants were included in this study. The reaching tasks were performed with their left and right hands. Participants were instructed to get ready after the warning cue and complete the reach as soon as they heard the Go cue. Half of the testing trials were set as control trials with an 80-dB Go cue. The other half of the trials had the Go cue replaced with 114-dB white noise to evoke the StartleReact effect, inducing reticulospinal tract facilitation. The response of the bilateral sternocleidomastoid muscle (SCM) and the anterior deltoid was recorded via surface electromyography. Startle trials were labeled as exhibiting a positive or negative StartleReact effect, according to whether the SCM was activated early (30–130 ms after the Go cue) or late, respectively. Functional near-infrared spectroscopy was used to synchronously record the oxyhemoglobin and deoxyhemoglobin fluctuations in bilateral motor-related cortical regions. The β values representing cortical responses were estimated via the statistical parametric mapping technique and included in the final analyses.

Results

Separate analyses of data from movements of the left or right side revealed significant activation of the right dorsolateral prefrontal cortex during RST facilitation. Moreover, left frontopolar cortex activation was greater in positive startle trials than in control or negative startle trials during left-side movements. Furthermore, decreased activity of the ipsilateral primary motor cortex in positive startle trials during ASP reaching tasks was observed.

Conclusion

The right dorsolateral prefrontal cortex and the frontoparietal network to which it belongs may be the regulatory center for the StartleReact effect and RST facilitation. In addition, the ascending reticular activating system may be involved. The decreased activity of the ipsilateral primary motor cortex suggests enhanced inhibition of the non-moving side during the ASP reaching task. These findings provide further insight into the SE and into RST facilitation.
Golgi fragmentation – One of the earliest organelle phenotypes in Alzheimer’s disease neurons
Authors: Haukedal Henriette , Corsi Giulia I. , Gadekar Veerendra P. , Doncheva Nadezhda T. , Kedia Shekhar , de Haan Noortje , Chandrasekaran Abinaya , Jensen Pia , Schiønning Pernille , Vallin Sarah , Marlet Frederik Ravnkilde , Poon Anna , Pires Carlota , Agha Fawzi Khoder , Wandall Hans H. , Cirera Susanna , Simonsen Anja Hviid , Nielsen Troels Tolstrup , Nielsen Jørgen Erik , Hyttel Poul , Muddashetty Ravi , Aldana Blanca I. , Gorodkin Jan , Nair Deepak , Meyer Morten , Larsen Martin Røssel , Freude Kristine
Published: February 2023

Alzheimer’s disease (AD) is the most common cause of dementia, with no current cure. Consequently, alternative approaches focusing on early pathological events in specific neuronal populations, besides targeting the well-studied amyloid beta (Aβ) accumulations and Tau tangles, are needed. In this study, we have investigated disease phenotypes specific to glutamatergic forebrain neurons and mapped the timeline of their occurrence, by implementing familial and sporadic human induced pluripotent stem cell models as well as the 5xFAD mouse model. We recapitulated characteristic late AD phenotypes, such as increased Aβ secretion and Tau hyperphosphorylation, as well as previously well documented mitochondrial and synaptic deficits. Intriguingly, we identified Golgi fragmentation as one of the earliest AD phenotypes, indicating potential impairments in protein processing and post-translational modifications. Computational analysis of RNA sequencing data revealed differentially expressed genes involved in glycosylation and glycan patterns, whilst total glycan profiling revealed minor glycosylation differences. This indicates general robustness of glycosylation besides the observed fragmented morphology. Importantly, we identified that genetic variants in Sortilin-related receptor 1 (SORL1) associated with AD could aggravate the Golgi fragmentation and subsequent glycosylation changes. In summary, we identified Golgi fragmentation as one of the earliest disease phenotypes in AD neurons in variousin vivoandin vitrocomplementary disease models, which can be exacerbatedviaadditional risk variants inSORL1.
Sphingolipids in neurodegenerative diseases
Authors: Pan Xueyang , Dutta Debdeep , Lu Shenzhao , Bellen Hugo J.
Published: February 2023

Neurodegenerative Diseases (NDDs) are a group of disorders that cause progressive deficits of neuronal function. Recent evidence argues that sphingolipid metabolism is affected in a surprisingly broad set of NDDs. These include some lysosomal storage diseases (LSDs), hereditary sensory and autonomous neuropathy (HSAN), hereditary spastic paraplegia (HSP), infantile neuroaxonal dystrophy (INAD), Friedreich’s ataxia (FRDA), as well as some forms of amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). Many of these diseases have been modeled in Drosophila melanogaster and are associated with elevated levels of ceramides. Similar changes have also been reported in vertebrate cells and mouse models. Here, we summarize studies using fly models and/or patient samples which demonstrate the nature of the defects in sphingolipid metabolism, the organelles that are implicated, the cell types that are initially affected, and potential therapeutics for these diseases.
Novel TP53RK variants cause varied clinical features of Galloway–Mowat syndrome without nephrotic syndrome in three unrelated Chinese patients
Authors: Chen Jing , Ye Gao-Bo , Huang Jin-Rong , Peng Min , Gu Wei-Yue , Xiong Pin , Zhu Hong-min
Published: February 2023

Objectives

Galloway–Mowat syndrome-4 (GAMOS4) is a very rare renal-neurological disease caused by TP53RK gene mutations. GAMOS4 is characterized by early-onset nephrotic syndrome, microcephaly, and brain anomalies. To date, only nine GAMOS4 cases with detailed clinical data (caused by eight deleterious variants in TP53RK) have been reported. This study aimed to examine the clinical and genetic characteristics of three unrelated GAMOS4 patients with TP53RK gene compound heterozygous mutations.

Methods

Whole-exome sequencing (WES) was used to identify four novel TP53RK variants in three unrelated Chinese children. Clinical characteristics such as biochemical parameters and image findings of patients were also evaluated. Furthermore, four studies of GAMOS4 patients with TP53RK variants were reviewed. In addition, clinical and genetic features were described after a retrospective analysis of clinical symptoms, laboratory data, and genetic test results.

Results

The three patients showed facial abnormalities, developmental delays, microcephaly, and aberrant cerebral imaging. Furthermore, patient 1 had slight proteinuria, while patient 2 had epilepsy. However, none of the individuals had nephrotic syndrome, and all were alive for more than 3 years of age. This is the first study to assess four variants in the TP53RK gene (NM_033550.4: c.15_16dup/p.A6Efs*29, c.745A > G/p.R249G, c.185G > A/p.R62H, and c.335A > G/p.Y112C).

Conclusion

The clinical characteristics of the three children with TP53RK mutations are significantly different from the known GAMOS4 traits, including early nephrotic syndrome and mortality mainly occurring in the first year of life. This study provides insights into the pathogenic TP53RK gene mutation spectrum and clinical phenotypes of GAMOS4.
Fatty acids and risk of dilated cardiomyopathy: A two-sample Mendelian randomization study
Authors: Zhang Jiexin , Luo Qiang , Hou Jun , Xiao Wenjing , Long Pan , Hu Yonghe , Chen Xin , Wang Han
Published: February 2023

Background

Previous observational studies have shown intimate associations between fatty acids (FAs) and dilated cardiomyopathy (DCM). However, due to the confounding factors and reverse causal association found in observational epidemiological studies, the etiological explanation is not credible.

Objective

To exclude possible confounding factors and reverse causal associations found in observational epidemiological studies, we used the two-sample Mendelian randomization (MR) analysis to verify the causal relationship between FAs and DCM risk.

Method

All data of 54 FAs were downloaded from the genome-wide association studies (GWAS) catalog, and the summary statistics of DCM were extracted from the HF Molecular Epidemiology for Therapeutic Targets Consortium GWAS. Two-sample MR analysis was conducted to evaluate the causal effect of FAs on DCM risk through several analytical methods, including MR-Egger, inverse variance weighting (IVW), maximum likelihood, weighted median estimator (WME), and the MR pleiotropy residual sum and outlier test (MRPRESSO). Directionality tests using MR-Steiger to assess the possibility of reverse causation.

Results

Our analysis identified two FAs, oleic acid and fatty acid (18:1)-OH, that may have a significant causal effect on DCM. MR analyses indicated that oleic acid was suggestively associated with a heightened risk of DCM (OR = 1.291, 95%CI: 1.044–1.595, P = 0.018). As a probable metabolite of oleic acid, fatty acid (18:1)-OH has a suggestive association with a lower risk of DCM (OR = 0.402, 95%CI: 0.167–0.966, P = 0.041). The results of the directionality test suggested that there was no reverse causality between exposure and outcome (P < 0.001). In contrast, the other 52 available FAs were discovered to have no significant causal relationships with DCM (P > 0.05).

Conclusion

Our findings propose that oleic acid and fatty acid (18:1)-OH may have causal relationships with DCM, indicating that the risk of DCM from oleic acid may be decreased by encouraging the conversion of oleic acid to fatty acid (18:1)-OH.
Lactate in the tumor microenvironment: A rising star for targeted tumor therapy
Authors: Li Zhangzuo , Wang Qi , Huang Xufeng , Yang Mengting , Zhou Shujing , Li Zhengrui , Fang Zhengzou , Tang Yidan , Chen Qian , Hou Hanjin , Li Li , Fei Fei , Wang Qiaowei , Wu Yuqing , Gong Aihua
Published: February 2023

Metabolic reprogramming is one of fourteen hallmarks of tumor cells, among which aerobic glycolysis, often known as the “Warburg effect,” is essential to the fast proliferation and aggressive metastasis of tumor cells. Lactate, on the other hand, as a ubiquitous molecule in the tumor microenvironment (TME), is generated primarily by tumor cells undergoing glycolysis. To prevent intracellular acidification, malignant cells often remove lactate along with H+, yet the acidification of TME is inevitable. Not only does the highly concentrated lactate within the TME serve as a substrate to supply energy to the malignant cells, but it also works as a signal to activate multiple pathways that enhance tumor metastasis and invasion, intratumoral angiogenesis, as well as immune escape. In this review, we aim to discuss the latest findings on lactate metabolism in tumor cells, particularly the capacity of extracellular lactate to influence cells in the tumor microenvironment. In addition, we examine current treatment techniques employing existing medications that target and interfere with lactate generation and transport in cancer therapy. New research shows that targeting lactate metabolism, lactate-regulated cells, and lactate action pathways are viable cancer therapy strategies.
Towards standardization of the parameters for opening the blood–brain barrier with focused ultrasound to treat glioblastoma multiforme: A systematic review of the devices, animal models, and therapeutic compounds used in rodent tumor models
Authors: Thombre Rasika , Mess Griffin , Kempski Leadingham Kelley M. , Kapoor Shivani , Hersh Andrew , Acord Molly , Kaovasia Tarana , Theodore Nicholas , Tyler Betty , Manbachi Amir
Published: February 2023

Glioblastoma multiforme (GBM) is a deadly and aggressive malignant brain cancer that is highly resistant to treatments. A particular challenge of treatment is caused by the blood–brain barrier (BBB), the relatively impermeable vasculature of the brain. The BBB prevents large molecules from entering the brain parenchyma. This protective characteristic of the BBB, however, also limits the delivery of therapeutic drugs for the treatment of brain tumors. To address this limitation, focused ultrasound (FUS) has been safely utilized to create transient openings in the BBB, allowing various high molecular weight drugs access to the brain. We performed a systematic review summarizing current research on treatment of GBMs using FUS-mediated BBB openings in in vivo mouse and rat models. The studies gathered here highlight how the treatment paradigm can allow for increased brain and tumor perfusion of drugs including chemotherapeutics, immunotherapeutics, gene therapeutics, nanoparticles, and more. Given the promising results detailed here, the aim of this review is to detail the commonly used parameters for FUS to open the BBB in rodent GBM models.
Fat necrosis: A consultant’s conundrum
Authors: Majithia Jinita , Haria Purvi , Popat Palak , Katdare Aparna , Chouhan Sonal , Gala Kunal Bharat , Kulkarni Suyash , Thakur Meenakshi
Published: February 2023

Fat necrosis of the breast is a benign non-suppurative inflammation of the adipose tissue and often mimics breast cancers, posing a diagnostic challenge for the clinician and radiologist. It has a myriad of appearances on different imaging techniques, ranging from the pathognomic oil cyst and benign dystrophic calcifications to indeterminate focal asymmetries, architectural distortions, and masses. A combination of different modalities can assist a radiologist in reaching a logical conclusion to avoid unnecessary interventions. The aim of this review article was to provide a comprehensive literature on the various imaging appearances of fat necrosis in the breast. Although a purely benign entity, the imaging appearances on mammography, contrast-enhanced mammography, ultrasound, and magnetic resonance imaging can be quite misleading, especially in post-therapy breasts. The purpose is to provide a comprehensive and all-inclusive review on fat necrosis with a proposed algorithm allowing a systematic approach to diagnosis.