bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut Microbiota Dysbiosis and Altered Bile Acid Catabolism Lead to Metabolic Disorder in Psoriasis Mice
Authors: Hao Yan , Zhou Pei , Zhu Ya-juan , Zou Song , Zhao Qixiang , Yu Jiadong , Hu Yawen , Li Jiong
Published: April 2022

Patients with psoriasis tend to have significant comorbidities, such as hyperlipemia, diabetes mellitus, and obesity, which belong to metabolic disorders. The specific mechanism through which psoriasis increases the metabolic disorder risk is uncertain. In this study, we demonstrated that the dysbiotic gut microbiota of 6-month-old psoriasis-like model mice (K14-VEGF-A-transgenic) exacerbated psoriasis disease and induced metabolic disorder when transferred into 2-month-old mice. By 16S rRNA gene sequencing, we confirmed that the Parabacteroides distasonis decreased with age in K14-VEGF mice, and P. distasonis also decreased in the transferred mice. Metabolomic screening identified an altered bile acid profile, including a decrease in chenodeoxycholic acid (CDCA) in the feces of transferred mice. Additionally, CDCA supplements prevented metabolic disorders in K14-VEGF-A-transgenic mice. Consequently, we found that aberrant bile acid metabolism may contribute to metabolic disorder in K14-VEGF-A-transgenic mice, indicating the possibility to prevent and treat the metabolic disorder in psoriasis mice by targeting gut microbial metabolites.
Correlation Between Improved Mating Efficiency and Weakened Scaffold-Kinase Interaction in the Mating Pheromone Response Pathway Revealed by Interspecies Complementation
Authors: Shi Tianfang , Zeng Junyuan , Zhou Jungang , Yu Yao , Lu Hong
Published: April 2022

Scaffold protein Ste5 and associated kinases, including Ste11, Ste7, and Fus3, are core components of the mating pheromone pathway, which is required to induce a mating response. Orthologs of these proteins are widely present in fungi, but to which extent one protein can be replaced by its ortholog is less well understood. Here, interspecies complementation was carried out to evaluate the functional homology of Ste5 and associated kinases in Kluyveromyces lactis, K. marxianus, and Saccharomyces cerevisiae. These three species occupy important positions in the evolution of hemiascomycetes. Results indicated that Ste5 and associated kinases in K. lactis and K. marxianus could be functionally replaced by their orthologs to different extents. However, the extent of sequence identity, either between full-length proteins or between domains, did not necessarily indicate the extent of functional replaceability. For example, Ste5, the most unconserved protein in sequence, achieved the highest average functional replaceability. Notably, swapping Ste5 between K. lactis and K. marxianus significantly promoted mating in both species and the weakened interaction between the Ste5 and Ste7 might contribute to this phenotype. Consistently, chimeric Ste5 displaying a higher affinity for Ste7 decreased the mating efficiency, while chimeric Ste5 displaying a lower affinity for Ste7 improved the mating efficiency. Furthermore, the length of a negatively charged segment in the Ste7-binding domain of Ste5 was negatively correlated with the mating efficiency in K. lactis and K. marxianus. Extending the length of the segment in KlSte5 improved its interaction with Ste7 and that might contribute to the reduced mating efficiency. Our study suggested a novel role of Ste5-Ste7 interaction in the negative regulation of the pheromone pathway. Meanwhile, Ste5 mutants displaying improved mating efficiency facilitated the breeding and selection of Kluyveromyces strains for industrial applications.
Metabolomics-Driven Identification of the Rate-Limiting Steps in 1-Propanol Production
Authors: Ohtake Toshiyuki , Kawase Naoki , Pontrelli Sammy , Nitta Katsuaki , Laviña Walter A. , Shen Claire R. , Putri Sastia P. , Liao James C. , Fukusaki Eiichiro
Published: April 2022

The concerted effort for bioproduction of higher alcohols and other commodity chemicals has yielded a consortium of metabolic engineering techniques to identify targets to enhance performance of engineered microbial strains. Here, we demonstrate the use of metabolomics as a tool to systematically identify targets for improved production phenotypes in Escherichia coli. Gas chromatography/mass spectrometry (GC/MS) and ion-pair LC-MS/MS were performed to investigate metabolic perturbations in various 1-propanol producing strains. Two initial strains were compared that differ in the expression of the citramalate and threonine pathways, which hold a synergistic relationship to maximize production yields. While this results in increased productivity, no change in titer was observed when the threonine pathway was overexpressed beyond native levels. Metabolomics revealed accumulation of upstream byproducts, norvaline and 2-aminobutyrate, both of which are derived from 2-ketobutyrate (2KB). Eliminating the competing pathway by gene knockouts or improving flux through overexpression of glycolysis gene effectively increased the intracellular 2KB pool. However, the increase in 2KB intracellular concentration yielded decreased production titers, indicating toxicity caused by 2KB and an insufficient turnover rate of 2KB to 1-propanol. Optimization of alcohol dehydrogenase YqhD activity using an ribosome binding site (RBS) library improved 1-propanol titer (g/L) and yield (g/g of glucose) by 38 and 29% in 72 h compared to the base strain, respectively. This study demonstrates the use of metabolomics as a powerful tool to aid systematic strain improvement for metabolically engineered organisms.
Adaptation by Type III CRISPR-Cas Systems: Breakthrough Findings and Open Questions
Authors: Zhang Xinfu , An Xinmin
Published: April 2022

CRISPR-Cas systems acquire heritable defense memory against invading nucleic acids through adaptation. Type III CRISPR-Cas systems have unique and intriguing features of defense and are important in method development for Genetics research. We started to understand the common and unique properties of type III CRISPR-Cas adaptation in recent years. This review summarizes our knowledge regarding CRISPR-Cas adaptation with the emphasis on type III systems and discusses open questions for type III adaptation studies.
Altered Expression of ACE2 and Co-receptors of SARS-CoV-2 in the Gut Mucosa of the SIV Model of HIV/AIDS
Authors: Hu Shuang , Buser Elise , Arredondo Juan , Relyea Dylan , Santos Rocha Clarissa , Dandekar Satya
Published: April 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of the COVID-19 pandemic, is initiated by its binding to the ACE2 receptor and other co-receptors on mucosal epithelial cells. Variable outcomes of the infection and disease severity can be influenced by pre-existing risk factors. Human immunodeficiency virus (HIV), the cause of AIDS, targets the gut mucosal immune system and impairs epithelial barriers and mucosal immunity. We sought to determine the impact and mechanisms of pre-existing HIV infection increasing mucosal vulnerability to SARS-CoV-2 infection and disease. We investigated changes in the expression of ACE2 and other SARS-CoV-2 receptors and related pathways in virally inflamed gut by using the SIV infected rhesus macaque model of HIV/AIDS. Immunohistochemical analysis showed sustained/enhanced ACE2 expression in the gut epithelium of SIV infected animals compared to uninfected controls. Gut mucosal transcriptomic analysis demonstrated enhanced expression of host factors that support SARS-CoV-2 entry, replication, and infection. Metabolomic analysis of gut luminal contents revealed the impact of SIV infection as demonstrated by impaired mitochondrial function and decreased immune response, which render the host more vulnerable to other pathogens. In summary, SIV infection resulted in sustained or increased ACE2 expression in an inflamed and immune-impaired gut mucosal microenvironment. Collectively, these mucosal changes increase the susceptibility to SARS-CoV-2 infection and disease severity and result in ineffective viral clearance. Our study highlights the use of the SIV model of AIDS to fill the knowledge gap of the enteric mechanisms of co-infections as risk factors for poor disease outcomes, generation of new viral variants and immune escape in COVID-19.
Cell Engineering and Cultivation of Chinese Hamster Ovary Cells for the Development of Orthogonal Eukaryotic Cell-free Translation Systems
Authors: Schloßhauer Jeffrey L. , Cavak Niño , Zemella Anne , Thoring Lena , Kubick Stefan
Published: April 2022

The investigation of protein structures, functions and interactions often requires modifications to adapt protein properties to the specific application. Among many possible methods to equip proteins with new chemical groups, the utilization of orthogonal aminoacyl-tRNA synthetase/tRNA pairs enables the site-specific incorporation of non-canonical amino acids at defined positions in the protein. The open nature of cell-free protein synthesis reactions provides an optimal environment, as the orthogonal components do not need to be transported across the cell membrane and the impact on cell viability is negligible. In the present work, it was shown that the expression of orthogonal aminoacyl-tRNA synthetases in CHO cells prior to cell disruption enhanced the modification of the pharmaceutically relevant adenosine A2a receptor. For this purpose, in complement to transient transfection of CHO cells, an approach based on CRISPR/Cas9 technology was selected to generate a translationally active cell lysate harboring endogenous orthogonal aminoacyl-tRNA synthetase.
Clinical and Prognostic Characteristics of Recurrent Intracerebral Hemorrhage: A Contrast to First-Ever ICH
Authors: Wan Yan , Guo Hongxiu , Bi Rentang , Chen Shaoli , Shen Jing , Li Man , Xia Yuanpeng , Zhang Lei , Sun Zhou , Chen Xiaolu , Cai Zhuoyuan , Wang Zhaowei , Gong Daokai , Xu Jingwen , Zhu Dongya , Hu Bo , He Quanwei
Published: April 2022

This study aimed to compare clinical and prognostic characteristics between recurrent and first-ever ICH. Four thousand twelve patients entered the study, and 64% of them were male. The median age is 62 years (interquartile range, 55–71). Among them, 3,750 (93.5%) patients had no experience of previous ICH, and 262 (6.5%) patients were considered as recurrent ICH. We compared demographic data, baseline clinical characteristics, imaging information, hematological parameters, and clinical outcomes between recurrent and first-ever ICH. We found that recurrent ICH was significantly associated with older age, more frequent history of ischemic heart disease, ischemic stroke, hypertension, and hyperlipidemia, while patients with recurrent ICH had previously received more antihypertensive therapy, and showed lower admission blood pressure (median, 160 vs. 167 mmHg) and higher baseline of National Institute of Health stroke scale (NIHSS) score (median, 10 vs. 9). We also demonstrated that recurrent ICH was an independent risk factor of 3-month function dependence after adjusting for many potentially competitive risk factors.
S-Ketamine Pretreatment Alleviates Anxiety-Like Behaviors and Mechanical Allodynia and Blocks the Pro-inflammatory Response in Striatum and Periaqueductal Gray From a Post-traumatic Stress Disorder Model
Authors: Yang Shuai , Xu Ke , Xu Xuan , Zhu Jixiang , Jin Yinan , Liu Qi , Xu Rui , Gu Xiaoping , Liu Yue , Huang Yulin , Ma Zhengliang
Published: April 2022

This study aims to explore the regulatory effect of S-ketamine on the mechanical allodynia, anxiety-like behaviors and microglia activation in adult male rats exposed to an animal model of post-traumatic stress disorder (PTSD). The rat PTSD model was established by the exposure to single-prolonged stress (SPS), and 1 day later, rats were intraperitoneally injected with 5 mg/kg S-ketamine or normal saline, respectively. Paw withdrawal mechanical threshold was measured 2 days before, and 1, 3, 5, 7, 10, 14, 21 and 28 days after injection to assess mechanical allodynia in the SPS-exposed rats. For anxiety-like behaviors, the open field test and elevated plus maze test were performed at 7 and 14 days after S-ketamine treatment in the SPS-exposed rats, respectively. SPS-induced rats presented pronounced mechanical allodynia and anxiety-like behaviors, which were alleviated by S-ketamine treatment. After behavioral tests, rats were sacrificed for collecting the anterior cingulate cortex (ACC), prefrontal cortex (PFC), dorsal striatum, and periaqueductal gray (PAG). Protein levels of TNF-α, IL-1β, p-NF-κB, and NF-κB in brain regions were examined by Western blot. In addition, microglia activation in each brain region was determined by immunofluorescence staining of the microglia-specific biomarker Iba-1. Interestingly, pro-inflammatory cytokines were significantly upregulated in the dorsal striatum and PAG, rather than ACC and PFC. Activated microglia was observed in the dorsal striatum and PAG as well, and upregulated p-NF-κB was detected in the dorsal striatum. Inflammatory response, phosphorylation of NF-κB and microglia activation in certain brain regions were significantly alleviated by S-ketamine treatment. Collectively, S-ketamine is a promising drug in alleviating mechanical allodynia, anxiety-like behaviors, and pro-inflammatory responses in discrete brain regions in a model of PTSD.
Embodied Object Representation Learning and Recognition
Authors: Van de Maele Toon , Verbelen Tim , Çatal Ozan , Dhoedt Bart
Published: April 2022

Scene understanding and decomposition is a crucial challenge for intelligent systems, whether it is for object manipulation, navigation, or any other task. Although current machine and deep learning approaches for object detection and classification obtain high accuracy, they typically do not leverage interaction with the world and are limited to a set of objects seen during training. Humans on the other hand learn to recognize and classify different objects by actively engaging with them on first encounter. Moreover, recent theories in neuroscience suggest that cortical columns in the neocortex play an important role in this process, by building predictive models about objects in their reference frame. In this article, we present an enactive embodied agent that implements such a generative model for object interaction. For each object category, our system instantiates a deep neural network, called Cortical Column Network (CCN), that represents the object in its own reference frame by learning a generative model that predicts the expected transform in pixel space, given an action. The model parameters are optimized through the active inference paradigm, i.e., the minimization of variational free energy. When provided with a visual observation, an ensemble of CCNs each vote on their belief of observing that specific object category, yielding a potential object classification. In case the likelihood on the selected category is too low, the object is detected as an unknown category, and the agent has the ability to instantiate a novel CCN for this category. We validate our system in an simulated environment, where it needs to learn to discern multiple objects from the YCB dataset. We show that classification accuracy improves as an embodied agent can gather more evidence, and that it is able to learn about novel, previously unseen objects. Finally, we show that an agent driven through active inference can choose their actions to reach a preferred observation.
Sex-Specific B Cell and Anti-Myelin Autoantibody Response After Peripheral Nerve Injury
Authors: Lee Hee Jong , Remacle Albert G. , Hullugundi Swathi K. , Dolkas Jennifer , Leung Jake B. , Chernov Andrei V. , Yaksh Tony L. , Strongin Alex Y. , Shubayev Veronica I.
Published: April 2022

Immunotherapy holds promise as a non-addictive treatment of refractory chronic pain states. Increasingly, sex is recognized to impact immune regulation of pain states, including mechanical allodynia (pain from non-painful stimulation) that follows peripheral nerve trauma. This study aims to assess the role of B cells in sex-specific responses to peripheral nerve trauma. Using a rat model of sciatic nerve chronic constriction injury (CCI), we analyzed sex differences in (i) the release of the immunodominant neural epitopes of myelin basic protein (MBP); (ii) the levels of serum immunoglobulin M (IgM)/immunoglobulin G (IgG) autoantibodies against the MBP epitopes; (iii) endoneurial B cell/CD20 levels; and (iv) mechanical sensitivity behavior after B cell/CD20 targeting with intravenous (IV) Rituximab (RTX) and control, IV immunoglobulin (IVIG), therapy. The persistent MBP epitope release in CCI nerves of both sexes was accompanied by the serum anti-MBP IgM autoantibody in female CCI rats alone. IV RTX therapy during CD20-reactive cell infiltration of nerves of both sexes reduced mechanical allodynia in females but not in males. IVIG and vehicle treatments had no effect in either sex. These findings provide strong evidence for sexual dimorphism in B-cell function after peripheral nervous system (PNS) trauma and autoimmune pathogenesis of neuropathic pain, potentially amenable to immunotherapeutic intervention, particularly in females. A myelin-targeted serum autoantibody may serve as a biomarker of such painful states. This insight into the biological basis of sex-specific response to neuraxial injury will help personalize regenerative and analgesic therapies.
Chronic Alcohol Dysregulates Glutamatergic Function in the Basolateral Amygdala in a Projection-and Sex-Specific Manner
Authors: Price Michaela E. , McCool Brian A.
Published: April 2022

Chronic intermittent ethanol and withdrawal (CIE/WD) produces alcohol dependence, facilitates anxiety-like behavior, and increases post-CIE alcohol intake. The basolateral amygdala (BLA) is one of several brain regions that regulates anxiety-like behavior and alcohol intake through downstream projections to the nucleus accumbens (NAC) and bed nucleus of the stria terminalis (BNST), respectively. Previous studies revealed that CIE/WD induces input- and sex-specific adaptations to glutamatergic function in the BLA. The BLA receives information from two distinct input pathways. Glutamatergic afferents from medial structures like the thalamus and prefrontal cortex enter the BLA through the stria terminalis whereas lateral cortical structures like the anterior insula cortex enter the BLA through the external capsule. CIE/WD increases presynaptic glutamatergic function at stria terminalis synapses and postsynaptic function at external capsule synapses. Previous studies sampled neurons throughout the BLA, but did not distinguish between projection-specific populations. The current study investigated BLA neurons that project to the NAC (BLA-NAC neurons) or the BNST (BLA-BNST neurons) as representative “reward” and “aversion” BLA neurons, and showed that CIE/WD alters glutamatergic function and excitability in a projection- and sex-specific manner. CIE/WD increases glutamate release from stria terminalis inputs only onto BLA-BNST neurons. At external capsule synapses, CIE/WD increases postsynaptic glutamatergic function in male BLA-NAC neurons and female BLA-BNST neurons. Subsequent experiments demonstrated that CIE/WD enhanced the excitability of male BLA-NAC neurons and BLA-BNST neurons in both sexes when glutamatergic but not GABAergic function was intact. Thus, CIE/WD-mediated increased glutamatergic function facilitates hyperexcitability in male BLA-NAC neurons and BLA-BNST neurons of both sexes.
Binaural Processing Deficits Due to Synaptopathy and Myelin Defects
Authors: Budak Maral , Roberts Michael T. , Grosh Karl , Corfas Gabriel , Booth Victoria , Zochowski Michal
Published: April 2022

Hidden hearing loss (HHL) is a deficit in auditory perception and speech intelligibility that occurs despite normal audiometric thresholds and results from noise exposure, aging, or myelin defects. While mechanisms causing perceptual deficits in HHL patients are still unknown, results from animal models indicate a role for peripheral auditory neuropathies in HHL. In humans, sound localization is particularly important for comprehending speech, especially in noisy environments, and its disruption may contribute to HHL. In this study, we hypothesized that neuropathies of cochlear spiral ganglion neurons (SGNs) that are observed in animal models of HHL disrupt the activity of neurons in the medial superior olive (MSO), a nucleus in the brainstem responsible for locating low-frequency sound in the horizontal plane using binaural temporal cues, leading to sound localization deficits. To test our hypothesis, we constructed a network model of the auditory processing system that simulates peripheral responses to sound stimuli and propagation of responses via SGNs to cochlear nuclei and MSO populations. To simulate peripheral auditory neuropathies, we used a previously developed biophysical SGN model with myelin defects at SGN heminodes (myelinopathy) and with loss of inner hair cell-SGN synapses (synaptopathy). Model results indicate that myelinopathy and synaptopathy in SGNs give rise to decreased interaural time difference (ITD) sensitivity of MSO cells, suggesting a possible mechanism for perceptual deficits in HHL patients. This model may be useful to understand downstream impacts of SGN-mediated disruptions on auditory processing and to eventually discover possible treatments for various mechanisms of HHL.
Carotid Endarterectomy for the Treatment of Carotid Near-Occlusion With Recurrent Symptoms
Authors: Zhang Jianbin , Chen Jie , Xu Xiaojie , Sun Mingsheng , Chen Shu , Liu Peng , Ye Zhidong
Published: April 2022

Objective

Report our preliminary experience of carotid endarterectomy (CEA) for the treatment of carotid near-occlusion (CNO) with recurrent symptoms.

Materials and Methods

Retrospectively analyze the demographics, treatment detail, and outcomes data of 122 patients with CNO from 2014 to 2020. According to whether distal full collapse exists, patients were classified into the full collapse group and the non-full collapse group. The incidence of death, myocardial infarction, stroke, and other variables were compared between the two groups.

Results

A total of 122 patients with CNO and recurrent symptoms were enrolled. The demographics were comparable between the two groups. Thirty-day incidence of primary endpoints was 1.85% in the full collapse group and 4.41% in the non-full collapse group. Twelve-month incidence of primary endpoints was 7.41% in the full collapse group and 4.41% in the non-full collapse group. One re-stenosis occurred in the non-full collapse group 8 months after CEA.

Conclusion

For patients with CNO with recurrent symptoms, CEA is not worse than the results described in historical control groups, despite whether distal full collapse exists. The shunt is important to avoid intraoperative hypoperfusion and postoperative hyperperfusion. The long-term results should be further evaluated.
Risk Factors of Impaired Perfusion in Patients With Symptomatic Internal Carotid Artery Steno-Occlusive Disease
Authors: Qiao Xinxin , Duan Jinfeng , Zhang Nan , Duan Yang , Wang Xinrui , Pei Yusong , Xu Zhihua , Yang Benqiang , Qi Miao , Li Jinze
Published: April 2022

Objective

To quantitatively evaluate the impaired perfusion status of patients with symptomatic internal carotid artery (ICA) steno-occlusive disease and to explore the risk factors of impaired perfusion with computed tomography perfusion (CTP).

Methods

The clinical and imaging data of 187 patients with ICA steno-occlusive disease were retrospectively analyzed. The ICA stenosis rate was divided into Grades I–IV (70–79%; 80–89%; 90–99%; 100%), and the circle of Willis was classified as four types (types I–IV). According to the literature, the value of cerebral blood flow/cerebral blood volume (CBF/CBV) of 7.55/min was used as cut-off to predict symptomatic patients. All patients were categorized into two groups: those with impaired perfusion [n = 99 (52.9%)] and those without impaired perfusion [n = 88 (47.1%)]. Symmetrical bilateral internal watershed areas were selected as the regions of interest (ROIs). Statistical analysis was made on the status of impaired perfusion and the risk factors of impaired perfusion.

Results

Univariate analysis revealed that systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), types of the circle of Willis, and clinical features at admission differed between the two groups (patients with or without impaired perfusion) (p < 0.05). Multiple logistic stepwise regression analysis showed that MAP [odds ratio (OR) = 0.946, 95% confidential interval (CI) = 0.917–0.974, p < 0.001] and type IV (type I vs. IV: OR = 4.987, 95% CI = 1.955–12.723, p = 0.001) at admission were independently associated with impaired perfusion in the internal watershed areas.

Conclusion

MAP and the type of circle of Willis at admission are independent risk factors associated with the impaired perfusion in patients with ICA steno-occlusive disease.
The Role of the Negative Regulation of Microglia-Mediated Neuroinflammation in Improving Emotional Behavior After Epileptic Seizures
Authors: Wu Qiong , Wang Hua , Liu Xueyan , Zhao Yajuan , Zhang Junmei
Published: April 2022

Objective

Studies have long shown that uncontrolled inflammatory responses in the brain play a key role in epilepsy pathogenesis. Microglias play an important role in epileptic-induced neuroinflammation, but their role after epileptic seizures is still poorly understood. Alleviating epilepsy and its comorbidities has become a key area of interest for pediatricians.

Methods

A pilocarpine-induced rat model of epilepsy was established. The rats were randomly divided into four groups: a control group, epilepsy group, TLR4 inhibitor group (epilepsy+TAK-242), and NF-κB antagonist group (epilepsy+BAY11–7082).

Results

1. The results of TUNEL staining showed that the expression in rats in the epilepsy group was the most obvious and was significantly different from that in rats in the control, EP+BAY and EP+TAK groups. 2. The expression of TLR4 and NF-κB was highest in rats in the epilepsy group and was significantly different from that in rats in the control, EP+BAY and EP+TAK groups. 3. The fluorescence intensity and number of IBA-1-positive cells in rats in the epilepsy group were highest and significantly different from those in rats in the control, EP+BAY and EP+TAK groups. Western blot analysis of IBA-1 showed that the expression in rats in the epilepsy group was the highest and was statistically significant. 4. CD68 was the highest in rats in the epilepsy group and was statistically significant. 5. In the open-field experiment, the central region residence time of rats in the EP group was delayed, the central region movement distance traveled was prolonged, the total distance traveled was prolonged, and the average speed was increased. Compared with rats in the EP group, rats in the EP+BAY and EP+ TAK groups exhibited improvements to different degrees.

Conclusion

At the tissue level, downregulation of the TLR4/NF-κB inflammatory pathway in epilepsy could inhibit microglial activation and the expression of the inflammatory factor CD68, could inhibit hyperphagocytosis, and inhibit the occurrence and exacerbation of epilepsy, thus improving cognitive and emotional disorders after epileptic seizures.
Researchers’ Ethical Concerns About Using Adaptive Deep Brain Stimulation for Enhancement
Authors: Kostick-Quenet Kristin , Kalwani Lavina , Koenig Barbara , Torgerson Laura , Sanchez Clarissa , Munoz Katrina , Hsu Rebecca L. , Sierra-Mercado Demetrio , Robinson Jill Oliver , Outram Simon , Pereira Stacey , McGuire Amy , Zuk Peter , Lazaro-Munoz Gabriel
Published: April 2022

The capacity of next-generation closed-loop or adaptive deep brain stimulation devices (aDBS) to read (measure neural activity) and write (stimulate brain regions or circuits) shows great potential to effectively manage movement, seizure, and psychiatric disorders, and also raises the possibility of using aDBS to electively (non-therapeutically) modulate mood, cognition, and prosociality. What separates aDBS from most neurotechnologies (e.g. transcranial stimulation) currently used for enhancement is that aDBS remains an invasive, surgically-implanted technology with a risk-benefit ratio significantly different when applied to diseased versus non-diseased individuals. Despite a large discourse about the ethics of enhancement, no empirical studies yet examine perspectives on enhancement from within the aDBS research community. We interviewed 23 aDBS researchers about their attitudes toward expanding aDBS use for enhancement. A thematic content analysis revealed that researchers share ethical concerns related to (1) safety and security; (2) enhancement as unnecessary, unnatural or aberrant; and (3) fairness, equality, and distributive justice. Most (70%) researchers felt that enhancement applications for DBS will eventually be technically feasible and that attempts to develop such applications for DBS are already happening (particularly for military purposes). However, researchers unanimously (100%) felt that DBS ideally should not be considered for enhancement until researchers better understand brain target localization and functioning. While many researchers acknowledged controversies highlighted by scholars and ethicists, such as potential impacts on personhood, authenticity, autonomy and privacy, their ethical concerns reflect considerations of both gravity and perceived near-term likelihood.
Longitudinal Influences of DRD4 Polymorphism and Early Maternal Caregiving on Personality Development and Problem Behavior in Middle Childhood and Adolescence
Authors: Zimmermann Peter , Spangler Gottfried
Published: April 2022

Most studies examining gene-environment effects on self-regulation focus on outcomes early childhood or adulthood. However, only a few studies investigate longitudinal effects during middle childhood and adolescence and compare two domains of early caregiving. In a longitudinal follow-up with a sample of N = 87, we studied the effects of differences in the DRD4 tandem repeat polymorphisms and two domains of early maternal caregiving quality on children’s personality development using Block’s California Child Q-Set (CCQ) at age six and age 12 and on problem behavior at ages six and seven. Early maternal regulation quality predicted later ego-resiliency and aggressiveness. In addition, significant gene-environment interactions revealed that children with the 7+ DRD4 tandem repeat polymorphism and poor maternal regulation quality in infancy showed lower scores in ego-resiliency and higher scores in ego-undercontrol and CCQ aggressiveness. In contrast, children who had experienced effective maternal regulation in infancy showed a comparable level in personality traits and problem behavior as the DRD4 7- group independent of the levels of maternal regulatory behavior. Similarly, longitudinal caregiving × DRD4 interactions were found for behavior problems in middle childhood, especially for oppositional-aggression, inattentive-hyperactivity, and social competence. Early caregiving effects were only found for maternal regulation quality, but not for maternal responsiveness. Effective early maternal regulation in infancy can moderate the negative effect of DRD4 7+ on children’s self-regulation in middle childhood and adolescence. However, maternal responsiveness has no comparable effects. It seems relevant to consider several dimensions of early caregiving and to also measure the environment in more detail in gene-environment studies.
TDP-43 Oligomerization and Phase Separation Properties Are Necessary for Autoregulation
Authors: Koehler Lydia C. , Grese Zachary R. , Bastos Alliny C. S. , Mamede Lohany D. , Heyduk Tomasz , Ayala Yuna M.
Published: April 2022

Loss of TDP-43 protein homeostasis and dysfunction, in particular TDP-43 aggregation, are tied to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 is an RNA binding protein tightly controlling its own expression levels through a negative feedback loop, involving TDP-43 recruitment to the 3′ untranslated region of its own transcript. Aberrant TDP-43 expression caused by autoregulation defects are linked to TDP-43 pathology. Therefore, interactions between TDP-43 and its own transcript are crucial to prevent TDP-43 aggregation and loss of function. However, the mechanisms that mediate this interaction remain ill-defined. We find that a central RNA sequence in the 3′ UTR, which mediates TDP-43 autoregulation, increases the liquid properties of TDP-43 phase separation. Furthermore, binding to this RNA sequence induces TDP-43 condensation in human cell lysates, suggesting that this interaction promotes TDP-43 self-assembly into dynamic ribonucleoprotein granules. In agreement with these findings, our experiments show that TDP-43 oligomerization and phase separation, mediated by the amino and carboxy-terminal domains, respectively, are essential for TDP-43 autoregulation. According to our additional observations, CLIP34-associated phase separation and autoregulation may be efficiently controlled by phosphorylation of the N-terminal domain. Importantly, we find that specific ALS-associated TDP-43 mutations, mainly M337V, and a shortened TDP-43 isoform recently tied to motor neuron toxicity in ALS, disrupt the liquid properties of TDP-43-RNA condensates as well as autoregulatory function. In addition, we find that M337V decreases the cellular clearance of TDP-43 and other RNA binding proteins associated with ALS/FTD. These observations suggest that loss of liquid properties in M337V condensates strongly affects protein homeostasis. Together, this work provides evidence for the central role of TDP-43 oligomerization and liquid-liquid phase separation linked to RNA binding in autoregulation. These mechanisms may be impaired by TDP-43 disease variants and controlled by specific cellular signaling.
Classification of Whisker Deflections From Evoked Responses in the Somatosensory Barrel Cortex With Spiking Neural Networks
Authors: Petschenig Horst , Bisio Marta , Maschietto Marta , Leparulo Alessandro , Legenstein Robert , Vassanelli Stefano
Published: April 2022

Spike-based neuromorphic hardware has great potential for low-energy brain-machine interfaces, leading to a novel paradigm for neuroprosthetics where spiking neurons in silicon read out and control activity of brain circuits. Neuromorphic processors can receive rich information about brain activity from both spikes and local field potentials (LFPs) recorded by implanted neural probes. However, it was unclear whether spiking neural networks (SNNs) implemented on such devices can effectively process that information. Here, we demonstrate that SNNs can be trained to classify whisker deflections of different amplitudes from evoked responses in a single barrel of the rat somatosensory cortex. We show that the classification performance is comparable or even superior to state-of-the-art machine learning approaches. We find that SNNs are rather insensitive to recorded signal type: both multi-unit spiking activity and LFPs yield similar results, where LFPs from cortical layers III and IV seem better suited than those of deep layers. In addition, no hand-crafted features need to be extracted from the data—multi-unit activity can directly be fed into these networks and a simple event-encoding of LFPs is sufficient for good performance. Furthermore, we find that the performance of SNNs is insensitive to the network state—their performance is similar during UP and DOWN states.
The Local Topological Reconfiguration in the Brain Network After Targeted Hub Dysfunction Attacks in Patients With Juvenile Myoclonic Epilepsy
Authors: Ke Ming , Li Huimin , Liu Guangyao
Published: April 2022

The central brain regions of brain networks have been extensively studied in terms of their roles in various diseases. This study provides a direct measure of the brain’s responses to targeted attacks on central regions, revealing the critical role these regions play in patients with juvenile myoclonic epilepsy (JME). The resting-state data of 37 patients with JME and 37 healthy subjects were collected, and brain functional networks were constructed for the two groups of data according to their Pearson correlation coefficients. The left middle cingulate gyrus was defined as the central brain region by the eigenvector centrality algorithm and was attacked by the CLM sequential failure model. The rich-club connection differences between the patients with JME and healthy controls before and after the attacks were compared according to graph theory indices and the number of rich-club connections. We found that the numbers of rich connections in the brain networks of the healthy control group and the group of patients with JME were significantly reduced [p < 0.05, false discovery rate (FDR) correction] before the CLM sequential failure attacks, and no significant differences were observed between the feeder connections and local connections. In the healthy control group, significant rich connection differences were obtained (p < 0.01, FDR correction), and no statistically significant differences were observed regarding the feeder connections and local connections in the brain network before and after CLM failure attacks on the central brain region. No significant differences were obtained between the rich connections, feeder connections, and local connections in patients with JME before and after CLM successive failure attacks on the central brain area. The rich connections, feeder connections, and local connections were not significantly different in the brain networks of the healthy control group and the group of patients with JME after CLM successive failure attacks on the central brain region. We concluded that the damage to the left middle cingulate gyrus is closely linked to various brain disorders, suggesting that this region is of great importance for understanding the pathophysiological basis of myoclonic seizures in patients with JME.
What Makes Organoids Good Models of Human Neurogenesis?
Authors: Yang Qian , Hong Yan , Zhao Ting , Song Hongjun , Ming Guo-li
Published: April 2022

Human neurogenesis occurs mainly in embryonic, fetal, and neonatal stages and generates tremendously diverse neural cell types that constitute the human nervous system. Studies on human neurogenesis have been limited due to a lack of access to human embryonic and fetal tissues. Brain organoids derived from human pluripotent stem cells not only recapitulate major developmental processes during neurogenesis, but also exhibit human-specific features, thus providing an unprecedented opportunity to study human neurodevelopment. First, three-dimensional brain organoids resemble early human neurogenesis with diverse stem cell pools, including the presence of primate-enriched outer radial glia cells. Second, brain organoids recapitulate human neurogenesis at the cellular level, generating diverse neuronal cell types and forming stratified cortical layers. Third, brain organoids also capture gliogenesis with the presence of human-specific astrocytes. Fourth, combined with genome-editing technologies, brain organoids are promising models for investigating functions of human-specific genes at different stages of human neurogenesis. Finally, human organoids derived from patient iPSCs can recapitulate specific disease phenotypes, providing unique models for studying developmental brain disorders of genetic and environmental causes, and for mechanistic studies and drug screening. The aim of this review is to illustrate why brain organoids are good models to study various steps of human neurogenesis, with a focus on corticogenesis. We also discuss limitations of current brain organoid models and future improvements.
Localization of the Priming Factors CAPS1 and CAPS2 in Mouse Sensory Neurons Is Determined by Their N-Termini
Authors: Staudt Angelina , Ratai Olga , Bouzouina Aicha , Fecher-Trost Claudia , Shaaban Ahmed , Bzeih Hawraa , Horn Alexander , Shaib Ali H. , Klose Margarete , Flockerzi Veit , Lauterbach Marcel A. , Rettig Jens , Becherer Ute
Published: April 2022

Both paralogs of the calcium-dependent activator protein for secretion (CAPS) are required for exocytosis of synaptic vesicles (SVs) and large dense core vesicles (LDCVs). Despite approximately 80% sequence identity, CAPS1 and CAPS2 have distinct functions in promoting exocytosis of SVs and LDCVs in dorsal root ganglion (DRG) neurons. However, the molecular mechanisms underlying these differences remain enigmatic. In this study, we applied high- and super-resolution imaging techniques to systematically assess the subcellular localization of CAPS paralogs in DRG neurons deficient in both CAPS1 and CAPS2. CAPS1 was found to be more enriched at the synapses. Using – in-depth sequence analysis, we identified a unique CAPS1 N-terminal sequence, which we introduced into CAPS2. This CAPS1/2 chimera reproduced the pre-synaptic localization of CAPS1 and partially rescued synaptic transmission in neurons devoid of CAPS1 and CAPS2. Using immunoprecipitation combined with mass spectrometry, we identified CAPS1-specific interaction partners that could be responsible for its pre-synaptic enrichment. Taken together, these data suggest an important role of the CAPS1-N terminus in the localization of the protein at pre-synapses.
Protein Tyrosine Phosphatase Receptor Type D Regulates Neuropathic Pain After Nerve Injury via the STING-IFN-I Pathway
Authors: Sun Chengkuan , Wu Guangzhi , Zhang Zhan , Cao Rangjuan , Cui Shusen
Published: April 2022

Neuropathic pain is usually caused by injury or dysfunction of the somatosensory system, and medicine is a common way of treatment. Currently, there are still no satisfactory drugs, like opioids and lidocaine, which carry a high risk of addiction. Protein tyrosine phosphatase receptor type D (PTPRD) is a known therapeutic target in addiction pathways and small molecule inhibitors targeting it, such as 7-butoxy illudalic acid analog (7-BIA), have recently been developed to tackle addition. PTPRD is also upregulated in the dorsal root ganglion (DRG) in a rat model of neuropathic pain, but is not yet clear whether PTPRD contributes to the development of neuropathic pain. Here, we established a chronic constriction injury (CCI) and evaluated PTPRD expression and its association with neuropathic pain. PTPRD expression was found to gradually increase after CCI in DRGs, and its expression was concomitant with the progressive development of hypersensitivity as assessed by both mechanical and thermal stimuli. Both PTPRD knockdown and administration of PTPRD inhibitor 7-BIA alleviated CCI-induced neuropathic pain while upregulating STING and IFN-α in the DRG. Treatment with H-151, a STING inhibitor, abolished the analgesic effects of PTPRD knockdown. Taken together, our study suggests that increased levels of PTPRD in the DRG following CCI are involved in the development of neuropathic pain via the STING-IFN-I pathway. 7-BIA, a small molecule inhibitor of PTPRD with anti-addiction effects, may represent a novel and safe therapeutic strategy for the clinical management of neuropathic pain without the risk of addiction.
A Severe Dementia Syndrome Caused by Intron Retention and Cryptic Splice Site Activation in STUB1 and Exacerbated by TBP Repeat Expansions
Authors: Reis Marlen Colleen , Patrun Julia , Ackl Nibal , Winter Pia , Scheifele Maximilian , Danek Adrian , Nolte Dagmar
Published: April 2022

Heterozygous pathogenic variants in the STIP1 homologous and U-box containing protein 1 (STUB1) gene have been identified as causes of autosomal dominant inherited spinocerebellar ataxia type 48 (SCA48). SCA48 is characterized by an ataxic movement disorder that is often, but not always, accompanied by a cognitive affective syndrome. We report a severe early onset dementia syndrome that mimics frontotemporal dementia and is caused by the intronic splice donor variant c.524+1G>A in STUB1. Impaired splicing was demonstrated by RNA analysis and in minigene assays of mutated and wild-type constructs of STUB1. The most striking consequence of this splicing impairment was retention of intron 3 in STUB1, which led to an in-frame insertion of 63 amino acids (aa) (p.Arg175_Glu176ins63) into the highly conserved coiled-coil domain of its encoded protein, C-terminus of HSP70-interacting protein (CHIP). To a lesser extent, activation of two cryptic splice sites in intron 3 was observed. The almost exclusively used one, c.524+86, was not predicted by in silico programs. Variant c.524+86 caused a frameshift (p.Arg175fs*93) that resulted in a truncated protein and presumably impairs the C-terminal U-box of CHIP, which normally functions as an E3 ubiquitin ligase. The cryptic splice site c.524+99 was rarely used and led to an in-frame insertion of 33 aa (p.Arg175_Glu176ins33) that resulted in disruption of the coiled-coil domain, as has been previously postulated for complete intron 3 retention. We additionally detected repeat expansions in the range of reduced penetrance in the TATA box-binding protein (TBP) gene by excluding other genes associated with dementia syndromes. The repeat expansion was heterozygous in one patient but compound heterozygous in the more severely affected patient. Therefore, we concluded that the observed severe dementia syndrome has a digenic background, making STUB1 and TBP important candidate genes responsible for early onset dementia syndromes.
Genetic Evidence Supporting the Causal Role of Homocysteine in Chronic Kidney Disease: A Mendelian Randomization Study
Authors: Xiong Yang , Zhang Yangchang , Zhang Fuxun , Wu Changjing , Luo Peiyi , Qin Feng , Yuan Jiuhong
Published: April 2022

Background

The causal relationship between homocysteine (Hcy) levels and chronic kidney disease (CKD) remains unclear. This study was performed to estimate the potential causal effects of Hcy on the estimated glomerular filtration rate (eGFR) and CKD.

Materials and Methods

The single nucleotide polymorphisms (SNPs) associated with one standard deviation (SD) Hcy increase were identified using the genome-wide association study (GWAS). The summary statistics of the eGFR and CKD were from the CKDGen project in the European ancestry and the Population Architecture using Genomics and Epidemiology (PAGE) project in the non-European ancestry. Two-sample Mendelian randomization (MR) analyses were used in this study to verify the causal effects among Hcy, eGFR, and CKD.

Results

The results showed that 1-SD Hcy increase was causally associated with eGFR decline in the CKDGen project (β = −0.027 log ml.min–1/1.73 m2, p < 0.01 for the overall cohort; β = −0.028 log ml.min–1/1.73 m2, p < 0.01 after excluding the patients with diabetes). In addition, 1-SD Hcy increase was associated with a 1.32-fold risk of CKD in the PAGE project (95% CI = 1.06–1.64, p < 0.05). The association was directionally similar in the CKDGen project [odds ratio (OR) = 1.08, 95% CI = 0.97–1.44, p = 0.098]. The pooled OR of CKD was 1.24 (95% CI = 1.07–1.44, p < 0.05) per 1-SD Hcy increase.

Conclusion

Using genetic data, Hcy increase is causally associated with renal function injury and further CKD.