bluuebunny/crossref_metadata_2025 huggingface dataset:
RETRACTED: Deep Learning for Autism Diagnosis and Facial Analysis in Children
Authors: Hosseini Mohammad-Parsa , Beary Madison , Hadsell Alex , Messersmith Ryan , Soltanian-Zadeh Hamid
Published: January 2022

In this paper, we introduce a deep learning model to classify children as either healthy or potentially having autism with 94.6% accuracy using Deep Learning. Patients with autism struggle with social skills, repetitive behaviors, and communication, both verbal and non-verbal. Although the disease is considered to be genetic, the highest rates of accurate diagnosis occur when the child is tested on behavioral characteristics and facial features. Patients have a common pattern of distinct facial deformities, allowing researchers to analyze only an image of the child to determine if the child has the disease. While there are other techniques and models used for facial analysis and autism classification on their own, our proposal bridges these two ideas allowing classification in a cheaper, more efficient method. Our deep learning model uses MobileNet and two dense layers to perform feature extraction and image classification. The model is trained and tested using 3,014 images, evenly split between children with autism and children without it; 90% of the data is used for training and 10% is used for testing. Based on our accuracy, we propose that the diagnosis of autism can be done effectively using only a picture. Additionally, there may be other diseases that are similarly diagnosable.
Constructing a Multiple Sclerosis Diagnosis Model Based on Microarray
Authors: Li Haoran , Wu Hongyun , Li Weiying , Zhou Jiapei , Yang Jie , Peng Wei
Published: January 2022

Introduction

Multiple sclerosis is an immune-mediated demyelinating disorder of the central nervous system. Because of the complexity of etiology, pathology, clinical manifestations, and the diversity of classification, the diagnosis of MS is very difficult. We found that McDonald Criteria is very strict and relies heavily on the evidence for DIS and DIT. Therefore, we hope to find a new method to supplement the evidence and improve the accuracy of MS diagnosis.

Results

We finally selected GSE61240, GSE18781, and GSE185047 based on the GPL570 platform to build a diagnosis model. We initially selected 54 MS susceptibility locus genes identified by IMSGC and WTCCC2 as predictors for the model. After Random Forests and other series of screening, the logistic regression model was established with 4 genes as the final predictors. In external validation, the model showed high accuracy with an AUC of 0.96 and an accuracy of 86.30%. Finally, we established a nomogram and an online prediction tool to better display the diagnosis model.

Conclusion

The diagnosis model based on microarray data in this study has a high degree of discrimination and calibration in the validation set, which is helpful for diagnosis in the absence of evidence for DIS and DIT. Only one SLE case was misdiagnosed as MS, indicating that the model has a high specificity (93.93%), which is useful for differential diagnosis. The significance of the study lies in proving that it is feasible to identify MS by peripheral blood RNA, and the further application of the model and be used as a supplement to McDonald Criteria still need to be trained with larger sample size.
Fine-Mapping of the PLCL2 Gene Identifies Candidate Variants Associated With Ischaemic Stroke Risk in Metabolic Syndrome Patients
Authors: Huang Xiaoya , Ye Qiang , Zhang Yanlei , Chen Yanyan , Li Jia , Sun Jun , Ye Zusen
Published: January 2022

A genome-wide association study (GWAS) reported PLCL2 on chromosome 3p24. 3 (rs4618210:A>G) as a novel susceptibility locus for myocardial infarction in the Japanese population. As the most common pathological process, atherosclerosis leads to metabolic syndrome (MetS)-related ischaemic stroke (IS) and myocardial infarction. Hypothesizing that polymorphisms of the PLCL2 gene might be associated with the onset and prognosis of IS in MetS patients, we performed the following study in a Chinese Han population. A total of 709 cases (patients with MetS plus IS) and 711 controls (patients with MetS) were enrolled. A fine-mapping strategy was adopted to identify tagged single nucleotide polymorphisms (SNPs) of the PLCL2 gene, and improved multiplex ligation detection reaction (iMLDR) technology was used to genotype the selected SNPs. Logistic regression was used to analyse the values of the selected SNPs for the risk of IS between the cases and controls, adjusting for sex, age, hypertension, dyslipidaemia, hyperglycaemia, smoking and drinking. To compare the mean age of IS onset among different risk score groups, a genetic risk score was constructed for each case. The cumulative risk of IS events in the case group was presented using a cumulative incidence curve. All cases were followed up for 3 months, and functional outcomes were recorded prospectively. Two SNPs (rs4685423 and rs4618210) were significantly related to the risk of IS in MetS patients. For rs4685423, patients who were AA homozygotes were less likely to suffer from IS than C-allele carriers (OR 0.718; 95% CI 0.567–0.909; multivariate-adjusted, P = 0.006). For rs4618210, A-allele carriers were less likely to develop IS than patients who were GG homozygotes (OR 0.679; 95% CI 0.548–0.841; multivariate-adjusted, P < 0.001). As the genetic risk score increased, the mean age at IS onset decreased (log-rank P = 0.010). There was no statistically significant difference in the distribution of the 90-day modified Rankin Scale (mRS) outcomes across the rs4685423 (P = 0.319) or rs4618210 polymorphisms (P = 0.148). Our findings suggested that genetic polymorphisms of PLCL2 might be associated with the onset of MetS-related IS. Further studies are warranted to validate our findings in other ethnic populations.
Vestibular Rehabilitation Telehealth During the SAEA-CoV-2 (COVID-19) Pandemic
Authors: Harrell Regan G. , Schubert Michael C. , Oxborough Sara , Whitney Susan L.
Published: January 2022

During the COVID-19 pandemic, physical therapists transitioned to provide telehealth in the United States. We sought to determine the experiences of physical therapists delivering telerehabilitation for vestibular disorders including barriers, preferences, and concerns. A survey was created using the results of a focus group and previously published studies. The survey was distributed across social media sites and through email- the link was sent to the orthopedic, neurologic, and geriatric academies of the American Physical Therapy Association list serves. The email was also shared with each of the 50 state chapters of the American Physical Therapy Association. The survey was broken down into five sections: demographic information, physical therapists' general impressions of telehealth, physical therapists' comfort level treating various vestibular diagnoses, and common barriers physical therapists experienced during telehealth sessions. There were 159 completed surveys. More than 80% of physical therapists surveyed agreed that telehealth was an effective platform for vestibular physical therapy. When asked whether physical therapists felt the patient had similar health outcomes with telehealth versus clinic care 68% of physical therapists agreed. For the physical therapists who treated posterior or horizontal canal benign paroxysmal positional vertigo via telehealth, more than 50% were comfortable treating these conditions via telehealth. In analyzing common peripheral vestibular diagnoses treated via telehealth including bilateral vestibular loss, Meniere's disease, and vestibular neuritis more than 75% of the physical therapists reported comfort treating these diagnoses. Similarly, more than 75% of physical therapists who treated central vestibular diagnoses- including mild traumatic brain injury and vestibular migraine- via telehealth reported being comfortable treating these diagnoses. Physical therapists reported several barriers to tele healthcare ranging from concerns about testing balance with no caregiver present (94%) to challenges with providing a written home exercise program (33%). Physical therapists report that telehealth is a viable mechanism for providing rehabilitation for persons with balance and vestibular disorders. For common diagnoses, most physical therapists were comfortable treating vestibular disorders via telehealth. While barriers remain including maintaining patient safety and being able to complete a thorough vestibular exam, telehealth for vestibular physical therapy services holds promise for the delivery of virtual care.
Restoring Function After Severe Spinal Cord Injury Through BioLuminescent-OptoGenetics
Authors: Petersen Eric D. , Sharkey Erik D. , Pal Akash , Shafau Lateef O. , Zenchak-Petersen Jessica , Peña Alex J. , Aggarwal Anu , Prakash Mansi , Hochgeschwender Ute
Published: January 2022

The ability to manipulate specific neuronal populations of the spinal cord following spinal cord injury (SCI) could prove highly beneficial for rehabilitation in patients through maintaining and strengthening still existing neuronal connections and/or facilitating the formation of new connections. A non-invasive and highly specific approach to neuronal stimulation is bioluminescent-optogenetics (BL-OG), where genetically expressed light emitting luciferases are tethered to light sensitive channelrhodopsins (luminopsins, LMO); neurons are activated by the addition of the luciferase substrate coelenterazine (CTZ). This approach utilizes ion channels for current conduction while activating the channels through the application of a small chemical compound, thus allowing non-invasive stimulation and recruitment of all targeted neurons. Rats were transduced in the lumbar spinal cord with AAV2/9 to express the excitatory LMO3 under control of a pan-neuronal or motor neuron-specific promoter. A day after contusion injury of the thoracic spine, rats received either CTZ or vehicle every other day for 2 weeks. Activation of either neuron population below the level of injury significantly improved locomotor recovery lasting beyond the treatment window. Utilizing histological and gene expression methods we identified neuronal plasticity as a likely mechanism underlying the functional recovery. These findings provide a foundation for a rational approach to spinal cord injury rehabilitation, thereby advancing approaches for functional recovery after SCI.

Bioluminescent optogenetic activation of spinal neurons results in accelerated and enhanced locomotor recovery after spinal cord injury in rats.
Trigeminal Nerve White Matter Fiber Abnormalities in Primary Trigeminal Neuralgia: A Diffusion Spectrum Imaging Study
Authors: Luo Si-ping , Chen Fan-fan , Zhang Han-wen , Lin Fan , Huang Guo-dong , Lei Yi
Published: January 2022

Objective

Diffusion spectrum imaging (DSI) was used to quantitatively study the changes in the trigeminal cistern segment in patients with trigeminal neuralgia (TN) and to further explore the value of acquiring DSI data from patients with TN.

Methods

To achieve high-resolution fiber tracking, 60 patients with TN and 35 healthy controls (HCs) were scanned with conventional magnetic resonance imaging (MRI) and DSI. The patients and the members of the control group were compared within and between groups. The correlations between quantitative parameters of DSI and the visual analog scale (VAS), and symptom duration and responsible vessel types were analyzed.

Results

Compared with unaffected side of patients in the TN group, the affected side showed significantly decreased quantitative anisotropy (QA) (p < 0.001), fractional anisotropy (FA) (p = 0.001), and general FA (GFA) (p < 0.001). The unaffected side exhibited significantly decreased QA (p + 0.001), FA (p = 0.001), and GFA (p < 0.001) and significantly increased axial diffusivity (AD) (p = 0.036) compared with the affected side of patients in the TN group and the average values of HCs. There were significantly decreased QA (p = 0.046) and FA (p = 0.008) between the unaffected side of patients and the average values of HCs. GFA can evidently distinguish arteries, veins, and features of unaffected side in TN patients.

Conclusion

Using high-resolution fiber tracking technology, DSI can provide quantitative information that can be used to detect the integrity of trigeminal white matter in patients with TN and can improve the understanding of the disease mechanism.
Automated Detection of Candidate Subjects With Cerebral Microbleeds Using Machine Learning
Authors: Sundaresan Vaanathi , Arthofer Christoph , Zamboni Giovanna , Dineen Robert A. , Rothwell Peter M. , Sotiropoulos Stamatios N. , Auer Dorothee P. , Tozer Daniel J. , Markus Hugh S. , Miller Karla L. , Dragonu Iulius , Sprigg Nikola , Alfaro-Almagro Fidel , Jenkinson Mark , Griffanti Ludovica
Published: January 2022

Cerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g., blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g., the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipeline's generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (within-dataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.
Deep Learning in Large and Multi-Site Structural Brain MR Imaging Datasets
Authors: Bento Mariana , Fantini Irene , Park Justin , Rittner Leticia , Frayne Richard
Published: January 2022

Large, multi-site, heterogeneous brain imaging datasets are increasingly required for the training, validation, and testing of advanced deep learning (DL)-based automated tools, including structural magnetic resonance (MR) image-based diagnostic and treatment monitoring approaches. When assembling a number of smaller datasets to form a larger dataset, understanding the underlying variability between different acquisition and processing protocols across the aggregated dataset (termed “batch effects”) is critical. The presence of variation in the training dataset is important as it more closely reflects the true underlying data distribution and, thus, may enhance the overall generalizability of the tool. However, the impact of batch effects must be carefully evaluated in order to avoid undesirable effects that, for example, may reduce performance measures. Batch effects can result from many sources, including differences in acquisition equipment, imaging technique and parameters, as well as applied processing methodologies. Their impact, both beneficial and adversarial, must be considered when developing tools to ensure that their outputs are related to the proposed clinical or research question (i.e., actual disease-related or pathological changes) and are not simply due to the peculiarities of underlying batch effects in the aggregated dataset. We reviewed applications of DL in structural brain MR imaging that aggregated images from neuroimaging datasets, typically acquired at multiple sites. We examined datasets containing both healthy control participants and patients that were acquired using varying acquisition protocols. First, we discussed issues around Data Access and enumerated the key characteristics of some commonly used publicly available brain datasets. Then we reviewed methods for correcting batch effects by exploring the two main classes of approaches: Data Harmonization that uses data standardization, quality control protocols or other similar algorithms and procedures to explicitly understand and minimize unwanted batch effects; and Domain Adaptation that develops DL tools that implicitly handle the batch effects by using approaches to achieve reliable and robust results. In this narrative review, we highlighted the advantages and disadvantages of both classes of DL approaches, and described key challenges to be addressed in future studies.
Altered Effective Connectivity Measured by Resting-State Functional Magnetic Resonance Imaging in Posterior Parietal-Frontal-Striatum Circuit in Patients With Disorder of Consciousness
Authors: Chen Linglong , Rao Bo , Li Sirui , Gao Lei , Xie Yu , Dai Xuan , Fu Kai , Peng Xu Zhi , Xu Haibo
Published: January 2022

Objective

Disorder of consciousness (DoC) resulting from severe brain injury is characterized by cortical and subcortical dysconnectivity. However, research on seed-based effective connectivity (EC) of DoC might be questioned as to the heterogeneity of prior assumptions.

Methods

Functional MRI data of 16 DoC patients and 16 demographically matched healthy individuals were analyzed. Revised coma recovery scale (CRS-R) scores of patients were acquired. Seed-based d mapping permutation of subject images (SDM-PSI) of meta-analysis was performed to quantitatively synthesize results from neuroimaging studies that evaluated resting-state functional activity in DoC patients. Spectral dynamic causal modeling (spDCM) was used to assess how EC altered between brain regions in DoC patients compared to healthy individuals.

Results

We found increased effective connectivity in left striatum and decreased effective connectivity in bilateral precuneus (preCUN)/posterior cingulate cortex (PCC), bilateral midcingulate cortex and left middle frontal gyrus in DoC compared with the healthy controls. The resulting pattern of interaction in DoC indicated disrupted connection and disturbance of posterior parietal-frontal-striatum, and reduced self-inhibition of preCUN/PCC. The strength of self-inhibition of preCUN/PCC was negatively correlated with the total score of CRS-R.

Conclusion

This impaired EC in DoC may underlie disruption in the posterior parietal-frontal-striatum circuit, particularly damage to the cortico-striatal connection and possible loss of preCUN/PCC function as the main regulatory hub.
Language Impairments in Individuals With Coffin-Siris Syndrome
Authors: Vasko Ashley , Schrier Vergano Samantha A.
Published: January 2022

Coffin-Siris syndrome (CSS, MIM 135900) is a now well-described, multiple congenital anomaly/intellectual disability syndrome classically characterized by fifth digit/nail hypoplasia, coarse facial features, and a range of organ-system related anomalies. Since its initial description in 1970, and the discovery of associated genes in 2011, CSS now encompasses a wide range of phenotypes and abilities caused by pathogenic variants in the BAF complex (often referred to as “BAFopathy”). It appears that the BAF complex leads to speech and language impairments in this population, and subsequently we have reviewed individuals in the CSS/BAF registry to understand the prevalence and degree of this particular learning difference. We have examined the frequency of delayed language acquisition, augmented communication device use, and speech intervention therapies. To aid in language progression, childhood speech interventions are necessary in children with a diagnosis of CSS. While the majority of children with pathogenic variants in the BAF complex have language-related struggles, the exact mechanism is not yet fully understood. At the time of writing, there are 284 individuals in the CSS/BAF registry with known variants in the following genes; ARID1B (n = 174), SMARCA4 (n = 41), ARID1A (n = 20), SMARCB1 (n = 20), ARID2 (n = 14), SOX11 (n = 10), and SMARCE1 (n = 5). While speech delays in individuals with CSS are expected, a full analysis of these delays has yet to be detailed. In the CSS/BAF registry, we identified 183 (64%) individuals with language-related challenges and 90 (32%) individuals that are non-verbal.
Effects of Baduanjin Exercise on Rehabilitation of Patients With Mild to Moderate Parkinson’s Disease
Authors: Dong Shuangshuang , Wang Yiqing , Wei Hongyu , Du Shouyun , Li Xiaojing , Zhu Jianbing , Wang Yi , Cai Zenglin
Published: January 2022

Objectives

Rehabilitation, aerobic exercise, and many traditional Chinese exercises are known to significantly improve balance in patients with Parkinson’s disease. Baduanjin, a traditional physical and mental exercise, has long been practiced for health care as it regulates organs, the nervous and motor systems.

Methods

We recruited 31 eligible participants. Patients underwent a 3-week Baduanjin program, including 35-min exercise daily. Scores on the Modified Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Non-motor Symptoms Scale (NMSS), and gait and balance tests were compared before and after the Baduanjin program.

Results

MDS-UPDRS-total (t = 4.669, P ≤ 0.001), MDS-UPDRS part-I (t = 5.805, P ≤ 0.001), MDS-UPDRS part-II (t = 5.234, P ≤ 0.001), MDS-UPDRS part-III (t = 3.274, P = 0.003), and NMSS (t = 4.815, P ≤ 0.001) scores significantly decreased after the 3-week intervention. Gait parameters like step (t = 2.289, P = 0.030) and cycle (t = 2.181, P = 0.038) durations also significantly improved, while Balance-check® indicators, including the total score (t = −2.147, P = 0.041) and grade (t = 3.432, P = 0.002) significantly differed before and after exercise.

Conclusion

Baduanjin exercise shows beneficial effects for non-motor symptoms, balance, gait, and daily activities in patients with Parkinson’s disease. Baduanjin can be included in the patients’ family exercise, which is conducive to their rehabilitation, as well as for obtaining important social and economic benefits.

Clinical Trial Registration

[www.ClinicalTrials.gov], identifier [ChiCTR-IPR-17011875].
Prediction of Protein–Protein Interactions Between Alsin DH/PH and Rac1 and Resulting Protein Dynamics
Authors: Cannariato Marco , Miceli Marcello , Cavaglià Marco , Deriu Marco A.
Published: January 2022

Alsin is a protein of 1,657 amino acids known for its crucial role in vesicular trafficking in neurons thanks to its ability to interact with two guanosine triphosphatases, Rac1 and Rab5. Evidence suggests that Rac1 can bind Alsin central region, composed by a Dbl Homology (DH) domain followed by a Pleckstrin Homology (PH) domain, leading to Alsin relocalization. However, Alsin three-dimensional structure and its relationship with known biological functions of this protein are still unknown. In this work, a homology model of the Alsin DH/PH domain was developed and studied through molecular dynamics both in the presence and in the absence of its binding partner, Rac1. Due to different conformations of DH domain, the presence of Rac1 seems to stabilize an open state of the protein, while the absence of its binding partner results in closed conformations. Furthermore, Rac1 interaction was able to reduce the fluctuations in the second conserved region of DH motif, which may be involved in the formation of a homodimer. Moreover, the dynamics of DH/PH was described through a Markov State Model to study the pathways linking the open and closed states. In conclusion, this work provided an all-atom model for the DH/PH domain of Alsin protein; moreover, molecular dynamics investigations suggested underlying molecular mechanisms in the signal transduction between Rac1 and Alsin, providing the basis for a deeper understanding of the whole structure–function relationship for Alsin protein.
Regional Homogeneity Abnormalities and Its Correlation With Impulsivity in Male Abstinent Methamphetamine Dependent Individuals
Authors: Zhou Yanan , Wang Qianjin , Ren Honghong , Wang Xuyi , Liao Yanhui , Yang Zhi , Hao Yuzhu , Wang Yunfei , Li Manyun , Ma Yuejiao , Wu Qiuxia , Wang Yingying , Yang Dong , Xin Jiang , Yang Winson Fu Zun , Wang Long , Liu Tieqiao
Published: January 2022

Methamphetamine (MA) use affects the brain structure and function. However, no studies have investigated the relationship between changes in regional homogeneity (ReHo) and impulsivity in MA dependent individuals (MADs). The aim of this study was to investigate the changes of brain activity under resting state in MADs and their relationship to impulsivity using ReHo method. Functional magnetic resonance imaging (fMRI) was performed to collect data from 46 MADs and 44 healthy controls (HCs) under resting state. ReHo method was used to investigate the differences in average ReHo values between the two groups. The ReHo values abnormalities of the brain regions found in inter-group comparisons were extracted and correlated with impulsivity. Compared to the HCs, MADs showed significant increased ReHo values in the bilateral striatum, while the ReHo values of the bilateral precentral gyrus and the bilateral postcentral gyrus decreased significantly. The ReHo values of the left precentral gyrus were negatively correlated with the BIS-attention, BIS-motor, and BIS-nonplanning subscale scores, while the ReHo values of the postcentral gyrus were only negatively correlated with the BIS-motor subscale scores in MADs. The abnormal spontaneous brain activity in the resting state of MADs revealed in this study may further improve our understanding of the neuro-matrix of MADs impulse control dysfunction and may help us to explore the neuropathological mechanism of MADs related dysfunction and rehabilitation.
Human Cortical Serotonin 2A Receptor Occupancy by Psilocybin Measured Using [11C]MDL 100,907 Dynamic PET and a Resting-State fMRI-Based Brain Parcellation
Authors: Barrett Frederick S. , Zhou Yun , Carbonaro Theresa M. , Roberts Joshua M. , Smith Gwenn S. , Griffiths Roland R. , Wong Dean F.
Published: January 2022

Psilocybin (a serotonin 2A, or 5-HT2A, receptor agonist) has shown preliminary efficacy as a treatment for mood and substance use disorders. The current report utilized positron emission tomography (PET) with the selective 5-HT2A receptor inverse agonist radioligand [11C]MDL 100,907 (a.k.a. M100,907) and cortical regions of interest (ROIs) derived from resting-state functional connectivity-based brain parcellations in 4 healthy volunteers (2 females) to determine regional occupancy/target engagement of 5-HT2A receptors after oral administration of a psychoactive dose of psilocybin (10 mg/70 kg). Average 5-HT2A receptor occupancy across all ROIs was 39.5% (± 10.9% SD). Three of the ROIs with greatest occupancy (between 63.12 and 74.72% occupancy) were within the default mode network (subgenual anterior cingulate and bilateral angular gyri). However, marked individual variability in regional occupancy was observed across individuals. These data support further investigation of the relationship between individual differences in the acute and enduring effects of psilocybin and the degree of regional 5-HT2A receptor occupancy.
Transsynaptic Long-Term Potentiation in the Hippocampus of Behaving Mice
Authors: Romero-Barragán Maria Teresa , Gruart Agnes , Delgado-García José M.
Published: January 2022

Long-term potentiation (LTP) is an experimental procedure that shares certain mechanisms with neuronal learning and memory processes and represents a well-known example of synaptic plasticity. LTP consists of an increase of the synaptic response to a control stimulus following the presentation of a high-frequency stimulation (HFS) train to an afferent pathway. This technique is studied mostly in the hippocampus due to the latter’s high susceptibility and its laminar nature which facilitates the location of defined synapses. Although most preceding studies have been performed in vitro, we have developed an experimental approach to carry out these experiments in alert behaving animals. The main goal of this study was to confirm the existence of synaptic changes in strength in synapses that are post-synaptic to the one presented with the HFS. We recorded field excitatory post-synaptic potentials (fEPSPs) evoked in five hippocampal synapses, from both hemispheres, of adult male mice. HFS was presented to the perforant pathway (PP). We characterized input/output curves, paired-pulse stimulation, and LTP of these synapses. We also performed depth-profile recordings to determine differences in fEPSP latencies. Collected data indicate that the five selected synapses have similar basic electrophysiological properties, a fact that enables an easier comparison of LTP characteristics. Importantly, we observed the presence of significant LTP in the contralateral CA1 (cCA1) area following the control stimulation of non-HFS-activated pathways. These results indicate that LTP appears as a physiological process present in synapses located far away from the HFS-stimulated afferent pathway.
Decreased Tactile Sensitivity Induced by Disownership: An Observational Study Utilizing the Rubber Hand Illusion
Authors: Ataka Kota , Sudo Tamami , Otaki Ryoji , Suzuki Eizaburo , Izumi Shin-Ichi
Published: January 2022

The sense of body ownership, the feeling that one’s own body belongs to oneself, is generated from the integration of visual, tactile, and proprioceptive information. However, long-term non-use of parts of the body due to physical dysfunction caused by trauma or illness may disturb multisensory integration, resulting in a decreased sense of body ownership. The rubber hand illusion (RHI) is an experimental method of manipulating the sense of ownership (SoO). In this illusion, subjects feel as if the rubber hand in front of them were their own hand. The RHI elicits the disownership phenomenon; not only does the rubber hand feels like one’s own hand, but one’s own hand does not feel like one’s own hand. The decrease of ownership of one’s own body induced by the bodily illusion is accompanied by neurophysiological changes, such as attenuation of somatosensory evoked potential and decreases in skin temperature. If the loss of the SoO is associated with decreased neurophysiological function, the dysfunction of patients complaining of the loss of ownership can be exacerbated; appropriate rehabilitation prescriptions are urgently required. The present study attempted to induce a sense of disownership of subjects’ own hands using the RHI and investigated whether the tactile sensitivity threshold was altered by disownership. Via questionnaire, subjects reported a decrease of ownership after the RHI manipulation; at the same time, tactile sensitivity thresholds were shown to increase in tactile evaluation using the Semmes-Weinstein monofilaments test. The tactile detection rate changes before and after the RHI were negatively correlated with the disownership-score changes. These results show that subjects’ sense of disownership, that their own hands did not belong to them, led to decreases in tactile sensitivity. The study findings also suggest that manipulating of illusory ownership can be a tool for estimating the degree of exacerbation of sensory impairment in patients. Consideration of new interventions that optimize the sense of body ownership may contribute to new rehabilitation strategies for post-stroke sensory impairment.
Social Regulation of Negative Valence Systems During Development
Authors: Hu Shannon , Packard Katherine , Opendak Maya
Published: January 2022

The ability to sense, perceive, and respond appropriately to aversive cues is critical for survival. Conversely, dysfunction in any of these pathway components can lead to heightened avoidance of neutral or rewarding cues, such as social partners. The underlying circuitry mediating both negative valence processing and social behavior is particularly sensitive to early life experience, but mechanisms linking experience to pathology remain elusive. Previous research in humans, rodents, and non-human primates has highlighted the unique neurobiology of the developing infant and the role of the caregiver in mediating the infant’s negative valence circuitry, and the importance of this early social relationship for scaffolding lasting social behavior. In this review, we summarize the current literature on the development of negative valence circuits in the infant and their social regulation by the caregiver following both typical and adversity-rearing. We focus on clinically-relevant research using infant rodents which highlights the amygdala and its interface with the mesolimbic dopamine system through innervation from the ventral tegmental area (VTA) as a locus of dysfunction following early-life adversity. We then describe how these circuits are recruited to perturb life-long social behavior following adversity and propose additional therapeutic targets in these circuits with an eye toward developing age-appropriate interventions.
From Bedside to the Bench—A Call for Novel Approaches to Prognostic Evaluation and Treatment of Empyema
Authors: Karandashova Sophia , Florova Galina , Idell Steven , Komissarov Andrey A.
Published: January 2022

Empyema, a severe complication of pneumonia, trauma, and surgery is characterized by fibrinopurulent effusions and loculations that can result in lung restriction and resistance to drainage. For decades, efforts have been focused on finding a universal treatment that could be applied to all patients with practice recommendations varying between intrapleural fibrinolytic therapy (IPFT) and surgical drainage. However, despite medical advances, the incidence of empyema has increased, suggesting a gap in our understanding of the pathophysiology of this disease and insufficient crosstalk between clinical practice and preclinical research, which slows the development of innovative, personalized therapies. The recent trend towards less invasive treatments in advanced stage empyema opens new opportunities for pharmacological interventions. Its remarkable efficacy in pediatric empyema makes IPFT the first line treatment. Unfortunately, treatment approaches used in pediatrics cannot be extrapolated to empyema in adults, where there is a high level of failure in IPFT when treating advanced stage disease. The risk of bleeding complications and lack of effective low dose IPFT for patients with contraindications to surgery (up to 30%) promote a debate regarding the choice of fibrinolysin, its dosage and schedule. These challenges, which together with a lack of point of care diagnostics to personalize treatment of empyema, contribute to high (up to 20%) mortality in empyema in adults and should be addressed preclinically using validated animal models. Modern preclinical studies are delivering innovative solutions for evaluation and treatment of empyema in clinical practice: low dose, targeted treatments, novel biomarkers to predict IPFT success or failure, novel delivery methods such as encapsulating fibrinolysin in echogenic liposomal carriers to increase the half-life of plasminogen activator. Translational research focused on understanding the pathophysiological mechanisms that control 1) the transition from acute to advanced-stage, chronic empyema, and 2) differences in outcomes of IPFT between pediatric and adult patients, will identify new molecular targets in empyema. We believe that seamless bidirectional communication between those working at the bedside and the bench would result in novel personalized approaches to improve pharmacological treatment outcomes, thus widening the window for use of IPFT in adult patients with advanced stage empyema.
Acute Oral, Subacute, and Developmental Toxicity Profiling of Naphthalene 2-Yl, 2-Chloro, 5-Nitrobenzoate: Assessment Based on Stress Response, Toxicity, and Adverse Outcome Pathways
Authors: Anwar Fareeha , Saleem Uzma , rehman Atta ur , Ahmad Bashir , Ismail Tariq , Mirza Muhammad Usman , Ahmad Sarfraz
Published: January 2022

The U.S. National Research Council (NRC) introduced new approaches to report toxicity studies. The NRC vision is to explore the toxicity pathways leading to the adverse effects in intact organisms by the exposure of the chemicals. This study examines the toxicity profiling of the naphthalene-2-yl 2-chloro-5-dinitrobenzoate (SF5) by adopting the vision of NRC that moves from traditional animal studies to the cellular pathways. Acute, subacute, and developmental toxicity studies were assayed according to the Organization for Economic Cooperation and Development (OECD) guidelines. The stress response pathway, toxicity pathway, and adverse effects outcome parameters were analyzed by using their standard protocols. The results showed that the acute toxicity study increases the liver enzyme levels. In a subacute toxicity study, alkaline phosphatase (ALP) levels were raised in both male and female animals. SF5 significantly increases the normal sperm count in the male animals corresponding to a decrease in the abnormality count. Developmental toxicity showed the normal skeletal and morphological parameters, except little hydrocephalus was observed in developmental toxicity. Doses of 20 mg/kg in males and 4 mg/kg in females showed decreased glutathione (GSH) levels in the kidney and liver. MDA levels were also increased in the kidney and liver. However, histopathological studies did not show any cellular change in these organs. No statistical difference was observed in histamine levels, testosterone, nuclear factor erythroid two-related factor-2 (Nrf2), and nuclear factor-kappa B (NF-κB), which showed no initiation of the stress response, toxicity, and adverse effect pathways. Immunomodulation was observed at low doses in subacute toxicity studies. It was concluded that SF5 did not produce abrupt and high-toxicity levels in organs and biochemical parameters. So, it is safe for further studies.
Standardizing Zebrafish Behavioral Paradigms Across Life Stages: An Effort Towards Translational Pharmacology
Authors: Petersen Barbara Dutra , Bertoncello Kanandra Taisa , Bonan Carla Denise
Published: January 2022

Zebrafish is a prominent vertebrate model, with many of its advantages related to its development, life cycle, and translational ability. While a great number of behavioral phenotypes and tasks to evaluate them are available, longitudinal studies across zebrafish life stages are scarce and made challenging because of the differences between protocols and endpoints assessed at each life stage. In this mini review, we highlight the relevance that longitudinal studies could have for neurobehavioral pharmacology using this model. We also present possible strategies to standardize behavior endpoints in domains related to human diseases throughout the life cycle, especially between larvae and adult fish. Furthermore, we discuss the remaining difficulties of these analyses and explore future advances needed to bridge this knowledge gap.
Serum and Glucocorticoid-Inducible Kinase 3/Nedd4-2 Signaling Pathway Participates in Podocyte Injury by Regulating the Stability of Nephrin
Authors: Dong Qing-Qing , Li Zi-Fang , Zhang Hui , Shu Hua-Pan , Tu Yu-Chi , Liao Qian-Qian , Yao Li-Jun
Published: January 2022

Serum and glucocorticoid-inducible kinase 3 (SGK3) is involved in maintaining podocyte function by regulating the protein levels of podocin and CD2-associated protein. Nephrin is also one of the slit diaphragm proteins of podocytes, but whether SGK3 participates in podocyte injury by regulating the levels of nephrin remains unclear. In this study, we focused on whether SGK3 affects nephrin levels and the mechanisms involved in the same. In the kidneys of adriamycin (ADR)-induced podocyte injury mouse model, the protein levels of SGK3 and nephrin were significantly decreased. Furthermore, the expression of SGK3 was negatively correlated with the output of proteinuria, and positively correlated with the levels of nephrin. In ADR-treated conditionally immortalized mouse podocyte cells (MPCs), the protein levels of nephrin and SGK3 were inhibited, while the constitutive expression of SGK3 reversed the ADR-induced decline in nephrin protein levels. Furthermore, ADR treatment or SGK3 inactivation enhanced the ubiquitin-proteasome degradation of nephrin in MPCs, and dramatically activated downstream effector proteins of SGK3, neural precursor cells expressing developmentally downregulated protein 4 subtype 2 (Nedd4-2) and glycogen synthase kinase-3 β (GSK3β). Similarly, Nedd4-2 or GSK3β overexpression resulted in increased activity of Nedd4-2 or GSK3β, and significantly downregulated nephrin levels. Interestingly, ubiquitin-mediated protein degradation of nephrin was regulated by Nedd4-2, rather than by GSK3β. In summary, SGK3 inactivation downregulated the levels of nephrin by increasing Nedd4-2 and GSK3β activity in ADR-induced podocyte injury model; in particular, the SGK3/Nedd4-2 signaling pathway was found to be involved in ubiquitin-mediated proteasome degradation of nephrin.
BRASSINAZOLE RESISTANT 1 Mediates Brassinosteroid-Induced Calvin Cycle to Promote Photosynthesis in Tomato
Authors: Yin Xiaowei , Tang Mingjia , Xia Xiaojian , Yu Jingquan
Published: January 2022

Calvin cycle is a sequence of enzymatic reactions that assimilate atmospheric CO2 in photosynthesis. Multiple components are known to participate in the induction or suppression of the Calvin cycle but the mechanism of its regulation by phytohormones is still unclear. Brassinosteroids (BRs) are steroid phytohormones that promote photosynthesis and crop yields. In this study, we study the role of BRs in regulating Calvin cycle genes to further understand the regulation of the Calvin cycle by phytohormones in tomatoes. BRs and their signal effector BRASSINAZOLE RESISTANT 1 (BZR1) can enhance the Calvin cycle activity and improve the photosynthetic ability. BRs increased the accumulation of dephosphorylated form of BZR1 by 94% and induced an 88–126% increase in the transcription of key genes in Calvin cycle FBA1, RCA1, FBP5, and PGK1. BZR1 activated the transcription of these Calvin cycle genes by directly binding to their promoters. Moreover, silencing these Calvin cycle genes impaired 24-epibrassinolide (EBR)-induced enhancement of photosynthetic rate, the quantum efficiency of PSII, and Vc,max and Jmax. Taken together, these results strongly suggest that BRs regulate the Calvin cycle in a BZR1-dependent manner in tomatoes. BRs that mediate coordinated regulation of photosynthetic genes are potential targets for increasing crop yields.
Protein Kinase Signaling Pathways in Plant-Colletotrichum Interaction
Authors: Jiang Lingyan , Zhang Shizi , Su Jianbin , Peck Scott C. , Luo Lijuan
Published: January 2022

Anthracnose is a fungal disease caused by members of Colletotrichum that affect a wide range of crop plants. Strategies to improve crop resistance are needed to reduce the yield losses; and one strategy is to manipulate protein kinases that catalyze reversible phosphorylation of proteins regulating both plant immune responses and fungal pathogenesis. Hence, in this review, we present a summary of the current knowledge of protein kinase signaling pathways in plant-Colletotrichum interaction as well as the relation to a more general understanding of protein kinases that contribute to plant immunity and pathogen virulence. We highlight the potential of combining genomic resources and phosphoproteomics research to unravel the key molecular components of plant-Colletotrichum interactions. Understanding the molecular interactions between plants and Colletotrichum would not only facilitate molecular breeding of resistant cultivars but also help the development of novel strategies for controlling the anthracnose disease.
Using Schema Modes for Case Conceptualization in Schema Therapy: An Applied Clinical Approach
Authors: Edwards David John Arthur
Published: January 2022

This article is situated within the framework of schema therapy and offers a comprehensive and clinically useful list of schema modes that have been identified as being relevant to conceptualizing complex psychological problems, such as those posed by personality disorders, and, in particular, the way that those problems are perpetuated. Drawing on the schema therapy literature, as well as other literature including that of cognitive behavior therapy and metacognitive therapy, over eighty modes are identified altogether, categorized under the widely accepted broad headings of Healthy Adult, Child modes, Parent modes and coping modes which are, in turn, divided into Surrender, Detached/Avoidant, and Overcompensator. An additional category is included: Repetitive Unproductive Thinking. This draws attention to the recognition by metacognitive therapists that such covert behaviors play a significant role in amplifying distress and perpetuating a range of psychological problems and symptoms. In addition to the modes themselves, several concepts are defined that are directly relevant to working with modes in practice. These include: default modes, blended modes, mode suites and mode sequences. Attention is also drawn to the way in which Child modes may be hidden “backstage” behind coping modes, and to the dyadic relationship between Child modes and Parent modes. Also relevant to practice are: (1) the recognition that Critic voices may have different sources and this has implications for treatment, (2) the concept of complex modes in which several submodes work together, and (3) the fact that in imagery work and image of a child may not represent a Vulnerable Child, but a Coping Child. The modes and mode processes described are directly relevant to clinical practice and, in addition to being grounded in the literature, have grown out of and proved to be of practical use in conceptualizing my own cases, and in supervising the cases of other clinicians working within the schema therapy framework.
The Distribution of Subjects in L2 Spanish by Greek Learners
Authors: Margaza Panagiota , Gavarró Anna
Published: January 2022

Our study examines the expression and position of subjects in L2 acquisition, two phenomena that are studied within the framework of the Interface Hypothesis (IH). The first version of the IH predicts that interface properties involving syntax and another cognitive domain may not be fully acquirable in a second language (Sorace and Filiaci, 2006; also Sorace, 2011). The second version of the IH predicts that formal properties involving the syntax-semantics interface are unproblematic to acquire in L2 grammars compared to the vulnerable properties integrating syntax with the higher level of pragmatics (Tsimpli and Sorace, 2006). We test these IH versions in L2 Spanish as acquired by L1 Greek speakers, a language combination understudied in the literature. Both languages share the null subject parameter, but still the IHs predict incomplete command at the syntax-pragmatics interface. Two acceptability judgment tasks were designed for Spanish: the first task tested null/overt subjects in referential contexts and the second task tested preverbal/postverbal subjects in informational contexts. Participants were L1 Greek intermediate and advanced learners of Spanish and native speakers of Spanish (15 subjects in each group). In the first task, both experimental groups showed target-like distribution of null/overt subjects in most non-contrastive and contrastive contexts, except for the advanced group in unambiguous referential contexts. In the second task, the respective groups accepted felicitous preverbal subjects with unergative verbs, but diverged from native-like distribution of postverbal subjects with unaccusative verbs in neutral contexts. The L2 groups showed a high preference for unfelicitous preverbal subjects with both intransitive verbs in informational contexts, contrary to the subject inversion patterns of the control group. The results obtained were not consistent with the IH predictions, and other factors such as the type of subject, verb class and context played a role in L2 performance.