bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Metabolomics Analysis in Tumor Metabolism Reprogramming
Authors: Han Jingjing , Li Qian , Chen Yu , Yang Yonglin
Published: December 2021

Metabolic reprogramming has been suggested as a hallmark of cancer progression. Metabolomic analysis of various metabolic profiles represents a powerful and technically feasible method to monitor dynamic changes in tumor metabolism and response to treatment over the course of the disease. To date, numerous original studies have highlighted the application of metabolomics to various aspects of tumor metabolic reprogramming research. In this review, we summarize how metabolomics techniques can help understand the effects that changes in the metabolic profile of the tumor microenvironment on the three major metabolic pathways of tumors. Various non-invasive biofluids are available that produce accurate and useful clinical information on tumor metabolism to identify early biomarkers of tumor development. Similarly, metabolomics can predict individual metabolic differences in response to tumor drugs, assess drug efficacy, and monitor drug resistance. On this basis, we also discuss the application of stable isotope tracer technology as a method for the study of tumor metabolism, which enables the tracking of metabolite activity in the body and deep metabolic pathways. We summarize the multifaceted application of metabolomics in cancer metabolic reprogramming to reveal its important role in cancer development and treatment.
Multifocal Transcranial Direct Current Stimulation Modulates Resting-State Functional Connectivity in Older Adults Depending on the Induced Current Density
Authors: Abellaneda-Pérez Kilian , Vaqué-Alcázar Lídia , Perellón-Alfonso Ruben , Solé-Padullés Cristina , Bargalló Núria , Salvador Ricardo , Ruffini Giulio , Nitsche Michael A. , Pascual-Leone Alvaro , Bartrés-Faz David
Published: December 2021

Combining non-invasive brain stimulation (NIBS) with resting-state functional magnetic resonance imaging (rs-fMRI) is a promising approach to characterize and potentially optimize the brain networks subtending cognition that changes as a function of age. However, whether multifocal NIBS approaches are able to modulate rs-fMRI brain dynamics in aged populations, and if these NIBS-induced changes are consistent with the simulated electric current distribution on the brain remains largely unknown. In the present investigation, thirty-one cognitively healthy older adults underwent two different multifocal real transcranial direct current stimulation (tDCS) conditions (C1 and C2) and a sham condition in a crossover design during a rs-fMRI acquisition. The real tDCS conditions were designed to electrically induce two distinct complex neural patterns, either targeting generalized frontoparietal cortical overactivity (C1) or a detachment between the frontal areas and the posteromedial cortex (C2). Data revealed that the two tDCS conditions modulated rs-fMRI differently. C1 increased the coactivation of multiple functional couplings as compared to sham, while a smaller number of connections increased in C1 as compared to C2. At the group level, C1-induced changes were topographically consistent with the calculated electric current density distribution. At the individual level, the extent of tDCS-induced rs-fMRI modulation in C1 was related with the magnitude of the simulated electric current density estimates. These results highlight that multifocal tDCS procedures can effectively change rs-fMRI neural functioning in advancing age, being the induced modulation consistent with the spatial distribution of the simulated electric current on the brain. Moreover, our data supports that individually tailoring NIBS-based interventions grounded on subject-specific structural data might be crucial to increase tDCS potential in future studies amongst older adults.
Feasibility of Cognitive-Motor Exergames in Geriatric Inpatient Rehabilitation: A Pilot Randomized Controlled Study
Authors: Altorfer Patrizia , Adcock Manuela , de Bruin Eling D. , Graf Florian , Giannouli Eleftheria
Published: December 2021

Objective: The aim of this pilot randomized clinical trial was to test the feasibility and efficacy of an exergame-based cognitive-motor training program in geriatric inpatients.

Methods: The study participants were randomly allocated to either the exergame intervention group or the control group. The control group received the standard rehabilitation treatment offered in the clinic. In addition to the standard rehabilitation program, the intervention group conducted supervised exergame training on 5 days per week using the Dividat Senso, an exergame system specifically designed for older adults. The primary outcome was feasibility, as measured by e.g., adherence rate, attrition rate, occurrence of adverse events, System Usability Scale (SUS) and NASA-TLX score. Secondary outcomes included measures of physical and cognitive functioning such as comfortable walking speed, maximal walking speed, dual task walking speed, Short Physical Performance Battery (SPPB), Timed Up and Go test (TUG), Color-Word Interference test (D-KEFS), Trail Making test A and B (TMT), Go/No-Go test and Step Reaction Time test (SRTT). All secondary outcome measures were assessed pre- and post-intervention.

Results: Thirty-nine persons were included in the study. Average adherence rate was 99%, there were no intervention-related dropouts and no adverse events. The mean System Usability Scale (SUS) score was 83.6 and the mean NASA-TLX score 45.5. Significant time-group interaction effects were found for the dual task walking speed, the Go/No-Go test and Step Reaction Time test (SRTT).

Conclusion: Exergaming is a feasible, safe and effective cognitive-motor training approach in inpatient rehabilitation of geriatric patients. Incorporating exergaming in the rehabilitation program of geriatric patients offers potential to reduce fall risk factors and to increase patients’ exercise motivation and rehabilitation success.
Molecular Insight Into the Therapeutic Potential of Long Non-coding RNA-Associated Competing Endogenous RNA Axes in Alzheimer’s Disease: A Systematic Scoping Review
Authors: Sabaie Hani , Amirinejad Nazanin , Asadi Mohammad Reza , Jalaiei Abbas , Daneshmandpour Yousef , Rezaei Omidvar , Taheri Mohammad , Rezazadeh Maryam
Published: December 2021

Alzheimer’s disease (AD) is a heterogeneous degenerative brain disorder with a rising prevalence worldwide. The two hallmarks that characterize the AD pathophysiology are amyloid plaques, generated via aggregated amyloid β, and neurofibrillary tangle, generated via accumulated phosphorylated tau. At the post-transcriptional and transcriptional levels, the regulatory functions of non-coding RNAs, in particular long non-coding RNAs (lncRNAs), have been ascertained in gene expressions. It is noteworthy that a number of lncRNAs feature a prevalent role in their potential of regulating gene expression through modulation of microRNAs via a process called the mechanism of competing endogenous RNA (ceRNA). Given the multifactorial nature of ceRNA interaction networks, they might be advantageous in complex disorders (e.g., AD) investigations at the therapeutic targets level. We carried out scoping review in this research to analyze validated loops of ceRNA in AD and focus on ceRNA axes associated with lncRNA. This scoping review was performed according to a six-stage methodology structure and PRISMA guideline. A systematic search of seven databases was conducted to find eligible articles prior to July 2021. Two reviewers independently performed publications screening and data extraction, and quantitative and qualitative analyses were conducted. Fourteen articles were identified that fulfill the inclusion criteria. Studies with different designs reported nine lncRNAs that were experimentally validated to act as ceRNA in AD in human-related studies, including BACE1-AS, SNHG1, RPPH1, NEAT1, LINC00094, SOX21-AS1, LINC00507, MAGI2-AS3, and LINC01311. The BACE1-AS/BACE1 was the most frequent ceRNA pair. Among miRNAs, miR-107 played a key role by regulating three different loops. Understanding the various aspects of this regulatory mechanism can help elucidate the unknown etiology of AD and provide new molecular targets for use in therapeutic and clinical applications.
Evolution of Brain Morphology in Spontaneously Hypertensive and Wistar-Kyoto Rats From Early Adulthood to Aging: A Longitudinal Magnetic Resonance Imaging Study
Authors: Yang Yingying , Zhang Quan , Ren Jialiang , Zhu Qingfeng , Wang Lixin , Zhang Yongzhi , Geng Zuojun
Published: December 2021

The influence of hypertension and aging alone on brain structure has been described extensively. Our understanding of the interaction of hypertension with aging to brain morphology is still limited. We aimed to detect the synergistic effects of hypertension and aging on brain morphology and to describe the evolution patterns of cerebral atrophy from spatial and temporal perspectives. In 8 spontaneously hypertensive rats (SHRs) and 5 Wistar-Kyoto rats, high-resolution magnetic resonance imaging scans were longitudinally acquired at 10, 24, 52, and 80 weeks. We analyzed the tissue volumes of gray matter, white matter, cerebral spinal fluid, and total intracranial volume (TIV), and then evaluated gray matter volume in detail using voxel-based morphometry (VBM) and region of interest-based methods. There were interactive effects on hypertension and aging in tissue volumes of gray matter, white matter, and TIV, of which gray matter atrophy was most pronounced, especially in elderly SHRs. We identified the vulnerable gray matter volume with combined effects of hypertension and aging in the septal region, bilateral caudate putamen, hippocampus, primary somatosensory cortex, cerebellum, periaqueductal gray, right accumbens nucleus, and thalamus. We automatically extracted the septal region, anterior cingulate cortex, primary somatosensory cortex, caudate putamen, hippocampus, and accumbens nucleus and revealed an inverted-U trajectory of volume change in SHRs, with volume increase at the early phase and decline at the late phase. Hypertension interacts with aging to affect brain volume changes such as severe atrophy in elderly SHRs.
Spatial Pattern Separation Testing Differentiates Alzheimer’s Disease Biomarker-Positive and Biomarker-Negative Older Adults With Amnestic Mild Cognitive Impairment
Authors: Laczó Martina , Lerch Ondrej , Martinkovic Lukas , Kalinova Jana , Markova Hana , Vyhnalek Martin , Hort Jakub , Laczó Jan
Published: December 2021

Background: The hippocampus, entorhinal cortex (EC), and basal forebrain (BF) are among the earliest regions affected by Alzheimer’s disease (AD) pathology. They play an essential role in spatial pattern separation, a process critical for accurate discrimination between similar locations.

Objective: We examined differences in spatial pattern separation performance between older adults with amnestic mild cognitive impairment (aMCI) with AD versus those with non-Alzheimer’s pathologic change (non-AD) and interrelations between volumes of the hippocampal, EC subregions and BF nuclei projecting to these subregions (medial septal nuclei and vertical limb of the diagonal band of Broca – Ch1-2 nuclei) with respect to performance.

Methods: Hundred and eighteen older adults were recruited from the Czech Brain Aging Study. Participants with AD aMCI (n = 37), non-AD aMCI (n = 26), mild AD dementia (n = 26), and cognitively normal older adults (CN; n = 29) underwent spatial pattern separation testing, cognitive assessment and brain magnetic resonance imaging.

Results: The AD aMCI group had less accurate spatial pattern separation performance than the non-AD aMCI (p = 0.039) and CN (p < 0.001) groups. The AD aMCI and non-AD groups did not differ in other cognitive tests. Decreased BF Ch1-2 volume was indirectly associated with worse performance through reduced hippocampal tail volume and reduced posteromedial EC and hippocampal tail or body volumes operating in serial.

Conclusion: The study demonstrates that spatial pattern separation testing differentiates AD biomarker positive and negative older adults with aMCI and provides evidence that BF Ch1-2 nuclei influence spatial pattern separation through the posteromedial EC and the posterior hippocampus.
Severe Hypoglycemia Contributing to Cognitive Dysfunction in Diabetic Mice Is Associated With Pericyte and Blood–Brain Barrier Dysfunction
Authors: Lin Lu , Wu Yubin , Chen Zhou , Huang Lishan , Wang Lijing , Liu Libin
Published: December 2021

Background: Severe hypoglycemia can cause cognitive impairment in diabetic patients, but the underlying molecular mechanism remains unclear.

Objective: To assess the effect of severe hypoglycemia on cognitive function in diabetic mice to clarify the relationship between the mechanism and dysfunction of pericytes and the blood–brain barrier (BBB).

Method: We established type 1 diabetes mellitus in 80 male C57BL/6J mice by intraperitoneal injection of streptozotocin (150 mg/kg). Further intraperitoneal injection of short-acting insulin induced severe hypoglycemia. The mice were divided into normal, diabetes, and diabetic + severe hypoglycemia groups, and their blood glucose and general weight index were examined. Pericyte and BBB morphology and function were detected by histological and western blot analyses, BBB permeability was detected by Evans blue staining, and cognitive function was detected with the Morris water maze.

Results: Severe hypoglycemia aggravated the histological damage, BBB damage, brain edema, and pericyte loss in the diabetic mice. It also reduced the expression of the BBB tight junction proteins occludin and claudin-5, the expression of the pericyte-specific markers PDGFR-β (platelet-derived growth factor receptor-β) and α-SMA, and increased the expression of the inflammatory factor MMP9. At the same time, diabetic mice with severe hypoglycemia had significantly reduced cognitive function.

Conclusion: Severe hypoglycemia leads to cognitive dysfunction in diabetic mice, and its possible mechanism is related to pericyte dysfunction and BBB destruction.
Characterizing Hippocampal Oscillatory Signatures Underlying Seizures in Temporal Lobe Epilepsy
Authors: Mokhothu Thato Mary , Tanaka Kazumasa Zen
Published: December 2021

Temporal Lobe Epilepsy (TLE) is a neurological condition characterized by focal brain hyperexcitability, resulting in abnormal neuronal discharge and uncontrollable seizures. The hippocampus, with its inherently highly synchronized firing patterns and relatively high excitability, is prone to epileptic seizures, and it is usually the focus of TLE. Researchers have identified hippocampal high-frequency oscillations (HFOs) as a salient feature in people with TLE and animal models of this disease, arising before or at the onset of the epileptic event. To a certain extent, these pathological HFOs have served as a marker and a potential target for seizure attenuation using electrical or optogenetic interventions. However, many questions remain about whether we can reliably distinguish pathological from non-pathological HFOs and whether they can tell us about the development of the disease. While this would be an arduous task to perform in humans, animal models of TLE provide an excellent opportunity to study the characteristics of HFOs in predicting how epilepsy evolves. This minireview will (1) summarize what we know about the oscillatory disruption in TLE, (2) summarize knowledge about oscillatory changes in the latent period and their role in predicting seizures, and (3) propose future studies essential to uncovering potential treatments based on early detection of pathological HFOs.
Inhibition Within the Lateral Habenula—Implications for Affective Disorders
Authors: Webster Jack F. , Lecca Salvatore , Wozny Christian
Published: December 2021

The lateral habenula (LHb) is a key brain region implicated in the pathology of major depressive disorder (MDD). Specifically, excitatory LHb neurons are known to be hyperactive in MDD, thus resulting in a greater excitatory output mainly to downstream inhibitory neurons in the rostromedial tegmental nucleus. This likely results in suppression of downstream dopaminergic ventral tegmental area neurons, therefore, resulting in an overall reduction in reward signalling. In line with this, increasing evidence implicates aberrant inhibitory signalling onto LHb neurons as a co-causative factor in MDD, likely as a result of disinhibition of excitatory neurons. Consistently, growing evidence now suggests that normalising inhibitory signalling within the LHb may be a potential therapeutic strategy for MDD. Despite these recent advances, however, the exact pharmacological and neural circuit mechanisms which control inhibitory signalling within the LHb are still incompletely understood. Thus, in this review article, we aim to provide an up-to-date summary of the current state of knowledge of the mechanisms by which inhibitory signalling is processed within the LHb, with a view of exploring how this may be targeted as a future therapy for MDD.
The Causes and Long-Term Consequences of Viral Encephalitis
Authors: Bohmwald Karen , Andrade Catalina A. , Gálvez Nicolás M. S. , Mora Valentina P. , Muñoz José T. , Kalergis Alexis M.
Published: December 2021

Reports regarding brain inflammation, known as encephalitis, have shown an increasing frequency during the past years. Encephalitis is a relevant concern to public health due to its high morbidity and mortality. Infectious or autoimmune diseases are the most common cause of encephalitis. The clinical symptoms of this pathology can vary depending on the brain zone affected, with mild ones such as fever, headache, confusion, and stiff neck, or severe ones, such as seizures, weakness, hallucinations, and coma, among others. Encephalitis can affect individuals of all ages, but it is frequently observed in pediatric and elderly populations, and the most common causes are viral infections. Several viral agents have been described to induce encephalitis, such as arboviruses, rhabdoviruses, enteroviruses, herpesviruses, retroviruses, orthomyxoviruses, orthopneumovirus, and coronaviruses, among others. Once a neurotropic virus reaches the brain parenchyma, the resident cells such as neurons, astrocytes, and microglia, can be infected, promoting the secretion of pro-inflammatory molecules and the subsequent immune cell infiltration that leads to brain damage. After resolving the viral infection, the local immune response can remain active, contributing to long-term neuropsychiatric disorders, neurocognitive impairment, and degenerative diseases. In this article, we will discuss how viruses can reach the brain, the impact of viral encephalitis on brain function, and we will focus especially on the neurocognitive sequelae reported even after viral clearance.
Sphingosine-1-Phosphate Signaling in Ischemic Stroke: From Bench to Bedside and Beyond
Authors: Zhang Shuo-Qi , Xiao Jun , Chen Man , Zhou Luo-Qi , Shang Ke , Qin Chuan , Tian Dai-Shi
Published: December 2021

Sphingosine-1-phosphate (S1P) signaling is being increasingly recognized as a strong modulator of immune cell migration and endothelial function. Fingolimod and other S1P modulators in ischemic stroke treatment have shown promise in emerging experimental models and small-scale clinical trials. In this article, we will review the current knowledge of the role of S1P signaling in brain ischemia from the aspects of inflammation and immune interventions, sustaining endothelial functions, regulation of blood-brain barrier integrity, and functional recovery. We will then discuss the current and future therapeutic perspectives of targeting S1P for the treatment of ischemic stroke. Mechanism studies would help to bridge the gap between preclinical studies and clinical practice. Future success of bench-to-bedside translation shall be based on in depth understanding of S1P signaling during stroke and on the ability to have a fine temporal and spatial regulation of the signal pathway.
Balance Training With Vibrotactile Neurofeedback and Ginkgo Biloba Extract in Age-Related Vertigo
Authors: Decker Lars , Basta Dietmar , Burkart Martin , Ernst Arne
Published: December 2021

Background:Balance training with vibrotactile neurofeedback (VNF) can improve balance and subjective impairment in age-related vertigo and dizziness.Ginkgo bilobadry extract EGb 761 has been shown to improve subjective impairment in chronic vertigo and the efficacy of conventional balance training. The combination was expected to work synergistically in this difficult-to-treat population.

Objectives:To demonstrate the efficacy of VNF added to EGb 761 for age-related vertigo and dizziness.

Design:Multicenter, prospective, controlled, randomized, single-blind, two-arm trial (German Clinical Trials Registerhttps://www.drks.deNo. DRKS00007633).

Setting:Specialist offices and tertiary care outpatient department.

Participants:One hundred and twenty subjects aged 60+ years with chronic dizziness for over 3 months, a Dizziness Handicap Inventory (DHI) Sum Score >25 and fall risk in balance-related situations as measured by the geriatric Standard Balance Deficit Test Composite Score (gSBDT-CS)>40. Patients with other distinct vestibular pathology (e.g., Meniére's disease, stroke, BPPV) were excluded.

Intervention:EGb 761 (80 mg twice daily for 12 weeks) plus 10 days of individually adapted balance training with VNF, randomized 1:1 to sensitive (active) or non-sensitive (sham) neurofeedback.

Measurements:The change in gSBDT-CS after 6 weeks (primary), other gSBDT outcomes, DHI, cognition, hearing, and safety.

Results:One hundred nine of 120 enrolled subjects received both treatments at least once. Over 12 weeks, the gSBDT-CS improved by 6.7 (active) vs. 4.5 (sham). There was a difference in favor of the active treatment of −2.4 (95% CI −5.4; 0.6) after 6 weeks. Under active treatment, more pronounced effects occurred in all secondary analyses and in nearly all secondary endpoints. The DHI sum score decreased from 44.1 to 31.1 in the total sample with a treatment group difference after 6 weeks of −3.1, 95% CI (−7.1; 0.9). No safety issues were reported.

Conclusion:Over 12 weeks, the combination of balance training with VNF andGinkgo bilobadry extract EGb 761 reached a clinically relevant improvement of age-related vertigo and dizziness with a good pharmacological safety profile.
Overlapping but Language-Specific Mechanisms in Morphosyntactic Processing in Highly Competent L2 Acquired at School Entry: fMRI Evidence From an Alternating Language Switching Task
Authors: Meykadeh Simin , Golfam Arsalan , Batouli Seyed Amir Hossein , Sommer Werner
Published: December 2021

Many bilingual individuals acquire their second language when entering primary school; however, very few studies have investigated morphosyntax processing in this population. Combining a whole-brain and region of interest (ROI)-based approach, we studied event-related fMRI during morphosyntactic processing, specifically person-number phi-features, in Turkish (L1) and Persian (L2) by highly proficient bilinguals who learned Persian at school entry. In a design with alternating language switching and pseudorandomized grammaticality conditions, two left-lateralized syntax-specific ROIs and 11 bilateral ROIs involved in executive functions (EF) were analyzed for the intensity of activation relative to a resting baseline. Our findings indicate a strong overlap of neural networks for L1 and L2, suggesting structural similarities of neuroanatomical organization. In all ROIs morphosyntactic processing invoked stronger activation in L1 than in L2. This may be a consequence of symmetrical switch costs in the alternating design used here, where the need for suppressing the non-required language is stronger for the dominant L1 when it is non-required as compared to the non-dominant L2, leading to a stronger rebound for L1 than L2 when the language is required. Both L1 and L2 revealed significant activation in syntax-specific areas in left hemisphere clusters and increased activation in EF-specific areas in right-hemisphere than left-hemisphere clusters, confirming syntax-specific functions of the left hemisphere, whereas the right hemisphere appears to subserve control functions required for switching languages. While previous reports indicate a leftward bias in planum temporale activation during auditory and linguistic processing, the present study shows the activation of the right planum temporale indicating its involvement in auditory attention. More pronounced grammaticality effect in left pars opercularis for L1 and in left pSTG for L2 indicate differences in the processing of morphosyntactic information in these brain regions. Nevertheless, the activation of pars opercularis and pSTG emphasize the centrality of these regions in the processing of person-number phi-features. Taken together, the present results confirm that morphosyntactic processing in bilinguals relates to composite, syntax-sensitive and EF-sensitive mechanisms in which some nodes of the language network are differentially involved.
Distillation of Regional Activity Reveals Hidden Content of Neural Information in Visual Processing
Authors: Pham Trung Quang , Nishiyama Shota , Sadato Norihiro , Chikazoe Junichi
Published: December 2021

Multivoxel pattern analysis (MVPA) has become a standard tool for decoding mental states from brain activity patterns. Recent studies have demonstrated that MVPA can be applied to decode activity patterns of a certain region from those of the other regions. By applying a similar region-to-region decoding technique, we examined whether the information represented in the visual areas can be explained by those represented in the other visual areas. We first predicted the brain activity patterns of an area on the visual pathway from the others, then subtracted the predicted patterns from their originals. Subsequently, the visual features were derived from these residuals. During the visual perception task, the elimination of the top-down signals enhanced the simple visual features represented in the early visual cortices. By contrast, the elimination of the bottom-up signals enhanced the complex visual features represented in the higher visual cortices. The directions of such modulation effects varied across visual perception/imagery tasks, indicating that the information flow across the visual cortices is dynamically altered, reflecting the contents of visual processing. These results demonstrated that the distillation approach is a useful tool to estimate the hidden content of information conveyed across brain regions.
Auditory Information Accelerates the Visuomotor Reaction Speed of Elite Badminton Players in Multisensory Environments
Authors: Hülsdünker Thorben , Riedel David , Käsbauer Hannes , Ruhnow Diemo , Mierau Andreas
Published: December 2021

Although vision is the dominating sensory system in sports, many situations require multisensory integration. Faster processing of auditory information in the brain may facilitate time-critical abilities such as reaction speed however previous research was limited by generic auditory and visual stimuli that did not consider audio-visual characteristics in ecologically valid environments. This study investigated the reaction speed in response to sport-specific monosensory (visual and auditory) and multisensory (audio-visual) stimulation. Neurophysiological analyses identified the neural processes contributing to differences in reaction speed. Nineteen elite badminton players participated in this study. In a first recording phase, the sound profile and shuttle speed of smash and drop strokes were identified on a badminton court using high-speed video cameras and binaural recordings. The speed and sound characteristics were transferred into auditory and visual stimuli and presented in a lab-based experiment, where participants reacted in response to sport-specific monosensory or multisensory stimulation. Auditory signal presentation was delayed by 26 ms to account for realistic audio-visual signal interaction on the court. N1 and N2 event-related potentials as indicators of auditory and visual information perception/processing, respectively were identified using a 64-channel EEG. Despite the 26 ms delay, auditory reactions were significantly faster than visual reactions (236.6 ms vs. 287.7 ms, p < 0.001) but still slower when compared to multisensory stimulation (224.4 ms, p = 0.002). Across conditions response times to smashes were faster when compared to drops (233.2 ms, 265.9 ms, p < 0.001). Faster reactions were paralleled by a lower latency and higher amplitude of the auditory N1 and visual N2 potentials. The results emphasize the potential of auditory information to accelerate the reaction time in sport-specific multisensory situations. This highlights auditory processes as a promising target for training interventions in racquet sports.
Extended Invariant Information Clustering Is Effective for Leave-One-Site-Out Cross-Validation in Resting State Functional Connectivity Modeling
Authors: Okamoto Naoki , Akama Hiroyuki
Published: December 2021

Herein, we propose a new deep neural network model based on invariant information clustering (IIC), proposed by Ji et al., to improve the modeling performance of the leave-one-site-out cross-validation (LOSO-CV) for a multi-source dataset. Our Extended IIC (EIIC) is a type of contrastive learning; however, unlike the original IIC, it is characterized by transfer learning with labeled data pairs, but without the need for a data augmentation technique. Each site in LOSO-CV is left out in turn from the remaining sites used for training and receives a value for modeling evaluation. We applied the EIIC to the resting state functional connectivity magnetic resonance imaging dataset of the Autism Brain Imaging Data Exchange. The challenging nature of brain analysis for autism spectrum disorder (ASD) can be attributed to the variability of subjects, particularly the rapid change in the neural system of children as the target ASD age group. However, EIIC demonstrated higher LOSO-CV classification accuracy for the majority of scanning locations than previously used methods. Particularly, with the adjustment of a mini-batch size, EIIC outperformed other classifiers with an accuracy >0.8 for the sites with highest mean age of the subjects. Considering its effectiveness, our proposed method might be promising for harmonization in other domains, owing to its simplicity and intrinsic flexibility.
Markov Chain Abstractions of Electrochemical Reaction-Diffusion in Synaptic Transmission for Neuromorphic Computing
Authors: Wagner Margot , Bartol Thomas M. , Sejnowski Terrence J. , Cauwenberghs Gert
Published: December 2021

Progress in computational neuroscience toward understanding brain function is challenged both by the complexity of molecular-scale electrochemical interactions at the level of individual neurons and synapses and the dimensionality of network dynamics across the brain covering a vast range of spatial and temporal scales. Our work abstracts an existing highly detailed, biophysically realistic 3D reaction-diffusion model of a chemical synapse to a compact internal state space representation that maps onto parallel neuromorphic hardware for efficient emulation at a very large scale and offers near-equivalence in input-output dynamics while preserving biologically interpretable tunable parameters.
Creating Detailed Metadata for an R Shiny Analysis of Rodent Behavior Sequence Data Detected Along One Light-Dark Cycle
Authors: Colomb Julien , Winter York
Published: December 2021

Automated mouse phenotyping through the high-throughput analysis of home cage behavior has brought hope of a more effective and efficient method for testing rodent models of diseases. Advanced video analysis software is able to derive behavioral sequence data sets from multiple-day recordings. However, no dedicated mechanisms exist for sharing or analyzing these types of data. In this article, we present a free, open-source software actionable through a web browser (an R Shiny application), which performs an analysis of home cage behavioral sequence data, which is designed to spot differences in circadian activity while preventing p-hacking. The software aligns time-series data to the light/dark cycle, and then uses different time windows to produce up to 162 behavior variables per animal. A principal component analysis strategy detected differences between groups. The behavior activity is represented graphically for further explorative analysis. A machine-learning approach was implemented, but it proved ineffective at separating the experimental groups. The software requires spreadsheets that provide information about the experiment (i.e., metadata), thus promoting a data management strategy that leads to FAIR data production. This encourages the publication of some metadata even when the data are kept private. We tested our software by comparing the behavior of female mice in videos recorded twice at 3 and 7 months in a home cage monitoring system. This study demonstrated that combining data management with data analysis leads to a more efficient and effective research process.
Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2C Receptors
Authors: Zeng Fanxing , Nye Jonathon A. , Voll Ronald J. , Mun Jiyoung , Goodman Mark M.
Published: December 2021

The serotonin 5-HT2C receptor (5-HT2CR) is abundantly expressed throughout the central nervous system, and involved in a variety of neuroendocrine and neurobehavioral processes. The development of a selective radioligand that will enable in vivo imaging and quantification of 5-HT2CR densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT2CR. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT2CR and high selectivity over 5-HT2A and 5-HT2B. [11C]7-Chloro-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (6) and [11C]7-iodo-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (9) were synthesized in high radiochemical yield of 37–44% [n = 10, decay corrected from end of (11C)CH3I synthesis] with high radiochemical purity via O-methylation with [11C]CH3I, respectively. MicroPET imaging studies in male rats with or without 5-HT2C antagonist SB-242084 showed that [11C]6 and [11C]9 display specific bindings to 5-HT2CR in the choroid plexus and hippocampus. In vivo microPET brain imaging studies in rhesus monkeys demonstrated that [11C]6 and [11C]9 exhibit excellent blood-brain barrier penetration. The contrast of bindings to the choroid plexus and hippocampus compared to the cerebellum peaked at 2.7 and 1.6, respectively, for [11C]6, and 3.7 and 2.7, respectively, for [11C]9, which were reduced by administration of a dose of SB-242084. Our results support the candidacy of [11C]6 and [11C]9 for further study as radioligands for in vivo quantitation of 5-HT2C sites by PET.
The Influence of MTHFR Polymorphism on Gray Matter Volume in Patients With Amnestic Mild Cognitive Impairment
Authors: You Mengzhe , Zhou Xia , Yin Wenwen , Wan Ke , Zhang Wei , Li Chenchen , Li Mingxu , Zhu Wenhao , Zhu Xiaoqun , Sun Zhongwu
Published: December 2021

The methylenetetrahydrofolate reductase (MTHFR) gene has been associated with Alzheimer’s disease (AD) pathogenesis. Amnestic mild cognitive impairment (aMCI) represents a prodromal stage of dementia and involves a high risk of progression into AD. Although the effects of the apolipoprotein E (APOE) gene on structural alterations in aMCI have been widely investigated, the effects of MTHFR C677T and interaction effects of MTHFR × APOE genotypes on gray matter atrophy in aMCI remain largely unknown. In the present study, 60 aMCI patients and 30 healthy controls were enrolled, and voxel-based morphometry analysis was performed to inspect the effects of diagnosis, different genotypes, and their interactions on gray matter atrophy. The results showed that aMCI patients had significant gray matter atrophy involving the bilateral hippocampus, the right parahippocampal gyrus, and the left superior temporal gyrus compared with healthy controls. Besides, a substantial reduction in gray matter volume was observed in the right hippocampus region in APOE ε4 carriers from the aMCI group, compared with APOE ε4 non-carriers. A significant interaction was found between diagnosis and MTHFR C677T genotype on the right precuneus in healthy controls and aMCI patients not carrying APOE ε4 allele. Our findings may provide new evidence substantiating the genetic effects of MTHFR C677T on brain structural alternation in patients with aMCI.
Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations
Authors: Martin-Batista Elva , Manville Rían W. , Rivero-Pérez Belinda , Bartolomé-Martín David , Alvarez de la Rosa Diego , Abbott Geoffrey W. , Giraldez Teresa
Published: December 2021

In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetrametric channel. Mutations in Kv7.2 and Kv7.3 are associated with hyperexcitability phenotypes including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE). SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), increases M-current density in neurons, leading to reduced excitability and protection against seizures. Herein, using two-electrode voltage clamp on Xenopus laevis oocytes, we demonstrate that SGK1.1 selectively activates heteromeric Kv7 subunit combinations underlying the M-current. Importantly, activated SGK1.1 increases M-channel activity in the presence of two different epilepsy mutations found in Kv7.2, R207W and A306T. In addition, proximity ligation assays in the N2a cell line allowed us to address the effect of these mutations on Kv7-SGK1.1-Nedd4 molecular associations, a proposed pathway underlying augmentation of M-channel activity by SGK1.1
A Model for Predicting Cation Selectivity and Permeability in AMPA and NMDA Receptors Based on Receptor Subunit Composition
Authors: Kumar Sampath , Kumar Sanjay S.
Published: December 2021

Glutamatergic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) receptors are implicated in diverse functions ranging from synaptic plasticity to cell death. They are heterotetrameric proteins whose subunits are derived from multiple distinct gene families. The subunit composition of these receptors determines their permeability to monovalent and/or divalent cations, but it is not entirely clear how this selectivity arises in native and recombinantly-expressed receptor populations. By analyzing the sequence of amino acids lining the selectivity filters within the pore forming membrane helices (M2) of these subunits and by correlating subunit stoichiometry of these receptors with their ability to permeate Na+ and/or Ca2+, we propose here a mathematical model for predicting cation selectivity and permeability in these receptors. The model proposed is based on principles of charge attractivity and charge neutralization within the pore forming region of these receptors; it accurately predicts and reconciles experimental data across various platforms including Ca2+ permeability of GluA2-lacking AMPARs and ion selectivity within GluN3-containing di- and tri-heteromeric NMDARs. Additionally, the model provides insights into biophysical mechanisms regulating cation selectivity and permeability of these receptors and the role of various subunits in these processes.
Efficacy and Safety of Adding Immune Checkpoint Inhibitors to Neoadjuvant Chemotherapy Against Triple-Negative Breast Cancer: A Meta-Analysis of Randomized Controlled Trials
Authors: Li Yunhai , Xing Lei , Li Fan , Liu Hong , Gan Lu , Yang Dejuan , Wang Mengxue , Yin Xuedong , Li Hongyuan , Ren Guosheng
Published: December 2021

Background

Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activity in multiple malignances including breast cancer. However, the responses can vary. This meta-analysis was conducted to evaluate the efficacy and safety profile of adding ICIs to neoadjuvant chemotherapy against triple-negative breast cancer (TNBC) and assess correlation of PD-L1 tumor status with responses.

Methods

Eligible studies were retrieved from the PubMed, Embase, and Web of Science databases. Randomized controlled trials (RCTs) that investigated ICI-containing versus ICI-free neoadjuvant therapy were included in this study. Meta-analyses were performed using Review Manager Version 5.2 software.

Results

This study included four RCTs containing 1795 patients with early TNBC. Compared with ICI-free neoadjuvant therapy, ICI-containing neoadjuvant therapy significantly increased the pathological complete response (pCR) rates in TNBC (odds ratio [OR] = 2.14, 95% confidence interval [CI]: 1.37–3.35, P < 0.001). In subgroup analysis, the addition of ICI to neoadjuvant chemotherapy was significantly associated with increased pCR rate in both PD-L1-positive TNBC (OR = 1.79, 95% CI: 1.33–2.41, P < 0.001) and PD-L1-negative TNBC (OR = 1.84, 95% CI: 1.14–2.99, P = 0.01). Patients with TNBC receiving ICI-containing neoadjuvant therapy had a better event-free survival (hazard ratio = 0.66, 95% CI: 0.48–0.89, P = 0.007) than those who receiving ICI-free neoadjuvant therapy. A significantly higher risk of adverse events including adrenal insufficiency, increased aspartate aminotransferase, dry skin, hepatitis, hyperthyroidism, hypothyroidism, infusion related reaction, pyrexia, and stomatitis was associated with ICI-containing neoadjuvant therapy.

Conclusion

ICI-containing neoadjuvant therapy significantly increased the pCR rate in TNBC patients, independently of PD-L1 status. The addition of ICI to neoadjuvant chemotherapy may be considered an option for TNBC patients.
Microscopic Extrathyroidal Extension Results in Increased Rate of Tumor Recurrence and Is an Independent Predictor of Patient’s Outcome in Middle Eastern Papillary Thyroid Carcinoma
Authors: Parvathareddy Sandeep Kumar , Siraj Abdul K. , Qadri Zeeshan , DeVera Felisa , Siddiqui Khawar , Al-Sobhi Saif S. , Al-Dayel Fouad , Al-Kuraya Khawla S.
Published: December 2021

Background

Papillary Thyroid Cancer (PTC) is the most common endocrine malignancy, with recurrence rate as high as 30%. A great deal of controversy surrounds the significance of microscopic extrathyroidal extension (m-ETE) as a prognostic factor. The most recent edition (8th) of American Joint Committee on Cancer (AJCC) staging system has removed m-ETE from the definition of pT3, which suggests that m-ETE may lack prognostic impact in PTC patients. Moreover, data about m-ETE prevalence and clinical impact on Middle Eastern PTC remains unknown. We therefore investigate the prevalence of m-ETE and its clinico-pathological correlation and prognostic impact in Middle Eastern PTC. We also compared the AJCC 7th and 8th staging systems and their prognostic performance.

Methods

PTCs from 1430 consecutive adult (> 18 years) patients from single tertiary care hospital were included in this study. A retrospective analysis of PTC patients’ survival and recurrence were compared between AJCC 8th and AJCC 7th staging systems using Proportion of Variation Explained (PVE) and Harrell’s C-index.

Results

Median follow up of the study cohort was 9.3 years. 31.2% (446/1430) of patients had m-ETE. In the overall cohort, m-ETE was associated with multiple adverse features such as older age (p < 0.0001), male sex (p = 0.0245), tall cell variant (p < 0.0001), bilateral tumors (p < 0.0001), multifocality (p < 0.0001), lymphovascular invasion (p < 0.0001), lymph node metastasis (p < 0.0001), distant metastasis (p = 0.0166), tumor recurrence (p < 0.0001), radioactive iodine refractoriness (p < 0.0001), BRAF mutation (p < 0.0001) and reduced recurrence-free survival (RFS; HR = 1.75; 95% CI = 1.30 – 2.35; p < 0.0001) irrespective of tumor size. Of the 611 patients with T3 disease based on AJCC 7th edition, 359 (58.8%) were down-staged in AJCC 8th edition classification. Overall, the prognostic performance of AJCC 8th edition was inferior to AJCC 7th on the basis of lower PVE (3.04% vs. 3.73%) and lower C-index (0.40 vs. 0.48).

Conclusions

In Middle Eastern PTC, m-ETE is significantly associated with compromised survival and acts as an independent predictor of RFS. Given these findings, m-ETE should be included in the thyroid cancer treatment guidelines.
Using Ultrasound-Based Multilayer Perceptron to Differentiate Early Breast Mucinous Cancer and its Subtypes From Fibroadenoma
Authors: Liang Ting , Shen Junhui , Zhang Shumei , Cong Shuzhen , Liu Juanjuan , Pei Shufang , Shang Shiyao , Huang Chunwang
Published: December 2021

Objectives

Mucinous breast cancer (MBC), particularly pure MBC (pMBC), often tend to be confused with fibroadenoma (FA) due to their similar images and firm masses, so some MBC cases are misdiagnosed to be FA, which may cause poor prognosis. We analyzed the ultrasonic features and aimed to identify the ability of multilayer perceptron (MLP) to classify early MBC and its subtypes and FA.

Materials and Methods

The study consisted of 193 patients diagnosed with pMBC, mMBC, or FA. The area under curve (AUC) was calculated to assess the effectiveness of age and 10 ultrasound features in differentiating MBC from FA. We used the pairwise comparison to examine the differences among MBC subtypes (pure and mixed types) and FA. We utilized the MLP to differentiate MBC and its subtypes from FA.

Results

The nine features with AUCs over 0.5 were as follows: age, echo pattern, shape, orientation, margin, echo rim, vascularity distribution, vascularity grade, and tumor size. In subtype analysis, the significant differences were obtained in 10 variables (p-value range, 0.000–0.037) among pMBC, mMBC, and FA, except posterior feature. Through MLP, the AUCs of predicting MBC and FA were both 0.919; the AUCs of predicting pMBC, mMBC, and FA were 0.875, 0.767, and 0.927, respectively.

Conclusion

Our study found that the MLP models based on ultrasonic characteristics and age can well distinguish MBC and its subtypes from FA. It may provide a critical insight into MBC preoperative clinical management.
Practical Guidelines on Implementing Hypofractionated Radiotherapy for Prostate Cancer in Africa
Authors: Swanson William , Samba Richard Ndi , Lavelle Michael , Elzawawy Ahmed , Sajo Erno , Ngwa Wilfred , Incrocci Luca
Published: December 2021

Among a growing body of literature in global oncology, several articles project increased cost savings and radiotherapy access by adopting hypofractionated radiotherapy (HFRT) in low- and middle-income countries (LMICs) like those in Africa. Clinical trials in Europe and the USA have demonstrated HFRT to be non-inferior to conventional radiotherapy for eligible patients with several cancers, including prostate cancer. This could be a highly recommended option to battle a severely large and growing cancer burden in resource-limited regions. However, a level of implementation research may be needed in limited resource-settings like in Africa. In this article, we present a list of evidence-based recommendations to practice HFRT on eligible prostate cancer patients. As literature on HFRT is still developing, these guidelines were compiled from review of several clinical trials and professionally accredited material with minimal resource requirements in mind. HFRT guidelines presented here include patient eligibility, prescription dose schedules, treatment planning and delivery techniques, and quality assurance procedures. The article provides recommendations for both moderately hypofractionated (2.4-3.4Gy per fraction) and ultrahypofractionated (5Gy or more per fraction) radiation therapy when administered by 3D-Conformal Radiotherapy, Intensity Modulated Radiation Therapy, or Image-Guided Radiotherapy. In each case radiation oncology health professionals must make the ultimate judgment to ensure safety as more LMIC centers adopt HFRT to combat the growing scourge of cancer.