bluuebunny/crossref_metadata_2025 huggingface dataset:
Supported Lipid Bilayers and the Study of Two-Dimensional Binding Kinetics
Authors: Dam Tommy , Chouliara Manto , Junghans Victoria , Jönsson Peter
Published: February 2022

Binding between protein molecules on contacting cells is essential in initiating and regulating several key biological processes. In contrast to interactions between molecules in solution, these events are restricted to the two-dimensional (2D) plane of the meeting cell surfaces. However, converting between the more commonly available binding kinetics measured in solution and the so-called 2D binding kinetics has proven a complicated task since for the latter several factors other than the protein-protein interaction per se have an impact. A few important examples of these are: protein density, membrane fluctuations, force on the bond and the use of auxiliary binding molecules. The development of model membranes, and in particular supported lipid bilayers (SLBs), has made it possible to simplify the studied contact to analyze these effects and to measure 2D binding kinetics of individual protein-protein interactions. We will in this review give an overview of, and discuss, how different SLB systems have been used for this and compare different methods to measure binding kinetics in cell-SLB contacts. Typically, the SLB is functionalized with fluorescently labelled ligands whose interaction with the corresponding receptor on a binding cell can be detected. This interaction can either be studied 1) by an accumulation of ligands in the cell-SLB contact, whose magnitude depends on the density of the proteins and binding affinity of the interaction, or 2) by tracking single ligands in the SLB, which upon interaction with a receptor result in a change of motion of the diffusing ligand. The advantages and disadvantages of other methods measuring 2D binding kinetics will also be discussed and compared to the fluorescence-based methods. Although binding kinetic measurements in cell-SLB contacts have provided novel information on how ligands interact with receptors in vivo the number of these measurements is still limited. This is influenced by the complexity of the system as well as the required experimental time. Moreover, the outcome can vary significantly between studies, highlighting the necessity for continued development of methods to study 2D binding kinetics with higher precision and ease.
Fragment-Based Drug Discovery by NMR. Where Are the Successes and Where can It Be Improved?
Authors: Mureddu Luca G. , Vuister Geerten W.
Published: February 2022

Over the last century, the definitions of pharmaceutical drug and drug discovery have changed considerably. Evolving from an almost exclusively serendipitous approach, drug discovery nowadays involves several distinct, yet sometimes interconnected stages aimed at obtaining molecules able to interact with a defined biomolecular target, and triggering a suitable biological response. At each of the stages, a wide range of techniques are typically employed to obtain the results required to move the project into the next stage. High Throughput Screening (HTS) and Fragment Based Drug Design (FBDD) are the two main approaches used to identify drug-like candidates in the early stages of drug discovery. Nuclear Magnetic Resonance (NMR) spectroscopy has many applications in FBDD and is used extensively in industry as well as in academia. In this manuscript, we discuss the paths of both successful and unsuccessful molecules where NMR had a crucial part in their development. We specifically focus on the techniques used and describe strengths and weaknesses of each stage by examining several case studies. More precisely, we examine the development history from the primary screening to the final lead optimisation of AZD3839 interacting with BACE-1, ABT-199 interacting with BCL2/XL and S64315 interacting with MCL-1. Based on these studies, we derive observations and conclusions regarding the FBDD process by NMR and discuss its potential improvements.
Time Trends in Stroke and Subtypes Mortality Attributable to Household Air Pollution in Chinese and Indian Adults: An Age-Period-Cohort Analysis Using the Global Burden of Disease Study 2019
Authors: Ma Yudiyang , Yang Donghui , Bai Jianjun , Zhao Yudi , Hu Qian , Yu Chuanhua
Published: February 2022

Household air pollution (HAP) exposure is recognized as a major health concern in areas relied on residential burning of solid fuels for cooking and heating. However, previous study has focused on mortality across time and reported changes in age-specific mortality globally but failed to distinguish cohort from period effects. Therefore, this study aimed to differentiate the relative contributions of period and cohort effects to overall time trends of HAP-attributable stroke mortality between the most presentative East and South Asia countries. Data were obtained from the Global Burden of Disease (GBD) database. The age, period, and cohort effects were estimated using the age-period-cohort (APC) model. The overall age-standardized mortality rates (ASMRs) of stroke in China decreased by 39.8% compared with 35.8% in India, while stroke subtypes in both the sexes and countries showed consecutive significant declines from 1990 to 2019. The age-specific and cohort-specific HAP-attributable stroke mortality declined over time in China and India. By APC analysis, substantially increasing age effects were presented for stroke and subtypes from 25 to 84 years. China had a rapid reduction in the independent period and cohort effects. Also, the risk of death for subarachnoid hemorrhage (SAH) had the most striking decline for both sexes in period and cohort effects. Reductions of India were less favorable than China, but the independent period and cohort effects progressively decreased during the entire period for both the sexes. Males experienced a slightly higher mortality risk than females in both countries. Although prominent reductions were observed in HAP-attributable stroke and subtypes mortality during the past 30 years, China and India still suffered uneven HAP-attributable stroke burden. Thus, it is of high significance to introduce advanced solid fuels replace technology and knowledge regarding clean fuel use.
Cuprizone Intoxication Results in Myelin Vacuole Formation
Authors: Joost Sarah , Schweiger Felix , Pfeiffer Friederike , Ertl Carolin , Keiler Jonas , Frank Marcus , Kipp Markus
Published: February 2022

Myelin damage is a histopathological hallmark of multiple sclerosis lesions. Results of post mortem studies suggest that impaired myelin-axon interaction characterized by focal myelin detachments is an early event during lesion genesis. In this study, we investigated the ultrastructural changes of the axon-myelin interface in the cuprizone model using serial block face scanning electron microscopy and immunohistochemistry. We show that non-inflammatory injury of oligodendrocytes by cuprizone intoxication results in myelin vacuole formation and axonal swellings, paralleled by early alterations of the node of Ranvier cytoarchitecture. This remarkable resemblance of ultrastructural myelin characteristics in multiple sclerosis and the cuprizone animal model suggests that the cuprizone model is a valuable tool to study early pathologies during lesion formation.
Microglia Loss and Astrocyte Activation Cause Dynamic Changes in Hippocampal [18F]DPA-714 Uptake in Mouse Models of Depression
Authors: Guo Jiamei , Qiu Tian , Wang Lixia , Shi Lei , Ai Ming , Xia Zhu , Peng Zhiping , Zheng Anhai , Li Xiao , Kuang Li
Published: February 2022

Major depression is a serious and chronic mental illness. However, its etiology is poorly understood. Although glial cells have been increasingly implicated in the pathogenesis of depression, the specific role of microglia and astrocytes in stress-induced depression remains unclear. Translocator protein (TSPO) has long been considered a marker of neuroinflammation and microglial activation. However, this protein is also present on astrocytes. Thus, it is necessary to explore the relationships between TSPO, microglia, and astrocytes in the context of depression. In this study, C57BL/6J male mice were subjected to chronic unpredictable stress (CUS) for 5 weeks. Subsequently, sucrose preference and tail suspension tests (TSTs) were performed to assess anhedonia and despair in these mice. [18F]DPA-714 positron emission tomography (PET) was adopted to dynamically assess the changes in glial cells before and 2, 4, or 5 weeks after CUS exposure. The numbers of TSPO+ cells, ionized calcium-binding adaptor molecule (Iba)-1+ microglial cells, TSPO+/Iba-1+ cells, glial fibrillary acidic protein (GFAP)+ astrocytes, TSPO+/GFAP+ cells, and TUNEL-stained microglia were quantified using immunofluorescence staining. Real-time PCR was used to evaluate interleukin (IL)-1β, IL-4, and IL-18 expression in the hippocampus. We observed that hippocampal [18F]DPA-714 uptake significantly increased after 2 weeks of CUS. However, the signal significantly decreased after 5 weeks of CUS. CUS significantly reduced the number of Iba-1+, TSPO+, and TSPO+/Iba-1+ cells in the hippocampus, especially in the CA1 and dentate gyrus (DG) subregions. However, this intervention increased the number of GFAP+ astrocytes in the CA2/CA3 subregions of the hippocampus. In addition, microglial apoptosis in the early stage of CUS appeared to be involved in microglia loss. Further, the expression of pro-inflammatory cytokines (IL-1β and IL-18) was significantly decreased after CUS. In contrast, the expression of the anti-inflammatory cytokine IL-4 was significantly increased after 2 weeks of CUS. These results suggested that the CUS-induced dynamic changes in hippocampal [18F]DPA-714 uptake and several cytokines may be due to combined microglial and astrocyte action. These findings provide a theoretical reference for the future clinical applications of TSPO PET.
Mild Traumatic Brain Injury-Induced Disruption of the Blood-Brain Barrier Triggers an Atypical Neuronal Response
Authors: Munoz-Ballester Carmen , Mahmutovic Dzenis , Rafiqzad Yusuf , Korot Alia , Robel Stefanie
Published: February 2022

Mild TBI (mTBI), which affects 75% of TBI survivors or more than 50 million people worldwide each year, can lead to consequences including sleep disturbances, cognitive impairment, mood swings, and post-traumatic epilepsy in a subset of patients. To interrupt the progression of these comorbidities, identifying early pathological events is key. Recent studies have shown that microbleeds, caused by mechanical impact, persist for months after mTBI and are correlated to worse mTBI outcomes. However, the impact of mTBI-induced blood-brain barrier damage on neurons is yet to be revealed. We used a well-characterized mouse model of mTBI that presents with frequent and widespread but size-restricted damage to the blood-brain barrier to assess how neurons respond to exposure of blood-borne factors in this pathological context. We used immunohistochemistry and histology to assess the expression of neuronal proteins in excitatory and inhibitory neurons after mTBI. We observed that the expression of NeuN, Parvalbumin, and CamKII was lost within minutes in areas with blood-brain barrier disruption. Yet, the neurons remained alive and could be detected using a fluorescent Nissl staining even 6 months later. A similar phenotype was observed after exposure of neurons to blood-borne factors due to endothelial cell ablation in the absence of a mechanical impact, suggesting that entrance of blood-borne factors into the brain is sufficient to induce the neuronal atypical response. Changes in postsynaptic spines were observed indicative of functional changes. Thus, this study demonstrates That exposure of neurons to blood-borne factors causes a rapid and sustained loss of neuronal proteins and changes in spine morphology in the absence of neurodegeneration, a finding that is likely relevant to many neuropathologies.
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase Family: Novel Prognostic Biomarkers and Tumor Microenvironment Regulators for Lower-Grade Glioma
Authors: Gong Siming , Wu Changwu , Köhler Franziska , Meixensberger Jürgen , Schopow Nikolas , Kallendrusch Sonja
Published: February 2022

Lower-grade glioma (LGG) is a group of tumors arising from the cells of the central nervous system. Although various therapy interventions are used, the prognosis remains different. Novel biomarkers are needed for the prognosis of disease and novel therapeutic strategies in LGG. The procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) family contains three members and is related to multiple cancers, yet it was not investigated in LGG. Data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) cohorts were used to analyze the role of PLOD in LGG. As the PLOD family is involved in processes, such as tumor formation and cancer metastasis, we focused on its relationship to the tumor microenvironment (TME) in LGG. A high expression of the PLOD family relates to poor prognosis and high infiltration of immune cells within the TME. The expression level of the PLOD family might become a novel biomarker for prognosis and is a potential target for individual treatment decisions in LGG.
Brain Connectometry Changes in Space Travelers After Long-Duration Spaceflight
Authors: Doroshin Andrei , Jillings Steven , Jeurissen Ben , Tomilovskaya Elena , Pechenkova Ekaterina , Nosikova Inna , Rumshiskaya Alena , Litvinova Liudmila , Rukavishnikov Ilya , De Laet Chloë , Schoenmaekers Catho , Sijbers Jan , Laureys Steven , Petrovichev Victor , Van Ombergen Angelique , Annen Jitka , Sunaert Stefan , Parizel Paul M. , Sinitsyn Valentin , zu Eulenburg Peter , Osipowicz Karol , Wuyts Floris L.
Published: February 2022

Humans undergo extreme physiological changes when subjected to long periods of weightlessness, and as we continue to become a space-faring species, it is imperative that we fully understand the physiological changes that occur in the human body, including the brain. In this study, we present findings of brain structural changes associated with long-duration spaceflight based on diffusion magnetic resonance imaging (dMRI) data. Twelve cosmonauts who spent an average of six months aboard the International Space Station (ISS) were scanned in an MRI scanner pre-flight, ten days after flight, and at a follow-up time point seven months after flight. We performed differential tractography, a technique that confines white matter fiber tracking to voxels showing microstructural changes. We found significant microstructural changes in several large white matter tracts, such as the corpus callosum, arcuate fasciculus, corticospinal, corticostriatal, and cerebellar tracts. This is the first paper to use fiber tractography to investigate which specific tracts exhibit structural changes after long-duration spaceflight and may direct future research to investigate brain functional and behavioral changes associated with these white matter pathways.
Cell-Type Specific Neuromodulation of Excitatory and Inhibitory Neurons via Muscarinic Acetylcholine Receptors in Layer 4 of Rat Barrel Cortex
Authors: Qi Guanxiao , Feldmeyer Dirk
Published: February 2022

The neuromodulator acetylcholine (ACh) plays an important role in arousal, attention, vigilance, learning and memory. ACh is released during different behavioural states and affects the brain microcircuit by regulating neuronal and synaptic properties. Here, we investigated how a low concentration of ACh (30 μM) affects the intrinsic properties of electrophysiologically and morphologically identified excitatory and inhibitory neurons in layer 4 (L4) of rat barrel cortex. ACh altered the membrane potential of L4 neurons in a heterogeneous manner. Nearly all L4 regular spiking (RS) excitatory neurons responded to bath-application of ACh with a M4 muscarinic ACh receptor-mediated hyperpolarisation. In contrast, in the majority of L4 fast spiking (FS) and non-fast spiking (nFS) interneurons 30 μM ACh induced a depolarisation while the remainder showed a hyperpolarisation or no response. The ACh-induced depolarisation of L4 FS interneurons was much weaker than that in L4 nFS interneurons. There was no clear difference in the response to ACh for three morphological subtypes of L4 FS interneurons. However, in four morpho-electrophysiological subtypes of L4 nFS interneurons, VIP+-like interneurons showed the strongest ACh-induced depolarisation; occasionally, even action potential firing was elicited. The ACh-induced depolarisation in L4 FS interneurons was exclusively mediated by M1 muscarinic ACh receptors; in L4 nFS interneurons it was mainly mediated by M1 and/or M3/5 muscarinic ACh receptors. In a subset of L4 nFS interneurons, a co-operative activation of muscarinic and nicotinic ACh receptors was also observed. The present study demonstrates that low-concentrations of ACh affect different L4 neuron types in a cell-type specific way. These effects result from a specific expression of different muscarinic and/or nicotinic ACh receptors on the somatodendritic compartments of L4 neurons. This suggests that even at low concentrations ACh may tune the excitability of L4 excitatory and inhibitory neurons and their synaptic microcircuits differentially depending on the behavioural state during which ACh is released.
ROBOCOP (ROBOtic Care of Poststroke Pain): Study Protocol for a Randomized Trial to Assess Robot-Assisted Functional and Motor Recovery and Impact on Poststroke Pain Development
Authors: Pignolo Loris , Tonin Paolo , Nicotera Pierluigi , Bagetta Giacinto , Scuteri Damiana
Published: February 2022

Background

Stroke is one of the most frequent causes of death and disability worldwide. It is accompanied by the impaired motor function of the upper extremities in over 69% of patients up to hemiplegia in the following 5 years in 56% of cases. This condition often is characterized by chronic poststroke pain, difficult to manage, further worsening quality of life. Poststroke pain occurs within 3–6 months. Robot-assisted neurorehabilitation using the Automatic Recovery Arm Motility Integrated System (ARAMIS) has proven efficacy in motor function recovery exploiting the movements and the strength of the unaffected arm. The rationale of the ROBOCOP (ROBOtic Care of Poststroke pain) randomized trial is the assessment of the impact of robot-assisted functional and motor recovery on the prevention of poststroke pain.

Methods

A total of 118 patients with hemiplegic arms due to stroke will be enrolled and randomly allocated with a 1:1 ratio to ARAMIS or conventional neurorehabilitation group. After a baseline screening at hospital discharge, ARAMIS or conventional rehabilitation will be performed for 8 weeks. The primary endpoint is the prevention of the development of poststroke pain and the secondary endpoints are prevention of spasticity and efficacy in clinical motor rehabilitation. The primary outcome measures consist in the visual analog scale and the doleur neuropatique 4 and the secondary outcome measures include: the Modified Ashworth Scale, the Resistance to Passive movement Scale; the Upper Extremity Subscale of the Fugl–Meyer Motor Assessment; the Action Research Arm Test; the Barthel Index for activities of daily living; and the magnetic resonance imaging (MRI) recovery-related parameters. After baseline, both primary and secondary outcome measures will be performed in the following time points: 1 month after stroke (t1, half of the rehabilitation); 2 months after stroke (t2, after rehabilitation); and 3 months (t3) and 6 months (t4) after stroke, critical for poststroke pain development.

Discussion

This is the first clinical trial investigating the efficacy of robot-assisted neurorehabilitation using ARAMIS on poststroke pain prevention. This study could remarkably improve the quality of life of stroke survivors.
Efficacy of Transcranial Direct Current Stimulation Over Dorsolateral Prefrontal Cortex in Patients With Minimally Conscious State
Authors: Peng Yuan , Zhao Jingpu , Lu Xiao , Dong Juntao , Zhang Shunxi , Zhang Jin , Liu Huihua , Zheng Xiuyuan , Wang Xin , Lan Yue , Yan Tiebin
Published: February 2022

Background

The treatment of patients in a minimally conscious state (MCS) remains challenging. Transcranial direct current stimulation (tDCS) is a non-invasive therapeutic method in treating neurologic diseases by regulating the cortical excitability. The aim is to investigate the effect of tDCS in patients with MCS in this study.

Methods

Eleven patients in MCS were enrolled in the study. All the patients received 5 daily sessions of 20-min sham tDCS, followed by 10 sessions of 20-min real tDCS. The anodal electrode and cathodal electrodes were placed over the left dorsolateral prefrontal cortex (DLPFC) and the right eyebrow, respectively. Assessment of Coma Recovery Scale-Revised (CRS-R) scores and resting-state functional MRI (rs-fMRI) scans was conducted three times in each patient: before tDCS (baseline, T0), post-sham tDCS at week 1 (T1), and post-real tDCS at week 2 (T2). The whole-brain functional connectivity (FC) was obtained by bilaterally computing FC from six seed regions: precuneus, middle frontal gyrus, supplemental motor area, angular gyrus, superior temporal gyrus, and occipital lobe. One-way repeated measure ANOVA was used to compare the differences of CRS-R scores and FC at T0, T1, and T2. The false discovery rate correction of p < 0.001 was adopted for controlling multiple comparisons in FC analysis.

Results

Five patients with MCS showed obvious clinical improvement represented by increased CRS-R scores post- 2-week real tDCS. The CRS-R scores did not change post- 1-week sham treatment. No side effects were reported during the study. The FC of the bilateral supplementary motor area, right angular gyrus, and right superior temporal gyrus were significantly enhanced after 2-week real tDCS compared with that after 1-week sham-tDCS. In addition, FC of bilateral occipital lobe and right precuneus were significantly enhanced post- 2-week real tDCS compared with the baseline.

Conclusion

Our findings indicated that tDCS over DLPFC could serve as a potentially effective therapy for improving the consciousness state in patients with MCS. The FC in rs-fMRI can be modulated by tDCS at both the stimulation site (left DLPFC) and the distant regions.
A Dynamic Nomogram to Predict the Risk of Stroke in Emergency Department Patients With Acute Dizziness
Authors: Bi Ying , Cao Fei
Published: February 2022

Objective

To develop a risk prediction tool for acute ischemic stroke (AIS) for patients presenting to the emergency department (ED) with acute dizziness/vertigo or imbalance.

Method

A prospective, multicenter cohort study was designed, and adult patients presenting with dizziness/vertigo or imbalance within 14 days were consecutively enrolled from the EDs of 4 tertiary hospitals between August 10, 2020, and June 10, 2021. Stroke was diagnosed by CT or MRI performed within 14 days of symptom onset. Participants were followed-up for 30 days. The least absolute shrinkage and selection operator (LASSO) logistic regression analysis was conducted to extract predictive factors that best identified patients at high risk of stroke to establish a prediction model. Model discrimination and calibration were assessed and its prediction performance was compared with the age, blood pressure, clinical features, duration, and diabetes (ABCD2) score, nystagmus scheme, and finger to nose test.

Results

In this study, 790 out of 2,360 patients were enrolled {median age, 60.0 years [interquartile range (IQR), 51–68 years]; 354 (44.8%) men}, with complete follow-up data available. AIS was identified in 80 patients. An online web service tool (https://neuroby.shinyapps.io/dynnomapp/) was developed for stroke risk prediction, including the variables of sex, trigger, isolated symptom, nausea, history of brief dizziness, high blood pressure, finger to nose test, and tandem gait test. The model exhibited excellent discrimination with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.889 (95% CI: 0.855–0.923), compared with the ABCD2 score, nystagmus scheme, and finger to nose test [0.712 (95% CI, 0.652–0.771), 0.602 (95% CI, 0.556–0.648), and 61.7 (95% CI, 0.568–0.666) respectively].

Conclusion

Our new prediction model exhibited good performance and could be useful for stroke identification in patients presenting with dizziness, vertigo, or imbalance. Further externally validation study is needed to increase the strength of our findings.
Testing the Reproducibility of the Effects of Transcranial Direct Current Stimulation: Failure to Modulate Beauty Perception by Brain Stimulation
Authors: Takahashi Kuri , Yotsumoto Yuko
Published: February 2022

Transcranial direct current stimulation (tDCS) has been recognized as a promising tool for investigating the causal relationship between specific brain areas of interest and behavior. However, the reproducibility of previous tDCS studies is often questioned because of failures in replication. This study focused on the effects of tDCS on one cognitive domain: beauty perception. To date, the modulation of beauty perception by tDCS has been shown in two studies:Cattaneo et al. (2014)andNakamura and Kawabata (2015). Here, we aimed at replicating their studies and investigating the effects of tDCS on beauty perception using the following parameters: (1) cathodal stimulation over the medial prefrontal cortex (mPFC) (Nakamura and Kawabata, 2015); (2) anodal stimulation over the left dorsolateral prefrontal cortex (lDLPFC) (Cattaneo et al., 2014). We also performed a more focal stimulation targeting the orbitofrontal cortex (OFC) to determine the optimal stimulation site for modulating beauty perception (3). Participants rated the subjectively-perceived beauty of the images before and after the tDCS administration. We divided images into four clusters according to the obtained scores in our preliminary study and examined changes in beauty ratings in each image cluster separately to exclude factors, such as stimuli attributions that may reduce tDCS effects. The results showed no strong effects of tDCS with the same parameters as in previous studies on beauty rating scores in any image cluster. Likewise, anodal stimulation over the OFC did not result in a change in rating scores. In contrast to previous studies, the current study did not corroborate the effects of tDCS on beauty perception. Our findings provide evidence regarding the recent reproducibility issue of tDCS effects and suggest the possible inflation of its effects on cognitive domains.
Electronic Cigarette Vaping Did Not Enhance the Neural Process of Working Memory for Regular Cigarette Smokers
Authors: Kim Dong-Youl , Jang Yujin , Heo Da-Woon , Jo Sungman , Kim Hyun-Chul , Lee Jong-Hwan
Published: February 2022

Background

Electronic cigarettes (e-cigs) as substitute devices for regular tobacco cigarettes (r-cigs) have been increasing in recent times. We investigated neuronal substrates of vaping e-cigs and smoking r-cigs from r-cig smokers.

Methods

Twenty-two r-cig smokers made two visits following overnight smoking cessation. Functional magnetic resonance imaging (fMRI) data were acquired while participants watched smoking images. Participants were then allowed to smoke either an e-cig or r-cig until satiated and fMRI data were acquired. Their craving levels and performance on the Montreal Imaging Stress Task and a 3-back alphabet/digit recognition task were obtained and analyzed using two-way repeated-measures analysis of variance. Regions-of-interest (ROIs) were identified by comparing the abstained and satiated conditions. Neuronal activation within ROIs was regressed on the craving and behavioral data separately.

Results

Craving was more substantially reduced by smoking r-cigs than by vaping e-cigs. The response time (RT) for the 3-back task was significantly shorter following smoking r-cigs than following vaping e-cigs (interaction: F (1, 17) = 5.3, p = 0.035). Neuronal activations of the right vermis (r = 0.43, p = 0.037, CI = [-0.05, 0.74]), right caudate (r = 0.51, p = 0.015, CI = [0.05, 0.79]), and right superior frontal gyrus (r = −0.70, p = 0.001, CI = [−0.88, −0.34]) were significantly correlated with the RT for the 3-back task only for smoking r-cigs.

Conclusion

Our findings suggest that insufficient satiety from vaping e-cigs for r-cigs smokers may be insignificant effect on working memory function.
In vivo Measurements of Electric Fields During Cranial Electrical Stimulation in the Human Brain
Authors: Wang Minmin , Feng Tao , Jiang Hongjie , Zhu Junming , Feng Wuwei , Chhatbar Pratik Y. , Zhang Jianmin , Zhang Shaomin
Published: February 2022

Cranial electrical stimulation (CES) has been applied at various current levels in both adults and children with neurological conditions with seemingly promising but somewhat inconsistent results. Stimulation-induced spatial electric fields (EFs) within a specific brain region are likely a significant contributing factor for the biological effects. Although several simulation models have been used to predict EF distributions in the brain, these models actually have not been validated by in vivo CES-induced EF measurements in the live human brain. This study directly measured the CES-induced voltage changes with implanted stereotactic-electroencephalographic (sEEG) electrodes in twenty-one epilepsy participants (16 adults and 5 children) and then compared these measured values with the simulated ones obtained from the personalized models. In addition, we further investigated the influence of stimulation frequency, intensity, electrode montage and age on EFs in parts of participants. We found both measured voltages and EFs obtained in vivo are highly correlated with the predicted ones in our cohort (Voltages: r = 0.93, p < 0.001; EFs: r = 0.73, p < 0.001). In white matter and gray matter, the measured voltages linearly increased when the stimulation intensity increased from 5 to 500 μA but showed no significant changes (averaged coefficient of variation <4.10%) with changing stimulation frequency from 0.5 to 200 Hz. Electrode montage, but not age, significantly affects the distribution of the EFs (n = 5, p < 0.01). Our in vivo measurements demonstrate that the individualized simulation model can reliably predict the CES-induced EFs in both adults and children. It also confirms that the CES-induced EFs highly depend on the electrode montages and individual anatomical features.
Spatial Stability of Functional Networks: A Measure to Assess the Robustness of Graph-Theoretical Metrics to Spatial Errors Related to Brain Parcellation
Authors: Bottino Francesca , Lucignani Martina , Pasquini Luca , Mastrogiovanni Michele , Gazzellini Simone , Ritrovato Matteo , Longo Daniela , Figà-Talamanca Lorenzo , Rossi Espagnet Maria Camilla , Napolitano Antonio
Published: February 2022

There is growing interest in studying human brain connectivity and in modelling the brain functional structure as a network. Brain network creation requires parcellation of the cerebral cortex to define nodes. Parcellation might be affected by possible errors due to inter- and intra-subject variability as a consequence of brain structural and physiological characteristics and shape variations related to ageing and diseases, acquisition noise, and misregistration. These errors could induce a knock-on effect on network measure variability. The aim of this study was to investigate spatial stability, a measure of functional connectivity variations induced by parcellation errors. We simulated parcellation variability with random small spatial changes and evaluated its effects on twenty-seven graph-theoretical measures. The study included subjects from three public online datasets. Two brain parcellations were performed using FreeSurfer with geometric atlases. Starting from these, 100 new parcellations were created by increasing the area of 30% of parcels, reducing the area of neighbour parcels, with a rearrangement of vertices. fMRI data were filtered with linear regression, CompCor, and motion correction. Adjacency matrices were constructed with 0.1, 0.2, 0.3, and 0.4 thresholds. Differences in spatial stability between datasets, atlases, and threshold were evaluated. The higher spatial stability resulted for Characteristic-path-length, Density, Transitivity, and Closeness-centrality, and the lower spatial stability resulted for Bonacich and Katz. Multivariate analysis showed a significant effect of atlas, datasets, and thresholds. Katz and Bonacich centrality, which was subject to larger variations, can be considered an unconventional graph measure, poorly implemented in the clinical field and not yet investigated for reliability assessment. Spatial stability (SS) is affected by threshold, and it decreases with increasing threshold for several measures. Moreover, SS seems to depend on atlas choice and scanning parameters. Our study highlights the importance of paying close attention to possible parcellation-related spatial errors, which may affect the reliability of functional connectivity measures.
Excitation and Inhibition Imbalance in Rett Syndrome
Authors: Li Wei
Published: February 2022

A loss of the excitation/inhibition (E/I) balance in the neural circuit has emerged as a common neuropathological feature in many neurodevelopmental disorders. Rett syndrome (RTT), a prevalent neurodevelopmental disorder that affects 1:10,000–15,000 women globally, is caused by loss-of-function mutations in the Methyl-CpG-binding Protein-2 (Mecp2) gene. E/I imbalance is recognized as the leading cellular and synaptic hallmark that is fundamental to diverse RTT neurological symptoms, including stereotypic hand movements, impaired motor coordination, breathing irregularities, seizures, and learning/memory dysfunctions. E/I balance in RTT is not homogeneously altered but demonstrates brain region and cell type specificity instead. In this review, I elaborate on the current understanding of the loss of E/I balance in a range of brain areas at molecular and cellular levels. I further describe how the underlying cellular mechanisms contribute to the disturbance of the proper E/I ratio. Last, I discuss current pharmacologic innervations for RTT and their role in modifying the E/I balance.
Working for Long Hours Is Associated With Dietary Fiber Insufficiency
Authors: Min Jeehee , Lee Dong-Wook , Kang Mo-Yeol , Myong Jun-Pyo , Kim Hyoung-Ryoul , Lee Jongin
Published: February 2022

It has been suggested that long working hours are associated with various diseases through dietary patterns. However, few studies have reported the association between working hours and dietary habits. Thus, the objective of this cross-sectional study was to explore the difference in dietary fiber intake by working hours. Data of a total of 10,760 workers in South Korea who participated in the Korea National Health and Nutrition Survey (KNHANES), a nation-wide survey, were analyzed to determine different distributions of dietary fiber insufficiency using multiple logistic regression models. Fiber insufficiency proportion was different from working hour groups. 70.1% of the total population eat fiber insufficiently. Working <40 h group showed 66.8% of fiber insufficiency. But working more than 52 h group marked 73.2% of fiber insufficiency. Logistic regression analysis of 10,760 nation-wide study participants revealed that working for 41–52 h a week (OR: 1.32, 95% CI: 1.18–1.47) and working for over 52 h a week (OR: 1.42, 95% CI: 1.25–1.62) were significantly associated with insufficient fiber intake compared to workers with standard working hours (30–40 h a week). These associations were still robust in an adjusted model, with working for 41–52 h a week (OR: 1.13, 95% CI: 1.01–1.27) and working for over 52 h (OR: 1.26, 95% CI: 1.09–1.45) showing high associations with dietary fiber insufficiency. Those with long working hours tend to have insufficient intake of dietary fiber. To promote desirable dietary habits, intervention programs on working conditions should be considered.
Psoas Muscle Index Can Be Used to Predict Long-Term Mortality in Young Male Patients With Acute-on-Chronic Liver Failure
Authors: Xu Manman , Li Tongzeng , Kong Ming , Geng Nan , Song Wenyan , Guo Guanya , Duan Zhongping , Han Ying , Chen Yu
Published: February 2022

Objective

The use of psoas muscle index (PMI) in acute-on-chronic liver failure (ACLF) has not been reported, and the aim of this study was to evaluate the predictive value of PMI for the prognosis of patients with ACLF.

Methods

In this study, male ACLF patients who underwent abdominal CT between 2015 and 2019 in our center were included to analyze the association between PMI and 1-year mortality in male ACLF patients, and subgroup analyses were performed according to age stratification (≤ 40 and >40 years).

Results

We included 116 male patients with confirmed ACLF, with a mean PMI of 5.98 ± 1.68 cm2/m2 and a 1-year mortality of 51.7% (60). Univariate COX regression analysis showed that PMI was a protective factor [hazard ratio (HR), 0.851, 95%CI: 0.734–0.987] for 1-year mortality in male patients with ACLF. Nevertheless, multivariate analysis did not find an independent relationship between PMI and 1-year mortality. Subgroup analysis by age found that adjusted for MELD score, PMI was independently associated with 1-year mortality in young (age ≤ 40 years) male patients with ACLF (HR 0.689, 95% CI: 0.496–0.958). While no effect of PMI on 1-year mortality in non-young (age > 40 years) male ACLF patients was found. Correlation analysis found that there was no significant correlation between PMI and age in young (age ≤ 40 years) male ACLF patients, but, PMI decreased with age (r = −0.246, P < 0.05) in non-young (age > 40 years) male ACLF patients.

Conclusion

PMI was found to be associated with 1-year mortality in male ACLF patients, especially in patients younger than 40 years, PMI predict 1-year mortality independent of MELD score.
Intestinal Microbiota Contributes to the Improvement of Alcoholic Hepatitis in Mice Treated With Schisandra chinensis Extract
Authors: Xiang Jun-Yan , Chi Yan-Yu , Han Jin-Xin , Shi Xinyu , Cai Yong , Xiang Hongyu , Xie Qiuhong
Published: February 2022

Alcoholic hepatitis (AH) has a high short-term mortality rate. Schisandra chinensis has the potential to ameliorate liver damage and be a source of prebiotics. We aimed to investigate whether Schisandra chinensis extract (SCE) can improve AH and the role of the small intestinal and cecal microbiota and their metabolites. UHPLC-QE-MS was used to analyze the chemical components of SCE. The chronic-plus-binge ethanol feeding model was used to induce AH in mice. 1H NMR was used to analyze intestinal metabolites. 16S rRNA-based high throughput sequencing was used to evaluate the effects of SCE on intestinal microbiota (IM). Intestinal microbiota transplantation was used to explore the role of IM in SCE treatment of AH. SCE ameliorated AH non-dose-dependently. SCE effectively improved liver inflammation and oxidative/nitrosative stress, strengthened intestinal barrier function, and regulated the composition of IM and the content of short-chain fatty acids (SCFAs) in AH mice. Samples from in vivo and in vitro SCE-altered IM improved liver status and regulated the IM. The administration of Lactobacillus plantarum and Bifidobacterium breve ameliorated AH to some extent. The administration of Enterococcus faecalis and Klebsiella oxytoca had partial beneficial effects on AH. Collectively, IM and metabolites were closely associated with the improvement of SCE on AH. The possible microbe targets were the growth inhibition of Escherichia-Shigella and the expansion of SCFA producers, such as Lactobacillus and Bifidobacterium. Schisandra chinensis can be considered as a safe and effective dietary supplement for the prevention and improvement of AH.
The Potential of Microextraction Techniques for the Analysis of Bioactive Compounds in Food
Authors: Pereira Jorge A. M. , Casado Natalia , Porto-Figueira Priscilla , Câmara José S.
Published: February 2022

For a long time, the importance of sample preparation and extraction in the analytical performance of the most diverse methodologies have been neglected. Cumbersome techniques, involving high sample and solvent volumes have been gradually miniaturized from solid-phase and liquid-liquid extractions formats and microextractions approaches are becoming the standard in different fields of research. In this context, this review is devoted to the analysis of bioactive compounds in foods using different microextraction approaches reported in the literature since 2015. But microextraction also represents an opportunity to mitigate the environmental impact of organic solvents usage, as well as lab equipment. For this reason, in the recent literature, phenolics and alkaloids extraction from fruits, medicinal herbs, juices, and coffee using different miniaturized formats of solid-phase extraction and liquid-liquid microextraction are the most popular applications. However, more ambitious analytical limits are continuously being reported and emergent sorbents based on carbon nanotubes and magnetic nanoparticles will certainly contribute to this trend. Additionally, ionic liquids and deep eutectic solvents constitute already the most recent forefront of innovation, substituting organic solvents and further improving the current microextraction approaches.
A Composite Biomarker of Derived Neutrophil–Lymphocyte Ratio and Platelet–Lymphocyte Ratio Correlates With Outcomes in Advanced Gastric Cancer Patients Treated With Anti-PD-1 Antibodies
Authors: Pan Yuting , Si Haiyan , Deng Guochao , Chen Shiyun , Zhang Nan , Zhou Qian , Wang ZhiKuan , Dai Guanghai
Published: February 2022

Background

The highly heterogeneous characteristics of GC may limit the accuracy of a single biomarker for screening populations benefiting from immunotherapy. However, the combination of multiple indicators can provide more directed information for the detection of potential immune benefit subgroups. At present, there are no recognized complex indexes to identify advanced GC (AGC) in patients who likely benefited from immunotherapy. The objective of this research is to explore whether the composite biomarker of derived neutrophil–lymphocyte ratio (dNLR) and platelet–lymphocyte ratio (PLR) can be used as a reliable prognostic factor for the survival of AGC patients receiving immunotherapy.

Methods

From December 2014 to May 2021, a total 238 AGC patients at a single Center were included in this retrospective cohort research study. The cutoff value of dNLR was obtained by the ROC curves to predict the disease progression rate at the 8th month and the cutoff value of PLR was estimated by the median value. The cutoff values of dNLR and PLR were 1.95 and 163.63, respectively. The high levels of dNLR (≥1.95) and PLR (≥163.63) were considered to be risk factors. Based on these two risk factors, patients were categorized into 3 groups: the risk factor number for the “good” group was 0, that for the “intermediate” group was 1, and that for the “poor” group was 2. The subjects were divided into two groups: dNLR/PLR-good and dNLR/PLR-intermediate/poor.

Results

Of the 238 patients, the median overall survival (mOS) and progression-free survival (mPFS) were 12.5 and 4.7 months, respectively. Multivariate analysis revealed that the good dNLR/PLR group was independently associated with better prognosis. The intermediate/poor dNLR/PLR group was independently correlated with an over 1.4 times greater risk of disease progression (4.1 months vs. 5.5 months; p = 0.016) and an over 1.54 times greater risk of death (11.1 months vs. 26.3 months; p = 0.033) than the good dNLR/PLR group. However, no clear differences in the disease control rate (DCR) and overall response rate (ORR) were observed between the intermediate/poor dNLR/PLR group and the good dNLR/PLR group (51.5% vs. 56.3%, 26.3% vs. 29.6%; p = 0.494, p = 0.609).

Conclusion

Our study firstly verifies that the composite biomarker of dNLR and PLR is an independent prognostic factor affecting survival of advanced AGC patients receiving immunotherapy. It may be difficult for patients with the intermediate/poor dNLR/PLR group to benefit from immunotherapy.
Management Strategies for Large Brain Metastases
Authors: Sarmey Nehaw , Kaisman-Elbaz Tehila , Mohammadi Alireza M.
Published: February 2022

Brain metastases represent the most common intracranial neoplasm and pose a significant disease burden on the individual and the healthcare system. Although whole brain radiation therapy was historically a first line approach, subsequent research and technological advancements have resulted in a larger armamentarium of strategies for treatment of these patients. While chemotherapeutic options remain limited, surgical resection and stereotactic radiosurgery, as well as their combination therapies, have shifted the paradigms for managing intracranial metastatic disease. Ultimately, no single treatment is shown to be consistently effective across patient groups in terms of overall survival, local and distant control, neurocognitive function, and performance status. However, close consideration of patient and tumor characteristics may help delineate more favorable treatment strategies for individual patients. Here the authors present a review of the recent literature surrounding surgery, whole brain radiation therapy, stereotactic radiosurgery, and combination approaches.
Treatment Modality for Stage IB Peripheral Non-Small Cell Lung Cancer With Visceral Pleural Invasion and ≤3 cm in Size
Authors: Huang Weijia , Deng Han-Yu , Lin Ming-Ying , Xu Kai , Zhang Yu-Xiao , Yuan Chi , Zhou Qinghua
Published: February 2022

Purpose

To compare the survival difference among lobectomy, segmentectomy, and wedge resection and investigate the role of adjuvant chemotherapy for early-stage small-sized non-small cell lung cancer (NSCLC) with visceral pleural invasion (VPI).

Methods

Patients diagnosed with stage IB peripheral NSCLC with VPI and ≤3 cm in size in the Surveillance, Epidemiology, and End Results database between 2004 and 2015 were included, and the pleural layer (PL) invasion status was identified to recognize the tumors with VPI, including PL1 and PL2. We conducted Cox proportional hazards model in multivariable analysis and subgroup analysis via propensity score matching (PSM) method and Cox regression method to figure out the optimal therapy for these patients.

Results

A total of 1,993 patients were included, all of whom received surgery, and the median follow-up was 33 months (range, 1–83 months). In multivariable analysis, age, gender, histology, pathological grade, lymph node examination, surgical approaches, and radiotherapy were independent prognostic factors for overall survival (OS). Lobectomy was superior to sublobar resection [hazard ratio (HR) = 1.41; 95% CI, 1.08–1.83], and wedge resection was associated with impaired survival compared to lobectomy (HR = 1.64; 95% CI, 1.22–2.20) in PSM analyses. In subgroup analysis, lobectomy was superior to sublobar resection among those aged <70 years (HR = 1.81; 95% CI, 1.13–2.90), female (HR = 1.75; 95% CI, 1.21–2.53), and 1–20 mm in size (HR = 1.61; 95% CI, 1.11–2.33). No survival benefit was observed for adjuvant chemotherapy.

Conclusions

Lobectomy was superior to wedge resection and comparable with segmentectomy for stage IB NSCLC (≤3 cm) with VPI, and adjuvant chemotherapy could not benefit these patients, even in those with sublobar resection. The preferred surgical procedure remains to be studied in prospective controlled trials.