bluuebunny/crossref_metadata_2025 huggingface dataset:
Cannabigerol Effect on Streptococcus mutans Biofilms—A Computational Approach to Confocal Image Analysis
Authors: Aqawi Muna , Steinberg Doron , Feuerstein Osnat , Friedman Michael , Gingichashvili Sarah
Published: April 2022

Biofilms are complex bacterial structures in which bacterial cells thrive as a community. Many bacterial species, including pathogens, form biofilms of high complexity and adaptability to a wide range of environmental conditions. One example of these is Streptococcus mutans, a gram-positive bacterium that has been associated with caries. Cannabigerol, a non-psychoactive cannabinoid, has been shown to affect S. mutans biofilms. In order to better characterize the effect of cannabigerol on biofilms of S. mutans, this paper provides a series of computational assays for biofilm analysis, applied on confocal images of S. mutans biofilms treated with cannabigerol. Confocal images are ubiquitous in biofilm analysis—they are often used to visualize the complex structure and molecular composition of biofilm macrocolonies. In this article, we demonstrate how confocal imaging data can be used to reveal more comprehensive insights into biofilm structure and measure specific anti-biofilm effects. This is accomplished by a series of computational assays, each focusing on a different aspect of biofilm structure.
Fungal Microbiota Dysbiosis and Ecological Alterations in Gastric Cancer
Authors: Yang Ping , Zhang Xiaoshan , Xu Rui , Adeel Khan , Lu Xiaofeng , Chen Min , Shen Han , Li Zhiyang , Xu Zhipeng
Published: April 2022

Changes in bacteriome composition have a strong association with gastric cancer (GC). However, the relationship between stomach fungal microbiota composition and human host immune factors remains largely unknown. With high-throughput internal transcribed spacer region 2 (ITS2) sequencing, we characterized gastric fungal microbiome among the GC (n = 22), matched para-GC (n = 22), and healthy individuals (n = 11). A total of 4.5 million valid tags were generated and stratified into 1,631 operational taxonomic units (OTUs), and 10 phyla and 301 genera were identified. The presence of GC was associated with a distinct gastric fungal mycobiome signature, characterized by a decreased biodiversity and richness and significant differences in fungal composition. In addition, fungal dysbiosis was reflected by the increased ratio of Basidiomycota to Ascomycota and a higher proportion of opportunistic fungi, such as Cutaneotrichosporon and Malassezia, as well as the loss of Rhizopus and Rhodotorula during the progression of cancers. A panel of GC-associated fungi (e.g., Cutaneotrichosporon and Rhodotorula) was found to adequately exhibit diagnostic value. Furthermore, the mRNA levels of cytokines and chemokines were detected and correlated with the specific fungal dysbiosis, indicating the possible mechanism of GC. This study reveals GC-associated mycobiome dysbiosis characterized by altered fungal composition and ecology and suggests that the fungal mycobiome might play a role in the pathogenesis of GC.
Retrieving the in vivo Scopoletin Fluorescence Excitation Band Allows the Non-invasive Investigation of the Plant–Pathogen Early Events in Tobacco Leaves
Authors: Agati Giovanni , Brunetti Cecilia , Tuccio Lorenza , Degano Ilaria , Tegli Stefania
Published: April 2022

In this study, we developed and applied a new spectroscopic fluorescence method for the in vivo detection of the early events in the interaction between tobacco (Nicotiana tabacum L.) plants and pathogenic bacteria. The leaf disks were infiltrated with a bacterial suspension in sterile physiological solution (SPS), or with SPS alone as control. The virulent Pseudomonas syringae pv. tabaci strain ATCC 11528, its non-pathogenic ΔhrpA mutant, and the avirulent P. syringae pv. tomato strain DC3000 were used. At different post-infiltration time–points, the in vivo fluorescence spectra on leaf disks were acquired by a fiber bundle-spectrofluorimeter. The excitation spectra of the leaf blue emission at 460 nm, which is mainly due to the accumulation of coumarins following a bacterial infiltration, were processed by using a two-bands Gaussian fitting that enabled us to isolate the scopoletin (SCT) contribution. The pH-dependent fluorescence of SCT and scopolin (SCL), as determined by in vitro data and their intracellular localization, as determined by confocal microscopy, suggested the use of the longer wavelength excitation band at 385 nm of 460 nm emission (F385_460) to follow the metabolic evolution of SCT during the plant–bacteria interaction. It was found to be directly correlated (R2 = 0.84) to the leaf SCT content, but not to that of SCL, determined by HPLC analysis. The technique applied to the time-course monitoring of the bacteria–plant interaction clearly showed that the amount and the timing of SCT accumulation, estimated by F385_460, was correlated with the resistance to the pathogen. As expected, this host defense response was delayed after P. syringae pv. tabaci ATCC 11528 infiltration, in comparison to P. syringae pv. tomato DC3000. Furthermore, no significant increase of F385_460 (SCT) was observed when using the non-pathogenic ΔhrpA mutant of P. syringae pv. tabaci ATCC 11528, which lacks a functional Type Three Secretion System (TTSS). Our study showed the reliability of the developed fluorimetric method for a rapid and non-invasive monitoring of bacteria-induced first events related to the metabolite-based defense response in tobacco leaves. This technique could allow a fast selection of pathogen-resistant cultivars, as well as the on-site early diagnosis of tobacco plant diseases by using suitable fluorescence sensors.
Comprehensive Analysis of mTORC1 Signaling Pathway–Related Genes in the Prognosis of HNSCC and the Response to Chemotherapy and Immunotherapy
Authors: Ding Zhao , Shen Hailong , Xu Ke , Wu Yu , Wang Shuhao , Yi Fangzheng , Wang Daming , Liu Yehai
Published: April 2022

Objective: The mammalian target of the rapamycin complex 1 (mTORC1) signaling pathway has emerged as a crucial player in the oncogenesis and development of head and neck squamous cell carcinoma (HNSCC), however, to date, no relevant gene signature has been identified. Therefore, we aimed to construct a novel gene signature based on the mTORC1 pathway for predicting the outcomes of patients with HNSCC and their response to treatment.

Methods: The gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The key prognostic genes associated with the mTORC1 pathway were screened by univariate Cox regression analyses. A prognostic signature was then established based on significant factors identified in the multivariate Cox regression analysis. The performance of the multigene signature was evaluated by the Kaplan–Meier (K–M) survival analysis and receiver operating characteristic (ROC) analysis. Based on the median risk score, patients were categorized into high- and low-risk groups. Subsequently, a hybrid prognostic nomogram was constructed and estimated by a calibration plot and decision curve analysis. Furthermore, immune cell infiltration and therapeutic responses were compared between the two risk groups. Finally, we measured the expression levels of seven genes by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC).

Results: The mTORC1 pathway–based signature was constructed using the seven identified genes (SEC11A, CYB5B, HPRT1, SLC2A3, SC5D, CORO1A, and PIK3R3). Patients in the high-risk group exhibited a lower overall survival (OS) rate than those in the low-risk group in both datasets. Through the univariate and multivariate Cox regression analyses, this gene signature was confirmed to be an independent prognostic risk factor for HNSCC. The constructed nomogram based on age, American Joint Committee on Cancer (AJCC) stage, and the risk score exhibited satisfactory performance in predicting the OS. In addition, immune cell infiltration and chemotherapeutic and immunotherapeutic responses differed significantly between the two risk groups. The expression levels of SEC11A and CYB5B were higher in HNSCC tissues than in normal tissues.

Conclusion: Our study established and verified an mTORC1 signaling pathway–related gene signature that could be used as a novel prognostic factor for HNSCC.
A Simple and Sensitive UPLC–UV Method for Simultaneous Determination of Isoniazid, Pyrazinamide, and Rifampicin in Human Plasma and Its Application in Therapeutic Drug Monitoring
Authors: Jiang Zhimei , Huang Liang , Zhang Lingli , Yu Qin , Lin Yunzhu , Fei Haotian , Shen Hongxin , Huang Hong
Published: April 2022

As the first-line clinical drugs for tuberculosis (TB), isoniazid (INH), pyrazinamide (PZA), and rifampicin (RMP) are playing important roles for preventing the rapid spread of TB. Precise quantification of these drugs in biological samples is crucial to evaluate or improve the efficacy of advanced TB drug delivery systems, which are designed for reducing drug resistance, minimizing side effects, etc. Herein, a simple and sensitive method based on UPLC–UV was established and investigated for simultaneous quantification of PZA, INH, and RMP in human plasma and was applied to anti-TB drug therapeutic drug monitoring. The analytes were implemented on an HSS T3 C18 column at 40°C. The separation was performed with a gradient elution with methanol–acetonitrile–water (3:3:94) at 0.1 ml/min. The analysis only involved plasma with a small volume of 100 µL and a rapid one-step protein precipitation with methanol–acetonitrile (1:1). The results showed that the calibration curves for INH, PZA, and RMP were linear in a range of 0.5–20 μg/ml, 5–60 μg/ml, and 5–60 μg/ml, respectively. The intra- and inter-day precisions were both smaller than 15%, and the lower limit of quantitation (LLOQ) was identifiable and reproducible at 0.5 μg/ml for INH and 5 μg/ml for both PZA and RMP, respectively. The target drugs in plasma were stable after 21 days of storage at −80°C. The results indicated that our developed method is suitable for the simultaneous monitoring of INH, PZA, and RMP in human plasma.
Toward Novel [18F]Fluorine-Labeled Radiotracers for the Imaging of α-Synuclein Fibrils
Authors: Uzuegbunam Bright C. , Li Junhao , Paslawski Wojciech , Weber Wolfgang , Svenningsson Per , Ågren Hans , Yousefi Behrooz Hooshyar
Published: April 2022

The accumulation of α-synuclein aggregates (α-syn) in the human brain is an occurrence common to all α-synucleinopathies. Non-invasive detection of these aggregates in a living brain with a target-specific radiotracer is not yet possible. We have recently discovered that the inclusion of a methylenedioxy group in the structure of diarylbisthiazole (DABTA)-based tracers improves binding affinity and selectivity to α-syn. Subsequently, complementary in silico modeling and machine learning (ML) of tracer–protein interactions were employed to predict surface sites and structure–property relations for the binding of the ligands. Based on this observation, we developed a small focused library of DABTAs from which 4-(benzo[d][1,3]dioxol-5-yl)-4′-(3-[18F]fluoro-4-methoxyphenyl)-2,2′-bithiazole [18F]d2, 6-(4′-(3-[18F]fluoro-4-methoxyphenyl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [18F]d4, 4-(benzo [d][1,3]dioxol-5-yl)-4′-(6-[18F]fluoropyridin-3-yl)-2,2′-bithiazole [18F]d6, and 6-(4′-(6-[18F]fluoropyridin-3-yl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [18F]d8 were selected based on their high binding affinity to α-syn and were further evaluated. Binding assay experiments carried out with the non-radioactive versions of the above tracers d2, d4, d6, and d8 showed high binding affinity of the ligands to α-syn: 1.22, 0.66, 1.21, and 0.10 nM, respectively, as well as excellent selectivity over β-amyloid plaques (Aβ) and microtubular tau aggregates (>200-fold selectivity). To obtain the tracers, their precursors were radiolabeled either via an innovative ruthenium-mediated (SNAr) reaction ([18F]d2 and [18F]d4) or typical SNAr reaction ([18F]d6 and [18F]d8) with moderate-to-high radiochemical yields (13% – 40%), and high molar activity > 60 GBq/μmol. Biodistribution experiments carried out with the tracers in healthy mice revealed that [18F]d2 and [18F]d4 showed suboptimal brain pharmacokinetics: 1.58 and 4.63 %ID/g at 5 min post-injection (p.i.), and 1.93 and 3.86 %ID/g at 60 min p.i., respectively. However, [18F]d6 and [18F]d8 showed improved brain pharmacokinetics: 5.79 and 5.13 %ID/g at 5 min p.i.; 1.75 and 1.07 %ID/g at 60 min p.i.; and 1.04 and 0.58 %ID/g at 120 min p.i., respectively. The brain uptake kinetics of [18F]d6 and [18F]d8 were confirmed in a dynamic PET study. Both tracers also showed no brain radiometabolites at 20 min p.i. in initial in vivo stability experiments carried out in healthy mice. [18F]d8 seems very promising based on its binding properties and in vivo stability, thus encouraging further validation of its usefulness as a radiotracer for the in vivo visualization of α-syn in preclinical and clinical settings. Additionally, in silico and ML-predicted values correlated with the experimental binding affinity of the ligands.
Microglia-Dependent and Independent Brain Cytoprotective Effects of Mycophenolate Mofetil During Neuronal Damage
Authors: Kleine Joshua , Hohmann Urszula , Hohmann Tim , Ghadban Chalid , Schmidt Miriam , Laabs Sebastian , Alessandri Beat , Dehghani Faramarz
Published: April 2022

Acute lesions of the central nervous system often lead to permanent limiting deficits. In addition to the initial primary damage, accompanying neuroinflammation is responsible for progression of damage. Mycophenolate mofetil (MMF) as a selective inhibitor of inosine 5-monophosphate dehydrogenase (IMPDH) was shown to modulate the inflammatory response and promote neuronal survival when applied in specific time windows after neuronal injury. The application of brain cytoprotective therapeutics early after neuronal damage is a fundamental requirement for a successful immunomodulation approach. This study was designed to evaluate whether MMF can still mediate brain cytoprotection when applied in predefined short time intervals following CNS injury. Furthermore, the role of microglia and changes in IMPDH2 protein expression were assessed. Organotypic hippocampal slice cultures (OHSC) were used as anin vitromodel and excitotoxically lesioned withN-methyl-aspartate (NMDA). Clodronate (Clo) was used to deplete microglia and analyze MMF mediated microglia independent effects. The temporal expression of IMPDH2 was studied in primary glial cell cultures treated with lipopolysaccharide (LPS). In excitotoxically lesioned OHSC a significant brain cytoprotective effect was observed between 8 and 36 h but not within 8 and 24 h after the NMDA damage. MMF mediated effects were mainly microglia dependent at 24, 36, 48 h after injury. However, further targets like astrocytes seem to be involved in protective effects 72 h post-injury. IMPDH2 expression was detected in primary microglia and astrocyte cell cultures. Our data indicate that MMF treatment in OHSC should still be started no later than 8–12 h after injury and should continue at least until 36 h post-injury. Microglia seem to be an essential mediator of the observed brain cytoprotective effects. However, a microglia-independent effect was also found, indicating involvement of astrocytes.
Effects of the Intermittent Theta Burst Stimulation of the Cerebellar Vermis on Balance Recovery After Stroke: A Study Protocol for a Randomized Controlled Trial
Authors: Wang Lin , Huang Guilan , Zhang Li , Yang Jinyu , Ren Caili , Liang Chengpan , Shen Ying , Su Bin
Published: April 2022

Background

The recovery of balance function is a critical segment in the rehabilitation treatment of stroke. The cerebellum is considered as the key structure involved in balance and motor control. The cerebellar vermis plays an important role in integrating vision, proprioception, and sensory skin input and may be a candidate stimulation target for regulating the motor network related with balance. However, evidence that the intermittent theta burst stimulation (iTBS) of cerebellar vermis can promote the recovery of balance function after stroke remains insufficient. Therefore, this study aims to explore the efficacy of the cerebellar vermis iTBS for the treatment of balance function in patients with stroke.

Methods and Analysis

Forty patients with stroke will be recruited in this prospective, randomized, sham-controlled trial. Participants will be randomized in a 1:1 ratio to receive either 15 sessions of cerebellar vermis iTBS (600 pulses) or sham stimulation. Additionally, a routine rehabilitation therapy follows the intervention. The primary outcome is the Berg Balance Scale, and the secondary outcomes are the Fugl–Meyer assessment of the lower extremity and modified Barthel index. The above outcomes will be assessed before intervention and at the end of each week. Pre- and post-iTBS resting-state functional magnetic resonance imaging (rs-fMRI) will be acquired, and the regional homogeneity, fractional amplitude of low-frequency fluctuation and functional connectivity will be calculated and analyzed.

Discussion

This protocol holds promise as a potential method to improve balance function in patients with stroke. If the outcomes of patients improve after the intervention, the study will provide new insights into improving balance function.

Ethics and Dissemination

This study has been approved by the Medical Research Ethics Committee of Wuxi Mental Health Center (Wuxi Tongren Rehabilitation Hospital). Results will be disseminated through (open-access) peer-reviewed publications, networks of scientists, professionals, and the public and presented at conferences.

Clinical Trial Registration Number

www.chictr.org.cn, identifier ChiCTR2100052590.
Melatonin as a Potential Neuroprotectant: Mechanisms in Subarachnoid Hemorrhage-Induced Early Brain Injury
Authors: Xu Chengyan , He Zixia , Li Jiabin
Published: April 2022

Subarachnoid hemorrhage (SAH) is a common cerebrovascular disease with high mortality and disability rates. Despite progressive advances in drugs and surgical techniques, neurological dysfunction in surviving SAH patients have not improved significantly. Traditionally, vasospasm has been considered the main cause of death and disability following SAH, but anti-vasospasm therapy has not benefited clinical prognosis. Many studies have proposed that early brain injury (EBI) may be the primary factor influencing the prognosis of SAH. Melatonin is an indole hormone and is the main hormone secreted by the pineal gland, with low daytime secretion levels and high nighttime secretion levels. Melatonin produces a wide range of biological effects through the neuroimmune endocrine network, and participates in various physiological activities in the central nervous system, reproductive system, immune system, and digestive system. Numerous studies have reported that melatonin has extensive physiological and pharmacological effects such as anti-oxidative stress, anti-inflammation, maintaining circadian rhythm, and regulating cellular and humoral immunity. In recent years, more and more studies have been conducted to explore the molecular mechanism underlying melatonin-induced neuroprotection. The studies suggest beneficial effects in the recovery of intracerebral hemorrhage, cerebral ischemia-reperfusion injury, spinal cord injury, Alzheimer’s disease, Parkinson’s disease and meningitis through anti-inflammatory, antioxidant and anti-apoptotic mechanisms. This review summarizes the recent studies on the application and mechanism of melatonin in SAH.
Association of Two Opposing Responses Results in the Emergence of a Novel Conditioned Response
Authors: Pribic Micaela R. , Black Aristide H. , Beale Asia D. , Gauvin Jessica A. , Chiang Lisa N. , Rose Jacqueline K.
Published: April 2022

Recent studies examining association of opposing responses, contrasting emotional valences, or counter motivational states have begun to elucidate how learning and memory processes can translate to clinical therapies for trauma or addiction. In the current study, association of opposing responses is tested in C. elegans. Due to its relatively simple and well-described nervous system, it was hypothesized that association of two oppositional stimuli presented in a delayed conditioning protocol would strengthen the behavioral response to the first stimulus (alpha conditioning). To test this, C. elegans were exposed to a tone vibration stimulus (to activate a mechanosensory-driven locomotor reversal response) paired with a blue light (to activate a forward locomotor response) at a 2-s delay. After five pairings, behavior was measured following a tone-alone stimulus. Worms that received stimulus pairing did not show an enhanced response to the first presented stimulus (tone vibration) but rather showed a marked increase in time spent in pause (cessation of movement), a new behavioral response (beta conditioning). This increase in pause behavior was accompanied by changes in measures of both backward and forward locomotion. Understanding the dynamics of conditioned behavior resulting from pairing of oppositional responses could provide further insight into how learning processes occur and may be applied.
Avoiding Catastrophe: Active Dendrites Enable Multi-Task Learning in Dynamic Environments
Authors: Iyer Abhiram , Grewal Karan , Velu Akash , Souza Lucas Oliveira , Forest Jeremy , Ahmad Subutai
Published: April 2022

A key challenge for AI is to build embodied systems that operate in dynamically changing environments. Such systems must adapt to changing task contexts and learn continuously. Although standard deep learning systems achieve state of the art results on static benchmarks, they often struggle in dynamic scenarios. In these settings, error signals from multiple contexts can interfere with one another, ultimately leading to a phenomenon known as catastrophic forgetting. In this article we investigate biologically inspired architectures as solutions to these problems. Specifically, we show that the biophysical properties of dendrites and local inhibitory systems enable networks to dynamically restrict and route information in a context-specific manner. Our key contributions are as follows: first, we propose a novel artificial neural network architecture that incorporates active dendrites and sparse representations into the standard deep learning framework. Next, we study the performance of this architecture on two separate benchmarks requiring task-based adaptation: Meta-World, a multi-task reinforcement learning environment where a robotic agent must learn to solve a variety of manipulation tasks simultaneously; and a continual learning benchmark in which the model's prediction task changes throughout training. Analysis on both benchmarks demonstrates the emergence of overlapping but distinct and sparse subnetworks, allowing the system to fluidly learn multiple tasks with minimal forgetting. Our neural implementation marks the first time a single architecture has achieved competitive results in both multi-task and continual learning settings. Our research sheds light on how biological properties of neurons can inform deep learning systems to address dynamic scenarios that are typically impossible for traditional ANNs to solve.
Current Challenges and Future Directions in Handling Stroke Patients With Patent Foramen Ovale—A Brief Review
Authors: Huber Charlotte , Wachter Rolf , Pelz Johann , Michalski Dominik
Published: April 2022

The role of patent foramen ovale (PFO) in stroke was debated for decades. Randomized clinical trials (RCTs) have shown fewer recurrent events after PFO closure in patients with cryptogenic stroke (CS). However, in clinical practice, treating stroke patients with coexisting PFO raises some questions. This brief review summarizes current knowledge and challenges in handling stroke patients with PFO and identifies issues for future research. The rationale for PFO closure was initially based on the concept of paradoxical embolism from deep vein thrombosis (DVT). However, RCTs did not consider such details, limiting their impact from a pathophysiological perspective. Only a few studies explored the coexistence of PFO and DVT in CS with varying results. Consequently, the PFO itself might play a role as a prothrombotic structure. Transesophageal echocardiography thus appears most appropriate for PFO detection, while a large shunt size or an associated atrial septum aneurysm qualify for a high-risk PFO. For drug-based treatment alone, studies did not find a definite superiority of oral anticoagulation over antiplatelet therapy. Remarkably, drug-based treatment in addition to PFO closure was not standardized in RCTs. The available literature rarely considers patients with transient ischemic attack (TIA), over 60 years of age, and competing etiologies like atrial fibrillation. In summary, RCTs suggest efficacy for closure of high-risk PFO only in a small subgroup of stroke patients. However, research is also needed to reevaluate the pathophysiological concept of PFO-related stroke and establish strategies for older and TIA patients and those with competing risk factors or low-risk PFO.
Case Report: Acute Necrotizing Encephalopathy Following COVID-19 Vaccine
Authors: Bensaidane Mohamed Reda , Picher-Martel Vincent , Émond François , De Serres Gaston , Dupré Nicolas , Beauchemin Philippe
Published: April 2022

Objectives

Acute necrotizing encephalopathy (ANE) is a rare neurological disorder arising from a para- or post-infectious “cytokine storm. ”It has recently been reported in association with coronavirus disease 2019 (COVID-19) infection.

Methods

A 56-year-old male with a diagnosis of ANE 48 h following the first dose of ChAdOx1 nCoV-19 vaccination was investigated. Cytokine analyses on serum and cerebrospinal fluid (CSF) were performed. The patient was treated with high-dose corticosteroids and followed clinically and radiologically.

Results

Favorable clinical and radiological outcomes were noted. There was an upregulation in serum levels of CXCL5, CXCL1, Il-8, IL-15, CCL2, TGF-B, and EGF, and up-regulation in CSF levels of CXCL5, IL-2, IL-3, and IL-8.

Discussion

As COVID-19 infection has been previously reported as a possible rare cause of ANE, we speculate on an aberrant immune response mechanism that was brought about by the vaccine. To increase our understanding of the pathogenesis of ANE in the context of COVID-19 vaccination and to better define its clinical features and outcomes, clinicians and scientists should continue reporting convincing cases of such entities.
Neural Synchrony and Network Dynamics in Social Interaction: A Hyper-Brain Cell Assembly Hypothesis
Authors: Müller Viktor
Published: April 2022

Mounting neurophysiological evidence suggests that interpersonal interaction relies on continual communication between cell assemblies within interacting brains and continual adjustments of these neuronal dynamic states between the brains. In this Hypothesis and Theory article, a Hyper-Brain Cell Assembly Hypothesis is suggested on the basis of a conceptual review of neural synchrony and network dynamics and their roles in emerging cell assemblies within the interacting brains. The proposed hypothesis states that such cell assemblies can emerge not only within, but also between the interacting brains. More precisely, the hyper-brain cell assembly encompasses and integrates oscillatory activity within and between brains, and represents a common hyper-brain unit, which has a certain relation to social behavior and interaction. Hyper-brain modules or communities, comprising nodes across two or several brains, are considered as one of the possible representations of the hypothesized hyper-brain cell assemblies, which can also have a multidimensional or multilayer structure. It is concluded that the neuronal dynamics during interpersonal interaction is brain-wide, i.e., it is based on common neuronal activity of several brains or, more generally, of the coupled physiological systems including brains.
Paradoxical Hyperexcitability in Disorders of Neurodevelopment
Authors: Antoine Michelle W.
Published: April 2022

Autism Spectrum Disorder (ASD), Rett syndrome (RTT) and Angelman Syndrome (AS) are neurodevelopmental disorders (NDDs) that share several clinical characteristics, including displays of repetitive movements, developmental delays, language deficits, intellectual disability, and increased susceptibility to epilepsy. While several reviews address the biological basis of non-seizure-related ASD phenotypes, here, I highlight some shared biological mechanisms that may contribute to increased seizure susceptibility. I focus on genetic studies identifying the anatomical origin of the seizure phenotype in loss-of-function, monogenic, mouse models of these NDDs, combined with insights gained from complementary studies quantifying levels of synaptic excitation and inhibition. Epilepsy is characterized by a sudden, abnormal increase in synchronous activity within neuronal networks, that is posited to arise from excess excitation, largely driven by reduced synaptic inhibition. Primarily for this reason, elevated network excitability is proposed to underlie the causal basis for the ASD, RTT, and AS phenotypes. Although, mouse models of these disorders replicate aspects of the human condition, i.e., hyperexcitability discharges or seizures on cortical electroencephalograms, measures at the synaptic level often reveal deficits in excitatory synaptic transmission, rather than too much excitation. Resolving this apparent paradox has direct implications regarding expected outcomes of manipulating GABAergic tone. In particular, in NDDs associated with seizures, cortical circuits can display reduced, rather than normal or increased levels of synaptic excitation, and therefore suggested treatments aimed at increasing inhibition could further promote hypoactivity instead of normality. In this review, I highlight shared mechanisms across animal models for ASD, RTT, and AS with reduced synaptic excitation that nevertheless promote hyperexcitability in cortical circuits.
Revealing the Impact of Mitochondrial Fitness During Early Neural Development Using Human Brain Organoids
Authors: Romero-Morales Alejandra I. , Gama Vivian
Published: April 2022

Mitochondrial homeostasis -including function, morphology, and inter-organelle communication- provides guidance to the intrinsic developmental programs of corticogenesis, while also being responsive to environmental and intercellular signals. Two- and three-dimensional platforms have become useful tools to interrogate the capacity of cells to generate neuronal and glia progeny in a background of metabolic dysregulation, but the mechanistic underpinnings underlying the role of mitochondria during human neurogenesis remain unexplored. Here we provide a concise overview of cortical development and the use of pluripotent stem cell models that have contributed to our understanding of mitochondrial and metabolic regulation of early human brain development. We finally discuss the effects of mitochondrial fitness dysregulation seen under stress conditions such as metabolic dysregulation, absence of developmental apoptosis, and hypoxia; and the avenues of research that can be explored with the use of brain organoids.
The Association of Nutritional Risk Screening 2002 With 1-Year Re-hospitalization and the Length of Initial Hospital Stay in Patients With Heart Failure
Authors: Chen Zhezhe , Jiang Hangpan , He Wujian , Li Duanbin , Lin Maoning , Wang Min , Shang Min , Zhang Wenbin
Published: April 2022

Backgrounds and Aims

Nutritional Risk Screening 2002 (NRS-2002) has been widely recommended for identifying the nutritional risk. However, the association between NRS-2002 and the prognosis of heart failure has not been fully addressed. This study aimed to explore the association of NRS-2002 with 1-year re-hospitalization and the length of initial hospital stay in heart failure patients.

Methods

This retrospective study included 2,830 heart failure patients. The primary endpoint was 1-year re-hospitalization for heart failure. The secondary endpoint was the length of initial hospital stay. The Log-binomial regression analysis was performed to determine the association between NRS-2002 and re-hospitalization. The Cox regression model was fitted to estimate hazard of discharge. The cumulative incidence curves of discharge were plotted using Kaplan–Meier method and log-rank test was performed. Exploratory analysis was also conducted according to the classification of heart failure and the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) fold-elevation.

Results

Among 2,830 heart failure patients, the mean age was 64.3 years and 66.4% were male. A total of 122 (4.3%) patients were considered at high nutritional risk. Log-binomial regression analysis demonstrated that higher NRS-2002 score was an independent risk factor of re-hospitalization ([1 vs. 0]: relative risks [RR] = 1.383, 95% CI = 1.152 to 1.660; [2 vs. 0]: RR = 1.425, 95% CI = 1.108 to 1.832; [3–7 vs. 0]: RR = 1.770, 95% CI = 1.310 to 2.393). Kaplan–Meier curve showed that the cumulative incidence of discharge was lower in high nutritional risk group (Log rank p < 0.001). Cox regression analysis also found that higher NRS-2002 score (2 or ≥3) was strongly associated with longer length of initial hospital stay ([2 vs. 0]: Hazard ratios [HR] = 0.854, 95% CI = 0.748 to 0.976; [3–7 vs. 0]: HR = 0.609, 95% CI = 0.503 to 0.737). Exploratory analysis showed that such association still remained irrespective of NT-proBNP fold-elevation, but only existed in patients with heart failure with preserved ejection fraction (HFpEF).

Conclusion

In patients with heart failure, high NRS-2002 score was strongly and independently associated with the incidence of 1-year re-hospitalization and the length of initial hospital stay.
Fat-Free Mass Index, Visceral Fat Level, and Muscle Mass Percentage Better Explain Deviations From the Expected Value of Aortic Pressure and Structural and Functional Arterial Properties Than Body Fat Indexes
Authors: Gómez-García Mariana , Torrado Juan , Pereira María , Bia Daniel , Zócalo Yanina
Published: April 2022

Bioelectrical impedance analysis (BIA)-derived indexes [e.g., fat (FMI) and fat-free mass indexes (FFMI), visceral fat level (VFL)] are used to characterize obesity as a cardiovascular risk factor (CRF). The BIA-derived index that better predicts arterial variability is still discussed.

Aims

To determine: (1) the association of classical [weight, height, body mass index (BMI), basal metabolic rate (BMR)] and BIA-derived indexes, with arterial properties deviations from expected values (arterial z-scores); (2) maximum arterial variations attributable to BIA-derived indexes; (3) whether the composition of total body, trunk and/or limbs is most closely associated with arterial variations.

Methods

Hemodynamic, structural, and functional parameters of different histological types of arteries were assessed (n = 538, 7–85 years). Classical and BIA-derived indexes [fat mass and percentage, FMI, VFL, muscle mass percentage (PMM), FFMI, and percentage] were measured (mono- and multi-segmental devices). Arterial z-scores were obtained using age-related equations derived from individuals not-exposed to CRFs (n = 1,688).

Results

First, regardless of the classical index considered, the associations with the arterial properties showed a specific hierarchy order: diameters and local stiffness > aortic and brachial blood pressure (BP) > regional stiffness. Second, all the associations of FMI and FFMI with z-scores were positive. Third, FFMI exceeded the association obtained with BMI and BMR, considering structural z-scores. In contrast, FMI did not exceed the association with z-scores achieved by BMI and BMR. Fourth, regardless of CRFs and classical indexes, arterial z-scores would be mainly explained by FFMI, VFL, and PMM. Fifth, regardless of the body-segment considered, the levels of association between FMI and z-scores did not exceed those found for classic and FFMI. Total fat mass and trunk indexes showed a greater strength of association with z-scores than the FMI of limbs. Sixth, compared to lower limb FFMI indexes, total and upper limbs FFMI showed higher levels of association with z-scores.

Conclusions

FFMI (but not FMI) exceeded the strength of association seen between BMI or BMR and structural z-scores. Regardless of the body segment analyzed, the associations between FMI and z-scores did not exceed those found with classic and FFMI. Arterial z-scores could be independently explained by FFMI, VFL, and PMM.
Lentils and Gluten Cross Contact
Authors: Thompson Tricia , Lyons Trisha Bury , Keller Amy
Published: April 2022

Lentils are naturally gluten-free and are recommended for people with celiac disease and other gluten-related disorders. However, like oats, they appear to be at a heightened risk of cross contact with gluten-containing grains. The purpose of this study was to spot check for the presence of errant gluten-containing grains in a variety of brands of lentils purchased in 2021. Twenty-five bags of different dry lentil products representing 24 brands were purchased online and at various grocery stores. Each bag of lentils was individually hand sorted. Two of the 25 packages of lentils contained errant gluten-containing grains. One 16-ounce (454 g) bag contained a grain of wheat. Another 16-ounce (454 g) bag contained a grain of wheat and a grain of barley. For a product to be considered gluten-free in the United States, it must contain <20 mg of gluten per kilogram (or 20 parts per million of gluten). A product at the 20-ppm level of gluten should contain no more than 2 intact gluten-containing grains per kilogram or 35.27 ounces (1,000 g) of food (or 1 intact gluten-containing grain in 17.64 ounces [500 g] of food). Based on these calculations, a 16-ounce (454 g) bag of lentils containing 1 intact gluten-containing grain would not be considered gluten-free. Lentils are at risk of cross contact with gluten-containing grain. Consumers should continue to sort through lentils removing foreign grain, and rinse sorted lentils under running water to remove grain dust before cooking.
NSUN2 Promotes Tumor Progression and Regulates Immune Infiltration in Nasopharyngeal Carcinoma
Authors: Tong Xinya , Xiang Yilan , Hu Yuanbo , Hu Yingying , Li He , Wang Huilin , Zhao Kong-Nan , Xue Xiangyang , Zhu Shanli
Published: April 2022

Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in the head and neck with a complex etiology, such as environmental factors, genetic factors, and Epstein–Barr virus infection. The NOP2/Sun domain family, member 2 (NSUN2) is a methyltransferase of m5C methylation modification that has been reported to be involved in the occurrence and progression of various tumors, but its role in NPC remains unclear. In this study, we found that NSUN2 was upregulated in NPC and predicted a poor prognosis for NPC patients in both GEO datasets and our tissue microarrays containing 125 NPC tissues. Next, we demonstrated that NSUN2 promoted the proliferation, migration, and invasion of NPC cells in vitro. Additionally, the differential expression genes between NSUN2-high and low expression patients were mainly enriched in multi-immune cell activation and proliferation. Furthermore, NSUN2 negatively regulates immune cell infiltration in the tumor microenvironment (TME) of NPC, which indicates that the NSUN2 level may be negatively correlated with the sensitivity of immunotherapy and chemotherapy. In conclusion, our findings highlight that NSUN2 might act as an important oncogene involved in NPC progression and serve as a potential biomarker to predict poor prognosis and drug sensitivity of NPC patients.
Diagnostic Performance of US and MRI in Predicting Malignancy of Soft Tissue Masses: Using a Scoring System
Authors: Shu Hua , Ma Qian , Li Ao , Wang Pingping , Gao Yingqian , Yao Qiyu , Hu Yu , Ye Xinhua
Published: April 2022

Objective

To assess the diagnostic performance of US and MRI in predicting malignancy of soft tissue masses by using a scoring system.

Methods

A total of 120 cases of pathologically confirmed soft tissue masses (71 cases of malignant lesions and 49 cases of benign lesions) were enrolled. All patients underwent ultrasound and MRI examination prior to biopsy or surgical excision. A scoring system based on the parameters of conventional US and MRI to distinguish malignant and benign masses was established by the regression model. The receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of US and MRI.

Results

Multivariate analysis showed that margin, maximum diameter, and vascular density were independent predictors for malignancy found by US, while maximum diameter, margin, and affected peripheral soft tissue were independent predictors for malignancy found by MRI. The mean scores of the benign and malignant groups were 2.8 ± 1.6, 5.1 ± 1.1 on US and 1.3 ± 1.2, 3.5 ± 0.9 on MRI. Based on the cut-off score of 3.5 and 2.5 calculated by ROC analysis, US and MRI had 92% and 87% sensitivity, 72% and 76% specificity, 86% and 89% accuracy, respectively. The combination of these two modalities achieved the sensitivity of 91%, specificity of 82%, and accuracy of 93%.

Conclusions

Both US and MRI can provide valuable information about the differential diagnosis between benign and malignant soft tissue masses. The combination of the two imaging-based scoring systems can increase the diagnostic performance, especially in specificity.
Incidence, Treatment, and Survival of Patients With T-Cell Lymphoma, T-Cell Large Granular Leukemia, and Concomitant Plasma Cell Dyscrasias
Authors: Braunstein Zachary , McLaughlin Eric , Ruiz Miguel , Wei Lai , Bumma Naresh , Benson Don , Devarakonda Srinivas , Chaudhry Maria , Khan Abdullah , Cottini Francesca , Hanel Walter , Baiocchi Robert , Chung Catherine , Addison Daniel , Couette Nina , Meara Alexa , Jarjour Wael , Porcu Pierluigi , Mishra Anjali , Reneau John C. , Rosko Ashley E. , Brammer Jonathan E.
Published: April 2022

T-Cell malignancies are a group of heterogeneous disorders composed of primary cutaneous T-cell lymphomas (CTCLs), peripheral T-cell lymphomas (PTCLs), and T-cell leukemias, including T-cell large granular lymphocytic leukemia (T-LGLL). Cases of patients with combined T-cell malignancies and plasma cell dyscrasias (PCD) are reported in the literature, but these are mostly limited to case reports or small case series with <10 patients. Here, we described the clinical course of 26 patients and report baseline characteristics and clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rates (ORRs) in this unique population. There was no survival difference in patients with CTCL or T-LGLL and concomitant PCD when treated with standard therapy directed at the T-cell malignancy when compared to historical controls. However, patients with PTCL and concomitant PCD had significantly inferior outcomes with rapid progression and worse OS and PFS at 1.7 years (p=0.006) and 4.8 months (p=0.08), respectively, when compared to historical controls for patients with PTCL, although the limited number of patients included in this analysis precludes drawing definitive conclusions. Treatment directed at the T-cell malignancy resulted in the eradication of the PCD clone in multiple patients (15.4%) including one with multiple myeloma (MM) who experienced a complete response after starting therapy directed at the T-cell malignancy. For patients with T-cell malignancies and concomitant PCD, treatment with standard T-cell-directed therapies is recommended based on this analysis with continued follow-up and monitoring of the concomitant PCD. Further studies are needed to definitively elucidate the increased risk of relapse in patients with PTCL and concomitant PCD, and larger, multi-center cohorts are needed to validate these findings across T-cell malignancies and PCDs.
Differential Diagnostic Value of Histology in MPLC and IPM: A Systematic Review and Meta-Analysis
Authors: Tian Sen , Li Fuqi , Pu Jin , Zheng Yi , Shi Hui , Dong Yuchao , Chen Ruohua , Bai Chong
Published: April 2022

Background

The paramount issue regarding multiple lung cancer (MLC) is whether it represents multiple primary lung cancer (MPLC) or intrapulmonary metastasis (IPM), as this directly affects both accurate staging and subsequent clinical management. As a classic method, histology has been widely utilized in clinical practice. However, studies examining the clinical value of histology in MLC have yielded inconsistent results; thus, this remains to be evaluated. Here, we performed a meta-analysis to assess the differential diagnostic value of histology in MPLC and IPM and to provide evidence-based medicine for clinical work.

Methods

PubMed, Embase, and Web of Science databases were searched to collect relevant literature according to PRISMA, and inclusion and exclusion criteria were set up to screen and assess the literature. The data required for reconstructing a 2 × 2 contingency table were extracted directly or calculated indirectly from the included studies, and statistical analysis was carried out by using Stata 15, Meta-DiSc 1.4, and Review Manager 5.4 software.

Results

A total of 34 studies including 1,075 pairs of tumors were included in this meta-analysis. Among these studies, 11 were about the M-M standard and the pooled sensitivity and specificity were 0.78 (95% CI: 0.71–0.84) and 0.47 (95% CI: 0.38–0.55), respectively; 20 studies were about CHA and the pooled sensitivity and specificity were 0.76 (95% CI: 0.72–0.80) and 0.74 (95% CI: 0.68–0.79), respectively; and 3 studies were about the “CHA & Lepidic” criteria and the pooled sensitivity and specificity were 0.96 (95% CI: 0.85–0.99) and 0.47 (95% CI: 0.21–0.73), respectively. The combined pooled sensitivity, specificity, PLR, NLR, DOR, and the area under the SROC curve of the 34 studies were 0.80 (95% CI: 0.73–0.86), 0.64 (95% CI: 0.51–0.76), 2.25 (95% CI: 1.59–3.17), 0.31 (95% CI: 0.23–0.43), 7.22 (95% CI: 4.06–12.81), and 0.81 (95% CI: 0.77–0.84), respectively.

Conclusion

The current evidence indicated that histology had a moderate differential diagnostic value between MPLC and IPM. Among the three subgroups, the “CHA & Lepidic” criteria showed the highest sensitivity and CHA showed the highest specificity. Further research is necessary to validate these findings and to improve clinical credibility.

Systematic Review Registration

PROSPERO, identifier CRD42022298180.