bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: Chronic Pulmonary Aspergillosis—An Unusual Long-Term Complication of Lung Cancer Treatment
Authors: Guziejko Katarzyna , Klukowska Katarzyna , Budzińska Urszula , Mróz Robert Marek
Published: January 2022

Background: Chronic pulmonary aspergillosis (CPA) is a rare complication of radiochemotherapy for lung cancer. It may develop months or years after radical treatment. The diagnosis of CPA is challenging and complex. Not only fungal infection but also cancer relapse always have to be taken under consideration. Antifungal therapy is the base treatment, especially in the case when a surgical procedure is not possible. Standard treatment for at least 6 months is recommended but the optimal duration of the antifungal therapy is unknown. We present the clinical case of CPA, in which we had to perform multidirectional diagnostic tests to confirm the diagnosis and modified treatment due to the recurrence of the disease.

Case Presentation: We report a patient who developed CPA three and a half years after concurrent radiochemotherapy for locally advanced non-small-cell lung cancer. Non-specific symptoms were the cause of delayed diagnosis of fungal infection. Samples collected during bronchoscopy allowed to exclude the recurrence of lung cancer and establish the diagnosis of CPA. The patient was treated with itraconazole for 6 months. A few months later, controlled chest CT scans revealed the progression of CPA. Initially, retreatment with itraconazole was implemented. Due to the progression of fungal infection, voriconazole was used in the second line of treatment. Unfortunately, this therapy was complicated by the side effects and deterioration of the patient's condition. The reintroduction of itraconazole resulted in clinical and radiological improvement. Treatment is scheduled for at least 12 months.

Conclusion: Chronic pulmonary aspergillosis (CPA) was the cause of clinical deterioration and radiological progression in a patient after the radical treatment of lung cancer. In the described case, the diagnosis of CPA was delayed because of the suspicion of the recurrence of lung cancer. As the surgery was not possible, antifungal therapy with itraconazole was implemented and the proper dosage and duration led to significant clinical improvement.
Retinal Image Enhancement Using Cycle-Constraint Adversarial Network
Authors: Wan Cheng , Zhou Xueting , You Qijing , Sun Jing , Shen Jianxin , Zhu Shaojun , Jiang Qin , Yang Weihua
Published: January 2022

Retinal images are the most intuitive medical images for the diagnosis of fundus diseases. Low-quality retinal images cause difficulties in computer-aided diagnosis systems and the clinical diagnosis of ophthalmologists. The high quality of retinal images is an important basis of precision medicine in ophthalmology. In this study, we propose a retinal image enhancement method based on deep learning to enhance multiple low-quality retinal images. A generative adversarial network is employed to build a symmetrical network, and a convolutional block attention module is introduced to improve the feature extraction capability. The retinal images in our dataset are sorted into two sets according to their quality: low and high quality. Generators and discriminators alternately learn the features of low/high-quality retinal images without the need for paired images. We analyze the proposed method both qualitatively and quantitatively on public datasets and a private dataset. The study results demonstrate that the proposed method is superior to other advanced algorithms, especially in enhancing color-distorted retinal images. It also performs well in the task of retinal vessel segmentation. The proposed network effectively enhances low-quality retinal images, aiding ophthalmologists and enabling computer-aided diagnosis in pathological analysis. Our method enhances multiple types of low-quality retinal images using a deep learning network.
Lipid Metabolism Affects Fetal Fraction and Screen Failures in Non-invasive Prenatal Testing
Authors: Cao Jun , Qiao Longwei , Jin Jieyu , Zhang Sheng , Chen Ping , Tang Haoyu , Yu Zheng , Shi Jingye , Wang Ting , Liang Yuting
Published: January 2022

Objective: To assess the association between lipid metabolism and fetal fraction, which is a critical factor in ensuring a highly accurate non-invasive prenatal testing (NIPT), and on the rate of screen failures or “no calls” in NIPT.

Methods: A total of 4,514 pregnant women at 12–26 weeks of gestation underwent NIPT sequencing and serum lipid measurements. Univariate analysis and multivariate regression models were used to evaluate the associations of serum lipid concentrations with the fetal fraction and the rate of screen failures.

Results: The fetal fraction decreased with increased low-density lipoprotein cholesterol and triglyceride (TG) levels, which were significant factors (standardized coefficient: −0.11). Conversely, high-density lipoprotein cholesterol and the interval between the two tests were positively correlated with the fetal fraction. The median fetal fraction was 10.88% (interquartile range, 8.28–13.89%) and this decreased with TG from 11.56% at ≤1.10 mmol/L to 9.51% at >2.30 mmol/L. Meanwhile, multivariate logistic regression analysis revealed that increased TG levels were independently associated with the risk of screen failures. The rate of screen failures showed an increase with TG levels from 1.20% at ≤1.70 mmol/L to 2.41% at >2.30 mmol/L.

Conclusions: The fetal fraction and the rate of screen failures in NIPT are affected by TG levels. Meanwhile, in pregnant women with high TG levels, delaying the time between NIPT blood collections can significantly increase the fetal fraction.
A Genomic Snapshot of the SARS-CoV-2 Pandemic in the Balearic Islands
Authors: López-Causapé Carla , Fraile-Ribot Pablo A. , Jiménez-Serrano Santiago , Cabot Gabriel , del Barrio-Tofiño Ester , Prado M. Carmen , Linares Juana María , López Aranzazu , Hurtado Adoración , Riera Elena , Serra Antoni , Roselló Eva , Carbó Lluis , Fernández-Baca M. Victoria , Gallegos Carmen , Saurina Juan , Arteaga Emilio , Salom M. Magdalena , Salvá Antonia , Nicolau Antoni , González-Candelas Fernando , Comas Iñaki , Oliver Antonio
Published: January 2022

Objective: To analyze the SARS-CoV-2 genomic epidemiology in the Balearic Islands, a unique setting in which the course of the pandemic has been influenced by a complex interplay between insularity, severe social restrictions and tourism travels.

Methods: Since the onset of the pandemic, more than 2,700 SARS-CoV-2 positive respiratory samples have been randomly selected and sequenced in the Balearic Islands. Genetic diversity of circulating variants was assessed by lineage assignment of consensus whole genome sequences with PANGOLIN and investigation of additional spike mutations.

Results: Consensus sequences were assigned to 46 different PANGO lineages and 75% of genomes were classified within a VOC, VUI, or VUM variant according to the WHO definitions. Highest genetic diversity was documented in the island of Majorca (42 different lineages detected). Globally, lineages B.1.1.7 and B.1.617.2/AY.X were identified as the 2 major lineages circulating in the Balearic Islands during the pandemic, distantly followed by lineages B.1.177/B.1.177.X. However, in Ibiza/Formentera lineage distribution was slightly different and lineage B.1.221 was the third most prevalent. Temporal distribution analysis showed that B.1 and B.1.5 lineages dominated the first epidemic wave, lineage B.1.177 dominated the second and third, and lineage B.1.617.2 the fourth. Of note, lineage B.1.1.7 became the most prevalent circulating lineage during first half of 2021; however, it was not associated with an increased in COVID-19 cases likely due to severe social restrictions and limited travels. Additional spike mutations were rarely documented with the exception of mutation S:Q613H which has been detected in several genomes (n = 25) since July 2021.

Conclusion: Virus evolution, mainly driven by the acquisition and selection of spike substitutions conferring biological advantages, social restrictions, and size population are apparently key factors for explaining the epidemic patterns registered in the Balearic Islands.
Identification and Validation of Reference Genes for Gene Expression Analysis in Different Development Stages of Amylostereum areolatum
Authors: Fu Ningning , Li Jiaxing , Wang Ming , Ren Lili , Zong Shixiang , Luo Youqing
Published: January 2022

A strict relationship exists between the Sirex noctilio and the Amylostereum areolatum, which is carried and spread by its partner. The growth and development of this symbiotic fungus is key to complete the life history of the Sirex woodwasp. Real-time quantitative polymerase chain reaction (RT-qPCR) is used to measure gene expression in samples of A. areolatum at different growth stages and explore the key genes and pathways involved in the growth and development of this symbiotic fungus. To obtain accurate RT-qPCR data, target genes need to be normalized by reference genes that are stably expressed under specific experimental conditions. In our study, the stability of 10 candidate reference genes in symbiotic fungal samples at different growth and development stages was evaluated using geNorm, NormFinder, BestKeeper, delta Ct methods, and RefFinder. Meanwhile, laccase1 was used to validate the stability of the selected reference gene. Under the experimental conditions of this study, p450, CYP, and γ-TUB were identified as suitable reference genes. This work is the first to systematically evaluate the reference genes for RT-qPCR results normalization during the growth of this symbiotic fungus, which lays a foundation for further gene expression experiments and understanding the symbiotic relationship and mechanism between S. noctilio and A. areolatum.
Evaluation of Error Production in Animal Fluency and Its Relationship to Frontal Tracts in Normal Aging and Mild Alzheimer’s Disease: A Combined LDA and Time-Course Analysis Investigation
Authors: Itaguchi Yoshihiro , Castro-Chavira Susana A. , Waterloo Knut , Johnsen Stein Harald , Rodríguez-Aranda Claudia
Published: January 2022

Semantic verbal fluency (VF), assessed by animal category, is a task widely used for early detection of dementia. A feature not regularly assessed is the occurrence of errors such as perseverations and intrusions. So far, no investigation has analyzed the how and when of error occurrence during semantic VF in aging populations, together with their possible neural correlates. The present study aims to address the issue using a combined methodology based on latent Dirichlet allocation (LDA) analysis for word classification together with a time-course analysis identifying exact time of errors’ occurrence. LDA is a modeling technique that discloses hidden semantic structures based on a given corpus of documents. We evaluated a sample of 66 participants divided into a healthy young group (n= 24), healthy older adult group (n= 23), and group of patients with mild Alzheimer’s disease (AD) (n= 19). We performed DTI analyses to evaluate the white matter integrity of three frontal tracts purportedly underlying error commission: anterior thalamic radiation, frontal aslant tract, and uncinate fasciculus. Contrasts of DTI metrics were performed on the older groups who were further classified into high-error rate and low-error rate subgroups. Results demonstrated a unique deployment of error commission in the patient group characterized by high incidence of intrusions in the first 15 s and higher rate of perseverations toward the end of the trial. Healthy groups predominantly showed very low incidence of perseverations. The DTI analyses revealed that the patients with AD committing high-error rate presented significantly more degenerated frontal tracts in the left hemisphere. Thus, our findings demonstrated that the appearance of intrusions, together with left hemisphere degeneration of frontal tracts, is a pathognomic trait of mild AD. Furthermore, our data suggest that the error commission of patients with AD arises from executive and working memory impairments related partly to deteriorated left frontal tracts.
Cognitive Sequelae of Silent Ischemic Lesions Following Carotid Artery Stenting: Possible Role of Age-Related Moderation
Authors: Huang Kuo-Lun , Ho Meng-Yang , Chang Yeu-Jhy , Chang Chien-Hung , Liu Chi-Hung , Wu Hsiu-Chuan , Chang Ting-Yu , Lee Tsong-Hai
Published: January 2022

Background: The occurrence of ischemic lesions is common in patients receiving carotid artery stenting (CAS), and most of them are clinically silent. However, few studies have directly addressed the cognitive sequelae of these procedure-related silent ischemic lesions (SILs).

Objective: In this study, we attempted to investigate the effects of SILs on cognition using a comprehensive battery of neuropsychological tests.

Method: Eighty-five patients with unilateral carotid stenosis and 25 age-matched healthy volunteers participated in this study. Brain MRI was performed within 1 week before and 1 week after CAS to monitor the occurrence of post-CAS SILs. A comprehensive battery tapping reading ability, verbal and non-verbal memory, visuospatial function, manual dexterity, executive function, and processing speed was administered 1 week before and 6 months after CAS. To control for practice effects on repeated cognitive testing, the reliable change index (RCI) derived from the healthy volunteers was used to determine the cognitive changes in patients with carotid stenosis.

Results: Among the 85 patients with carotid stenosis, 21 patients received medical treatment (MED group), and procedure-related SILs were noted in 17 patients (SIL+ group) but not observed in 47 patients (SIL– group) after undergoing CAS. Two-way (group × phase) ANOVA revealed that the volunteer group showed improved scores in most cognitive tests while only limited improvement was noted in the SIL– group. The MED and control groups tended to show improvement in the follow-up cognitive testing than the SIL+ group. However, most of the cognitive changes for each patient group did not exceed the upper or lower limits (z = ±1.0) of the RCI.

Conclusions: Although the occurrence of procedure-related SILs is common in patients undergoing CAS, their impacts on cognitive changes after CAS may be limited. The practice effect should be taken into consideration when interpreting cognitive changes following CAS.
Effects of α-Lipoic Acid on Phagocytosis of Oligomeric Beta-Amyloid1–42 in BV-2 Mouse Microglial Cells
Authors: Ko Chih-Yuan , Xu Jian-Hua , Chang Yu-Wei , Lo Yangming Martin , Wu James Swi-Bea , Huang Wen-Chung , Shen Szu-Chuan
Published: January 2022

Background and objectives: This study aimed to investigate the enhancing effect of vitamin-like alpha-lipoic acid (ALA) on phagocytosis of oligomeric beta-amyloid (oAβ)1–42 in BV-2 mouse microglial cells.

Methods: An in vitro model was established to investigate phagocytosis of oAβ1–42 in BV-2 cells. Transmission electron microscopy images indicated that the morphology of prepared oAβ1–42 was spherical particles. BV-2 cells treated with ALA were incubated with 5(6)-carboxyfluorescein-labeled oAβ1–42 (FAM-oAβ1–42) for 24 h, followed by flow cytometer analysis, western blotting, real-time quantitative PCR, and immunocytochemistry (ICC) analysis to assess the in vitro phagocytosis ability of oAβ1–42.

Results: Alpha-lipoic acid significantly increased messenger RNA (mRNA) expression of the CD36 receptor in BV-2 cells. ICC analysis showed that ALA significantly elevated CD36 protein expression in BV-2 cells both with and without oAβ1–42 treatment. Results from the flow cytometry analysis indicated that the CD36 receptor inhibitor significantly attenuated ALA-promoted phagocytosis of FAM-oAβ1–42 in BV-2 cells. Moreover, ICC analysis revealed that ALA caused the translocation of peroxisome proliferator-activated receptor-γ (PPAR-γ), which is known to regulate the expression of CD36 mRNA in BV-2 cells. ALA also elevated both the mRNA and protein expression of cyclooxygenase-2 (COX-2), which is a key enzyme involved in the synthesis of 15-deoxy-Δ12,14-prostaglandin J2 in BV-2 cells.

Conclusion: We postulated that ALA enhances oAβ1–42 phagocytosis by upregulating the COX-2/15-deoxy-Δ12,14-prostaglandin J2/PPAR-γ/CD36 pathway in BV-2 cells. Finally, future studies should be conducted with an in vivo study to confirm the findings.
Bidirectional Regulation of Hippocampal Synaptic Plasticity and Modulation of Cumulative Spatial Memory by Dopamine D2-Like Receptors
Authors: Caragea Violeta-Maria , Manahan-Vaughan Denise
Published: January 2022

Dopamine is a key factor in the enablement of cognition and hippocampal information processing. Its action in the hippocampus is mediated by D1/D5 and D2-like (D2, D3, D4) receptors. While D1/D5-receptors are well recognized as strong modulators of hippocampal synaptic plasticity and information storage, much less is known about the role of D2-like receptors (D2R) in these processes. Here, we explored to what extent D2R contribute to synaptic plasticity and cumulative spatial memory derived from semantic and episodic-like information storage. In freely behaving adult rats, we also assessed to what extent short and long-term forms of synaptic plasticity are influenced by pharmacological activation or blockade of D2R. Antagonism of D2R by means of intracerebral treatment with remoxipride, completely prevented the expression of both short-term (<1 h) and long-term potentiation (>4 h), as well as the expression of short-term depression (STD, <1 h) in the hippocampal CA1 region. Scrutiny of involvement of D2R in spatial learning revealed that D2R-antagonism prevented retention of a semantic spatial memory task, and also significantly impaired retention of recent spatiotemporal aspects of an episodic-like memory task. Taken together, these findings indicate that D2R are required for bidirectional synaptic plasticity in the hippocampal CA1 region. Furthermore, they are critically involved in enabling cumulative and episodic-like forms of spatial learning.
A Graph-Based Framework for Multiscale Modeling of Physiological Transport
Authors: Deepa Maheshvare M. , Raha Soumyendu , Pal Debnath
Published: January 2022

Trillions of chemical reactions occur in the human body every second, where the generated products are not only consumed locally but also transported to various locations in a systematic manner to sustain homeostasis. Current solutions to model these biological phenomena are restricted in computability and scalability due to the use of continuum approaches in which it is practically impossible to encapsulate the complexity of the physiological processes occurring at diverse scales. Here, we present a discrete modeling framework defined on an interacting graph that offers the flexibility to model multiscale systems by translating the physical space into a metamodel. We discretize the graph-based metamodel into functional units composed of well-mixed volumes with vascular and cellular subdomains; the operators defined over these volumes define the transport dynamics. We predict glucose drift governed by advective–dispersive transport in the vascular subdomains of an islet vasculature and cross-validate the flow and concentration fields with finite-element–based COMSOL simulations. Vascular and cellular subdomains are coupled to model the nutrient exchange occurring in response to the gradient arising out of reaction and perfusion dynamics. The application of our framework for modeling biologically relevant test systems shows how our approach can assimilate both multi-omics data from in vitro–in vivo studies and vascular topology from imaging studies for examining the structure–function relationship of complex vasculatures. The framework can advance simulation of whole-body networks at user-defined levels and is expected to find major use in personalized medicine and drug discovery.
Clinical Features and Therapeutic Effects of Anti-leucine-rich Glioma Inactivated 1 Encephalitis: A Systematic Review
Authors: Teng Yuou , Li Ting , Yang Zhizhong , Su Mingwan , Ni Jingnian , Wei Mingqing , Shi Jing , Tian Jinzhou
Published: January 2022

Background: Clinical presentations and treatment programs about anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis still remain incompletely understood.

Objective: This study analyzed the clinical features and therapeutic effects of anti-LGI1 encephalitis.

Methods: PubMed, EMBASE, and the Cochrane Library were searched to identify published English and Chinese articles until April 2021. Data were extracted, analyzed, and recorded in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.

Results: A total of 80 publications detailing 485 subjects matched our inclusion criteria. Short-term memory loss (75.22%), faciobrachial dystonic seizures (FBDS) (52.53%), other seizures excluding FBDS (68.48%), psychiatric symptoms (57.67%), and sleep disturbances (34.30%) were the most frequently described symptoms in anti-LGI1 encephalitis. Hyponatremia (54.90%) was the most common hematologic examination change. The risk of incidence rate of malignant tumors was higher than in healthy people. The positive rate of anti-LGI1 in serum (99.79%) was higher than CSF (77.38%). Steroids (93.02%), IVIG (87.50%), and combined use (96.67%) all had a high remission rate in the initial visit. A total of 35 of 215 cases relapsed, of which 6/35 (17.14%) did not use first-line treatment, and 21 (60.00%) did not maintain long-term treatment. Plasma exchange (PE) could be combined in severe patients, immunosuppressant could be used for refractory patients or for recurrence and using an anti-epileptic drug to control seizures may benefit cognition.

Conclusions: Short-term memory loss, FBDS, psychiatric symptoms, and hyponatremia were key features in identifying anti-LGI1 encephalitis. Serum and CSF antibody tests should be considered in diagnosis criteria. Steroids with IVIG should be recommended, PE was combined for use in severe patients, immunosuppressant therapy might improve outcomes if recurrence or progression occurred, and control seizures might benefit cognition. The useful ways to reduce relapse rate were early identification, clear diagnosis, rapid treatment, and maintaining long-term treatment. The follow-up advice was suggested according to the research of paraneoplastic syndrome, and concern about tumors was vital as well.
Comparison of Shod and Unshod Gait in Patients With Parkinson's Disease With Subthalamic and Nigral Stimulation
Authors: Horn Martin A. , Gulberti Alessandro , Hidding Ute , Gerloff Christian , Hamel Wolfgang , Moll Christian K. E. , Pötter-Nerger Monika
Published: January 2022

Background: The Parkinsonian [i.e., Parkinson's disease (PD)] gait disorder represents a therapeutical challenge with residual symptoms despite the use of deep brain stimulation of the subthalamic nucleus (STN DBS) and medical and rehabilitative strategies. The aim of this study was to assess the effect of different DBS modes as combined stimulation of the STN and substantia nigra (STN+SN DBS) and environmental rehabilitative factors as footwear on gait kinematics.

Methods: This single-center, randomized, double-blind, crossover clinical trial assessed shod and unshod gait in patients with PD with medication in different DBS conditions (i.e., STIM OFF, STN DBS, and STN+SN DBS) during different gait tasks (i.e., normal gait, fast gait, and gait during dual task) and compared gait characteristics to healthy controls. Notably, 15 patients participated in the study, and 11 patients were analyzed after a dropout of four patients due to DBS-induced side effects.

Results: Gait was modulated by both factors, namely, footwear and DBS mode, in patients with PD. Footwear impacted gait characteristics in patients with PD similarly to controls with longer step length, lower cadence, and shorter single-support time. Interestingly, DBS exerted specific effects depending on gait tasks with increased cognitive load. STN+SN DBS was the most efficient DBS mode compared to STIM OFF and STN DBS with intense effects as step length increment during dual task.

Conclusion: The PD gait disorder is a multifactorial symptom, impacted by environmental factors as footwear and modulated by DBS. DBS effects on gait were specific depending on the gait task, with the most obvious effects with STN+SN DBS during gait with increased cognitive load.
The Effects of Virtual Height Exposure on Postural Control and Psychophysiological Stress Are Moderated by Individual Height Intolerance
Authors: Bzdúšková Diana , Marko Martin , Hirjaková Zuzana , Kimijanová Jana , Hlavačka František , Riečanský Igor
Published: January 2022

Virtual reality (VR) enables individuals to be exposed to naturalistic environments in laboratory settings, offering new possibilities for research in human neuroscience and treatment of mental disorders. We used VR to study psychological, autonomic and postural reactions to heights in individuals with varying intensity of fear of heights. Study participants (N = 42) were immersed in a VR of an unprotected open-air elevator platform in an urban area, while standing on an unstable ground. Virtual elevation of the platform (up to 40 m above the ground level) elicited robust and reliable psychophysiological activation including increased distress, heart rate, and electrodermal activity, which was higher in individuals suffering from fear of heights. In these individuals, compared with individuals with low fear of heights, the VR height exposure resulted in higher velocity of postural movements as well as decreased low-frequency (<0.5 Hz) and increased high-frequency (>1 Hz) body sway oscillations. This indicates that individuals with strong fear of heights react to heights with maladaptive rigidity of posture due to increased weight of visual input for balance control, while the visual information is less reliable at heights. Our findings show that exposure to height in a naturalistic VR environment elicits a complex reaction involving correlated changes of the emotional state, autonomic activity, and postural balance, which are exaggerated in individuals with fear of heights.
Rostral Anterior Cingulate Cortex–Ventrolateral Periaqueductal Gray Circuit Underlies Electroacupuncture to Alleviate Hyperalgesia but Not Anxiety-Like Behaviors in Mice With Spared Nerve Injury
Authors: Zhu Xixiao , Xu Yingling , Shen Zui , Zhang Haiyan , Xiao Siqi , Zhu Yichen , Wu Mengwei , Chen Yeqing , Wu Zemin , Xu Yunyun , He Xiaofen , Liu Boyu , Liu Jinggen , Du Junying , Sun Jing , Fang Jianqiao , Shao Xiaomei
Published: January 2022

Neuropathic pain is a common cause of chronic pain and is often accompanied by negative emotions, making it complex and difficult to treat. However, the neural circuit mechanisms underlying these symptoms remain unclear. Herein, we present a novel pathway associated with comorbid chronic pain and anxiety. Using chemogenetic methods, we found that activation of glutamatergic projections from the rostral anterior cingulate cortex (rACCGlu) to the ventrolateral periaqueductal gray (vlPAG) induced both hyperalgesia and anxiety-like behaviors in sham mice. Inhibition of the rACCGlu-vlPAG pathway reduced anxiety-like behaviors and hyperalgesia in the spared nerve injury (SNI) mice model; moreover, electroacupuncture (EA) effectively alleviated these symptoms. Investigation of the related mechanisms revealed that the chemogenetic activation of the rACCGlu-vlPAG circuit effectively blocked the analgesic effect of EA in the SNI mice model but did not affect the chronic pain-induced negative emotions. This study revealed a novel pathway, the rACCGlu-vlPAG pathway, that mediates neuropathic pain and pain-induced anxiety.
Synapses, Microglia, and Lipids in Alzheimer’s Disease
Authors: Paasila Patrick J. , Aramideh Jason A. , Sutherland Greg T. , Graeber Manuel B.
Published: January 2022

Alzheimer’s disease (AD) is characterised by synaptic dysfunction accompanied by the microscopically visible accumulation of pathological protein deposits and cellular dystrophy involving both neurons and glia. Late-stage AD shows pronounced loss of synapses and neurons across several differentially affected brain regions. Recent studies of advanced AD using post-mortem brain samples have demonstrated the direct involvement of microglia in synaptic changes. Variants of the Apolipoprotein E and Triggering Receptors Expressed on Myeloid Cells gene represent important determinants of microglial activity but also of lipid metabolism in cells of the central nervous system. Here we review evidence that may help to explain how abnormal lipid metabolism, microglial activation, and synaptic pathophysiology are inter-related in AD.
Synchronization of the Processes of Autonomic Control of Blood Circulation in Humans Is Different in the Awake State and in Sleep Stages
Authors: Karavaev Anatoly S. , Skazkina Viktoriia V. , Borovkova Ekaterina I. , Prokhorov Mikhail D. , Hramkov Aleksey N. , Ponomarenko Vladimir I. , Runnova Anastasiya E. , Gridnev Vladimir I. , Kiselev Anton R. , Kuznetsov Nikolay V. , Chechurin Leonid S. , Penzel Thomas
Published: January 2022

The influence of higher nervous activity on the processes of autonomic control of the cardiovascular system and baroreflex regulation is of considerable interest, both for understanding the fundamental laws of the functioning of the human body and for developing methods for diagnostics and treatment of pathologies. The complexity of the analyzed systems limits the possibilities of research in this area and requires the development of new tools. Earlier we propose a method for studying the collective dynamics of the processes of autonomic control of blood circulation in the awake state and in different stages of sleep. The method is based on estimating a quantitative measure representing the total percentage of phase synchronization between the low-frequency oscillations in heart rate and blood pressure. Analysis of electrocardiogram and invasive blood pressure signals in apnea patients in the awake state and in different sleep stages showed a high sensitivity of the proposed measure. It is shown that in slow-wave sleep the degree of synchronization of the studied rhythms is higher than in the awake state and lower than in sleep with rapid eye movement. The results reflect the modulation of the processes of autonomic control of blood circulation by higher nervous activity and can be used for the quantitative assessment of this modulation.
Identification of the Risk Genes Associated With Vulnerability to Addiction: Major Findings From Transgenic Animals
Authors: Jordan Chloe J. , Xi Zheng-Xiong
Published: January 2022

Understanding risk factors for substance use disorders (SUD) can facilitate medication development for SUD treatment. While a rich literature exists discussing environmental factors that influence SUD, fewer articles have focused on genetic factors that convey vulnerability to drug use. Methods to identify SUD risk genes include Genome-Wide Association Studies (GWAS) and transgenic approaches. GWAS have identified hundreds of gene variants or single nucleotide polymorphisms (SNPs). However, few genes identified by GWAS have been verified by clinical or preclinical studies. In contrast, significant progress has been made in transgenic approaches to identify risk genes for SUD. In this article, we review recent progress in identifying candidate genes contributing to drug use and addiction using transgenic approaches. A central hypothesis is if a particular gene variant (e.g., resulting in reduction or deletion of a protein) is associated with increases in drug self-administration or relapse to drug seeking, this gene variant may be considered a risk factor for drug use and addiction. Accordingly, we identified several candidate genes such as those that encode dopamine D2 and D3 receptors, mGluR2, M4 muscarinic acetylcholine receptors, and α5 nicotinic acetylcholine receptors, which appear to meet the risk-gene criteria when their expression is decreased. Here, we describe the role of these receptors in drug reward and addiction, and then summarize major findings from the gene-knockout mice or rats in animal models of addiction. Lastly, we briefly discuss future research directions in identifying addiction-related risk genes and in risk gene-based medication development for the treatment of addiction.
Sub- and Supra-Second Timing in Auditory Perception: Evidence for Cross-Domain Relationships
Authors: Szelag Elzbieta , Stanczyk Magdalena , Szymaszek Aneta
Published: January 2022

Previous studies indicate that there are at least two levels of temporal processing: the sub- and supra-second domains. The relationship between these domains remains unclear. The aim of this study was to test whether performance on the sub-second level is related to that on the supra-second one, or whether these two domains operate independently. Participants were 118 healthy adults (mean age = 23 years). The sub-second level was studied with a temporal-order judgment task and indexed by the Temporal Order Threshold (TOT), on which lower values corresponded to better performance. On the basis of TOT results, the initial sample was classified into two groups characterized by either higher temporal efficiency (HTE) or lower temporal efficiency (LTE). Next, the efficiency of performance on the supra-second level was studied in these two groups using the subjective accentuation task, in which participants listened to monotonous sequences of beats and were asked to mentally accentuate every n-th beat to create individual rhythmic patterns. The extent of temporal integration was assessed on the basis of the number of beats being united and better performance corresponded to longer units. The novel results are differences between groups in this temporal integration. The HTE group integrated beats in significantly longer units than did the LTE group. Moreover, for tasks with higher mental load, the HTE group relied more on a constant time strategy, whereas the LTE group relied more on mental counting, probably because of less efficient temporal integration. These findings provide insight into associations between sub- and supra-second levels of processing and point to a common time keeping system, which is active independently of temporal domain.
An Impending Paradigm Shift in Motor Imagery Based Brain-Computer Interfaces
Authors: Papadopoulos Sotirios , Bonaiuto James , Mattout Jérémie
Published: January 2022

The development of reliable assistive devices for patients that suffer from motor impairments following central nervous system lesions remains a major challenge in the field of non-invasive Brain-Computer Interfaces (BCIs). These approaches are predominated by electroencephalography and rely on advanced signal processing and machine learning methods to extract neural correlates of motor activity. However, despite tremendous and still ongoing efforts, their value as effective clinical tools remains limited. We advocate that a rather overlooked research avenue lies in efforts to question neurophysiological markers traditionally targeted in non-invasive motor BCIs. We propose an alternative approach grounded by recent fundamental advances in non-invasive neurophysiology, specifically subject-specific feature extraction of sensorimotor bursts of activity recorded via (possibly magnetoencephalography-optimized) electroencephalography. This path holds promise in overcoming a significant proportion of existing limitations, and could foster the wider adoption of online BCIs in rehabilitation protocols.
Detection and Functional Evaluation of the P2X7 Receptor in hiPSC Derived Neurons and Microglia-Like Cells
Authors: Francistiová Linda , Vörös Kinga , Lovász Zsófia , Dinnyés András , Kobolák Julianna
Published: January 2022

A large body of evidence suggests the involvement of the ATP-gated purinergic receptor P2X7 (P2X7R) in neurodegenerative diseases, including Alzheimer’s disease. While it is well-described to be present and functional on microglia cells contributing to inflammatory responses, some reports suggest a neuronal expression of the receptor as well. Here, we present experimental results showing P2X7 receptors to be expressed on human hiPSC-derived microglia-like cells, hiPSC-derived neuronal progenitors and hiPSC-derived matured neuronal cells. By applying cell surface protein detection assays, we show that P2X7R is not localized on the cell membrane, despite being detected in neuronal cells and thus may not be available for directly mediating neurotoxicity. On hiPSC-derived microglia-like cells, a clear membranous expression was detected. Additionally, we have not observed differences in P2X7R functions between control and familial Alzheimer’s disease patient-derived neuronal cells. Functional assays employing a P2X7R antagonist JNJ 47965567 confirm these findings by showing P2X7R-dependent modulation of microglia-like cells viability upon treatment with P2X7R agonists ATP and BzATP, while the same effect was absent from neuronal cells. Since the majority of P2X7R research was done on rodent models, our work on human hiPSC-derived cells presents a valuable contribution to the field, extending the work on animal models to the human cellular system and toward clinical translation.
Relationship Between Dietary Omega-3 and Omega-6 Polyunsaturated Fatty Acids Level and Sarcopenia. A Meta-Analysis of Observational Studies
Authors: Zhang Yi , Guo Hongbin , Liang Jieyu , Xiao Wenfeng , Li Yusheng
Published: January 2022

Objective: This study investigates the relationship between dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) levels and sarcopenia.

Methods: A comprehensive literature search in the databases of PubMed, Web of Science, and Embase (up to July 2021) were conducted to identify the observational studies on the relationship between dietary omega-3 and omega-6 PUFAs level and sarcopenia. The pooled odds ratio (OR) of sarcopenia for the highest vs. lowest dietary omega-3 and omega-6 PUFAs level and the standard mean difference (SMD) of dietary omega-3 and omega-6 PUFAs levels for sarcopenia vs. control subjects were calculated.

Results: A total of six studies were identified in this meta-analysis. The overall multi-variable adjusted OR showed that dietary omega-3 PUFAs level was inversely associated with sarcopenia (OR = 0.41, 95% CI: 0.26–0.65; P = 0.0001). Moreover, the overall combined SMD showed that the dietary omega-3 PUFAs level in sarcopenia was lower than that in control subjects (SMD = −0.19, 95% CI: −0.32 to −0.07; P = 0.002). With regard to dietary omega-6 PUFAs level, the overall multi-variable adjusted OR suggested no significant relationship between dietary omega-6 PUFAs level and sarcopenia (OR = 0.64, 95% CI: 0.33–1.24; P = 0.19). However, the overall combined SMD showed that the dietary omega-6 PUFAs level in sarcopenia was slightly lower than that in control subjects (SMD = −0.15, 95% CI: −0.27 to −0.02; P = 0.02).

Conclusion: Our results suggested that the dietary omega-3 PUFAs level was inversely associated with sarcopenia. However, current evidence is still insufficient to demonstrate the definite relationship between dietary omega-6 PUFAs levels and sarcopenia. More well-designed prospective cohort studies with the dietary omega-3/omega-6 PUFAs ratio are still needed.
Combined Analysis of Gut Microbiota and Plasma Metabolites Reveals the Effect of Red-Fleshed Apple Anthocyanin Extract on Dysfunction of Mice Reproductive System Induced by Busulfan
Authors: Wang Bin , Xu Jihua , Jiang Shenhui , Wang Yanbo , Zhu Jun , Zhang Yugang
Published: January 2022

Busulfan is currently an indispensable anti-cancer drug, but the side effects on male reproductive system are so serious. Meanwhile, red-fleshed apples are natural products with high anthocyanin content. In this research, we analyzed the effect of red-fleshed apple anthocyanin extract (RAAE) on busulfan-treated mice. Compared with the busulfan group, main plasma biochemical indicators were significantly improved after RAAE treatment. Compared with BA0 (busulfan without RAAE) group, total antioxidant capacity(T-AOC) and the activity of superoxide dismutase (SOD) and glutathione catalase (GSH-Px) in RAAE treatment groups were obviously increased, while the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly decreased. Malondialdehyde (MDA) was significantly decreased in the RAAE groups. In addition, we found RAAE alleviated busulfan-disrupted spermatogenesis through improving genes expression which are important for spermatogenesis, such as DDX4, PGK2, and TP1. Furthermore, we found that RAAE increased beneficial bacteria Akkermansia and Lactobacillaceae, and significantly depleted harmful bacteria Erysipelotrichia. The correlation studies indicated that RAAE ameliorated busulfan-induced rise in LysoPC levels through regulating gut microbial community and their associated metabolites. In conclusion, this study extends our understanding of the alleviated effect of RAAE on busulfan-induced male reproductive dysfunction through regulating the relationships between gut microbiota and metabolites.
Exosomal Long Non-Coding RNA ANCR Mediates Drug Resistance in Osteosarcoma
Authors: Hu Xin , Wen Yang , Tan Lin-yun , Wang Jie , Tang Fan , Wang Yi-tian , Zheng Chuan-xi , Zhang Yu-qi , Gong Tao-jun , Min Li
Published: January 2022

Osteosarcoma (OS) is rare cancer with bimodal age distribution with peaks observed in children and young adults. Typically, OS is treated with pre-surgery neoadjuvant therapy, surgical excision, and post-surgery chemotherapy. However, the efficacy of treatment on disease prognosis and objective response is not currently optimal, often resulting in drug resistance; in turn, highlighting the need to understand mechanisms driving resistance to therapy in OS patients. Using Doxycycline (Dox)-sensitive and resistant variants of OS cells lines KHOS and U2OS, we found that the resistant variants KHOS-DR and U2OS-DR have significantly higher in vitro proliferation. Treating the Dox-sensitive KHOS/U2OS cells with exosomes isolated from KHOS-DR/U2OS-DR made them resistant to treatment with Dox in vitro and in vivo and enhanced tumor growth and progression, while decreasing overall survival. Expression of the long non-coding RNA (lncRNA) ANCR was significantly higher in the KHOS-DR and U2OS-DR variants. SiRNA-mediated knockdown of ANCR decreased in vitro proliferation, while increasing sensitivity to Dox treatment in the KHOS-DR/U2OS-DR cells. Expression of the exosomal lncRNA ANCR was critical for drug resistance and OS tumor progression in xenografts and was correlated to resistance to Adriamycin and overall survival is patients with OS. These results establish lncRNA ANCR as a critical mediator of resistance to therapy in OS patients, highlighting it as a potential therapeutic target in OS patients.
Oncological Outcomes After Hippocampus-Sparing Whole-Brain Radiotherapy in Cancer Patients With Newly Diagnosed Brain Oligometastases: A Single-Arm Prospective Observational Cohort Study in Taiwan
Authors: Lin Shinn-Yn , Tsan Din-Li , Chuang Chi-Cheng , Yang Chi-Cheng , Pai Ping-Ching , Wang Chih-Liang , Wu Yi-Ming , Lee Cheng-Chi , Lin Chia-Hsin , Wei Kuo-Chen , Chou Wen-Chi
Published: January 2022

Background

Promisingly, the technique of hippocampus sparing during WBRT (HS-WBRT) might preserve NCFs. In this research, we examined oncological outcomes, with emphasis on neurologic/non-neurologic causes of death, CNS progression, and leptomeningeal disease (LMD) recurrence in cancer patients who underwent HS-WBRT.

Methods

One hundred and fourteen cancer patients with newly diagnosed brain oligometastases underwent HS-WBRT were consecutively enrolled. The cumulative incidence of cancer-specific deaths (neurologic or non-neurologic), LMD recurrence, and the composite endpoint of CNS progression (CNS-CE) as the first event were computed with a competing-risks approach to characterize the oncological outcomes after HS-WBRT.

Results

Patients with intact brain metastases had a significantly increased likelihood of dying from non-neurologic causes of death associated with early manifestation of progressive systemic disease (hazard ratio for non-neurologic death, 1.78; 95% CI, 1.08–2.95; p = 0.025; competing-risks Fine–Gray regression), which reciprocally rendered them unlikely to encounter LMD recurrence or any pattern of CNS progression (HR for CNS-CE as the first event, 0.13; 95% CI, 0.02–0.97; p = 0.047; competing-risks Fine–Gray regression). By contrast, patients with resection cavities post-craniotomy had reciprocally increased likelihood of CNS progression which might be associated with neurologic death eventually.

Conclusions

Patterns of oncological endpoints including neurologic/non-neurologic death and cumulative incidence of CNS progression manifesting as LMD recurrence are clearly clarified and contrasted between patients with intact BMs and those with resection cavities, indicating they are clinically distinct subgroups.

Trial Registration

ClinicalTrials.gov, Identifier: NCT02504788, NCT03223675.
The HeyL-Aromatase Axis Promotes Cancer Stem Cell Properties by Endogenous Estrogen-Induced Autophagy in Castration-Resistant Prostate Cancer
Authors: Lin Qimei , Cao Jiasong , Du Xiaoling , Yang Kuo , Shen Yongmei , Wang Weishu , Klocker Helmut , Shi Jiandang , Zhang Ju
Published: January 2022

Treatment of patients with castration-resistant prostate cancer (CRPC) remains a major clinical challenge. We previously showed that estrogenic effects contribute to CRPC progression and are primarily caused by the increased endogenous estradiol produced via highly expressed aromatase. However, the mechanism of aromatase upregulation and its role in CRPC are poorly described. In this study, we report that HeyL is aberrantly upregulated in CRPC tissues, and its expression is positively correlated with aromatase levels. HeyL overexpression increased endogenous estradiol levels and estrogen receptor-α (ERα) transcriptional activity by upregulating CYP19A1 expression, which encodes aromatase, enhancing prostate cancer stem cell (PCSC) properties in PC3 cells. Mechanistically, HeyL bound to the CYP19A1 promoter and activated its transcription. HeyL overexpression significantly promoted bicalutamide resistance in LNCaP cells, which was reversed by the aromatase inhibitor letrozole. In PC3 cells, the HeyL-aromatase axis promoted the PCSC phenotype by upregulating autophagy-related genes, while the autophagy inhibitor chloroquine (CQ) suppressed the aromatase-induced PCSC phenotype. The activated HeyL-aromatase axis promoted PCSC autophagy via ERα-mediated estrogenic effects. Taken together, our results indicated that the HeyL-aromatase axis could increase endogenous estradiol levels and activate ERα to suppress PCSC apoptosis by promoting autophagy, which enhances the understanding of how endogenous estrogenic effects influence CRPC development.