bluuebunny/crossref_metadata_2025 huggingface dataset:
NLRP3 Inflammasome Activation of Mast Cells by Estrogen via the Nuclear-Initiated Signaling Pathway Contributes to the Development of Endometriosis
Authors: Guo Xinyue , Xu Xinxin , Li Tiantian , Yu Qin , Wang Jianzhang , Chen Yichen , Ding Shaojie , Zhu Libo , Zou Gen , Zhang Xinmei
Published: September 2021

Endometriosis is an estrogen-dependent gynecological disease. The pathogenesis of endometriosis remains controversial, although it is generally accepted that the inflammatory immune response plays a crucial role in this process. Mast cells (MCs) are multifunctional innate immune cells that accumulate in endometriotic lesions. However, the molecular mechanism by which estrogen modulates MCs in the development of endometriosis is not well understood. Here we report that estrogen can induce the expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) through estrogen receptor (ER)-α via the estrogen responsive element (ERE) in MCs. Such transcriptional regulation is necessary for the activation of NLRP3 inflammasome and the production of mature interleukin (IL)-1β in MCs. Targeted inhibition of NLRP3 significantly restrained lesion progression and fibrogenesis in a mouse model of endometriosis. Collectively, these findings suggest that MCs contribute to the development of endometriosis through NLRP3 inflammasome activation mediated by nuclear-initiated estrogen signaling pathway.
Comprehensive Immune Profiling of a Kidney Transplant Recipient With Peri-Operative SARS-CoV-2 Infection: A Case Report
Authors: Sherwood Karen R. , Nicholl David D. M. , Fenninger Franz , Wu Vivian , Wong Paaksum , Benedicto Vince , Cina Davide P. , Wang Meng , Pobran Taylor D. , De Marco Mari L. , Márquez Anna Citlali , Jassem Agatha N. , Sekirov Inna , Morshed Muhammad G. , Bardi Mohammad , Sekhon Mypinder , Keown Paul , Kadatz Matthew , Lan James H.
Published: September 2021

To date there is limited data on the immune profile and outcomes of solid organ transplant recipients who encounter COVID-19 infection early post-transplant. Here we present a unique case where the kidney recipient’s transplant surgery coincided with a positive SARS-CoV-2 test and the patient subsequently developed symptomatic COVID-19 perioperatively. We performed comprehensive immunological monitoring of cellular, proteomic, and serological changes during the first 4 critical months post-infection. We showed that continuation of basiliximab induction and maintenance of triple immunosuppression did not significantly impair the host’s ability to mount a robust immune response against symptomatic COVID-19 infection diagnosed within the first week post-transplant.
Identifying Habitats of Conservation Priority in the São Vicente Submarine Canyon in Southwestern Portugal
Authors: Nestorowicz Iga-Maria , Oliveira Frederico , Monteiro Pedro , Bentes Luís , Henriques Nuno Sales , Aguilar Ricardo , Horta e Costa Barbara , Gonçalves Jorge M. S.
Published: September 2021

Identifying vulnerable marine habitats is fundamental to promote evidence-based management and a sustainable use of our oceans. Although progress in the mapping of marine benthic habitats has been made, complex ecosystems such as submarine canyons remain largely unexplored, hampering evidence-based management from taking place in these ubiquitous features worldwide. Data from a remotely operated vehicle (ROV) survey in the upper São Vicente Submarine Canyon in southwestern Portugal from 2011, was analysed to carry out a comprehensive assessment of megabenthic habitats, particularly those of conservation concern occuring between 90 and 560 m. Underwater videos from three exploratory dives, covering a total of 8.8 kilometers, were analyzed through multivariate and visual assessments, and the identified habitats were assessed against a set of criteria derived from current definitions of priority habitats. Thirteen potential priority habitats were characterized, out of which four distinct “coral gardens” and one “deep-sea sponge aggregation” are aligned with OSPAR definitions of priority habitats, and one corresponds to the habitat of a strictly protected sea urchin listed in the Habitats Directive. Three circalittoral sponge aggregations were also suggested based on the abundance of indicator species. The specific composition and diversity of priority habitats as described here, has not yet been described in any other canyon in the NE Atlantic region. Depth was revealed to be particularly important for the distribution of habitats, followed by relief and substratum. The approach presented in this study contributes to improve the understanding about submarine canyons, which is paramount to implement knowledge-based protection measures. Furthermore, it can be used to support future mapping efforts of deep-sea environments such as submarine canyons.
Assessment of Benthic Ecological Quality Status Using Multi-Biotic Indices Based on Macrofaunal Assemblages in a Semi-Enclosed Bay
Authors: Lu Xin , Xu Jing , Xu Zhaodong , Liu Xiaoshou
Published: September 2021

Semi-enclosed bays have physical and chemical characteristics influenced by both land and sea systems and the quality of the benthic environment is always of great concern. Macrofauna are considered good indicators for evaluating the benthic ecological quality status owing to their biological characteristics. In this study, six biotic indices, namely the Shannon–Wiener diversity index (H′), Abundance-Biomass Comparison (ABC) curve, AZTI’s Marine Biotic Index (AMBI), multivariate-AMBI (M-AMBI), BOPA index, and BENTIX index, were used to evaluate the adaptability of different biological indices in the bioassessment of the benthic environment in a semi-enclosed bay. In the annual environmental assessment of the study area, the average values of the six indices (H′, ABC curve, AMBI, M-AMBI, BOPA, and BENTIX) were 4.494, 0.182, 2.433, 0.791, 0.033, and 3.813, respectively; accordingly, H′, M-AMBI, and BOPA met the high standards whereas the other indices met the good standards, indicating that the whole study bay was slightly disturbed and had good ecological quality. From the perspective of spatial variation, the benthic environment in the middle of the bay was better than that in the north; the environmental problems in the northeast were particularly noteworthy. In terms of temporal patterns, the benthic environment in winter and summer was significantly better than that in spring and autumn, with obvious seasonal differences. The present results indicate that the H′ and ABC curve based on benthic abundance and biomass should be avoided for environmental assessment in mariculture areas. AMBI and M-AMBI should be used with caution when the percentage of unassigned species is high, in which case H′ is the appropriate choice. When there are few unassigned species, M-AMBI is more conducive for accurate evaluation of the benthic environment than AMBI and H′.
Development and Validation of Predictors for the Survival of Patients With COVID-19 Based on Machine Learning
Authors: Zhao Yongfeng , Chen Qianjun , Liu Tao , Luo Ping , Zhou Yi , Liu Minghui , Xiong Bei , Zhou Fuling
Published: September 2021

Background: The outbreak of COVID-19 attracted the attention of the whole world. Our study aimed to explore the predictors for the survival of patients with COVID-19 by machine learning.

Methods: We conducted a retrospective analysis and used the idea of machine learning to train the data of COVID-19 patients in Leishenshan Hospital through the logical regression algorithm provided by scikit-learn.

Results: Of 2010 patients, 42 deaths were recorded until March 29, 2020. The mortality rate was 2.09%. There were 6,812 records after data features combination and data arrangement, 3,025 records with high-quality after deleting incomplete data by manual checking, and 5,738 records after data balancing finally by the method of Borderline-1 Smote. The results of 10 times of data training by logistic regression model showed that albumin, saturation of pulse oxygen at admission, alanine aminotransferase, and percentage of neutrophils were possibly associated with the survival of patients. The results of 10 times of data training including age, sex, and height beyond the laboratory measurements showed that percentage of neutrophils, saturation of pulse oxygen at admission, alanine aminotransferase, sex, and albumin were possibly associated with the survival of patients. The rates of precision, recall, and f1-score of the two training models were all higher than 0.9 and relatively stable.

Conclusions: We demonstrated that percentage of neutrophils, saturation of pulse oxygen at admission, alanine aminotransferase, sex, and albumin were possibly associated with the survival of patients with COVID-19.
The Hidden Genomic Diversity, Specialized Metabolite Capacity, and Revised Taxonomy of Burkholderia Sensu Lato
Authors: Mullins Alex J. , Mahenthiralingam Eshwar
Published: September 2021

Burkholderia sensu lato is a collection of closely related genera within the family Burkholderiaceae that includes species of environmental, industrial, biotechnological, and clinical importance. Multiple species within the complex are the source of diverse specialized metabolites, many of which have been identified through genome mining of their biosynthetic gene clusters (BGCs). However, the full, true genomic diversity of these species and genera, and their biosynthetic capacity have not been investigated. This study sought to cluster and classify over 4000 Burkholderia sensu lato genome assemblies into distinct genomic taxa representing named and uncharacterized species. We delineated 235 species groups by average nucleotide identity analyses that formed seven distinct phylogenomic clades, representing the genera of Burkholderia sensu lato: Burkholderia, Paraburkholderia, Trinickia, Caballeronia, Mycetohabitans, Robbsia, and Pararobbisa. A total of 137 genomic taxa aligned with named species possessing a sequenced type strain, while 93 uncharacterized species groups were demarcated. The 95% ANI threshold proved capable of delineating most genomic species and was only increased to resolve several closely related species. These analyses enabled the assessment of species classifications of over 4000 genomes, and the correction of over 400 genome taxonomic assignments in public databases into existing and uncharacterized genomic species groups. These species groups were genome mined for BGCs, their specialized metabolite capacity calculated per species and genus, and the number of distinct BGCs per species estimated through kmer-based de-replication. Mycetohabitans species dedicated a larger proportion of their relatively small genomes to specialized metabolite biosynthesis, while Burkholderia species harbored more BGCs on average per genome and possessed the most distinct BGCs per species compared to the remaining genera. Exploring the hidden genomic diversity of this important multi-genus complex contributes to our understanding of their taxonomy and evolutionary relationships, and supports future efforts toward natural product discovery.
Impacts of Ser/Thr Protein Kinase Stk1 on the Proteome, Twitching Motility, and Competitive Advantage in Pseudomonas aeruginosa
Authors: Zhu Xuan , Feng Chao , Zhou Lantian , Li Zhenzhen , Zhang Yue , Pan Jianyi
Published: September 2021

Pseudomonas aeruginosa is a ubiquitous gram-negative bacterium in the environment and a leading cause of nosocomial infections worldwide. Therefore, it is listed by the WHO as a human pathogen that urgently needs the development of new antibacterial drugs. Recent findings have demonstrated that eukaryote-type Ser/Thr protein kinases play a vital role in regulating various bacterial physiological processes by catalyzing protein phosphorylation. Stk1 has proven to be a Ser/Thr protein kinase in P. aeruginosa. However, the regulatory roles of Stk1 have not yet been revealed. Thus, we constructed a stk1 knockout mutant (∆stk1) from the P. aeruginosa PAO1 strain and employed a Tandem Mass Tag (TMT) labeling-based quantitative proteomic strategy to characterize proteome-wide changes in response to the stk1 knockout. In total, 620 differentially expressed proteins, among which 288 proteins were upregulated and 332 proteins were downregulated, were identified in ∆stk1 compared with P. aeruginosa PAO1. A detailed bioinformatics analysis of these differentially expressed proteins was performed, including GO annotation, protein domain profile, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, subcellular localization and enrichment analysis. Notably, the downregulation of type IV pilus-related proteins and upregulation of T6SS-H1-related proteins were found in the ∆stk1 strain, and the results were corroborated by quantitative PCR at the mRNA level. Further experiments confirmed that the loss of stk1 weakens bacterial twitching motility and promotes a growth competition advantage, which are, respectively, mediated by type IV pilus-related proteins and T6SS-H1-related proteins. These findings contribute to a better understanding of the physiological role of Stk1, and proteomic data will help further investigations of the roles and mechanisms of Stk1 in P. aeruginosa, although the detailed regulation and mechanism of Stk1 still need to be revealed.
The Biocontrol and Plant Growth-Promoting Properties of Streptomyces alfalfae XN-04 Revealed by Functional and Genomic Analysis
Authors: Chen Jing , Hu Lifang , Chen Na , Jia Ruimin , Ma Qing , Wang Yang
Published: September 2021

Fusarium wilt of cotton, caused by the pathogenic fungal Fusarium oxysporum f. sp. vasinfectum (Fov), is a devastating disease of cotton, dramatically affecting cotton production and quality. With the increase of pathogen resistance, controlling Fusarium wilt disease has become a significant challenge. Biocontrol agents (BCAs) can be used as an additional solution to traditional crop breeding and chemical control. In this study, an actinomycete with high inhibitory activity against Fov was isolated from rhizosphere soil and identified as Streptomyces alfalfae based on phylogenetic analyses. Next, an integrative approach combining genome mining and metabolites detection was applied to decipher the significant biocontrol and plant growth-promoting properties of XN-04. Bioinformatic analysis and bioassays revealed that the antagonistic activity of XN-04 against Fov was associated with the production of various extracellular hydrolytic enzymes and diffusible antifungal metabolites. Genome analysis revealed that XN-04 harbors 34 secondary metabolite biosynthesis gene clusters. The ability of XN-04 to promote plant growth was correlated with an extensive set of genes involved in indoleacetic acid biosynthesis, 1-aminocyclopropane-1-carboxylic acid deaminase activity, phosphate solubilization, and iron metabolism. Colonization experiments indicated that EGFP-labeled XN-04 had accumulated on the maturation zones of cotton roots. These results suggest that S. alfalfae XN-04 could be a multifunctional BCA and biofertilizer used in agriculture.
Gait-Related Brain Activation During Motor Imagery of Complex and Simple Ambulation in Parkinson's Disease With Freezing of Gait
Authors: Huang Hui-Chun , Chen Chun-Ming , Lu Ming-Kuei , Liu Bey-Ling , Li Chia-Ing , Chen Jui-Cheng , Wang Guei-Jane , Lin Hsiu-Chen , Duann Jeng-Ren , Tsai Chon-Haw
Published: September 2021

Background: Freezing of gait (FOG) in Parkinson's disease (PD) is a devastating clinical phenomenon that has a detrimental impact on patients. It tends to be triggered more often during turning (complex) than during forwarding straight (simple) walking. The neural mechanism underlying this phenomenon remains unclear and requires further elucidation.

Objective: To investigate the differences in cerebral functional magnetic resonance imaging responses between PD patients with and without FOG during explicitly video-guided motor imagery (MI) of various complex (normal, freezing) and simple (normal, freezing) walking conditions.

Methods: We recruited 34 PD patients, namely, 20 with FOG and 14 without FOG, and 15 normal controls. Participants underwent video-guided MI of turning and straight walking, with and without freezing, while their brain blood oxygen level-dependent (BOLD) activities were measured. Gait analysis was performed.

Results: While comparing FOG turning with FOG straight walking, freezers showed higher activation of the superior occipital gyrus, left precentral gyrus, and right postcentral gyrus compared with non-freezers. Normal controls also manifest similar findings compared with non-freezers, except no difference was noted in occipital gyrus activity between the two groups. Freezers also displayed a higher effect size in the locomotor regions than non-freezers during imagery of normal turning.

Conclusions: Our findings suggest that freezers require a higher drive of cortical and locomotion regions to overcome the overinhibition of the pathways in freezers than in non-freezers. Compared with simple walking, increased dorsal visual pathway and deep locomotion region activities might play pivotal roles in tackling FOG in freezers during complex walking.
SpikePropamine: Differentiable Plasticity in Spiking Neural Networks
Authors: Schmidgall Samuel , Ashkanazy Julia , Lawson Wallace , Hays Joe
Published: September 2021

The adaptive changes in synaptic efficacy that occur between spiking neurons have been demonstrated to play a critical role in learning for biological neural networks. Despite this source of inspiration, many learning focused applications using Spiking Neural Networks (SNNs) retain static synaptic connections, preventing additional learning after the initial training period. Here, we introduce a framework for simultaneously learning the underlying fixed-weights and the rules governing the dynamics of synaptic plasticity and neuromodulated synaptic plasticity in SNNs through gradient descent. We further demonstrate the capabilities of this framework on a series of challenging benchmarks, learning the parameters of several plasticity rules including BCM, Oja's, and their respective set of neuromodulatory variants. The experimental results display that SNNs augmented with differentiable plasticity are sufficient for solving a set of challenging temporal learning tasks that a traditional SNN fails to solve, even in the presence of significant noise. These networks are also shown to be capable of producing locomotion on a high-dimensional robotic learning task, where near-minimal degradation in performance is observed in the presence of novel conditions not seen during the initial training period.
An ALE Meta-Analysis of Specific Functional MRI Studies on Subcortical Vascular Cognitive Impairment
Authors: Xu Wenwen , Song Yu , Chen Shanshan , Xue Chen , Hu Guanjie , Qi Wenzhang , Ma Wenying , Lin Xingjian , Chen Jiu
Published: September 2021

Background: Subcortical vascular cognitive impairment (sVCI), caused by cerebral small vessel disease, accounts for the majority of vascular cognitive impairment, and is characterized by an insidious onset and impaired memory and executive function. If not recognized early, it inevitably develops into vascular dementia. Several quantitative studies have reported the consistent results of brain regions in sVCI patients that can be used to predict dementia conversion. The purpose of the study was to explore the exact abnormalities within the brain in sVCI patients by combining the coordinates reported in previous studies.

Methods: The PubMed, Embase, and Web of Science databases were thoroughly searched to obtain neuroimaging articles on the amplitude of low-frequency fluctuation, regional homogeneity, and functional connectivity in sVCI patients. According to the activation likelihood estimation (ALE) algorithm, a meta-analysis based on coordinate and functional connectivity modeling was conducted.

Results: The quantitative meta-analysis included 20 functional imaging studies on sVCI patients. Alterations in specific brain regions were mainly concentrated in the frontal lobes including the middle frontal gyrus, superior frontal gyrus, medial frontal gyrus, and precentral gyrus; parietal lobes including the precuneus, angular gyrus, postcentral gyrus, and inferior parietal lobule; occipital lobes including the lingual gyrus and cuneus; temporal lobes including the fusiform gyrus and middle temporal gyrus; and the limbic system including the cingulate gyrus. These specific brain regions belonged to important networks known as the default mode network, the executive control network, and the visual network.

Conclusion: The present study determined specific abnormal brain regions in sVCI patients, and these brain regions with specific changes were found to belong to important brain functional networks. The findings objectively present the exact abnormalities within the brain, which help further understand the pathogenesis of sVCI and identify them as potential imaging biomarkers. The results may also provide a basis for new approaches to treatment.
Non-stenotic Carotid Plaques in Embolic Stroke of Unknown Source
Authors: Kamtchum-Tatuene Joseph , Nomani Ali Z. , Falcione Sarina , Munsterman Danielle , Sykes Gina , Joy Twinkle , Spronk Elena , Vargas Maria Isabel , Jickling Glen C.
Published: September 2021

Embolic stroke of unknown source (ESUS) represents one in five ischemic strokes. Ipsilateral non-stenotic carotid plaques are identified in 40% of all ESUS. In this narrative review, we summarize the evidence supporting the potential causal relationship between ESUS and non-stenotic carotid plaques; discuss the remaining challenges in establishing the causal link between non-stenotic plaques and ESUS and describe biomarkers of potential interest for future research. In support of the causal relationship between ESUS and non-stenotic carotid plaques, studies have shown that plaques with high-risk features are five times more prevalent in the ipsilateral vs. the contralateral carotid and there is a lower incidence of atrial fibrillation during follow-up in patients with ipsilateral non-stenotic carotid plaques. However, non-stenotic carotid plaques with or without high-risk features often coexist with other potential etiologies of stroke, notably atrial fibrillation (8.5%), intracranial atherosclerosis (8.4%), patent foramen ovale (5–9%), and atrial cardiopathy (2.4%). Such puzzling clinical associations make it challenging to confirm the causal link between non-stenotic plaques and ESUS. There are several ongoing studies exploring whether select protein and RNA biomarkers of plaque progression or vulnerability could facilitate the reclassification of some ESUS as large vessel strokes or help to optimize secondary prevention strategies.
EEG Characteristics to Hyperventilation by Age and Sex in Patients With Various Neurological Disorders
Authors: Khachidze Irma , Gugushvili Manana , Advadze Maia
Published: September 2021

Introduction: Hyperventilation provocation test(s) (HPT) concomitant to electroencephalography (EEG) may detect hidden disorders of the nervous system (CNS). There are various types of abnormal EEG in responses to HPT that provoke different interpretations. However, it is not evident how the onset time of pathological EEG responses to hyperventilation (PERH) reveals dysfunction of the CNS in humans. It is also not clear if age and biological sex affect EEG characteristics in response to HPT. Our previous studies have revealed three types of PERH (disorganization of basic rhythm, paroxysmal discharges, epileptiform activity) concerning the manifestation time of first, second, and third minutes. The current work aims to classify the PERH with regards to age (3–6, 7–12, 13–18, 19–30, 31–50, 50 > year) and the biological sex of the patients.

Methods: This study examined the EEG of 985 outpatients with various functional disorders of the CNS. The patients were assigned to one of three experimental groups based on the time occurrence of PERH in response to the HPT.

Results: The disorganized basic EEG rhythm in the first, second, third minute of HPT was observed across all age and sex groups. All three types of PERH in the first minute were comparable for both sexes. However, some discrepancies between females compared to males were observed in the second and third minutes. All three types of PERH in the first and the second minutes were found only in women. The second type of PERH has revealed at the second minute of PHT in 13–18-year-old five girls.

Conclusion: The three main types of PERH were detected at the first minute in all age groups and sex in patients with various CNS dysfunctions. It is diagnostically informative should be used as a marker during the monitoring of treatment. The specific activity of the brain's response to HPT depends on time, age, sex. The data indicate that taking into account sex differences and age during HPT leads to better results. The sensitivity and severity of the NS reaction toward hypocapnia, stress, and emotion increase in women. Therefore, in such cases should not be recommended to expand functional loads.
Effects of Slow Oscillatory Transcranial Alternating Current Stimulation on Motor Cortical Excitability Assessed by Transcranial Magnetic Stimulation
Authors: Geffen Asher , Bland Nicholas , Sale Martin V.
Published: September 2021

Graphical Abstract

Thirty healthy participants received 60 trials of intermittent SO (0.75 Hz) tACS (1 trial = 16 s on + 16 s off) at an intensity of 2 mA. Motor cortical excitability was assessed using TMS-induced MEPs (blue waveforms) acquired across different oscillatory phases during (i.e., online; red arrows) and outlasting (i.e., offline; green arrows) tACS, as well as at the start and end of the stimulation session (blue arrows). Mean MEP amplitude increased by ∼41% from pre- to post-tACS (P = 0.013); however, MEP amplitudes were not modulated with respect to the tACS phase.
THINGSvision: A Python Toolbox for Streamlining the Extraction of Activations From Deep Neural Networks
Authors: Muttenthaler Lukas , Hebart Martin N.
Published: September 2021

Over the past decade, deep neural network (DNN) models have received a lot of attention due to their near-human object classification performance and their excellent prediction of signals recorded from biological visual systems. To better understand the function of these networks and relate them to hypotheses about brain activity and behavior, researchers need to extract the activations to images across different DNN layers. The abundance of different DNN variants, however, can often be unwieldy, and the task of extracting DNN activations from different layers may be non-trivial and error-prone for someone without a strong computational background. Thus, researchers in the fields of cognitive science and computational neuroscience would benefit from a library or package that supports a user in the extraction task. THINGSvision is a new Python module that aims at closing this gap by providing a simple and unified tool for extracting layer activations for a wide range of pretrained and randomly-initialized neural network architectures, even for users with little to no programming experience. We demonstrate the general utility of THINGsvision by relating extracted DNN activations to a number of functional MRI and behavioral datasets using representational similarity analysis, which can be performed as an integral part of the toolbox. Together, THINGSvision enables researchers across diverse fields to extract features in a streamlined manner for their custom image dataset, thereby improving the ease of relating DNNs, brain activity, and behavior, and improving the reproducibility of findings in these research fields.
Evidence for Cognitive Decline in Chronic Pain: A Systematic Review and Meta-Analysis
Authors: Zhang Xueying , Gao Rui , Zhang Changteng , Chen Hai , Wang Ruiqun , Zhao Qi , Zhu Tao , Chen Chan
Published: September 2021

Background: People with chronic pain (CP) sometimes report impaired cognitive function, including a deficit of attention, memory, executive planning, and information processing. However, the association between CP and cognitive decline was still not clear. Our study aimed to assess the association of CP as a risk factor with cognitive decline among adults.

Methods: We included data from clinical studies. Publications were identified using a systematic search strategy from PubMed, Embase, and Cochrane Library databases from inception to October 10, 2020. We used the mean cognitive outcome data and the standard deviations from each group. The standardized mean difference (SMD) or odds ratio (OR), and 95% confidence intervals (CI) were performed for each cognitive decline outcome. I2-values were assessed to quantify the heterogeneities.

Results: We included 37 studies with a total of 52,373 patients with CP and 80,434 healthy control participants. Because these studies used different evaluative methods, we analyzed these studies. The results showed CP was associated with cognitive decline when the short-form 36 health survey questionnaire (SF-36) mental component summary (SMD = −1.50, 95% CI = −2.19 to −0.81), the Montreal cognitive assessment (SMD = −1.11, 95% CI = −1.60 to −0.61), performance validity testing (SMD = 3.05, 95% CI = 1.74 to 4.37), or operation span (SMD = −1.83, 95% CI = −2.98 to −0.68) were used. However, we got opposite results when the studies using International Classification of Diseases and Related Health Problems classification (OR = 1.58, 95% CI = 0.97 to 2.56), the Mini-Mental State Examination (SMD = −0.42, 95% CI = −0.94 to 0.10; OR = 1.14, 95% CI = 0.91 to 1.42), and Repeatable Battery for the Assessment of Neuropsychological Status memory component (SMD = −0.06, 95% CI = −0.37 to 0.25).

Conclusion: There may be an association between CP and the incidence of cognitive decline when some cognitive, evaluative methods were used, such as short-form 36 health survey questionnaire, Montreal cognitive assessment, performance validity testing, and operation span.
Parvalbumin Interneurons and Perineuronal Nets in the Hippocampus and Retrosplenial Cortex of Adult Male Mice After Early Social Isolation Stress and Perinatal NMDA Receptor Antagonist Treatment
Authors: Klimczak Patrycja , Rizzo Arianna , Castillo-Gómez Esther , Perez-Rando Marta , Gramuntell Yaiza , Beltran Marc , Nacher Juan
Published: September 2021

Both early life aversive experiences and intrinsic alterations in early postnatal neurodevelopment are considered predisposing factors for psychiatric disorders, such as schizophrenia. The prefrontal cortex and the hippocampus have protracted postnatal development and are affected in schizophrenic patients. Interestingly, similar alterations have been observed in the retrosplenial cortex (RSC). Studies in patients and animal models of schizophrenia have found alterations in cortical parvalbumin (PV) expressing interneurons, making them good candidates to study the etiopathology of this disorder. Some of the alterations observed in PV+ interneurons may be mediated by perineuronal nets (PNNs), specialized regions of the extracellular matrix, which frequently surround these inhibitory neurons. In this study, we have used a double hit model (DHM) combining a single perinatal injection of an NMDAR antagonist (MK801) to disturb early postnatal development and post-weaning social isolation as an early life aversive experience. We have investigated PV expressing interneurons and PNNs in the hippocampus and the RSC of adult male mice, using unbiased stereology. In the CA1, but not in the CA3 region, of the hippocampus, the number of PNNs and PV + PNN+ cells was affected by the drug treatment, and a significant decrease of these parameters was observed in the groups of animals that received MK801. The percentage of PNNs surrounding PV+ cells was significantly decreased after treatment in both hippocampal regions; however, the impact of isolation was observed only in CA1, where isolated animals presented lower percentages. In the RSC, we observed significant effects of isolation, MK801 and the interaction of both interventions on the studied parameters; in the DHM, we observed a significantly lower number of PV+, PNNs, and PV+PNN+cells when compared to control mice. Similar significant decreases were observed for the groups of animals that were just isolated or treated with MK801. To our knowledge, this is the first report on such alterations in the RSC in an animal model combining neurodevelopmental alterations and aversive experiences during infancy/adolescence. These results show the impact of early-life events on different cortical regions, especially on the structure and plasticity of PV+ neurons and their involvement in the emergence of certain psychiatric disorders.
Origanum majorana L.: A Nutritional Supplement With Immunomodulatory Effects
Authors: Wang Senye , Zhou Li , Attia Fatma Al-Zahra K. K. , Tang Qi , Wang Mengke , Liu Zhenhua , Waterhouse Geoffrey I. N. , Liu Lijun , Kang Wenyi
Published: September 2021

Origanum majorana L. is an aromatic herb that has been grown in several Mediterranean countries since ancient times, but became popular during the Middle Ages as a medicinal plant and seasoning ingredient. O. majorana has many pharmacological effects, but its immunoreactive components and mechanisms are still unclear. In this study, four compounds were isolated and identified from O. majorana by a spectral analysis, including 1H and 13C-NMR. They were 1H-indole-2-carboxylic acid (1), (+)-laricresol (2), (+)-isolaricresol (3), and procumboside B (4, pB), which were isolated for the first time in O. majorana. The immunomodulatory effects of the four compounds were screened, and pB had good immunomodulatory activity on RAW 264.7 cells. The immunomodulatory mechanism of pB was proved, in which pB could increase the secretion of nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS) and simultaneously upregulate the expression of CD80 and CD86 on the cell surface. These results suggested that the mechanism of pB may be related to the activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs)-signaling pathways. O. majorana is rich in nutrients and is commonly used in diets, so it can be used as a nutritional supplement with immunomodulatory effects.
Analysis of Immune Landscape Reveals Prognostic Significance of Cytotoxic CD4+ T Cells in the Central Region of pMMR CRC
Authors: Qi Jingwen , Liu Xiaoyan , Yan Peian , He Shangwen , Lin Yuhao , Huang Zhiwei , Zhang Shenyan , Xie Siyu , Li Yanfeng , Lu Xiaofei , Wu Yingjun , Zhou Yangshu , Yuan Juanjuan , Cai Ting , Zheng Xiaojun , Ding Yanqing , Yang Wei
Published: September 2021

Background

Mismatch repair proficient colorectal cancer (pMMR CRC) lacks effective treatments and has a poor prognosis, which can be attributed to the complexity of tumor microenvironment. The coordinated function of immune cells is vital to anti-tumor immunity. However, the spatial characteristics of immune cells in the pMMR CRC immune microenvironment and their relationship with clinical prognosis are not fully understood. Meanwhile, the immune modulatory effect of neoadjuvant chemotherapy (NCT), which is the first-line treatment of pMMR CRC, needs further investigation. Therefore, this study aims to explore the spatial dynamics of immune cells and its prognostic value in pMMR CRC.

Methods

We analyzed the various immune cells in formalin-fixed, paraffin-embedded tumor tissues which were collected from 77 patients with stage II/III of pMMR CRC, including 39 non-NCT treated and 38 NCT treated patients. We used the optimized multiplex immunohistochemistry (mIHC) to identify and quantify the density, type and location of immune cells in pMMR CRC. Multivariate survival analysis was performed to assess the relationship of immune profiles and clinical prognosis of pMMR CRC patients.

Results

The densities of most T cell subsets, B cells and macrophages were higher in the central region of the pMMR CRC than in the invasion margin. Tumor infiltrating lymphocytes (TILs), especially the infiltration of CD4+ GzmB+ T cells in the central region of the tumor was identified to be positively correlated with the prognosis of the patients. Multivariate analysis confirmed that CD4+ GzmB+ T cells population was an independent predictor of disease-free survival (DFS) in non-NCT group. Meanwhile, NCT enhanced the infiltration of CD4+ GzmB+ T cells in the central region of the pMMR CRC, which was also identified as an independent protective factor of overall survival (OS) and DFS in NCT group.

Conclusion

We demonstrated that the level of CD4+ GzmB+ T cells located in the center of tumor could provide great prognostic value for pMMR CRC patients. And the application of neoadjuvant chemotherapy further improves the infiltration of CD4+ GzmB+ T cells in the central compartment. Further studies into the application of CD4+ GzmB+ T cells in tumor immunotherapy are needed.
Gene Expression Profiling for Differential Diagnosis of Liver Metastases: A Multicenter, Retrospective Cohort Study
Authors: Wang Qifeng , Li Fen , Jiang Qingming , Sun Yifeng , Liao Qiong , An Huimin , Li Yunzhu , Li Zhenyu , Fan Lifang , Guo Fang , Xu Qinghua , Wo Yixin , Ren Wanli , Yue Junqiu , Meng Bin , Liu Weiping , Zhou Xiaoyan
Published: September 2021

Background

Liver metastases (LM) are the most common tumors encountered in the liver and continue to be a significant cause of morbidity and mortality. Identification of the primary tumor of any LM is crucial for the implementation of effective and tailored treatment approaches, which still represents a difficult problem in clinical practice.

Methods

The resection or biopsy specimens and associated clinicopathologic data were archived from seven independent centers between January 2017 and December 2020. The primary tumor sites of liver tumors were verified through evaluation of available medical records, pathological and imaging information. The performance of a 90-gene expression assay for the determination of the site of tumor origin was assessed.

Result

A total of 130 LM covering 15 tumor types and 16 primary liver tumor specimens that met all quality control criteria were analyzed by the 90-gene expression assay. Among 130 LM cases, tumors were most frequently located in the colorectum, ovary and breast. Overall, the analysis of the 90-gene signature showed 93.1% and 100% agreement rates with the reference diagnosis in LM and primary liver tumor, respectively. For the common primary tumor types, the concordance rate was 100%, 95.7%, 100%, 93.8%, 87.5% for classifying the LM from the ovary, colorectum, breast, neuroendocrine, and pancreas, respectively.

Conclusion

The overall accuracy of 93.8% demonstrates encouraging performance of the 90-gene expression assay in identifying the primary sites of liver tumors. Future incorporation of the 90-gene expression assay in clinical diagnosis will aid oncologists in applying precise treatments, leading to improved care and outcomes for LM patients.
Allergic Rhinitis Improvement in Asthmatic Children After Using Acaricidal Bait: A Randomized, Double-Blind, Cross-Placebo Study
Authors: Chen Ming , Wu Yufen , Yuan Shuhua , Tang Mingyu , Zhang Lei , Chen Jiande , Li Luanluan , Wu Jinhong , Zhang Jing , Yin Yong
Published: September 2021

Objective: This study aimed to evaluate the effects of acaricidal bait use on the house dust mite (HDM) allergen concentration and occurrence of allergic rhinitis (AR) and asthma symptoms in children sensitized to HDMs.

Study Design: Sixty-six children (3–12 years old) with AR and asthma sensitized to HDMs were randomly assigned to receive an acaricidal bait intervention for 8 weeks and a placebo intervention for 8 weeks separated by a 4-week washout period. The visual analog scale (VAS) score, rhinitis control assessment test (RCAT) score, rhinoconjunctivitis quality of life questionnaire (RQLQ) score, asthma control questionnaire-5 (ACQ-5) score and HDM allergen levels were monitored.

Results: HDM allergen levels were significantly decreased after 8 weeks (Δder p2+f2 2.282 (3.516) μg/g vs. 0.147 (0.25) μg/g, P < 0.05) in the acaricidal bait group compared with the placebo group. The VAS, RCAT and RQLQ scores in the acaricidal bait group were also significantly improved (ΔVAS 7.5 (16) vs. 3 (18), P < 0.05; ΔRCAT−3 (5) vs. 0 (7), P < 0.05; ΔRQLQ 4.5 (8) vs. 1 (8), P < 0.05), but the ACQ-5 score did not improve (ΔACQ-5 0.2 (0.4) vs. 0 (0.65), P > 0.05).

Conclusion: Acaricidal bait reduced HDM exposure and improved rhinitis symptoms. This trial is registered at www.chictr.org.cn.
Use of Hypnosis in Paediatric Gastrointestinal Endoscopy: A Pilot Study
Authors: Tran Léa Chantal , Coopman Stéphanie , Rivallain Céline , Aumar Madeleine , Guimber Dominique , Nicolas Audrey , Darras Valérie , Turck Dominique , Gottrand Frédéric , Ley Delphine
Published: September 2021

Objectives: Experience of hypnosis in gastrointestinal (GI) endoscopy is scarce in children. Our aims were to assess the rate of successful GI endoscopy performed using hypnosis alone or in combination with midazolam, with or without additional equimolar mixture of oxygen and nitrous oxide (EMONO), and to identify predictive factors of successful endoscopy in children.

Methods: This prospective single-centre study included children older than 6 years requiring a diagnostic esophagogastroduodenoscopy (EGD) or rectosigmoidoscopy. Ericksonian hypnosis was performed alone or in combination with midazolam, with or without additional EMONO. Successful endoscopy was defined by a complete and well-tolerated procedure. Levels of satisfaction of the endoscopist, nurse, and patient were assessed.

Results: One hundred forty children [70 boys, median age: 12 years (Q1–Q3: 9–14)] were included over a 14-month period. They underwent EGD in 51.4% (n = 72) and rectosigmoidoscopy in 48.6% (n = 68) of cases. EMONO and midazolam were combined with hypnosis in 136 cases (97.1%). Successful endoscopy rate reached 82.9%. The procedure was interrupted due to poor tolerance and was rescheduled under general anaesthesia in 11 patients (7.9%). Predictive factors for successful endoscopy were older age (13 vs. 8 years, OR: 1.34, CI 95% [1.10–1.62], p = 0.003) and type of endoscopy (EGD vs. rectosigmoidoscopy, OR: 16.34 [2.14–124.68], p = 0.007). A good cooperation of the patient was reported by the endoscopist and the nurse in 88.4 and 86.9% of cases, respectively. Ninety-two per cent of patients mentioned that the procedure went well.

Conclusions: Our study suggests that hypnosis combined with EMONO and/or midazolam is of additional value to perform diagnostic EGD or rectosigmoidoscopy in children older than 6 years without systematic need for general anaesthesia.
Dissolving Polymer Microneedles for Transdermal Delivery of Insulin
Authors: Zhang Na , Zhou Xinxin , Liu Libo , Zhao Lini , Xie Hui , Yang Zhihang
Published: September 2021

It’s of great significance to develop insulin-loaded dissolving microneedles (MNs) which are fabricated with various methods and materials for transdermal delivery of insulin to effectively and efficiently treat diabetes. In this work, we present a kind of FITC-insulin tip-loaded dissolving MNs fabricated with the mixture of polyvinyl alcohol (PVA) and sucrose using homemade PDMS MNs mold under vacuum conditions. The uniform appearance of MN arrays contributes to controlling the drug dosage well as required. Sufficient mechanical strength for penetrating tough stratum corneum can be obtained by vacuum frozen-drying for at least 6 h after peeling MNs off the mold. About 90% of the FITC-insulin is localized in the conical MN tips and can be released into the skin within 2 min after insertion. The in vivo insulin absorption study and hypoglycemic effect in diabetic mice demonstrate that the proposed insulin-loaded MNs can efficiently deliver the insulin to the systemic circulation and exhibit a similar effect to hypodermic injection on hypoglycemic administration. Together these results suggested that the efficient MN fabrication process proposed in this work shows great potential for mass production and practical application of drug-loaded dissolving MNs in the future.
Berberine Potentiates Insulin Secretion and Prevents β-cell Dysfunction Through the miR-204/SIRT1 Signaling Pathway
Authors: Lv Xiaoyan , Zhao Yali , Yang Xuehan , Han Hao , Ge Yue , Zhang Meishuang , Zhang Hansi , Zhang Ming , Chen Li
Published: September 2021

Pancreatic β-cell dysfunction is a key link during the progression of type 2 diabetes (T2DM), and SIRT1 participates in the regulation of various physiological activities of islet β-cells. However, as a key link in signal transduction, it is not clear how SIRT1 is regulated. By TargetScan prediction, we found that miR-204, which is enriched in islets, has highly complementary binding sites with SIRT1. Therefore, we speculate that miR-204 may be the upstream regulatory target of SIRT1 in islets and thus participate in the occurrence of β-cell dysfunction. In this study, we explored the association between miR-204 and β-cell dysfunction, the therapeutic effects of berberine (BBR) on β-cell function and the possible mechanisms. We found that miR-204 increased and SIRT1 mRNA and protein levels decreased significantly in islets both in vivo and in vitro. MIN6 cells induced by palmitic acid exhibited increased apoptosis, and the accumulation of insulin and ATP in the supernatant decreased. Importantly, palmitic acid treatment combined with miR-204 silencing showed opposite changes. MiR-204 overexpression in MIN6 cells increased apoptosis and decreased insulin and ATP production and SIRT1 expression. SIRT1 overexpression reversed the damage to β-cells caused by miR-204. The BBR treatment effectively improved insulin synthesis, reduced miR-204 levels, and increased SIRT1 expression in islet tissue in diabetic mice. Overexpression of miR-204 reversed the protective effect of BBR on apoptosis and insulin secretion in MIN6 cells. Our study identifies a novel correlation between miR-204 and β-cell dysfunction in T2DM and shows that administration of BBR leads to remission of β-cell dysfunction by regulating the miR-204/SIRT1 pathway.