bluuebunny/crossref_metadata_2025 huggingface dataset:
Cellular Interaction Analysis Characterizing Immunosuppressive Microenvironment Functions in MM Tumorigenesis From Precursor Stages
Authors: Liu Zhenhao , Zhang Siwen , Li Hong , Guo Jiaojiao , Wu Dan , Zhou Wen , Xie Lu
Published: March 2022

Cell–cell interaction event (CCEs) dysregulation may relate to the heterogeneity of the tumor microenvironment (TME) and would affect therapeutic responses and clinical outcomes. To reveal the alteration of the immune microenvironment in bone marrow from a healthy state to multiple myeloma (MM), scRNA-seq data of the four states, including healthy state normal bone marrow (NBM) and three disease states (MGUS, SMM, and MM), were collected for analysis. With immune microenvironment reconstruction, the cell types, including NK cells, CD8+T cells, and CD4+T cells, with a higher percentage in disease states were associated with prognosis of MM patients. Furthermore, CCEs were annotated and dysregulated CCEs were identified. The number of CCEs were significantly changed between disease states and NBM. The dysregulated CCEs participated in regulation of immune cell proliferation and immune response, such as MIF-TNFRSF14 interacted between early B cells and CD8+T cells. Moreover, CCE genes related to drug response, including bortezomib and melphalan, provide candidate therapeutic markers for MM treatment. Furthermore, MM patients were separated into three risk groups based on the CCE prognostic signature. Immunoregulation-related differentiation and activation of CD4+T cells corresponded to the progression status with moderate risk. These results provide a comprehensive understanding of the critical role of intercellular communication in the immune microenvironment over the evolution of premalignant MM, which is related to the tumorigenesis and progression of MM, which moreover, suggests a way of potential target selection for clinical intervention.
Construction of a Novel Immune-Related mRNA Signature to Predict the Prognosis and Immune Characteristics of Human Colorectal Cancer
Authors: Li Jianxin , Han Ting , Wang Xin , Wang Yinchun , Chen Xuan , Chen Wangsheng , Yang Qingqiang
Published: March 2022

Background: Anti-cancer immunotherapeutic approaches have gained significant efficacy in multiple cancer types. However, not all patients with colorectal cancer (CRC) could benefit from immunotherapy due to tumor heterogeneity. The purpose of this study was to construct an immune-related signature for predicting the immune characteristics and prognosis of CRC.

Methods: RNA-sequencing data and corresponding clinical information of patients with CRC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and immune-related genes (IRGs) were downloaded from the Immunology Database and Analysis Portal (ImmPort). Then, we utilized univariate, lasso regression, and multivariate cox regression to identify prognostic IRGs and develop the immune-related signature. Subsequently, a nomogram was established based on the signature and other prognostic factors, and its predictive capacity was assessed by receiver operating characteristic (ROC) and decision curve analysis (DCA). Finally, associations between the signature and the immune characteristics of CRC were assessed.

Results: In total, 472 samples downloaded from TCGA were divided into the training cohort (236 samples) and internal validation cohort (236 samples), and the GEO cohort was downloaded as an external validation cohort (122 samples). A total of 476 differently expressed IRGs were identified, 17 of which were significantly correlated to the prognosis of CRC patients. Finally, 10 IRGs were filtered out to construct the risk score signature, and patients were divided into low- and high-risk groups according to the median of risk scores in the training cohort. The high-risk score was significantly correlated with unfavorable survival outcomes and aggressive clinicopathological characteristics in CRC patients, and the results were further confirmed in the internal validation cohort, entire TCGA cohort, and external validation cohort. Immune infiltration analysis revealed that patients in the low-risk group infiltrated with high tumor-infiltrating immune cell (TIIC) abundances compared to the high-risk group. Moreover, we also found that the immune checkpoint biomarkers were significantly overexpressed in the low-risk group.

Conclusion: The prognostic signature established by IRGs showed a promising clinical value for predicting the prognosis and immune characteristics of human CRC, which contribute to individualized treatment decisions.
Genomic Evidence Supports the Recognition of Endometriosis as an Inflammatory Systemic Disease and Reveals Disease-Specific Therapeutic Potentials of Targeting Neutrophil Degranulation
Authors: Bao Chaohui , Wang Hengru , Fang Hai
Published: March 2022

Background

Endometriosis, classically viewed as a localized disease, is increasingly recognized as a systemic disease with multi-organ effects. This disease is highlighted by systemic inflammation in affected organs and by high comorbidity with immune-mediated diseases.

Results

We provide genomic evidence to support the recognition of endometriosis as an inflammatory systemic disease. This was achieved through our genomics-led target prioritization, called ‘END’, that leverages the value of multi-layered genomic datasets (including genome-wide associations in disease, regulatory genomics, and protein interactome). Our prioritization recovered existing proof-of-concept therapeutic targeting in endometriosis and outperformed competing prioritization approaches (Open Targets and Naïve prioritization). Target genes at the leading prioritization revealed molecular hallmarks (and possibly the cellular basis as well) that are consistent with systemic disease manifestations. Pathway crosstalk-based attack analysis identified the critical gene AKT1. In the context of this gene, we further identified genes that are already targeted by licensed medications in other diseases, such as ESR1. Such analysis was supported by current interests targeting the PI3K/AKT/mTOR pathway in endometriosis and by the fact that therapeutic agents targeting ESR1 are now under active clinical trials in disease. The construction of cross-disease prioritization map enabled the identification of shared and distinct targets between endometriosis and immune-mediated diseases. Shared target genes identified opportunities for repurposing existing immunomodulators, particularly ﻿disease-modifying anti-rheumatic drugs (such as TNF, IL6 and IL6R blockades, and JAK inhibitors). Genes highly prioritized only in endometriosis revealed disease-specific therapeutic potentials of targeting neutrophil degranulation – the exocytosis that can facilitate metastasis-like spread to distant organs causing inflammatory-like microenvironments.

Conclusion

Improved target prioritization, along with an atlas of in silico predicted targets and repurposed drugs (available at https://23verse.github.io/end), provides genomic insights into endometriosis, reveals disease-specific therapeutic potentials, and expands the existing theories on the origin of disease.
Proteomic and Single-Cell Transcriptomic Dissection of Human Plasmacytoid Dendritic Cell Response to Influenza Virus
Authors: Ghanem Mustafa H. , Shih Andrew J. , Khalili Houman , Werth Emily G. , Chakrabarty Jayanta K. , Brown Lewis M. , Simpfendorfer Kim R. , Gregersen Peter K.
Published: March 2022

Plasmacytoid dendritic cells [pDCs] represent a rare innate immune subset uniquely endowed with the capacity to produce substantial amounts of type-I interferons. This function of pDCs is critical for effective antiviral defenses and has been implicated in autoimmunity. While IFN-I and select cytokines have been recognized as pDC secreted products, a comprehensive agnostic profiling of the pDC secretome in response to a physiologic stimulus has not been reported. We applied LC-MS/MS to catalogue the repertoire of proteins secreted by pDCs in the unperturbed condition and in response to challenge with influenza H1N1. We report the identification of a baseline pDC secretome, and the repertoire of virus-induced proteins including most type-I interferons, various cytokines, chemokines and granzyme B. Additionally, using single-cell RNA-seq [scRNA-seq], we perform multidimensional analyses of pDC transcriptional diversity immediately ex vivo and following stimulation. Our data evidence preexisting pDC heterogeneity, with subsequent highly specialized roles within the pDC population upon stimulation ranging from dedicated cytokine super-producers to cells with APC-like traits. Dynamic expression of transcription factors and surface markers characterize subclusters within activated pDCs. Integrating the proteomic and transcriptomic datasets confirms the pDC-subcluster origin of the proteins identified in the secretome. Our findings represent the most comprehensive molecular characterization of primary human pDCs at baseline, and in response to influenza virus, reported to date.
Enhanced Migratory Ability of Neutrophils Toward Epidermis Contributes to the Development of Psoriasis via Crosstalk With Keratinocytes by Releasing IL-17A
Authors: Liu Xiu-ting , Shi Zhen-rui , Lu Si-yao , Hong Dan , Qiu Xiao-nan , Tan Guo-zhen , Xiong Hui , Guo Qing , Wang Liangchun
Published: March 2022

Microabscess of neutrophils in epidermis is one of the histological hallmarks of psoriasis. The axis of neutrophil–keratinocyte has been thought to play a critical role in the pathogenesis of psoriasis. However, the features and mechanism of interaction between the two cell types remain largely unknown. Herein, we found that blood neutrophils were increased in psoriasis patients, positively correlated with disease severity and highly expressed CD66b, but not CD11b and CD62L compared to healthy controls. Keratinocytes expressed high levels of psoriasis-related inflammatory mediators by direct and indirect interaction with neutrophils isolated from psoriasis patients and healthy controls. The capacity of neutrophils in provoking keratinocytes inflammatory response was comparable between the two groups and is dependent on IL-17A produced by itself. Neutrophils isolated from psoriasis patients displayed more transcriptome changes related to integrin and increased migration capacity toward keratinocytes with high CD11b expression on cell surface. Of interest, neutrophils were more susceptible to keratinocyte stimulation than to fibroblasts and human umbilical vein endothelial cells (HUVECs) in terms of CD11b expression and the production of ROS and NETs. In conclusion, neutrophils from psoriasis patients gain a strong capacity of IL-17A production and integrins expression that possibly facilitates their abilities to promote production of psoriasis-related inflammatory mediators and migration, a phenomenon likely induced by their interaction with keratinocytes but not with fibroblasts. These findings provide a proof-of-concept that development of new drugs targeting migration of neutrophils could be a more specific and safe solution to treat psoriasis.
The S1 Subunit of the SARS-CoV-2 Spike Protein Activates Human Monocytes to Produce Cytokines Linked to COVID-19: Relevance to Galectin-3
Authors: Schroeder John T. , Bieneman Anja P.
Published: March 2022

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly evolved into a pandemic –the likes of which has not been experienced in 100 years. While novel vaccines show great efficacy, and therapeutics continue to be developed, the persistence of disease, with the concomitant threat of emergent variants, continues to impose massive health and socioeconomic issues worldwide. Studies show that in susceptible individuals, SARS-CoV-2 infection can rapidly progress toward lung injury and acute respiratory distress syndrome (ARDS), with evidence for an underlying dysregulated innate immune response or cytokine release syndrome (CRS). The mechanisms responsible for this CRS remain poorly understood, yet hyper-inflammatory features were also evident with predecessor viruses within the β-coronaviridae family, namely SARS-CoV-1 and the Middle East Respiratory Syndrome (MERS)-CoV. It is further known that the spike protein (S) of SARS-CoV-2 (as first reported for other β-coronaviruses) possesses a so-called galectin-fold within the N-terminal domain of the S1 subunit (S1-NTD). This fold (or pocket) shows structural homology nearly identical to that of human galectin-3 (Gal-3). In this respect, we have recently shown that Gal-3, when associated with epithelial cells or anchored to a solid phase matrix, facilitates the activation of innate immune cells, including basophils, DC, and monocytes. A synthesis of these findings prompted us to test whether segments of the SARS-CoV-2 spike protein might also activate innate immune cells in a manner similar to that observed in our Gal-3 studies. Indeed, by immobilizing S components onto microtiter wells, we show that only the S1 subunit (with the NTD) activates human monocytes to produce a near identical pattern of cytokines as those reported in COVID-19-related CRS. In contrast, both the S1-CTD/RBD, which binds ACE2, and the S2 subunit (stalk), failed to mediate the same effect. Overall, these findings provide evidence that the SARS-CoV-2 spike protein can activate monocytes for cytokines central to COVID-19, thus providing insight into the innate immune mechanisms underlying the CRS and the potential for therapeutic interventions.
Age-Associated Seroprevalence of Coronavirus Antibodies: Population-Based Serosurveys in 2013 and 2020, British Columbia, Canada
Authors: Tanunliong Guadalein , Liu Aaron C. , Kaweski Samantha , Irvine Mike , Reyes Romina C. , Purych Dale , Krajden Mel , Morshed Muhammad , Sekirov Inna , Gantt Soren , Skowronski Danuta M. , Jassem Agatha N.
Published: March 2022

Background

Older adults have been disproportionately affected during the SARS-CoV-2 pandemic, including higher risk of severe disease and long-COVID. Prior exposure to endemic human coronaviruses (HCoV) may modulate the response to SARS-CoV-2 infection and contribute to age-related observations. We hypothesized that cross-reactive antibodies to SARS-CoV-2 are associated with antibodies to HCoV and that both increase with age.

Methods

To assess SARS-CoV-2 unexposed individuals, we drew upon archived anonymized residual sero-surveys conducted in British Columbia (BC), Canada, including before SARS-CoV-2 emergence (May, 2013) and before widespread community circulation in BC (May, 2020). Fifty sera, sex-balanced per ten-year age band, were sought among individuals ≤10 to ≥80 years old, supplemented as indicated by sera from March and September 2020. Sera were tested on the Meso Scale Diagnostics (MSD) electrochemiluminescent multiplex immunoassay to quantify IgG antibody against the Spike proteins of HCoV, including alpha (HCoV-229E, HCoV-NL63) and beta (HCoV-HKU1, HCoV-OC43) viruses, and the 2003 epidemic beta coronavirus, SARS-CoV-1. Cross-reactive antibodies to Spike, Nucleocapsid, and the Receptor Binding Domain (RBD) of SARS-CoV-2 were similarly measured, with SARS-CoV-2 sero-positivity overall defined by positivity on ≥2 targets.

Results

Samples included 407 sera from 2013, of which 17 were children ≤10 years. The 2020 samples included 488 sera, of which 88 were children ≤10 years. Anti-Spike antibodies to all four endemic HCoV were acquired by 10 years of age. There were 20/407 (5%) sera in 2013 and 8/488 (2%) in 2020 that were considered sero-positive for SARS-CoV-2 based on MSD testing. Of note, antibody to the single SARS-CoV-2 RBD target was detected in 329/407 (81%) of 2013 sera and 91/488 (19%) of 2020 sera. Among the SARS-CoV-2 overall sero-negative population, age was correlated with anti-HCoV antibody levels and these, notably 229E and HKU1, were correlated with cross-reactive anti-SARS-CoV-2 RBD titres. SARS-CoV-2 overall sero-positive individuals showed higher titres to HCoV more generally.

Conclusion

Most people have an HCoV priming exposure by 10 years of age and IgG levels are stable thereafter. Anti-HCoV antibodies can cross-react with SARS-CoV-2 epitopes. These immunological interactions warrant further investigation with respect to their implications for COVID-19 clinical outcomes.
Efficacy and Safety of BCG Revaccination With M. bovis BCG Moscow to Prevent COVID-19 Infection in Health Care Workers: A Randomized Phase II Clinical Trial
Authors: dos Anjos Laura Raniere Borges , da Costa Adeliane Castro , Cardoso Amanda da Rocha Oliveira , Guimarães Rafael Alves , Rodrigues Roberta Luiza , Ribeiro Kaio Mota , Borges Kellen Christina Malheiros , Carvalho Ana Carolina de Oliveira , Dias Carla Iré Schnier , Rezende Aline de Oliveira , Souza Carine de Castro , Ferreira Renato Rodney Mota , Saraiva Guylherme , Barbosa Lilia Cristina de Souza , Vieira Tayro da Silva , Conte Marcus Barreto , Rabahi Marcelo Fouad , Kipnis André , Junqueira-Kipnis Ana Paula
Published: March 2022

The Bacillus Calmette-Guérin (BCG) vaccine, which is widely used to protect children against tuberculosis, can also improve immune response against viral infections. This unicentric, randomized-controlled clinical trial assessed the efficacy and safety of revaccination with BCG Moscow in reducing the positivity and symptoms of COVID-19 in health care workers (HCWs) during the COVID-19 pandemic. HCWs who had negative COVID-19 IgM and IgG and who dedicated at least eight hours per week in facilities that attended to individuals suspected of having COVID-19 were included in the study and were followed for 7, 15, 30, 60, and 180 days by telemedicine. The HCWs were randomly allocated to a revaccinated with BCG group, which received the BCG vaccine, or an unvaccinated group. Revaccination with BCG Moscow was found to be safe, and its efficacy ranged from 30.0% (95.0%CI -78.0 to 72.0%) to 31.0% (95.0%CI -74.0 to 74.0%). Mycobacterium bovis BCG Moscow did not induce NK cell activation at 15–20 days post-revaccination. As hypothesized, revaccination with BCG Moscow was associated with a lower incidence of COVID-19 positivity, though the results did not reach statistical significance. Further studies should be carried out to assess whether revaccination with BCG is able to protect HCWs against COVID-19. The protocol of this clinical trial was registered on August 5th, 2020, at REBEC (Registro Brasileiro de Ensaios Clínicos, RBR-4kjqtg - ensaiosclinicos.gov.br/rg/RBR-4kjqtg/1) and the WHO (# U1111-1256-3892). The clinical trial protocol was approved by the Comissão Nacional de ética de pesquisa- CONEP (CAAE 31783720.0.0000.5078).
Influence of Soybean Meal on Intestinal Mucosa Metabolome and Effects of Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway in Mirror Carp (Cyprinus carpio Songpu)
Authors: Zhao Jingyi , Xu Qiyou
Published: March 2022

This study aimed to explore the influence of soybean meal on intestinal mucosa metabolome and signaling pathway of mirror carp (Cyprinus carpio Songpu) by integrating liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics. Fish meal (Con) was control group, soybean meal (Dou) group, AMPK activator (300 mg kg–1 Metformin, Met) and AMPK inhibitor (0.2 mg kg–1 Compound-c, c-Com) which added to soybean meal were experimental groups. The metabolome profiles of the intestinal mucosa were determined in fish fed diets Con, Dou, Met, and c-Com on 7th and 59th day. The results were shown: compared with the Con group, the weight gain rate and the specific growth rate of fish experimental groups were significantly decreased (P < 0.05), feed conversion ratio (FCR) was significantly increased (P < 0.05). Compared with the Con group, sphingosine, glycocholic acid, majorities of sugar metabolites were up-regulated, and phosphatidylcholine (PC) and lysophosphatidylcholine (LysoPC), amino acids were reduced significantly in all experiment groups (P < 0.05). Oxidized glutathione was up-regulated in Dou on 7th day, Met on 7th and 59th day (P < 0.05). ADP (adenosine diphosphate) and AMP (adenosine monophpsphate) were up-regulated in Dou, Met, c-Com on 59th day (P < 0.05). Compared with the Dou group, sphingosine was down-regulated on 7th day, up-regulated on 59th day in Met and on 7th and 59th day in c-Com (P < 0.05). Oxidized glutathione and isocitrate on 7th day, L-Valine, L-histidine, and L-isoleucine on 59th day were up-regulated in Met (P < 0.05). Nucleoside metabolites and ADP were up-regulated in c-Com on 7th day (P < 0.05). In conclusion, soybean meal influenced intestinal mucosa metabolic processes, including lipid, amino acid, sugar, apoptosis, and oxidative injury; and changed energy metabolism in intestinal mucosa, enriched in the AMPK, TOR, FoxO signaling pathway; Metformin could aggravate oxidative damage, alleciated apoptosis for the short term, and aggravate apoptosis, improve carbohydrate catabolism and amino acid anabolism for the long term; Compound-c exacerbated apoptosis. repaired oxidative damage, and enhanced nucleoside catabolism.
Emergence of Lyme Disease on the French Riviera, a Retrospective Survey
Authors: Sevestre Jacques , Benichou Antoine , Rio Vanessa , Delaunay Pascal , Gonfrier Géraldine , Martaresche Cécile , Carlo Virginie , Nakam Sarah , Mondain Véronique , Carles Michel , Jeandel Pierre Yves , Durant Jacques
Published: March 2022

Background

The French Riviera has been declared free of Lyme Borreliosis (LB) for years. Many patients are referred for presumed LB, sometimes with atypical clinical signs and/or doubtful serology, calling the diagnosis into question.

Methods

Patients were assessed for LB diagnosis, depending on clinical presentation, laboratory findings, and further examination by other medical professionals.

Results

Among 255 patients, 45 (18%) were classified as confirmed LB cases [including 28 ongoing LB (10%) and 17 past LB (8%)], and for 210 (82%) a Lyme borreliosis diagnosis was ruled out. Among ongoing LB, 56% had been exposed to or bitten by ticks, exclusively in rural locations of the Alpes-Maritimes. As a result of the diagnostic procedure, 132 (52%) patients had been treated. An alternative diagnosis was established for 134 (52%) patients, covering a wide range of conditions, including mainly psychological (28%) and neurological conditions (25%) or inflammatory and systemic diseases (22%).

Conclusions

Our results strongly suggest the endemicity of LB in the Alpes-Maritimes region. Confirmed LB accounted for 18% of patients while 52% were diagnosed with other conditions.
Toward Microbial Recycling and Upcycling of Plastics: Prospects and Challenges
Authors: Verschoor Jo-Anne , Kusumawardhani Hadiastri , Ram Arthur F. J. , de Winde Johannes H.
Published: March 2022

Annually, 400 Mt of plastics are produced of which roughly 40% is discarded within a year. Current plastic waste management approaches focus on applying physical, thermal, and chemical treatments of plastic polymers. However, these methods have severe limitations leading to the loss of valuable materials and resources. Another major drawback is the rapid accumulation of plastics into the environment causing one of the biggest environmental threats of the twenty-first century. Therefore, to complement current plastic management approaches novel routes toward plastic degradation and upcycling need to be developed. Enzymatic degradation and conversion of plastics present a promising approach toward sustainable recycling of plastics and plastics building blocks. However, the quest for novel enzymes that efficiently operate in cost-effective, large-scale plastics degradation poses many challenges. To date, a wide range of experimental set-ups has been reported, in many cases lacking a detailed investigation of microbial species exhibiting plastics degrading properties as well as of their corresponding plastics degrading enzymes. The apparent lack of consistent approaches compromises the necessary discovery of a wide range of novel enzymes. In this review, we discuss prospects and possibilities for efficient enzymatic degradation, recycling, and upcycling of plastics, in correlation with their wide diversity and broad utilization. Current methods for the identification and optimization of plastics degrading enzymes are compared and discussed. We present a framework for a standardized workflow, allowing transparent discovery and optimization of novel enzymes for efficient and sustainable plastics degradation in the future.
LncRNA FAM13A-AS1 Promotes Renal Carcinoma Tumorigenesis Through Sponging miR-141-3p to Upregulate NEK6 Expression
Authors: Wang Xin Jun , Li Si , Fang Jiang , Yan Zhi Jian , Luo Guang Cheng
Published: March 2022

Long non-coding RNAs are a diverse catalog of RNAs that have been implicated in various aspects of tumorigenesis. Emerging evidence indicates that they play crucial roles in tumor growth, disease progression, and drug resistance. However, the clinical significance of lncRNAs in tumor behavior prediction and disease prognosis as well as the underlying mechanism in renal cell carcinoma (RCC) remains elusive. By analyzing the gene expression profiles of 539 RCC patients from the TCGA cohort and 40 RCC patients from an independent cohort, we identified FAM13A-AS1, a poorly studied lncRNA, upregulated in RCC patients. Knockdown experiments revealed that FAM13A-AS1 promotes cell proliferation, migration, and invasion by interacting with miR-141-3p. FAM13A-AS1 regulates the expression of NEK6 by decoying miR-141-3p. In addition, there was a strong positive correlation between the expression of FAM13A-AS1 and NEK6 in RCC patients. In summary, our results demonstrate the oncogenic role of FAM13A-AS1 in RCC and suggest that it promotes tumorigenesis by upregulating the expression of NEK6 by competitively binding to miR-141-3p.
Extracellular Vesicles Contribute to the Metabolism of Transthyretin Amyloid in Hereditary Transthyretin Amyloidosis
Authors: Yamaguchi Hiroki , Kawahara Hironori , Kodera Noriyuki , Kumaki Ayanori , Tada Yasutake , Tang Zixin , Sakai Kenji , Ono Kenjiro , Yamada Masahito , Hanayama Rikinari
Published: March 2022

Hereditary (variant) transthyretin amyloidosis (ATTRv amyloidosis), which is caused by variants in the transthyretin (TTR) gene, leads to TTR amyloid deposits in multiple organs and various symptoms such as limb ataxia, muscle weakness, and cardiac failure. Interaction between amyloid proteins and extracellular vesicles (EVs), which are secreted by various cells, is known to promote the clearance of the proteins, but it is unclear whether EVs are involved in the formation and deposition of TTR amyloid in ATTRv amyloidosis. To clarify the relationship between ATTRv amyloidosis and EVs, serum-derived EVs were analyzed. In this study, we showed that cell-derived EVs are involved in the formation of TTR amyloid deposits on the membrane of small EVs, as well as the deposition of TTR amyloid in cells. Human serum-derived small EVs also altered the degree of aggregation and deposition of TTR. Furthermore, the amount of TTR aggregates in serum-derived small EVs in patients with ATTRv amyloidosis was lower than that in healthy controls. These results indicate that EVs contribute to the metabolism of TTR amyloid, and suggest that TTR in serum-derived small EVs is a potential target for future ATTRv amyloidosis diagnosis and therapy.
NeuralDock: Rapid and Conformation-Agnostic Docking of Small Molecules
Authors: Sha Congzhou M. , Wang Jian , Dokholyan Nikolay V.
Published: March 2022

Virtual screening is a cost- and time-effective alternative to traditional high-throughput screening in the drug discovery process. Both virtual screening approaches, structure-based molecular docking and ligand-based cheminformatics, suffer from computational cost, low accuracy, and/or reliance on prior knowledge of a ligand that binds to a given target. Here, we propose a neural network framework, NeuralDock, which accelerates the process of high-quality computational docking by a factor of 106, and does not require prior knowledge of a ligand that binds to a given target. By approximating both protein-small molecule conformational sampling and energy-based scoring, NeuralDock accurately predicts the binding energy, and affinity of a protein-small molecule pair, based on protein pocket 3D structure and small molecule topology. We use NeuralDock and 25 GPUs to dock 937 million molecules from the ZINC database against superoxide dismutase-1 in 21 h, which we validate with physical docking using MedusaDock. Due to its speed and accuracy, NeuralDock may be useful in brute-force virtual screening of massive chemical libraries and training of generative drug models.
Dual-Specificity Phosphatase 14 Regulates Zebrafish Hair Cell Formation Through Activation of p38 Signaling Pathway
Authors: Wei Guanyun , Zhang Xu , Cai Chengyun , Sheng Jiajing , Xu Mengting , Wang Cheng , Gu Qiuxiang , Guo Chao , Chen Fangyi , Liu Dong , Qian Fuping
Published: March 2022

Most cases of acquired hearing loss are due to degeneration and subsequent loss of cochlear hair cells. Whereas mammalian hair cells are not replaced when lost, in zebrafish, they constantly renew and regenerate after injury. However, the molecular mechanism among this difference remains unknown. Dual-specificity phosphatase 14 (DUSP14) is an important negative modulator of mitogen-activated protein kinase (MAPK) signaling pathways. Our study was to investigate the effects of DUSP14 on supporting cell development and hair cell regeneration and explore the potential mechanism. Our results showed that dusp14 gene is highly expressed in zebrafish developing neuromasts and otic vesicles. Behavior analysis showed that dusp14 deficiency resulted in hearing defects in zebrafish larvae, which were reversed by dusp14 mRNA treatment. Moreover, knockdown of dusp14 gene caused a significant decrease in the number of neuromasts and hair cells in both neuromast and otic vesicle, mainly due to the inhibition of the proliferation of supporting cells, which results in a decrease in the number of supporting cells and ultimately in the regeneration of hair cells. We further found significant changes in a series of MAPK pathway genes through transcriptome sequencing analysis of dusp14-deficient zebrafish, especially mapk12b gene in p38 signaling. Additionally, inhibiting p38 signaling effectively rescued all phenotypes caused by dusp14 deficiency, including hair cell and supporting cell reduction. These results suggest that DUSP14 might be a key gene to regulate supporting cell development and hair cell regeneration and is a potential target for the treatment of hearing loss.
Subthalamic Beta Activity in Parkinson's Disease May Be Linked to Dorsal Striatum Gray Matter Volume and Prefrontal Cortical Thickness: A Pilot Study
Authors: Sanmartino Florencia , Cruz-Gómez Álvaro J. , Rashid-López Raúl , Lozano-Soto Elena , López-Sosa Fernando , Zuazo Amaya , Riqué-Dormido Jesús , Espinosa-Rosso Raúl , González-Rosa Javier J.
Published: March 2022

Background

Excessive oscillations at beta frequencies (13–35 Hz) in the subthalamic nucleus (STN) represent a pathophysiological hallmark of Parkinson's disease (PD), which correlates well with parkinsonian symptoms and is reduced in response to standard disease treatments. However, the association of disease-specific regional gray matter (GM) atrophy or cortical thickness (CT) with the presence of STN beta oscillatory activity has been poorly investigated but is of relevance given the potential of these variables for extracting information about PD pathophysiology. This exploratory study investigated the involvement of regional GM volume and CT in the basal ganglia-cortical network and its potential association with the presence of STN beta oscillatory activity in PD.

Methods

We acquired preoperative GM densities on T1-weighted magnetic resonance imaging scans and we carried out regional estimation of GM volume and CT. LFP activities from the STN were recorded post-operatively in 7 cognitively preserved PD patients off dopaminergic medication undergoing deep-brain stimulation surgery. Oscillatory beta power was determined by power spectral density of 4-min resting state STN LFP activity. Spearman partial correlations and regression analysis were used to screen the presence of STN beta power for their relationship with GM volume and CT measurements.

Results

After controlling for the effects of age, educational level, and disease duration, and after correcting for multiple testing, enhanced STN beta power showed significant and negative correlations between, first, volume of the right putamen and left caudate nucleus, and second, smaller CT in frontal regions involving the left rostral middle frontal gyrus (MFG) and left medial orbitofrontal gyrus. A lower volume in the right putamen and a lower CT in the left MFG demonstrated the strongest associations with increased STN beta power.

Conclusions

These tentative results seem to suggest that STN LFP beta frequencies may be mainly linked to different but ongoing parallel neurodegenerative processes, on the one hand, to GM volume reduction in dorsal striatum, and on the other hand, to CT reduction of prefrontal-“associative” regions. These findings could further delineate the brain structural interactions underpinning the exaggerated STN beta activity commonly observed in PD patients.
Uncovering Essential Tremor Genetics: The Promise of Long-Read Sequencing
Authors: Marsili Luca , Duque Kevin R. , Bode Rachel L. , Kauffman Marcelo A. , Espay Alberto J.
Published: March 2022

Long-read sequencing (LRS) technologies have been recently introduced to overcome intrinsic limitations of widely-used next-generation sequencing (NGS) technologies, namely the sequencing limited to short-read fragments (150–300 base pairs). Since its introduction, LRS has permitted many successes in unraveling hidden mutational mechanisms. One area in clinical neurology in need of rethinking as it applies to genetic mechanisms is essential tremor (ET). This disorder, among the most common in neurology, is a syndrome often exhibiting an autosomal dominant pattern of inheritance whose large phenotypic spectrum suggest a multitude of genetic etiologies. Exome sequencing has revealed the genetic etiology only in rare ET families (FUS, SORT1, SCN4A, NOS3, KCNS2, HAPLN4/BRAL2, and USP46). We hypothesize that a reason for this shortcoming may be non-classical genetic mechanism(s) underpinning ET, among them trinucleotide, tetranucleotide, or pentanucleotide repeat disorders. In support of this hypothesis, trinucleotide (e.g., GGC repeats in NOTCH2NLC) and pentanucleotide repeat disorders (e.g., ATTTC repeats in STARD7) have been revealed as pathogenic in patients with a past history of what has come to be referred to as “ET plus,” bilateral hand tremor associated with epilepsy and/or leukoencephalopathy. A systematic review of LRS in neurodegenerative disorders showed that 10 of the 22 (45%) genetic etiologies ascertained by LRS include tremor in their phenotypic spectrum, suggesting that future clinical applications of LRS for tremor disorders may uncover genetic subtypes of familial ET that have eluded NGS, particularly those with associated leukoencephalopathy or family history of epilepsy. LRS provides a pathway for potentially uncovering novel genes and genetic mechanisms, helping narrow the large proportion of “idiopathic” ET.
Thoracic Excursion Is a Biomarker for Evaluating Respiratory Function in Amyotrophic Lateral Sclerosis
Authors: Iguchi Naohiko , Mano Tomoo , Iwasa Naoki , Ozaki Maki , Yamada Nanami , Kikutsuji Naoya , Kido Akira , Sugie Kazuma
Published: March 2022

Objective

To evaluate the usefulness of thoracic excursion as a biomarker in patients with amyotrophic lateral sclerosis (ALS).

Methods

We measured the forced the vital capacity (FVC), thoracic excursion, baseline-to-peak diaphragmatic compound muscle action potential (DCMAP) amplitude, diaphragm thickness at full inspiration (DTfi), Medical Research Council (MRC) sum score for muscle strength, and arterial partial pressures of oxygen and carbon dioxide and administered the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and modified Medical Research Council (mMRC) Dyspnea Scale. The test–retest reliability of thoracic excursion was determined.

Results and Conclusions

Thirty-four patients with ALS and 26 age- and sex-matched healthy participants were enrolled. Thoracic excursion measurement had excellent test–retest reliability (intraclass coefficient: 0.974). Thoracic excursion was more strongly correlated with FVC (r = 0.678, p < 0.001) than DCMAP amplitude (r = 0.501, p = 0.003) and DTfi (r = 0.597, p < 0.001). It was also correlated with ALSFRS-R score (r = 0.610, p < 0.001), MRC sum score (r = 0.470, p = 0.005), and mMRC Dyspnea Scale score (r = −0.446, p = 0.008) and was the most sensitive parameter for assessing dyspnea and FVC. Thoracic excursion decreased as FVC declined in the early and late stages, there were no differences in DCMAP amplitude and DTfi between the early and late stages, and ALSFRS-R score and MRC sum score decreased only in the late stage. Thoracic excursion was well correlated with respiratory function and is useful for predicting respiratory and general dysfunction in patients with ALS regardless of stage.
Does Amount of Information Support Aesthetic Values?
Authors: Grzywacz Norberto M. , Aleem Hassan
Published: March 2022

Obtaining information from the world is important for survival. The brain, therefore, has special mechanisms to extract as much information as possible from sensory stimuli. Hence, given its importance, the amount of available information may underlie aesthetic values. Such information-based aesthetic values would be significant because they would compete with others to drive decision-making. In this article, we ask, “What is the evidence that amount of information support aesthetic values?” An important concept in the measurement of informational volume is entropy. Research on aesthetic values has thus used Shannon entropy to evaluate the contribution of quantity of information. We review here the concepts of information and aesthetic values, and research on the visual and auditory systems to probe whether the brain uses entropy or other relevant measures, specially, Fisher information, in aesthetic decisions. We conclude that information measures contribute to these decisions in two ways: first, the absolute quantity of information can modulate aesthetic preferences for certain sensory patterns. However, the preference for volume of information is highly individualized, with information-measures competing with organizing principles, such as rhythm and symmetry. In addition, people tend to be resistant to too much entropy, but not necessarily, high amounts of Fisher information. We show that this resistance may stem in part from the distribution of amount of information in natural sensory stimuli. Second, the measurement of entropic-like quantities over time reveal that they can modulate aesthetic decisions by varying degrees of surprise given temporally integrated expectations. We propose that amount of information underpins complex aesthetic values, possibly informing the brain on the allocation of resources or the situational appropriateness of some cognitive models.
Micro-Coevolution of Genetics Rather Than Diet With Enterotype in Pigs
Authors: Ma Ning , Sun Yiwei , Chen Jiashun , Qi Zengkai , Liu Chunchen , Ma Xi
Published: March 2022

Based on the characteristic of low diarrhea in native Chinese breeds, we introduce the enterotype model for piglets, which is a new perspective to decipher the colonization and the transition of the gut microbiota among various pig breeds. After eliminating environmental influences represented by diet, the microbiota, mainly shaped by host genetics, is focused. Three representative enterotype clusters were identified, which were represented by Bacteroides, Streptococcus, and Lactobacillus. Chinese native breeds were distributed in enterotype 1 (E1) and E3, which collectively drove the diversification and functionality of the microbial community of various Chinese pig breeds. Next, the Lactobacillus reuteri (L. reuteri), which is the representative strain of E3, was specifically isolated in all three enterotypes. The excellent stress-resistance of L. reuteri-E3 not only highlighted the stronger disease resistance of Chinese breeds but also had a great potential to intervene in weaned piglet diseases. Enterotype classification based on host genetics is much more deterministic and predictable, clarifying the driver of the host-microbiome dynamics and constructing the picture of the micro-coevolution of human host genetics with the gut microbiome.
Biofortification: Effect of Iodine Fortified Food in the Healthy Population, Double-Arm Nutritional Study
Authors: Baldassano Sara , Di Gaudio Francesca , Sabatino Leo , Caldarella Rosalia , De Pasquale Claudio , Di Rosa Luigi , Nuzzo Domenico , Picone Pasquale , Vasto Sonya
Published: March 2022

It is estimated that one-third of the world’s population lives in areas where iodine (I) is scarce and its deficiency is responsible for many related disorders, such as goiter, reproductive failure, hearing loss, growth impairment, congenital I deficiency syndrome, and numerous kinds of brain injury. Mineral deficiencies can be overcomeviadietary diversification and mineral supplementation. An alternative or even complementary way is represented by the intake of biofortified foods, which can tackle this lack of micronutrients. In this short-term double-arm nutritional intervention study, a cohort of ten people was supplemented with curly endive leaf biofortified with I and ten people with curly endive without biofortification (Intervention Study on Iodine Biofortification Vegetables (Nutri-I-Food – Full-Text View -ClinicalTrials.gov). The effects on whole-body homeostasis and specifically on I, glucose, lipid, and hepatic, iron metabolism was investigated. Blood samples were obtained at baseline and after 12 days of supplementation with curly endive and compared with controls. Hematochemical and urinary parameters were analyzed at baseline and after 12 days. The results showed that short-term I curly endive intervention did not affect the whole body homeostasis in healthy people and revealed an increase in I concentration in urine samples and an increase in vitamin D, calcium, and potassium concentration in blood samples only in the biofortified cohort respect to controls. This study suggests that short-term consumption of I curly endive crops is safe and could positively impact body health.
Paclitaxel Chemotherapy Elicits Widespread Brain Anisotropy Changes in a Comprehensive Mouse Model of Breast Cancer Survivorship: Evidence From In Vivo Diffusion Weighted Imaging
Authors: Otto Lauren D. , Russart Kathryn L. G. , Kulkarni Praveen , McTigue Dana M. , Ferris Craig F. , Pyter Leah M.
Published: March 2022

Breast cancer is one of the most common diseases in the United States with 1 in 8 women developing the disease in her lifetime. Women who develop breast cancer are often post-menopausal and undergo a complex sequence of treatments including surgery, chemotherapy, and aromatase inhibitor therapy. Both independently and through potential interactions, these factors and treatments are associated with behavioral comorbidities reported in patients (e.g., fatigue), although the underlying neurobiological mechanisms are poorly understood. Currently, brain imaging is the most feasible way to assess neurobiology in patients. Indeed, breast cancer patients display alterations in white matter connections and chemotherapy is associated with decreased white and gray matter in the corpus callosum and cortex as well as decreased hippocampal volume. However, imaging in breast cancer rodent models is lacking, impeding translation of the mechanistic neurobiological findings made possible through modeling. Furthermore, current rodent models of breast cancer often lack the complexity of typical multimodal breast cancer treatments, thereby limiting translational value. The present study aimed to develop a comprehensive model of post-menopausal breast cancer survival using immunocompetent ovariectomized mice, including an orthotopic syngeneic tumor, surgical tumor removal, chemotherapy, and aromatase inhibitor therapy. Using this model, we systematically investigated the cumulative effects of chemotherapy and hormone replacement therapy on neurostructure and behavior using diffusion weighted imaging, open field test, and spontaneous alternation test. Our previous findings, in a simplified chemotherapy-only model, indicate that this regimen of chemotherapy causes circulating and central inflammation concurrent with reduced locomotor activity. The current study, in the more comprehensive model, has recapitulated the peripheral inflammation coincident with reduced locomotor activity as well as demonstrated that chemotherapy also drives widespread changes in brain anisotropy. Validating the clinical relevance of this comprehensive rodent breast cancer model will allow for additional neurobiological investigations of the interactions among various cancer components associated with behavioral comorbidities, as well as the relationship between these mechanisms and neurostructural imaging changes that can be measured in cancer patients.
Gracillin Shows Potential Efficacy Against Non-Small Cell Lung Cancer Through Inhibiting the mTOR Pathway
Authors: Li Yamei , Liu Hai , Liu Xiaoxuan , Xiao Bang , Zhang Minhong , Luo Yaoling , Li Mingchun , Yang Jianqiong
Published: March 2022

The leading cause of cancer deaths is lung cancer, non-small cell lung cancer (NSCLC), the most common type of lung cancers, remains a difficult cancer to treat and cure. It is urgent to develop new products to treat NSCLS. Gracillin, extracted from Reineckia carnea, Dioscorea villosa, and other medicinal plants, has anti-tumor potential with toxic effect on a variety of tumor cells such as NSCLC. However, the anti-NSCLC mechanism of gracillin is not completely clear. In this study, A549 cells and athymic nude mice were used as models to evaluate the anti-NSCLC effects of gracillin. The antiproliferative activity of gracillin on A549 cells was conducted by CCK-8, and obvious autophagy was observed in gracillin-treated A549 through transmission electron microscopy. Furthermore, the expressions of Beclin-1, LC3-II, and WIPI1 were upregulated, while the expression of p62 was downregulated in gracillin-treated A549. The further mechanism study found that the mTOR signaling pathway was significantly inhibited by gracillin. Accordingly, the PI3K/Akt pathway positively regulating mTOR was inhibited, and AMPK negatively regulating mTOR was activated. Meanwhile, LC3-II transformation was found to be significantly reduced after WIPI1 was silenced in A549 cells but increased after gracillin treatment. It also proves that WIPI is involved in the process of gracillin regulating A549 autophagy. At last, the anti-tumor growth activity of gracillin in vivo was validated in A549-bearing athymic nude mice. In conclusion, gracillin has anti-NSCLC activity by inducing autophagy. The mechanism maybe that gracillin inhibited the mTOR signaling pathway. Gracillin has the potential to be a candidate product for the treatment of NSCLC in the future.