bluuebunny/crossref_metadata_2025 huggingface dataset:
Peroxiredoxin 4 Interacts With Domeless and Participates in Antibacterial Immune Response Through the JAK/STAT Pathway
Authors: Ran Xiao-qin , Gao Lin , Yan Meng , Kang Cui-jie
Published: May 2022

The JAK/STAT pathway plays an important role in the development and immune responses of animals. In vertebrates, families of cytokines or growth factors act as activators of the JAK/STAT pathway; however, the activators for the JAK/STAT signaling pathway in arthropods are largely unknown. Herein we report a new ligand, peroxiredoxin 4 (Prx4), for the Domeless in the JAK/STAT pathway of shrimpMarsupenaeus japonicus. Prx4 was induced to secrete into the extracellular surroundings uponVibriochallenge, which then facilitated the anti-Vibrioactivity of shrimp by activating the phosphorylation and nuclear translocation of STAT and the expression of STAT-responsive antimicrobial peptides. Blocking the expression of Prx4in vivoabrogated the activation of the JAK/STAT pathway byVibrioinfection, while injection of Prx4 protein activated the pathway. The interaction between Prx4 and Domeless was proved by immuno-precipitation and protein pull-down assays. Moreover, two cysteine residues in Prx4 that are critical for the interaction and Prx4’s anti-Vibriorole were identified, and the binding site in Domeless for Prx4 was proved to be the cytokine-binding homology module fragment. Taken together, our study revealed a new function for Prx4 enzyme and established a new enzyme-type ligand for the activation of the JAK/STAT pathway in an aquatic arthropod.
Nordic Blue Carbon Ecosystems: Status and Outlook
Authors: Krause-Jensen Dorte , Gundersen Hege , Björk Mats , Gullström Martin , Dahl Martin , Asplund Maria E. , Boström Christoffer , Holmer Marianne , Banta Gary T. , Graversen Anna Elizabeth Løvgren , Pedersen Morten Foldager , Bekkby Trine , Frigstad Helene , Skjellum Solrun Figenschau , Thormar Jonas , Gyldenkærne Steen , Howard Jennifer , Pidgeon Emily , Ragnarsdóttir Sunna Björk , Mols-Mortensen Agnes , Hancke Kasper
Published: May 2022

Vegetated coastal and marine habitats in the Nordic region include salt marshes, eelgrass meadows and, in particular, brown macroalgae (kelp forests and rockweed beds). Such habitats contribute to storage of organic carbon (Blue Carbon – BC) and support coastal protection, biodiversity and water quality. Protection and restoration of these habitats therefore have the potential to deliver climate change mitigation and co-benefits. Here we present the existing knowledge on Nordic BC habitats in terms of habitat area, C-stocks and sequestration rates, co-benefits, policies and management status to inspire a coherent Nordic BC roadmap. The area extent of BC habitats in the region is incompletely assessed, but available information sums up to 1,440 km2 salt marshes, 1,861 (potentially 2,735) km2 seagrass meadows, and 16,532 km2 (potentially 130,735 km2, including coarse Greenland estimates) brown macroalgae, yielding a total of 19,833 (potentially 134,910) km2. Saltmarshes and seagrass meadows have experienced major declines over the past century, while macroalgal trends are more diverse. Based on limited salt marsh data, sediment C-stocks average 3,311 g Corg m-2 (top 40-100 cm) and sequestration rates average 142 g Corg m-2 yr-1. Eelgrass C-stocks average 2,414 g Corg m-2 (top 25 cm) and initial data for sequestration rates range 5-33 g Corg m-2, quantified for one Greenland site and one short term restoration. For Nordic brown macroalgae, peer-reviewed estimates of sediment C-stock and sequestration are lacking. Overall, the review reveals substantial Nordic BC-stocks, but highlights that evidence is still insufficient to provide a robust estimate of all Nordic BC-stocks and sequestration rates. Needed are better quantification of habitat area, C-stocks and fluxes, particularly for macroalgae, as well as identification of target areas for BC management. The review also points to directives and regulations protecting Nordic marine vegetation, and local restoration initiatives with potential to increase C-sequestration but underlines that increased coordination at national and Nordic scales and across sectors is needed. We propose a Nordic BC roadmap for science and management to maximize the potential of BC habitats to mitigate climate change and support coastal protection, biodiversity and additional ecosystem functions.
Key Knowledge Gaps to Fill at the Cell-To-Ecosystem Level in Marine B-Vitamin Cycling
Authors: Wienhausen Gerrit , Bittner Meriel J. , Paerl Ryan W.
Published: May 2022

B-vitamins are essential micronutrients for marine plankton. Additionally, we now know many marine plankton cannot synthesize B-vitamins de novo (from scratch) and thus are reliant on external supplies. Details of B-vitamin exchange, whether ‘active’ or ‘passive’ (i.e. through cell secretion or mortality), are lacking and as a result we struggle to predict microbial physiology, community composition and biogeochemistry. We argue that significant advances in understanding of the impact of B-vitamin exchange and cycling on marine community structure and biogeochemistry can be made by focusing on unknowns related to the ‘in’s and out’s’ of B-vitamin transport, exchange between plankton, and ecosystem scale processing/transformation of B-vitamins. We point out that it is particularly necessary to reach beyond traditional categorization of populations as B-vitamin auxotrophs (requiring supplied vitamin) or prototrophs (de novo vitamin synthesizers) and begin addressing which populations are net ‘providers’ and/or ‘consumers’. This is a particularly interesting problem as organisms cannot be confidently categorized as net ‘providers’ and/or ‘consumers’ based on genome-based prediction, and it is possible the two roles may change over time and environmental conditions. We posit that greater knowledge of B-vitamin exchange, e.g. cross-feeding, acquisition and secretion systems, environmental triggers of ‘provision’ and ‘consumption’, will reveal unforeseen networking and novel niches across marine planktonic communities. Last, we advocate for further experiments tracking the responses of isolates or natural communities relative to vitamin availability, tracing flow of B-vitamins between cells using novel approaches (e.g. isotopic, fluorometric), and greater consideration of altered B-vitamin exchange and cycling under future climate scenarios.
Renal Water Conservation and Plasma Creatinine in Colorectal Cancer Surgery: A Single-Group Clinical Study
Authors: Li Yuhong , He Rui , Hu Shuangyan , Hahn Robert G.
Published: May 2022

Elevation of plasma creatinine after surgery is associated with postoperative morbidity and mortality. We studied whether lengthy surgery might induce renal conservation of water strong enough to exceed the renal capacity to excrete creatinine. Colorectal cancer surgery was performed via laparoscopy in 126 patients. Blood and urine were sampled before surgery, in the postoperative care unit, and 1 day after surgery. The Fluid Retention Index (FRI), which is a composite index of renal water conservation, was calculated. The mean FRI before surgery was 2.4, indicating that patients were well-hydrated. The FRI increased to 2.8 after surgery, and further to 3.5 on the first postoperative day. Plasma creatinine increased in 66 (52%) of the patients while plasma proteins were diluted by 15%. Patients with urinary creatinine > 8.5 mmol/L before surgery were more likely to later show elevation of plasma creatinine (68 vs. 46%, P < 0.04). The final FRI was higher in those with perioperative elevation of plasma creatinine (median 3.7 vs. 3.4; P < 0.01) and a similar difference was found for the final urinary creatinine concentration (8.5 vs. 7.2 mmol/L; P < 0.01). The gastrointestinal recovery time was prolonged when >2 L of Ringer's had been infused during the surgery. We conclude that colorectal surgery initiated a process of renal water conservation that extended into the postoperative period. The water conservation was more intense and the urinary concentration of creatinine was higher in those who had a perioperative rise in plasma creatinine.
A Machine Learning-Based System for Real-Time Polyp Detection (DeFrame): A Retrospective Study
Authors: Chen Shuijiao , Lu Shuang , Tang Yingxin , Wang Dechun , Sun Xinzi , Yi Jun , Liu Benyuan , Cao Yu , Chen Yongheng , Liu Xiaowei
Published: May 2022

Background and Aims

Recent studies have shown that artificial intelligence-based computer-aided detection systems possess great potential in reducing the heterogeneous performance of doctors during endoscopy. However, most existing studies are based on high-quality static images available in open-source databases with relatively small data volumes, and, hence, are not applicable for routine clinical practice. This research aims to integrate multiple deep learning algorithms and develop a system (DeFrame) that can be used to accurately detect intestinal polyps in real time during clinical endoscopy.

Methods

A total of 681 colonoscopy videos were collected for retrospective analysis at Xiangya Hospital of Central South University from June 2019 to June 2020. To train the machine learning (ML)-based system, 6,833 images were extracted from 48 collected videos, and 1,544 images were collected from public datasets. The DeFrame system was further validated with two datasets, consisting of 24,486 images extracted from 176 collected videos and 12,283 images extracted from 259 collected videos. The remaining 198 collected full-length videos were used for the final test of the system. The measurement metrics were sensitivity and specificity in validation dataset 1, precision, recall and F1 score in validation dataset 2, and the overall performance when tested in the complete video perspective.

Results

A sensitivity and specificity of 79.54 and 95.83%, respectively, was obtained for the DeFrame system for detecting intestinal polyps. The recall and precision of the system for polyp detection were determined to be 95.43 and 92.12%, respectively. When tested using full colonoscopy videos, the system achieved a recall of 100% and precision of 80.80%.

Conclusion

We have developed a fast, accurate, and reliable DeFrame system for detecting polyps, which, to some extent, is feasible for use in routine clinical practice.
Microbial Community, Fermentation Quality, and in vitro Degradability of Ensiling Caragana With Lactic Acid Bacteria and Rice Bran
Authors: You Jingtao , Zhang Huan , Zhu Hongfu , Xue Yanlin , Cai Yimin , Zhang Guijie
Published: May 2022

This study aimed to assess the effects of microbial inoculants and growth stage on fermentation quality, microbial community, and in vitro degradability of Caragana silage from different varieties. Caragana intermedia (CI) and Caragana korshinskii (CK) harvested at the budding (BU) and blooming (BL) stages were used as raw materials to prepare silage, respectively. The silages at each growth stage were treated for ensiling alone (control), with 5% rice bran (RB), a combination of RB with commercial Lactobacillus plantarum (RB + LP), and a combination of RB with a selected strain Lactobacillus plantarum L694 (RB + L694). The results showed that the crude protein (CP) content of CI was higher than that of CK, and delay in harvest resulted in greater CP content in Caragana at BL stage. After 60 days of fermentation, the concentrations of lactic acid (LA) in the RB + L694 treatments were higher than those in control treatments (p < 0.05), while the pH, concentrations of NH3-N, neutral detergent fiber with the addition of α-amylase (aNDF) were lower than those in control treatments (p < 0.05). RB + L694 treatments could decrease acid detergent fiber (ADF) content except in CIBL. In CK silages, adding RB + L694 could reduce bacterial diversity and richness (p < 0.05). Compared with the control, RB + L694 treatment contained higher Lactobacillus and Enterobacter (p < 0.05). In vitro NDF and DM degradability (IVNDFD and IVDMD) was mostly affected by growth period, and additive RB + l694 treatment had higher IVDMD and lower IVNDFD than other treatments (p < 0.05). Consequently, the varieties, growth stages, and additives could influence the fermentation process, while the blooming stage should be selected in both Caragana. Furthermore, the results showed that RB and L. plantarum could exert a positive effect on fermentation quality of Caragana silage by shifting bacterial community composition, and RB + L694 treatments outperformed other additives.
A Satellite dsRNA Attenuates the Induction of Helper Virus-Mediated Symptoms in Aspergillus flavus
Authors: Jiang Yinhui , Yang Bi , Liu Xiang , Tian Xun , Wang Qinrong , Wang Bi , Zhang Qifang , Yu Wenfeng , Qi Xiaolan , Jiang Yanping , Hsiang Tom
Published: May 2022

Aspergillus flavus is an important fungal pathogen of animals and plants. Previously, we reported a novel partitivirus, Aspergillus flavus partitivirus 1 (AfPV1), infecting A. flavus. In this study, we obtained a small double-stranded (ds) RNA segment (734 bp), which is a satellite RNA of the helper virus, AfPV1. The presence of AfPV1 altered the colony morphology, decreased the number of conidiophores, created significantly larger vacuoles, and caused more sensitivity to osmotic, oxidative, and UV stresses in A. flavus, but the small RNA segment could attenuate the above symptoms caused by the helper virus AfPV1 in A. flavus. Moreover, AfPV1 infection reduced the pathogenicity of A. flavus in corn (Zea mays), honeycomb moth (Galleria mellonella), mice (Mus musculus), and the adhesion of conidia to host epithelial cells, and increased conidial death by macrophages. However, the small RNA segment could also attenuate the above symptoms caused by the helper virus AfPV1 in A. flavus, perhaps by reducing the genomic accumulation of the helper virus AfPV1 in A. flavus. We used this model to investigate transcriptional genes regulated by AfPV1 and the small RNA segment in A. flavus, and their role in generating different phenotypes. We found that the pathways of the genes regulated by AfPV1 in its host were similar to those of retroviral viruses. Therefore, some pathways may be of benefit to non-retroviral viral integration or endogenization into the genomes of its host. Moreover, some potential antiviral substances were also found in A. flavus using this system.
Schrödinger and the Possible Existence of Different Types of Life
Authors: Hernández Greco
Published: May 2022

Eighty years ago, Nobel Prize-winner physicist Erwin Schrödinger gave three lectures in Dublin’s Trinity College, titled What is Life? The physical aspect of the living cell to explain life in terms of the chemistry and physics laws. Life definitions rely on the cellular theory, which poses in the first place that life is made up of cells. The recent discovery of giant viruses, along with the development of synthetic cells at the beginning of century 21st, has challenged the current idea of what life is. Thus, rather than having arrived at a close answer to Schrödinger’s question, modern biology has touched down at a novel scenario in which several types of life—as opposed to only one—actually might exist on Earth and possibly the Universe. Eighty years after the Dublin lectures, the Schrödinger question could be: “What are lives”?
Antimicrobial Mechanism and Secondary Metabolite Profiles of Biocontrol Agent Streptomyces lydicus M01 Based on Ultra-High-Performance Liquid Chromatography Connected to a Quadrupole Time-of-Flight Mass Spectrometer Analysis and Genome Sequencing
Authors: Wang Mingxuan , Li Jing , Cong Wenjie , Zhang Jianguo
Published: May 2022

Streptomyces lydicus was used as biopesticide for crop protection in agriculture, however, the antimicrobial mechanism remains unclear and no systematic research on the secondary metabolites of S. lydicus has been reported. In this study, the extract of S. lydicus M01 culture was used to treat plant pathogen Alternaria alternata and morphological changes in the plasma membrane and cell wall of hyphae and conidia were observed. Fluorescence microscopy combined with different dyes showed that the accumulation of reactive oxygen species and cell death were also induced. To investigate the secondary metabolites in the culture filtrate, an online detection strategy of ultra-high-performance liquid chromatography connected to a quadrupole time-of-flight mass spectrometer (UPLC-Q-TOF-MS) was used for identification. The results revealed an excess of 120 metabolites, mainly consisted of fungicides, antibacterial agents, herbicides, insecticides, and plant growth regulators, such as IAA. Among which the five dominant components were oxadixyl, chloreturon, S-metolachlor, fentrazamide, and bucarpolate. On the other hand, the complete genome of S. lydicus M01 was sequenced and a number of key function gene clusters that contribute to the biosynthesis of active secondary metabolites were revealed. This is the first systematic characterization of S. lydicus secondary metabolites, and these results offer novel and valuable evidence for a comprehensive understanding of the biocontrol agent S. lydicus and its application in agriculture.
Epstein–Barr Virus and Human Cytomegalovirus Infection in Intestinal Mucosa of Chinese Patients With Inflammatory Bowel Disease
Authors: Wang Wei , Chen Xin , Pan Jie , Zhang Xianhui , Zhang Liyun
Published: May 2022

Objective

This study aimed to determine the frequency of Epstein–Barr virus (EBV), cytomegalovirus (CMV) in mucosa and blood of inflammatory bowel disease (IBD) patients in China and evaluate their correlation with the clinical disease activities.

Methods

Peripheral blood and endoscopic fresh colonic mucosal samples were collected from a cohort of 287 IBD patients and 50 controls. Viral DNA load was analyzed through quantitative real-time PCR. The clinical disease activity of ulcerative colitis (UC) and Crohn’s disease (CD) was assessed by the Mayo Clinic Score and Crohn’s disease activity index, respectively.

Results

Among 287 IBD patients, 228 (79.4%) were positive for EBV and 99 (34.5%) were positive for CMV. EBV and CMV infection rates are significantly higher than those in the control group (28.0%, p < 0.05; 4.0%, p < 0.05). In addition, EBV/CMV prevalence increases as clinical activities progress [For EBV infection, the prevalence was 53.93% (48/89) in the mild group, 87.00% (87/100) in the moderate group, and 94.90% (93/98) in the severe group; and for CMV infection, the prevalence was 3.37% (3/89) in the mild group, 27.00% (27/100) in the moderate group, and 70.41% (69/98) in the severe group]. EBV and CMV loads are related to clinical disease activities (p < 0.05). In addition, viral load in the intestinal mucosa of patients with acute exacerbation of IBD is higher than that of patients in remission.

Conclusion

High prevalence of EBV and CMV is found in patients with IBD, and their prevalence is related to clinical disease activities. In addition, the viral load in the intestinal mucosa is associated with the status of mucosa in the same patients (active phase versus remission phase). Detection of viral load on mucosal specimens with quantitative real-time PCR is a feasible method to monitor EBV and CMV infection in IBD patients.
Metapath Aggregated Graph Neural Network and Tripartite Heterogeneous Networks for Microbe-Disease Prediction
Authors: Chen Yali , Lei Xiujuan
Published: May 2022

More and more studies have shown that understanding microbe-disease associations cannot only reveal the pathogenesis of diseases, but also promote the diagnosis and prognosis of diseases. Because traditional medical experiments are time-consuming and expensive, many computational methods have been proposed in recent years to identify potential microbe-disease associations. In this study, we propose a method based on heterogeneous network and metapath aggregated graph neural network (MAGNN) to predict microbe-disease associations, called MATHNMDA. First, we introduce microbe-drug interactions, drug-disease associations, and microbe-disease associations to construct a microbe-drug-disease heterogeneous network. Then we take the heterogeneous network as input to MAGNN. Second, for each layer of MAGNN, we carry out intra-metapath aggregation with a multi-head attention mechanism to learn the structural and semantic information embedded in the target node context, the metapath-based neighbor nodes, and the context between them, by encoding the metapath instances under the metapath definition mode. We then use inter-metapath aggregation with an attention mechanism to combine the semantic information of all different metapaths. Third, we can get the final embedding of microbe nodes and disease nodes based on the output of the last layer in the MAGNN. Finally, we predict potential microbe-disease associations by reconstructing the microbe-disease association matrix. In addition, we evaluated the performance of MATHNMDA by comparing it with that of its variants, some state-of-the-art methods, and different datasets. The results suggest that MATHNMDA is an effective prediction method. The case studies on asthma, inflammatory bowel disease (IBD), and coronavirus disease 2019 (COVID-19) further validate the effectiveness of MATHNMDA.
Proteome-Wide and Protein-Specific Multi-Epitope Vaccine Constructs Against the Rift Valley Fever Virus Outbreak Using Integrated Omics Approaches
Authors: Albutti Aqel
Published: May 2022

Rift Valley fever (RVF) is a viral disease caused by a member of the Bunyavirales family causing severe infections in humans. The RVF virus is an enveloped, negative-sense, single-stranded RNA virus that can infect both animals and humans. The symptoms associated with these infections span from minor (fever and headaches) to severe (meningoencephalitis and hemorrhagic fever syndrome) symptoms. Despite the outbreaks of the RVF virus being reported in different parts of the world, no effective therapy is available. Herein, the development of an efficient vaccine is critical for the control of infections associated with the RVF virus. Moreover, computational vaccine approaches are helpful in the design of specific, safe, and stable peptide-based designs when compared to the conventional methods of vaccine development. In this study, the whole proteome of the virus, comprising four proteins (NP, L, GP, and NSP), was screened to find putative vaccine epitope sequences (T cell, B cell, and HTL) specific for each protein. These shortlisted epitopes were then combined with flexible linkers to design protein-specific and proteome-wide immunogenic multi-epitope-based vaccine constructs. The results revealed that these multi-epitope vaccine constructs (MEVCs) are strongly antigenic and non-allergenic in nature. The efficacy of these constructs was further validated by docking with immune receptors, which revealed strong binding interactions with human TLR8. Using the MD simulation approach, the binding stability and residual flexibility of the best vaccine construct (proteome-wide) were confirmed, which revealed stable dynamic and favorable features. Furthermore, in-silico cloning and immune simulation analysis confirmed the expression and production of immune factors, that is, IgM, IgG, and IL-6, against the proposed vaccine designs. Additionally, 3D models of all the MEVC constructs have been developed and evaluated for potential immunization against the RVF virus. Finally, the proteome-wide vaccine candidate (MEVC-PW-RVFV) with the highest immune reinforcement potential provides new insights into the development of future vaccines against the emerging RVF virus.
An Epistatic Network Describes oppA and glgB as Relevant Genes for Mycobacterium tuberculosis
Authors: Posada-Reyes Ali-Berenice , Balderas-Martínez Yalbi I. , Ávila-Ríos Santiago , Vinuesa Pablo , Fonseca-Coronado Salvador
Published: May 2022

Mycobacterium tuberculosis is an acid-fast bacterium that causes tuberculosis worldwide. The role of epistatic interactions among different loci of the M. tuberculosis genome under selective pressure may be crucial for understanding the disease and the molecular basis of antibiotic resistance acquisition. Here, we analyzed polymorphic loci interactions by applying a model-free method for epistasis detection, SpydrPick, on a pan–genome-wide alignment created from a set of 254 complete reference genomes. By means of the analysis of an epistatic network created with the detected epistatic interactions, we found that glgB (α-1,4-glucan branching enzyme) and oppA (oligopeptide-binding protein) are putative targets of co-selection in M. tuberculosis as they were associated in the network with M. tuberculosis genes related to virulence, pathogenesis, transport system modulators of the immune response, and antibiotic resistance. In addition, our work unveiled potential pharmacological applications for genotypic antibiotic resistance inherent to the mutations of glgB and oppA as they epistatically interact with fprA and embC, two genes recently included as antibiotic-resistant genes in the catalog of the World Health Organization. Our findings showed that this approach allows the identification of relevant epistatic interactions that may lead to a better understanding of M. tuberculosis by deciphering the complex interactions of molecules involved in its metabolism, virulence, and pathogenesis and that may be applied to different bacterial populations.
Cell-Target-Specific Anti-Inflammatory Effect of Empagliflozin: In Vitro Evidence in Human Cardiomyocytes
Authors: Giannattasio Silvia , Citarella Anna , Trocchianesi Sofia , Filardi Tiziana , Morano Susanna , Lenzi Andrea , Ferretti Elisabetta , Crescioli Clara
Published: May 2022

The antidiabetic sodium–glucose cotransporter type 2 inhibitor (SGLT2i) empagliflozin efficiently reduces heart failure (HF) hospitalization and cardiovascular death in type 2 diabetes (T2D). Empagliflozin-cardioprotection likely includes anti-inflammatory effects, regardless glucose lowering, but the underlying mechanisms remain unclear. Inflammation is a primary event in diabetic cardiomyopathy (DCM) and HF development. The interferon (IFN)γ-induced 10-kDa protein (IP-10/CXCL10), a T helper 1 (Th1)-type chemokine, promotes cardiac inflammation, fibrosis, and diseases, including DCM, ideally representing a therapeutic target. This preliminary study aims to explore whether empagliflozin directly affects Th1-challenged human cardiomyocytes, in terms of CXCL10 targeting. To this purpose, empagliflozin dose–response curves were performed in cultured human cardiomyocytes maintained within a Th1-dominant inflammatory microenvironment (IFNγ/TNFα), and CXCL10 release with the intracellular IFNγ-dependent signaling pathway (Stat-1) was investigated. To verify possible drug–cell-target specificity, the same assays were run in human skeletal muscle cells. Empagliflozin dose dependently inhibited CXCL10 secretion (IC50 = 76,14 × 10-9 M) in association with Stat-1 pathway impairment only in Th1-induced human cardiomyocytes, suggesting drug-selective cell-type-targeting. As CXCL10 plays multifaceted functions in cardiac remodeling toward HF and currently there is no effective method to prevent it, these preliminary data might be hypothesis generating to open new scenarios in the translational approach to SGLT2i-dependent cardioprotection.
Electrophysiological Characteristics of Dorsal Raphe Nucleus in Tail Suspension Test
Authors: Zhou Liuchang , Liu Dan , Xie Zedan , Deng Di , Shi Guoqi , Zhao Jinlan , Bai Shasha , Yang Lei , Zhang Rong , Shi Yafei
Published: May 2022

The dorsal raphe nucleus (DRN) is a major source of serotonin in the central nervous system, which is closely related to depression-like behaviors and is modulated by local GABAergic interneurons. Although serotonin neurons are known to be activated by struggling behavior in tail suspension test (TST), the exact electrophysiological characteristics are still unclear. Here, we combined in vivo electrode recording and behavioral test to explore the mice neuron electrophysiology in DRN during TST and observed that gamma oscillation was related to despair-like behaviors whereas burst fraction was crucial for survival-like behaviors. We reported the identification of a subpopulation of DRN neurons which change their firing rates when mice get into and during TST immobile states. Both increase (putative despair units, D units for short) and decrease (putative survival units, S units for short) in firing rate were observed. Furthermore, using optogenetics to identify parvalbumin-positive (PV+) and serotonin transporter-positive (SERT+) neurons, we found that SERT+ neurons were almost S units. Interestingly, those that have been identified PV+ neurons include ~20% of D units and ~50% of S units. These results suggest that electrophysiological characteristics incorporated in despair-like behavior studies can provide new insight into the study of anti-depression targets, and GABAergic interneuron is a complex key hub to the coding and regulation of local neural network.
Kdm6b Haploinsufficiency Causes ASD/ADHD-Like Behavioral Deficits in Mice
Authors: Gao Yuen , Aljazi Mohammad B. , He Jin
Published: May 2022

Autism spectrum disorder (ASD) is a neurodevelopmental disease that has intellectual disability (ID) and attention-deficit/hyperactivity disorder (ADHD) as its common comorbidities. Recent genetic and clinical studies report that KDM6B, a gene encoding a histone H3 lysine 27-specific demethylase, is one of the highest ASD risk genes. However, the relationship between KDM6B mutations and neurodevelopmental diseases remains unclear. Here we use an animal model to show that genetic deletion of one Kdm6b allele in mice leads to autistic-like impaired sociability and object recognition memory. In addition, the mutant mice display markedly increased locomotor activity and impulsivity, two ADHD-like behavioral traits that are ameliorated by methylphenidate treatment. Thus, our study not only uncovers a potential causal link between disruptive KDM6B mutations and ASD/ADHD-like behavioral deficits but also provides a new mouse model for studying the cellular and molecular mechanisms underlying the Kdm6b-mutation-related neurodevelopmental diseases.
A Supervised-Reinforced Successive Training Framework for a Fuzzy Inference System and Its Application in Robotic Odor Source Searching
Authors: Chen Xinxing , Leng Yuquan , Fu Chenglong
Published: May 2022

Fuzzy inference systems have been widely applied in robotic control. Previous studies proposed various methods to tune the fuzzy rules and the parameters of the membership functions (MFs). Training the systems with only supervised learning requires a large amount of input-output data, and the performance of the trained system is confined by that of the target system. Training the systems with only reinforcement learning (RL) does not require prior knowledge but is time-consuming, and the initialization of the system remains a problem. In this paper, a supervised-reinforced successive training framework is proposed for a multi-continuous-output fuzzy inference system (MCOFIS). The parameters of the fuzzy inference system are first tuned by a limited number of input-output data from an existing controller with supervised training and then are utilized to initialize the system in the reinforcement training stage. The proposed framework is applied in a robotic odor source searching task and the evaluation results demonstrate that the performance of the fuzzy inference system trained by the successive framework is superior to the systems trained by only supervised learning or RL. The system trained by the proposed framework can achieve around a 10% higher success rate compared to the systems trained by only supervised learning or RL.
Galectin-3 Promotes Müller Glia Clearance Phagocytosis via MERTK and Reduces Harmful Müller Glia Activation in Inherited and Induced Retinal Degeneration
Authors: Lew Deborah S. , McGrath Morgan J. , Finnemann Silvia C.
Published: May 2022

Clearance phagocytosis is a documented function of Müller glia in the retina. However, the molecular mechanisms of Müller glia phagocytosis remain largely undefined. Here, we show that extracellular galectin-3 and protein S promote clearance phagocytosis by immortalized human MIO-M1 Müller cells in an additive, saturable manner. Galectin-3 promotes phagocytosis by primary Müller glia from wild-type (WT) mice but not from mice that lack the engulfment receptor MERTK and therefore develop postnatal photoreceptor degeneration. Probing a possible functional link between Müller galectin-3 and MERTK, we discovered that mertk−/− Müller glia in situ show excess galectin-3 at postnatal day 20 (P20), an age prior to detectable photoreceptor degeneration. Moreover, double knockout (DKO) mice lacking both galectin-3 and MERTK show increased activation of Müller cells (but not of microglia) at P20 and more pronounced photoreceptor loss at P35 compared to mice lacking MERTK alone. Exploring the well-established sodium iodate injury model, we also found more severe activation specifically of Müller glia, and worse retinal damage in mice lacking galectin-3 compared to WT mice. Indeed, galectin-3 deficiency significantly increased sensitivity to injury, yielding Müller activation and retinal damage at a sodium iodate concentration that had no effect on the WT retina. Altogether, our results from both inherited and acutely induced models of retinal degeneration agree that eliminating galectin-3 exacerbates Müller cell activation and retinal degeneration. These data identify an important protective role for the MERTK ligand galectin-3 in the retina in restraining Müller glia activation.
Humoral and Cellular Response to Spike of Delta SARS-CoV-2 Variant in Vaccinated Patients With Multiple Sclerosis
Authors: Petrone Linda , Tortorella Carla , Aiello Alessandra , Farroni Chiara , Ruggieri Serena , Castilletti Concetta , Meschi Silvia , Cuzzi Gilda , Vanini Valentina , Palmieri Fabrizio , Prosperini Luca , Haggiag Shalom , Galgani Simona , Grifoni Alba , Sette Alessandro , Gasperini Claudio , Nicastri Emanuele , Goletti Delia
Published: May 2022

Objectives

We assessed vaccination-induced antibody and cellular response against spike from the ancestral strain and from the Delta Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) variant in patients with Multiple Sclerosis (MS) treated with disease modifying treatments.

Methods

We enrolled 47 patients with MS and nine controls (“no MS”) having completed the vaccination schedule within 4–6 months from the first dose. The Interferon (IFN)-γ-response to spike peptides derived from the ancestral and the Delta SARS-CoV-2 was measured by enzyme-linked immunoassay (ELISA). Anti-Receptor Binding Domain (RBD) IgG were also evaluated.

Results

No significant differences were found comparing the IFN-γ-specific immune response between MS and “no MS” subjects to the ancestral (P = 0.62) or Delta peptide pools (P = 0.68). Nevertheless, a reduced IFN-γ-specific response to the ancestral or to the Delta pools was observed in subjects taking fingolimod or cladribine compared to subjects treated with ocrelizumab or IFN-β. The antibody response was significantly reduced in patients with MS compared to “no MS” subjects (P = 0.0452) mainly in patients taking ocrelizumab or fingolimod.

Conclusions

Cellular responses to Delta SARS-CoV-2 variant remain largely intact in patients with MS. However, the magnitude of these responses depends on the specific therapy.
The Mechanism of Short-Term Monocular Pattern Deprivation-Induced Perceptual Eye Dominance Plasticity
Authors: Tao Jiayu , Yang Zhijie , Li Jinwei , Cheng Zhenhui , Li Jing , Huang Jinfeng , Wu Di , Zhang Pan
Published: May 2022

Previously published studies have reported that 150 min of short-term monocular deprivation temporarily changes perceptual eye dominance. However, the possible mechanisms underlying monocular deprivation-induced perceptual eye dominance plasticity remain unclear. Using a binocular phase and contrast co-measurement task and a multi-pathway contrast-gain control model (MCM), we studied the effect of 150 min of monocular pattern deprivation (MPD) in normal adult subjects. The perceived phase and contrast varied significantly with the interocular contrast ratio, and after MPD, the patched eye (PE) became dominant. Most importantly, we focused on the potential mechanisms of the deprivation effect. The data of an averaged subject was best fitted by a model, which assumed a monocular signal enhancement of the PE after the MPD. The present findings might have important implications for investigations of binocular vision in both normal and amblyopic populations.
A Systematic Approach for Explaining Time and Frequency Features Extracted by Convolutional Neural Networks From Raw Electroencephalography Data
Authors: Ellis Charles A. , Miller Robyn L. , Calhoun Vince D.
Published: May 2022

In recent years, the use of convolutional neural networks (CNNs) for raw resting-state electroencephalography (EEG) analysis has grown increasingly common. However, relative to earlier machine learning and deep learning methods with manually extracted features, CNNs for raw EEG analysis present unique problems for explainability. As such, a growing group of methods have been developed that provide insight into the spectral features learned by CNNs. However, spectral power is not the only important form of information within EEG, and the capacity to understand the roles of specific multispectral waveforms identified by CNNs could be very helpful. In this study, we present a novel model visualization-based approach that adapts the traditional CNN architecture to increase interpretability and combines that inherent interpretability with a systematic evaluation of the model via a series of novel explainability methods. Our approach evaluates the importance of spectrally distinct first-layer clusters of filters before examining the contributions of identified waveforms and spectra to cluster importance. We evaluate our approach within the context of automated sleep stage classification and find that, for the most part, our explainability results are highly consistent with clinical guidelines. Our approach is the first to systematically evaluate both waveform and spectral feature importance in CNNs trained on resting-state EEG data.
Machine Learning Analysis Reveals Biomarkers for the Detection of Neurological Diseases
Authors: Lam Simon , Arif Muhammad , Song Xiya , Uhlén Mathias , Mardinoglu Adil
Published: May 2022

It is critical to identify biomarkers for neurological diseases (NLDs) to accelerate drug discovery for effective treatment of patients of diseases that currently lack such treatments. In this work, we retrieved genotyping and clinical data from 1,223 UK Biobank participants to identify genetic and clinical biomarkers for NLDs, including Alzheimer's disease (AD), Parkinson's disease (PD), motor neuron disease (MND), and myasthenia gravis (MG). Using a machine learning modeling approach with Monte Carlo randomization, we identified a panel of informative diagnostic biomarkers for predicting AD, PD, MND, and MG, including classical liver disease markers such as alanine aminotransferase, alkaline phosphatase, and bilirubin. A multinomial model trained on accessible clinical markers could correctly predict an NLD diagnosis with an accuracy of 88.3%. We also explored genetic biomarkers. In a genome-wide association study of AD, PD, MND, and MG patients, we identified single nucleotide polymorphisms (SNPs) implicated in several craniofacial disorders such as apnoea and branchiootic syndrome. We found evidence for shared genetic risk loci among NLDs, including SNPs in cancer-related genes and SNPs known to be associated with non-brain cancers such as Wilms tumor, leukemia, and colon cancer. This indicates overlapping genetic characterizations among NLDs which challenges current clinical definitions of the neurological disorders. Taken together, this work demonstrates the value of data-driven approaches to identify novel biomarkers in the absence of any known or promising biomarkers.
Analysis of Pyroptosis-Related Signature for Predicting Prognosis and Tumor Immune Microenvironment in Pancreatic Cancer
Authors: Li Lincheng , Deng Zhaoda , Xiao Zhaohui , Zou Wenbo , Liu Rong
Published: May 2022

Pancreatic cancer (PC) has a poor prognosis, which is attributable to its high aggressiveness and lack of effective therapies. Although immunotherapy has been used for the treatment of various tumor, its efficacy in pancreatic cancer is not satisfactory. As a caspase-1-dependent programmed cell death, pyroptosis s involved in the pathological process of many tumors. Nevertheless, the vital role of the pyroptosis-related gene (PRG) in PC remains unknown. In this study, univariate COX regression was performed for 33 pyroptosis-related genes. Based on these prognosis-related PRGs, all PC patients in the Cancer Genome Atlas (TCGA) database were divided into four subtypes. Then, pyroptosis score (PP-score) was established to quantify pyroptosis level for individual PC patients using principal component analysis (PCA) algorithms. Assessment of pyroptosis level within individual PC patients may predict tumor classification and patient prognosis. Finally, a signature was constructed in TCGA and verified in ICGC. In addition, immunocheckpoint analysis revealed the possibility that the low-risk group would benefit more from immunocheckpoint therapy. Taken together, pyroptosis-related genes play a significant role in tumor immunotherapy and can be utilized to predict the prognosis of PC patients.
Overcoming Resistance to Checkpoint Inhibitors: Natural Killer Cells in Non-Small Cell Lung Cancer
Authors: Gemelli Maria , Noonan Douglas M. , Carlini Valentina , Pelosi Giuseppe , Barberis Massimo , Ricotta Riccardo , Albini Adriana
Published: May 2022

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatments over the last 10 years, with even increasing indications in many neoplasms. Non-small cell lung cancer (NSCLC) is considered highly immunogenic, and ICIs have found a wide set of applications in this area, in both early and advanced lines of treatment, significantly changing the prognosis of these patients. Unfortunately, not all patients can benefit from the treatment, and resistance to ICIs can develop at any time. In addition to T lymphocytes, which are the major target, a variety of other cells present in the tumor microenvironment (TME) act in a complex cross-talk between tumor, stromal, and immune cells. An imbalance between activating and inhibitory signals can shift TME from an “anti-” to a “pro-tumorigenic” phenotype and vice versa. Natural killer cells (NKs) are able to recognize cancer cells, based on MHC I (self and non-self) and independently from antigen presentation. They represent an important link between innate and adaptive immune responses. Little data are available about the role of pro-inflammatory NKs in NSCLC and how they can influence the response to ICIs. NKs express several ligands of the checkpoint family, such as PD-1, TIGIT, TIM-3, LAG3, CD96, IL1R8, and NKG2A. We and others have shown that TME can also shape NKs, converting them into a pro-tumoral, pro-angiogenic “nurturing” phenotype through “decidualization.” The features of these NKs include expression of CD56, CD9, CD49a, and CXCR3; low CD16; and poor cytotoxicity. During ICI therapy, tumor-infiltrating or associated NKs can respond to the inhibitors or counteract the effect by acting as pro-inflammatory. There is a growing interest in NKs as a promising therapeutic target, as a basis for adoptive therapy and chimeric antigen receptor (CAR)-NK technology. In this review, we analyzed current evidence on NK function in NSCLC, focusing on their possible influence in response to ICI treatment and resistance development, addressing their prognostic and predictive roles and the rationale for exploiting NKs as a tool to overcome resistance in NSCLC, and envisaging a way to repolarize decidual NK (dNK)-like cells in lung cancer.
Can Pre-biopsy Second-Look Breast Ultrasound Affect Clinical Management? Experience From a Single Tertiary Hospital
Authors: Ma Li , Qin Jing , Kong Lingyan , Zhao Jialin , Xiao Mengsu , Wang Hongyan , Zhang Jing , Jiang Yuxin , Li Jianchu , Liu He , Zhu Qingli
Published: May 2022

Objectives

Interpretation discrepancy is a major disadvantage of breast imaging. This study aimed to determine the clinical benefit of the pre-biopsy second-look breast ultrasound (US).

Methods

Patients with suspicious breast masses referred to our tertiary hospital for US-guided breast biopsy were retrospectively reviewed between August 2017 and November 2019. Here, second-look assessments were performed by experienced specialized breast radiologists via performing a bilateral breast US scan plus reviewing former imaging studies, and results were compared with the initial assessment. Interpretation changes in terms of biopsy recommendation and surgical management (i.e., lumpectomy to mastectomy) were analyzed.

Results

A total of 537 patients were enrolled in this study. Interpretation discrepancies occurred in 109 patients (20%; 95% CI, 17%–24%). Among them, there were 84 patients (16%; 95% CI, 13%–19%) whose masses were re-classified as BI-RADS 3 by the second-look US and underwent 2-year follow-up, showing 82 benign, 1 malignant, and 1 high-risk lesions. On the other hand, 16 patients (3%; 95% CI, 2%–5%) undertook biopsy at an additional site, identifying 10 new malignant lesions, 3 high-risk lesions, and 3 benign lesions, resulting in surgical management changes in 12 patients. In addition, nine (2%; 95% CI, 1%–3%) patients received discrepant disease ranges, which also altered surgical management. Overall, 21 patients (4%; 95% CI, 3%–6%) got their surgical management altered by the second-look US.

Conclusion

Pre-biopsy second-look assessment of breast US can reduce unnecessary biopsies in 16% of patients and alter surgical management in 4% of patients, suggesting it is a practical and valuable method for patient care improvement.
Plasma VEGF and Leptin Values in Patients With Gastric Intestinal Metaplasia and Metabolic Syndrome
Authors: Pappas-Gogos George , Tepelenis Kostas , Goussia Anna , Tellis Constantinos , Fousekis Fotis , Glantzounis Georgios K. , Vlachos Konstantinos
Published: May 2022

Intestinal metaplasia of the stomach (IM) is considered a pre-cancerous lesion and is a potential precursor to adenocarcinoma. Metabolic syndrome (MetS) has been associated with lesions to the gastrointestinal tract such as the risk of developing Barett esophagus. Vascular endothelial growth factor and leptin have been associated with either gastrointestinal tract carcinogenesis or MetS. In this context, this study was designed to analyze plasma levels of VEGF and leptin in patients with IM and MetS. Four groups of 137 participants (a control group and three patient groups, IM, MetS and IM- MetS) were created. Inclusion criteria for the presence of IM were endoscopic findings and histological confirmation, while for MetS the ATP III and IDF guidelines. Levels of plasma vascular endothelial growth factor (VEGF) and leptin (Leptin) were determined. VEGF levels were increased in IM (IM vs Control, p=0,011) and IM-MetS groups (IM-MetS vs Control, p <0.001 and IM-MetS vs MetS, p=0.001). Leptin levels were found to be increased in the MetS group (MetS vs. Control, p <0.001 and MetS vs IM, p <0.001) and in IM-MetS (IM-MetS vs Control, p = 0.002, IM-MetS vs IM, p=0.033). Patients with intestinal metaplasia and metabolic syndrome (I M - Me t S g r o u p) have elevated levels of VEGF, while leptin levels were associated predominantly with MetS and not with IM.