bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of SARS-CoV-2 Immunity in Convalescent Children and Adolescents
Authors: Tsang Hing Wai , Chua Gilbert T. , To Kelvin K. W. , Wong Joshua S. C. , Tu Wenwei , Kwok Janette S. Y. , Wong Wilfred H. S. , Wang Xiwei , Zhang Yanmei , Rosa Duque Jaime S. , Chan Godfrey C. F. , Chu Wai Kit , Pang CP , Tam Paul K. H. , Lau Yu Lung , Wong Ian C. K. , Leung WH , Yuen Kwok-Yung , Kwan Mike Y. W. , Ip Patrick
Published: December 2021

Persistence of protective immunity for SARS-CoV-2 is important against reinfection. Knowledge on SARS-CoV-2 immunity in pediatric patients is currently lacking. We opted to assess the SARS-CoV-2 adaptive immunity in recovered children and adolescents, addressing the pediatrics specific immunity towards COVID-19. Two independent assays were performed to investigate humoral and cellular immunological memory in pediatric convalescent COVID-19 patients. Specifically, RBD IgG, CD4+, and CD8+ T cell responses were identified and quantified in recovered children and adolescents. SARS-CoV-2-specific RBD IgG detected in recovered patients had a half-life of 121.6 days and estimated duration of 7.9 months compared with baseline levels in controls. The specific T cell response was shown to be independent of days after diagnosis. Both CD4+ and CD8+ T cells showed robust responses not only to spike (S) peptides (a main target of vaccine platforms) but were also similarly activated when stimulated by membrane (M) and nuclear (N) peptides. Importantly, we found the differences in the adaptive responses were correlated with the age of the recovered patients. The CD4+ T cell response to SARS-CoV-2 S peptide in children aged <12 years correlated with higher SARS-CoV-2 RBD IgG levels, suggesting the importance of a T cell-dependent humoral response in younger children under 12 years. Both cellular and humoral immunity against SARS-CoV-2 infections can be induced in pediatric patients. Our important findings provide fundamental knowledge on the immune memory responses to SARS-CoV-2 in recovered pediatric patients.
Diversity of Vascular Niches in Bones and Joints During Homeostasis, Ageing, and Diseases
Authors: Kumar Naveen , Saraber Pepijn , Ding Zhangfan , Kusumbe Anjali P.
Published: December 2021

The bones and joints in the skeletal system are composed of diverse cell types, including vascular niches, bone cells, connective tissue cells and mineral deposits and regulate whole-body homeostasis. The capacity of maintaining strength and generation of blood lineages lies within the skeletal system. Bone harbours blood and immune cells and their progenitors, and vascular cells provide several immune cell type niches. Blood vessels in bone are phenotypically and functionally diverse, with distinct capillary subtypes exhibiting striking changes with age. The bone vasculature has a special impact on osteogenesis and haematopoiesis, and dysregulation of the vasculature is associated with diverse blood and bone diseases. Ageing is associated with perturbed haematopoiesis, loss of osteogenesis, increased adipogenesis and diminished immune response and immune cell production. Endothelial and perivascular cells impact immune cell production and play a crucial role during inflammation. Here, we discuss normal and maladapted vascular niches in bone during development, homeostasis, ageing and bone diseases such as rheumatoid arthritis and osteoarthritis. Further, we discuss the role of vascular niches during bone malignancy.
Crystal Structures of Bat and Human Coronavirus ORF8 Protein Ig-Like Domain Provide Insights Into the Diversity of Immune Responses
Authors: Chen Xiaoxue , Zhou Zhechong , Huang Chunliu , Zhou Ziliang , Kang Sisi , Huang Zhaoxia , Jiang Guanmin , Hong Zhongsi , Chen Qiuyue , Yang Mei , He Suhua , Liu Siqi , Chen Jie , Li Kenan , Li Xin , Liao Jing , Chen Jun , Chen Shoudeng
Published: December 2021

ORF8 is a viral immunoglobulin-like (Ig-like) domain protein encoded by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome. It tends to evolve rapidly and interfere with immune responses. However, the structural characteristics of various coronavirus ORF8 proteins and their subsequent effects on biological functions remain unclear. Herein, we determined the crystal structures of SARS-CoV-2 ORF8 (S84) (one of the epidemic isoforms) and the bat coronavirus RaTG13 ORF8 variant at 1.62 Å and 1.76 Å resolution, respectively. Comparison of these ORF8 proteins demonstrates that the 62-77 residues in Ig-like domain of coronavirus ORF8 adopt different conformations. Combined with mutagenesis assays, the residue Cys20 of ORF8 is responsible for forming the covalent disulfide-linked dimer in crystal packing and in vitro biochemical conditions. Furthermore, immune cell-binding assays indicate that various ORF8 (SARS-CoV-2 ORF8 (L84), ORF8 (S84), and RaTG13 ORF8) proteins have different interaction capabilities with human CD14+ monocytes in human peripheral blood. These results provide new insights into the specific characteristics of various coronavirus ORF8 and suggest that ORF8 variants may influence disease-related immune responses.
Case Report: Metagenomics Next-Generation Sequencing for Diagnosing Cerebral Infarction and Infection Caused by Hematogenous Disseminated Mucormycosis in a Patient With Acute Lymphoblastic Leukemia
Authors: Wen Bingbing , Cai Lisheng , Cai Yun , Du Xin
Published: December 2021

Disseminated mucormycosis, a serious complication, is associated with high mortality in patients with acute leukemia after chemotherapy. Blood cultures are always negative because of recurrent empirical antifungal treatments. The identification of pathogens is important for diagnosis and therapy. In this case report, we diagnosed culture-negative disseminated mucormycosis with Rhizomucor miehei infection leading to cerebral infarction in a patient with leukemia using metagenomics next-generation sequencing (mNGS) form peripheral blood, cerebral spinal fluid, and bronchoalveolar lavage fluid. mNGS technology can be applied to precisely diagnose culture-negative disseminated mucormycosis.
Pain Management in Acute Pancreatitis: A Systematic Review and Meta-Analysis of Randomised Controlled Trials
Authors: Cai Wenhao , Liu Fei , Wen Yongjian , Han Chenxia , Prasad Manya , Xia Qing , Singh Vikesh K. , Sutton Robert , Huang Wei
Published: December 2021

Background: Pain management is an important priority in the treatment of acute pancreatitis (AP). Current evidence and guideline recommendations are inconsistent on the most effective analgesic protocol. This systematic review and meta-analysis of randomised controlled trials (RCTs) aimed to compare the safety and efficacy of analgesics for pain relief in AP.

Methods: A literature search was performed to identify all RCTs assessing analgesics in patients with AP. The primary outcome was the number of participants who needed rescue analgesia. Study quality was assessed using Jadad score. Pooled odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CI) were analysed using a random-effects model.

Results: Twelve studies comprising 699 patients with AP (83% mild AP) were analysed. The tested analgesics significantly decreased the need for rescue analgesia (3 studies, OR.36, 95% CI 0.21 to 0.60) vs. placebo or conventional treatment. The analgesics also improved the pain score [Visual Analogue Scale (Δ-VAS)] at 24 h (WMD 18.46, 0.84 to 36.07) and by the 3rd to 7th days (WMD 11.57, 0.87 to 22.28). Opioids vs. non-opioids were associated with a decrease in the need for rescue analgesia (6 studies, OR 0.25, 95% CI 0.07 to 0.86, p = 0.03) but without significance in pain score. In subgroup analyses, opioids were similar to non-steroidal anti-inflammatory drugs (NSAIDs) regarding the primary outcome (4 studies, OR 0.56, 95% CI 0.24 to 1.32, p = 0.18). There were no significant differences in other clinical outcomes and rate of adverse events. Other studies, comparing epidural anaesthesia vs. patient-controlled analgesia and opioid (buprenorphine) vs. opioid (pethidine) did not show significant difference in primary outcome. Study quality issues significantly contributed to overall study heterogeneity.

Conclusions: NSAIDs and opioids are equally effective in decreasing the need for rescue analgesia in patients with mild AP. The relative paucity of trials and high-quality data in this setting is notable and the optimal analgesic strategy for patients with moderately severe and severe AP still requires to be determined.
Randomized Controlled Trial Comparing 1-Year Outcomes of Low-Energy Femtosecond Laser-Assisted Cataract Surgery versus Conventional Phacoemulsification
Authors: Liu Yu-Chi , Setiawan Melina , Chin Jia Ying , Wu Benjamin , Ong Hon Shing , Lamoureux Ecosse , Mehta Jodhbir S.
Published: December 2021

Purpose: To compare 1-year clinical outcomes, phacoemulsification energy, aqueous profiles, and patient-reported outcomes of low-energy femtosecond laser-assisted cataract surgery (FLACS) vs. conventional phacoemulsification.

Methods: The study is a randomized controlled trial (RCT) with paired-eye design. Eighty-five patients were randomized to receive FLACS (Ziemer LDV Z8) in one eye and conventional phacoemulsification in the fellow eye. Clinical data including phacoemulsification energy parameters (cumulative dissipated energy, phacoemulsification power, and phacoemulsification time), uncorrected and corrected distance visual acuities (UCDVA and BCDVA), manifest refraction spherical equivalent (MRSE), central corneal thickness (CCT), endothelial cell count (ECC), anterior chamber flare, and post-operative complications were obtained for 1 year. Aqueous humor was collected for the analysis of prostaglandin (PGE)2, cytokines and chemokines concentrations. Patients' reported-outcomes on surgical experiences were evaluated using an in-house questionnaire.

Results: Compared to conventional phacoemulsification, the low-energy assisted FLACS group had significantly less ECC reduction at 3 months (1.5 ± 0.3% vs. 7.0 ± 2.4%; P < 0.01) and 1 year (8.2 ± 2.8% vs. 11.2 ± 3.6%; P = 0.03). There were no significant differences in the phacoemulsification energy parameters, UCDVA, BCDVA, MRSE, CCT, occurrence of post-operative complications between the 2 groups throughout post-operative 1 year. Patients' subjective surgical experiences, including the surgical duration and perceived inconvenience, were comparable between the 2 groups. FLACS resulted in significantly higher aqueous PGE2 (P < 0.01), interleukin (IL)-6 (P = 0.03), IL-8 (P = 0.03), and interferon (IFN)-γ (P = 0.04) concentrations and greater anterior chamber flare at 1 day (P = 0.02).

Conclusions: Our RCT presented 1-year longitudinal clinical and laboratory data. The long-term ECC result was more favorable in low-energy FLACS. The rest of the intraoperative and post-operative outcomes, as well as patient-reported outcomes, were comparable between these two procedures.
Characterization of a Novel Chromosome-Encoded AmpC β-Lactamase Gene, blaPRC–1, in an Isolate of a Newly Classified Pseudomonas Species, Pseudomonas wenzhouensis A20, From Animal Farm Sewage
Authors: Zhang Peiyao , Dong Xu , Zhou Kexin , Zhu Tingting , Liang Jialei , Shi Weina , Gao Mengdi , Feng Chunlin , Li Qiaoling , Zhang Xueya , Ren Ping , Lu Junwan , Lin Xi , Li Kewei , Zhu Mei , Bao Qiyu , Zhang Hailin
Published: December 2021

In this work, we characterized a novel chromosome-encoded AmpC β-lactamase gene,blaPRC–1, in an isolate of a newly classifiedPseudomonasspecies designatedPseudomonas wenzhouensisA20, which was isolated from sewage discharged from an animal farm in Wenzhou, China. Susceptibility testing, molecular cloning, and enzyme kinetic parameter analysis were performed to determine the function and enzymatic properties of the β-lactamase. Sequencing and comparative genomic analysis were conducted to clarify the phylogenetic relationship and genetic context of theblaPRC–1gene. PRC-1 is a 379-amino acid AmpC β-lactamase with a molecular weight of 41.48 kDa and a predicted pI of 6.44, sharing the highest amino acid identity (57.7%) with the functionally characterized AmpC β-lactamase PDC-211 (ARX71249).blaPRC–1confers resistance to many β-lactam antibiotics, including penicillins (penicillin G, amoxicillin, and amoxicillin-clavulanic acid) and cephalosporins (cefazolin, ceftriaxone, and cefotaxime). The kinetic properties of PRC-1 were compatible with those of a typical class C β-lactamase showing hydrolytic activities against β-lactam antibiotics, and the hydrolytic activity was strongly inhibited by avibactam. The genetic context ofblaPRC–1was relatively conserved, and no mobile genetic element was predicted in its surrounding region. Identification of a novel β-lactamase gene in an unusual environmental bacterium reveals that there might be numerous unknown resistance mechanisms in bacterial populations, which may pose potential risks to human health due to universal horizontal gene transfer between microorganisms. It is therefore of great value to carry out extensive research on the mechanism of antibiotic resistance.
Characteristic and Otopathogenic Analysis of a Vibrio alginolyticus Strain Responsible for Chronic Otitis Externa in China
Authors: Zhou Ke , Tian Ke-yong , Liu Xin-qin , Liu Wei , Zhang Xin-yu , Liu Jia-yun , Sun Fei
Published: December 2021

Vibrio alginolyticus, a Gram-negative rod bacterium found in marine environments, is known to cause opportunistic infections in humans, including ear infections, which can be difficult to diagnose. We investigated the microbiological and otopathogenic characteristics of a V. alginolyticus strain isolated from an ear exudate specimen obtained from a patient with chronic otitis externa to provide a basis for the future diagnosis of V. alginolyticus-associated infections. The identification of V. alginolyticus was accomplished using a combination of matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS), classical biochemical identification methods, and the use of Vibrio-selective media and advanced molecular identification methodologies. Antimicrobial susceptibility testing revealed that the strain was resistant to ampicillin and sensitive to β-lactam, aminoglycosides, fluoroquinolones, and sulfonamide antibiotics. The potential otopathogenic effects of V. alginolyticus were determined through the performance of cell viability, cell apoptosis, and cell death assays in tympanic membrane (TM) keratinocytes and HEI-OC1 cells treated with V. alginolyticus-conditioned medium using cell-counting kit (CCK)-8 assay, a wound-healing migration assay, Annexin V/propidium iodide (PI) flow cytometric analysis, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL staining). The results indicated that the identified V. alginolyticus strain exerts cytotoxic effects on keratinocytes and HEI-OC1 cells by inhibiting cell proliferation and migration and inducing apoptosis and cell death. To evaluate the ototoxicity of V. alginolyticus, the cell density and morphological integrity of hair cells (HCs) and spiral ganglion neurons (SGNs) were analyzed after exposing cochlear organotypic explants to the bacterial supernatant, which revealed the pre-dominant susceptibility and vulnerability of HCs and SGNs in the basal cochlear region to the ototoxic insults exerted by V. alginolyticus. Our investigation highlights the challenges associated with the identification and characteristic analysis of the Vibrio strain isolated in this case and ultimately aims to increase the understanding and awareness of clinicians and microbiologists for the improved diagnosis of V. alginolyticus-associated ear infections and the recognition of its potential otopathogenic and ototoxic effects.
Regulation of the Coral-Associated Bacteria and Symbiodiniaceae in Acropora valida Under Ocean Acidification
Authors: Ge Ruiqi , Liang Jiayuan , Yu Kefu , Chen Biao , Yu Xiaopeng , Deng Chuanqi , Chen Jinni , Xu Yongqian , Qin Liangyun
Published: December 2021

Ocean acidification is one of many stressors that coral reef ecosystems are currently contending with. Thus, understanding the response of key symbiotic microbes to ocean acidification is of great significance for understanding the adaptation mechanism and development trend of coral holobionts. Here, high-throughput sequencing technology was employed to investigate the coral-associated bacteria and Symbiodiniaceae of the ecologically important coral Acropora valida exposed to different pH gradients. After 30 days of acclimatization, we set four acidification gradients (pH 8.2, 7.8, 7.4, and 7.2, respectively), and each pH condition was applied for 10 days, with the whole experiment lasting for 70 days. Although the Symbiodiniaceae density decreased significantly, the coral did not appear to be bleached, and the real-time photosynthetic rate did not change significantly, indicating that A. valida has strong tolerance to acidification. Moreover, the Symbiodiniaceae community composition was hardly affected by ocean acidification, with the C1 subclade (Cladocopium goreaui) being dominant among the Symbiodiniaceae dominant types. The relative abundance of the Symbiodiniaceae background types was significantly higher at pH 7.2, indicating that ocean acidification might increase the stability of the community composition by regulating the Symbiodiniaceae rare biosphere. Furthermore, the stable symbiosis between the C1 subclade and coral host may contribute to the stability of the real-time photosynthetic efficiency. Finally, concerning the coral-associated bacteria, the stable symbiosis between Endozoicomonas and coral host is likely to help them adapt to ocean acidification. The significant increase in the relative abundance of Cyanobacteria at pH 7.2 may also compensate for the photosynthesis efficiency of a coral holobiont. In summary, this study suggests that the combined response of key symbiotic microbes helps the whole coral host resist the threats of ocean acidification.
Identification of DIR1-Dependant Cellular Responses in Guard Cell Systemic Acquired Resistance
Authors: David Lisa , Kang Jianing , Nicklay Josh , Dufresne Craig , Chen Sixue
Published: December 2021

After localized invasion by bacterial pathogens, systemic acquired resistance (SAR) is induced in uninfected plant tissues, resulting in enhanced defense against a broad range of pathogens. Although SAR requires mobilization of signaling molecules via the plant vasculature, the specific molecular mechanisms remain elusive. The lipid transfer protein defective in induced resistance 1 (DIR1) was identified in Arabidopsis thaliana by screening for mutants that were defective in SAR. Here, we demonstrate that stomatal response to pathogens is altered in systemic leaves by SAR, and this guard cell SAR defense requires DIR1. Using a multi-omics approach, we have determined potential SAR signaling mechanisms specific for guard cells in systemic leaves by profiling metabolite, lipid, and protein differences between guard cells in the wild type and dir1-1 mutant during SAR. We identified two long-chain 18 C and 22 C fatty acids and two 16 C wax esters as putative SAR-related molecules dependent on DIR1. Proteins and metabolites related to amino acid biosynthesis and response to stimulus were also changed in guard cells of dir1-1 compared to the wild type. Identification of guard cell-specific SAR-related molecules may lead to new avenues of genetic modification/molecular breeding for disease-resistant plants.
Retrograde Amnesia – A Question of Disturbed Calcium Levels?
Authors: Montag Dirk
Published: December 2021

Retrograde amnesia is the inability to remember events or information. The successful acquisition and memory of information is required before retrograde amnesia may occur. Often, the trigger for retrograde amnesia is a traumatic event. Loss of memories may be caused in two ways: either by loss/erasure of the memory itself or by the inability to access the memory, which is still present. In general, memories and learning are associated with a positive connotation although the extinction of unpleasant experiences and memories of traumatic events may be highly welcome. In contrast to the many experimental models addressing learning deficits caused by anterograde amnesia, the incapability to acquire new information, retrograde amnesia could so far only be investigated sporadically in human patients and in a limited number of model systems. Apart from models and diseases in which neurodegeneration or dementia like Alzheimer’s disease result in loss of memory, retrograde amnesia can be elicited by various drugs of which alcohol is the most prominent one and exemplifies the non-specific effects and the variable duration. External or internal impacts like traumatic brain injury, stroke, or electroconvulsive treatments may similarly result in variable degrees of retrograde amnesia. In this review, I will discuss a new genetic approach to induce retrograde amnesia in a mouse model and raise the hypothesis that retrograde amnesia is caused by altered intracellular calcium homeostasis. Recently, we observed that neuronal loss of neuroplastin resulted in retrograde amnesia specifically for associative memories. Neuroplastin is tightly linked to the expression of the main Ca2+ extruding pumps, the plasma membrane calcium ATPases (PMCAs). Therefore, neuronal loss of neuroplastin may block the retrieval and storage of associative memories by interference with Ca2+ signaling cascades. The possibility to elicit retrograde amnesia in a controlled manner allows to investigate the underlying mechanisms and may provide a deeper understanding of the molecular and circuit processes of memory.
Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway
Authors: Bentea Eduard , De Pauw Laura , Verbruggen Lise , Winfrey Lila C. , Deneyer Lauren , Moore Cynthia , Albertini Giulia , Sato Hideyo , Van Eeckhaut Ann , Meshul Charles K. , Massie Ann
Published: December 2021

The astrocytic cystine/glutamate antiporter system xc– (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson’s disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT–/–) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT+/+) littermates. Contrary to adult mice, aged xCT–/– mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT+/+ littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT–/– mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice (Bentea et al., 2015a), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT–/– mice when compared to age-matched xCT+/+ littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT–/– mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system xc– in mechanisms of dopaminergic cell loss and its interaction with aging.
First off Label Endovascular Clinical Experience to Treat Diffuse Cerebral Venous Sinus Thrombosis Using the INARI FlowTriever System: Case Report
Authors: Bushnaq Saif , Kareem Samer Abdul , Liaw Nicholas , Alenzi Bader , Ahmed Muhammad Khaleeq , Bushnaq Merna , Zaidat Osama O.
Published: December 2021

Anticoagulation with heparin is the current mainstay treatment for Cerebral Venous Sinus Thrombosis (CVST). Endovascular treatment is increasingly being used to treat patients with CVST who are non-responsive to anticoagulation. These more aggressive interventions include catheter-based local chemical thrombolysis, balloon angioplasty and mechanical thrombectomy with uncertain safety and efficacy. Here we describe the first reported clinical experience using the INARI FlowTriever system to treat a patient presented with focal weakness and found to have diffuse CVST.
Magnetic Resonance Imaging Sequence Identification Using a Metadata Learning Approach
Authors: Liang Shuai , Beaton Derek , Arnott Stephen R. , Gee Tom , Zamyadi Mojdeh , Bartha Robert , Symons Sean , MacQueen Glenda M. , Hassel Stefanie , Lerch Jason P. , Anagnostou Evdokia , Lam Raymond W. , Frey Benicio N. , Milev Roumen , Müller Daniel J. , Kennedy Sidney H. , Scott Christopher J. M. ,   The ONDRI Investigators
Published: December 2021

Despite the wide application of the magnetic resonance imaging (MRI) technique, there are no widely used standards on naming and describing MRI sequences. The absence of consistent naming conventions presents a major challenge in automating image processing since most MRI software require a priori knowledge of the type of the MRI sequences to be processed. This issue becomes increasingly critical with the current efforts toward open-sharing of MRI data in the neuroscience community. This manuscript reports an MRI sequence detection method using imaging metadata and a supervised machine learning technique. Three datasets from the Brain Center for Ontario Data Exploration (Brain-CODE) data platform, each involving MRI data from multiple research institutes, are used to build and test our model. The preliminary results show that a random forest model can be trained to accurately identify MRI sequence types, and to recognize MRI scans that do not belong to any of the known sequence types. Therefore the proposed approach can be used to automate processing of MRI data that involves a large number of variations in sequence names, and to help standardize sequence naming in ongoing data collections. This study highlights the potential of the machine learning approaches in helping manage health data.
Emerging Significance of Ginsenosides as Potentially Reversal Agents of Chemoresistance in Cancer Therapy
Authors: Xu Jin-Feng , Wan Yan , Tang Fei , Chen Lu , Yang Yu , Xia Jia , Wu Jiao-Jiao , Ao Hui , Peng Cheng
Published: December 2021

Chemoresistance has become a prevalent phenomenon in cancer therapy, which alleviates the effect of chemotherapy and makes it difficult to break the bottleneck of the survival rate of tumor patients. Current approaches for reversing chemoresistance are poorly effective and may cause numerous new problems. Therefore, it is urgent to develop novel and efficient drugs derived from natural non-toxic compounds for the reversal of chemoresistance. Researches in vivo and in vitro suggest that ginsenosides are undoubtedly low-toxic and effective options for the reversal of chemoresistance. The underlying mechanism of reversal of chemoresistance is correlated with inhibition of drug transporters, induction of apoptosis, and modulation of the tumor microenvironment(TME), as well as the modulation of signaling pathways, such as nuclear factor erythroid-2 related factor 2 (NRF2)/AKT, lncRNA cancer susceptibility candidate 2(CASC2)/ protein tyrosine phosphatase gene (PTEN), AKT/ sirtuin1(SIRT1), epidermal growth factor receptor (EGFR)/ phosphatidylinositol 3-kinase (PI3K)/AKT, PI3K/AKT/ mammalian target of rapamycin(mTOR) and nuclear factor-κB (NF-κB). Since the effects and the mechanisms of ginsenosides on chemoresistance reversal have not yet been reviewed, this review summarized comprehensively experimental data in vivo and in vitro to elucidate the functional roles of ginsenosides in chemoresistance reversal and shed light on the future research of ginsenosides.
Human Metabolites of Hamaforton™ (Hamamelis virginiana L. Extract) Modulates Fibroblast Extracellular Matrix Components in Response to UV-A Irradiation
Authors: Natella Fausta , Guantario Barbara , Ambra Roberto , Ranaldi Giulia , Intorre Federica , Burki Carolina , Canali Raffaella
Published: December 2021

Hamamelis virginiana L. a rich source of both condensed and hydrolyzable tannins, utilized to treat dermatological disorders. Since no experimental and clinical data is available for its use as oral formulation in skin related disorders, the purpose of this study was to investigate the effects of Hamaforton™ (Hamamelis virginiana extract) metabolites on gene dysregulation induced by ultraviolet A radiation in cultured human dermal fibroblasts. A combination of in vivo and ex vivo experimental designs has been exploited in order to take into account the polyphenol metabolic transformation that occurs in humans. 12 healthy volunteers received either a capsule of Hamaforton™ or a placebo in a randomized, blinded crossover trial. After Hamaforton™ ingestion, the kinetic of appearance of galloyl derivatives was measured in plasma. Then, in the ex vivo experiment, the serum isolated after supplementation was used as a source of Hamaforton™ metabolites to enrich the culture medium of dermal fibroblasts exposed to ultraviolet A radiation. Three different gallic acid metabolites (4-O-methyl gallic acid, 4-O-methyl gallic acid sulphate and trimethyl gallic acid glucuronide) were identified in volunteer plasma. While, ultraviolet A irradiation of dermal fibroblasts affected the expression of extracellular matrix genes, the presence of Hamaforton™ metabolites in the culture media did not affect the expression of most of those genes. However, the activation of the expression of 10 different genes involved in repair processes for the maintenance of skin integrity, suggest that the metabolites can play a role in damage recovery. To our knowledge, this is the first study that demonstrates the bioavailability of Hamaforton™ phenolic compounds, and the effects of its metabolites on cultured dermal fibroblast response to ultraviolet A irradiation.
Soluble Epoxide Hydrolase Deletion Limits High-Fat Diet-Induced Inflammation
Authors: Wagner Karen M. , Yang Jun , Morisseau Christophe , Hammock Bruce D.
Published: December 2021

The soluble epoxide hydrolase (sEH) enzyme is a major regulator of bioactive lipids. The enzyme is highly expressed in liver and kidney and modulates levels of endogenous epoxy-fatty acids, which have pleiotropic biological effects including limiting inflammation, neuroinflammation, and hypertension. It has been hypothesized that inhibiting sEH has beneficial effects on limiting obesity and metabolic disease as well. There is a body of literature published on these effects, but typically only male subjects have been included. Here, we investigate the role of sEH in both male and female mice and use a global sEH knockout mouse model to compare the effects of diet and diet-induced obesity. The results demonstrate that sEH activity in the liver is modulated by high-fat diets more in male than in female mice. In addition, we characterized the sEH activity in high fat content tissues and demonstrated the influence of diet on levels of bioactive epoxy-fatty acids. The sEH KO animals had generally increased epoxy-fatty acids compared to wild-type mice but gained less body weight on higher-fat diets. Generally, proinflammatory prostaglandins and triglycerides were also lower in livers of sEH KO mice fed HFD. Thus, sEH activity, prostaglandins, and triglycerides increase in male mice on high-fat diet but are all limited by sEH ablation. Additionally, these changes also occur in female mice though at a different magnitude and are also improved by knockout of the sEH enzyme.
Mechanism of Improving Aspirin Resistance: Blood-Activating Herbs Combined With Aspirin in Treating Atherosclerotic Cardiovascular Diseases
Authors: Zhao Yixi , Yang Shengjie , Wu Min
Published: December 2021

Atherosclerotic thrombotic disease continues to maintain a high morbidity and mortality rate worldwide at present. Aspirin, which is reckoned as the cornerstone of primary and secondary prevention of atherosclerotic cardiovascular diseases (ASCVDs), has been applied in clinics extensively. However, cardiovascular events continue to occur even though people utilize aspirin appropriately. Therefore, the concept of aspirin resistance (AR) was put forward by scholars, which is of great significance for the prediction of the clinical outcome of diseases. The pathogenesis of AR may be incorporated with low patient compliance, insufficient dose, genetic polymorphism, increased platelet transformation, inflammation, and the degenerative changes and calcification of platelets. The improvement of AR in the treatment of ASCVDs has gradually become a research hot spot in recent years. Traditional Chinese medicine (TCM) regards individuals as a whole and treats them from a holistic view, which has been found to have advantages in clinical studies on the treatment of AR. Many kinds of blood-activating TCM have the effect of improving AR. The potential mechanism for the improvement of AR by blood-activating herbs combined with aspirin was explored. The combination of blood-activating herbs and aspirin to improve AR is likely to turn into a hot topic of research in the future.
Machine Learning Enables Accurate and Rapid Prediction of Active Molecules Against Breast Cancer Cells
Authors: He Shuyun , Zhao Duancheng , Ling Yanle , Cai Hanxuan , Cai Yike , Zhang Jiquan , Wang Ling
Published: December 2021

Breast cancer (BC) has surpassed lung cancer as the most frequently occurring cancer, and it is the leading cause of cancer-related death in women. Therefore, there is an urgent need to discover or design new drug candidates for BC treatment. In this study, we first collected a series of structurally diverse datasets consisting of 33,757 active and 21,152 inactive compounds for 13 breast cancer cell lines and one normal breast cell line commonly used in in vitro antiproliferative assays. Predictive models were then developed using five conventional machine learning algorithms, including naïve Bayesian, support vector machine, k-Nearest Neighbors, random forest, and extreme gradient boosting, as well as five deep learning algorithms, including deep neural networks, graph convolutional networks, graph attention network, message passing neural networks, and Attentive FP. A total of 476 single models and 112 fusion models were constructed based on three types of molecular representations including molecular descriptors, fingerprints, and graphs. The evaluation results demonstrate that the best model for each BC cell subtype can achieve high predictive accuracy for the test sets with AUC values of 0.689–0.993. Moreover, important structural fragments related to BC cell inhibition were identified and interpreted. To facilitate the use of the model, an online webserver called ChemBC (http://chembc.idruglab.cn/) and its local version software (https://github.com/idruglab/ChemBC) were developed to predict whether compounds have potential inhibitory activity against BC cells.
Pacing Electrocardiogram Detection With Memory-Based Autoencoder and Metric Learning
Authors: Ge Zhaoyang , Cheng Huiqing , Tong Zhuang , Yang Lihong , Zhou Bing , Wang Zongmin
Published: December 2021

Remote ECG diagnosis has been widely used in the clinical ECG workflow. Especially for patients with pacemaker, in the limited information of patient's medical history, doctors need to determine whether the patient is wearing a pacemaker and also diagnose other abnormalities. An automatic detection pacing ECG method can help cardiologists reduce the workload and the rates of misdiagnosis. In this paper, we propose a novel autoencoder framework that can detect the pacing ECG from the remote ECG. First, we design a memory module in the traditional autoencoder. The memory module is to record and query the typical features of the training pacing ECG type. The framework does not directly feed features of the encoder into the decoder but uses the features to retrieve the most relevant items in the memory module. In the training process, the memory items are updated to represent the latent features of the input pacing ECG. In the detection process, the reconstruction data of the decoder is obtained by the fusion features in the memory module. Therefore, the reconstructed data of the decoder tends to be close to the pacing ECG. Meanwhile, we introduce an objective function based on the idea of metric learning. In the context of pacing ECG detection, comparing the error of objective function of the input data and reconstructed data can be used as an indicator of detection. According to the objective function, if the input data does not belong to pacing ECG, the objective function may get a large error. Furthermore, we introduce a new database named the pacing ECG database including 800 patients with a total of 8,000 heartbeats. Experimental results demonstrate that our method achieves an average F1-score of 0.918. To further validate the generalization of the proposed method, we also experiment on a widely used MIT-BIH arrhythmia database.
Rotor Localization and Phase Mapping of Cardiac Excitation Waves Using Deep Neural Networks
Authors: Lebert Jan , Ravi Namita , Fenton Flavio H. , Christoph Jan
Published: December 2021

The analysis of electrical impulse phenomena in cardiac muscle tissue is important for the diagnosis of heart rhythm disorders and other cardiac pathophysiology. Cardiac mapping techniques acquire local temporal measurements and combine them to visualize the spread of electrophysiological wave phenomena across the heart surface. However, low spatial resolution, sparse measurement locations, noise and other artifacts make it challenging to accurately visualize spatio-temporal activity. For instance, electro-anatomical catheter mapping is severely limited by the sparsity of the measurements, and optical mapping is prone to noise and motion artifacts. In the past, several approaches have been proposed to create more reliable maps from noisy or sparse mapping data. Here, we demonstrate that deep learning can be used to compute phase maps and detect phase singularities in optical mapping videos of ventricular fibrillation, as well as in very noisy, low-resolution and extremely sparse simulated data of reentrant wave chaos mimicking catheter mapping data. The self-supervised deep learning approach is fundamentally different from classical phase mapping techniques. Rather than encoding a phase signal from time-series data, a deep neural network instead learns to directly associate phase maps and the positions of phase singularities with short spatio-temporal sequences of electrical data. We tested several neural network architectures, based on a convolutional neural network (CNN) with an encoding and decoding structure, to predict phase maps or rotor core positions either directly or indirectly via the prediction of phase maps and a subsequent classical calculation of phase singularities. Predictions can be performed across different data, with models being trained on one species and then successfully applied to another, or being trained solely on simulated data and then applied to experimental data. Neural networks provide a promising alternative to conventional phase mapping and rotor core localization methods. Future uses may include the analysis of optical mapping studies in basic cardiovascular research, as well as the mapping of atrial fibrillation in the clinical setting.
Unique Sensitivity of Uterine Tissue and the Immune System for Endometriotic Lesion Formation
Authors: Morris Stephanie A. , Korach Kenneth S. , Burns Katherine A.
Published: December 2021

Endometriosis is a debilitating disease that affects about 10% of reproductive-aged adolescents and women. The etiology of the disease is unknown; however, a prevailing hypothesis is that endometriosis develops from retrograde menstruation, where endometrial tissue and fluids flow back through the oviducts into the peritoneal cavity. There is no cure for endometriosis, and symptoms are treated palliatively. Despite the advances in knowledge, the complexity of endometriosis etiology is still unknown. Recent work by our group suggests that the initiation of endometriosis is immune-dependent. Using a mouse model of endometriosis, we hypothesized the initiation of endometriosis is immune regulated and uterine endometrium specific. In the absence of a functional immune system non-obese diabetic/severe combined immunodeficiency (NOD/SCID mice), endometriotic lesions did not form. Uterine endometrial tissue forms endometriotic lesions, whereas tissues with differing basal expression levels of estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2), similar cellular composition to uterus (i.e. bladder, mammary gland, and lung), and treated with estradiol did not form lesions. As MMP7 is known to play a major role in the organization/reorganization of the endometrium during the menstrual cycle, blocking metalloproteinase (MMP) activity significantly decreased the invasive properties of these cells. Together, these findings suggest that endometriosis is immune and uterine specific and that MMP7 likely plays a role in the ability of uterine tissue and the innate immune system to establish and maintain endometriotic lesions.
Genetic Control and High Temperature Effects on Starch Biosynthesis and Grain Quality in Rice
Authors: Zhang Hua , Xu Heng , Jiang Yingying , Zhang Heng , Wang Shiyu , Wang Fulin , Zhu Ying
Published: December 2021

Grain quality is one of the key targets to be improved for rice breeders and covers cooking, eating, nutritional, appearance, milling, and sensory properties. Cooking and eating quality are mostly of concern to consumers and mainly determined by starch structure and composition. Although many starch synthesis enzymes have been identified and starch synthesis system has been established for a long time, novel functions of some starch synthesis genes have continually been found, and many important regulatory factors for seed development and grain quality control have recently been identified. Here, we summarize the progress in this field as comprehensively as possible and hopefully reveal some underlying molecular mechanisms controlling eating quality in rice. The regulatory network of amylose content (AC) determination is emphasized, as AC is the most important index for rice eating quality (REQ). Moreover, the regulatory mechanism of REQ, especially AC influenced by high temperature which is concerned as a most harmful environmental factor during grain filling is highlighted in this review.
Expression GWAS of PGIP1 Identifies STOP1-Dependent and STOP1-Independent Regulation of PGIP1 in Aluminum Stress Signaling in Arabidopsis
Authors: Agrahari Raj Kishan , Enomoto Takuo , Ito Hiroki , Nakano Yuki , Yanase Emiko , Watanabe Toshihiro , Sadhukhan Ayan , Iuchi Satoshi , Kobayashi Masatomo , Panda Sanjib Kumar , Yamamoto Yoshiharu Y. , Koyama Hiroyuki , Kobayashi Yuriko
Published: December 2021

To elucidate the unknown regulatory mechanisms involved in aluminum (Al)-induced expression of POLYGALACTURONASE-INHIBITING PROTEIN 1 (PGIP1), which is one of the downstream genes of SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) regulating Al-tolerance genes, we conducted a genome-wide association analysis of gene expression levels (eGWAS) of PGIP1 in the shoots under Al stress using 83 Arabidopsis thaliana accessions. The eGWAS, conducted through a mixed linear model, revealed 17 suggestive SNPs across the genome having the association with the expression level variation in PGIP1. The GWAS-detected SNPs were directly located inside transcription factors and other genes involved in stress signaling, which were expressed in response to Al. These candidate genes carried different expression level and amino acid polymorphisms. Among them, three genes encoding NAC domain-containing protein 27 (NAC027), TRX superfamily protein, and R-R-type MYB protein were associated with the suppression of PGIP1 expression in their mutants, and accordingly, the system affected Al tolerance. We also found the involvement of Al-induced endogenous nitric oxide (NO) signaling, which induces NAC027 and R-R-type MYB genes to regulate PGIP1 expression. In this study, we provide genetic evidence that STOP1-independent NO signaling pathway and STOP1-dependent regulation in phosphoinositide (PI) signaling pathway are involved in the regulation of PGIP1 expression under Al stress.
Abscisic Acid Mediates Grafting-Induced Cold Tolerance of Watermelon via Interaction With Melatonin and Methyl Jasmonate
Authors: Guo Yanliang , Yan Jingyi , Su Zhuangzhuang , Chang Jingjing , Yang Jianqiang , Wei Chunhua , Zhang Yong , Ma Jianxiang , Zhang Xian , Li Hao
Published: December 2021

Grafting is widely used to increase plant defense responses to various stresses. Grafting-induced cold tolerance is associated with the increase of the antioxidant potential of plants; however, the underlying mechanisms remain unclear. Here, we found that pumpkin rootstocks promote antioxidant enzyme activities and alleviate cold-induced oxidative damage, accompanied by increased abscisic acid (ABA), melatonin, and methyl jasmonate (MeJA) levels in leaves. Increased ABA accumulation in leaves was attributed partly to the increased ABA levels in rootstocks. ABA induced antioxidant enzymes activities and the accumulation of melatonin and MeJA, while inhibition of ABA synthesis blocked the rootstock-induced antioxidant activity and the accumulation of melatonin and MeJA under cold stress. Melatonin and MeJA application also enhanced ABA accumulation in leaves after cold exposure, whereas inhibition of melatonin or MeJA synthesis attenuated the rootstock-induced increase of ABA. Moreover, melatonin and MeJA application alleviated cold-induced oxidative stress, but inhibition of melatonin or MeJA synthesis lowered the rootstock- or ABA-induced antioxidant potential and tolerance to cold. These findings indicate that ABA plays an important role in the grafting-induced cold tolerance by promoting the accumulation of melatonin and MeJA, which in turn, promote ABA accumulation, forming a positive feedback loop.