bluuebunny/crossref_metadata_2025 huggingface dataset:
Use ggbreak to Effectively Utilize Plotting Space to Deal With Large Datasets and Outliers
Authors: Xu Shuangbin , Chen Meijun , Feng Tingze , Zhan Li , Zhou Lang , Yu Guangchuang
Published: November 2021

With the rapid increase of large-scale datasets, biomedical data visualization is facing challenges. The data may be large, have different orders of magnitude, contain extreme values, and the data distribution is not clear. Here we present an R package ggbreak that allows users to create broken axes using ggplot2 syntax. It can effectively use the plotting area to deal with large datasets (especially for long sequential data), data with different magnitudes, and contain outliers. The ggbreak package increases the available visual space for a better presentation of the data and detailed annotation, thus improves our ability to interpret the data. The ggbreak package is fully compatible with ggplot2 and it is easy to superpose additional layers and applies scale and theme to adjust the plot using the ggplot2 syntax. The ggbreak package is open-source software released under the Artistic-2.0 license, and it is freely available on CRAN (https://CRAN.R-project.org/package=ggbreak) and Github (https://github.com/YuLab-SMU/ggbreak).
Sex Disparities of Genomic Determinants in Response to Immune Checkpoint Inhibitors in Melanoma
Authors: Shi Fuyan , Zhang Wenjing , Yang Yichen , Yang Yitao , Zhao Junyi , Xie Mengqi , Sheng Chao , Wang Suzhen , Wang Qinghua
Published: November 2021

Background

Despite the acknowledged sex-related differences in immune response and immune checkpoint inhibitor (ICI) efficacy, little is known about the sex disparities in melanoma of novel genomic determinants for ICI therapies.

Methods

Pretreatment genomic profiles and clinical characteristics of 631 melanoma patients treated with ICIs (i.e., inhibitors of CTLA-4, PD-1/PD-L1, or both) were comprehensively curated. Genomic factors, i.e., significantly mutated genes (SMGs), mutational signatures, and molecular subtypes were identified, and their associations with ICI treatment efficacy in male and female patients were evaluated.

Results

Of the 15 SMGs identified in this study, three genes (i.e., CFH, DGKG, and PPP6C) were found to exhibit sex differences with respect to ICI efficacy. Among these, CFH mutations exhibited both response rate and survival benefits in male, but not in female patients. A total of four mutational signatures (i.e., signatures 1, 4, 7, and 11) were extracted. Male patients with signature 4 (also known as smoking-related signature) had an inferior ICI response rate and overall survival. However, this association was not significant in females. An immune subtype based on mutational activities was found to be significantly associated with poor ICI survival in female patients.

Conclusion

We uncovered several sex-dependent genomic correlates of response to ICI treatment, such as male-biased CFH mutations and signature 4 and the female-biased immune resistance subtype. The findings derived from this research provide clues for exploring different immunotherapeutic approaches in male and female patients with melanoma.
Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib?
Authors: Zhao Shankun , Wu Weizhou , Jiang Hao , Ma Lei , Pan Chengyi , Jin Chong , Mo Jinggang , Wang Liezhi , Wang Kunpeng
Published: November 2021

Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the “ClinicalTrials.gov” for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.
Immunosuppression Affects Neutrophil Functions: Does Calcineurin-NFAT Signaling Matter?
Authors: Vymazal Ondřej , Bendíčková Kamila , De Zuani Marco , Vlková Marcela , Hortová-Kohoutková Marcela , Frič Jan
Published: November 2021

Neutrophils are innate immune cells with important roles in antimicrobial defense. However, impaired or dysregulated neutrophil function can result in host tissue damage, loss of homeostasis, hyperinflammation or pathological immunosuppression. A central link between neutrophil activation and immune outcomes is emerging to be the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, which is activated by neutrophil detection of a microbial threatviapattern recognition receptors and results in inflammatory cytokine production. This potent pro-inflammatory pathway is also the target of several immunosuppressive drugs used for the treatment of autoimmune disorders, during solid organ and hematopoietic cell transplantations, and as a part of anti-cancer therapy: but what effects these drugs have on neutrophil function, and their broader consequences for immune homeostasis and microbial defense are not yet known. Here, we bring together the emerging literature describing pathology- and drug- induced neutrophil impairment, with particular focus on their effects on calcineurin-NFAT signaling in the innate immune compartment.
Metabolic Changes in Scylla paramamosain During Adaptation to an Acute Decrease in Salinity
Authors: Yao Hongzhi , Li Xing , Chen Yuhao , Liang Guoling , Gao Gao , Wang Huan , Wang Chunlin , Mu Changkao
Published: November 2021

The mud crab Scylla paramamosain is an important euryhaline mariculture species. However, acute decreases in salinity seriously impact its survival and can result in large production losses. In this study, we evaluated metabolic changes in S. paramamosain exposed to an acute salinity reduction from 23 psu to 3 psu. After the salinity decrease, hemolymph osmolality declined from 726.75 to 642.38 mOsm/kg H2O, which was close to the physiological equilibrium state. Activities of osmolality regulation-related enzymes in the gills, including Na+-K+-ATPase, CA, and V-ATPase all increased. Using LC-MS analysis, we identified 519 metabolites (mainly lipids). Additionally, 13 significant metabolic pathways (P < 0.05) were identified via enrichment analysis, which were mainly related to signal pathways, lipids, and transportation. Our correlation analysis, which combined LC-MS and previous GC-MS data, yielded 28 significant metabolic pathways. Amino acids and energy metabolism accounted for most of these pathways, and lipid metabolism pathways were insignificant. Our results showed that amino acids and energy metabolism were the dominant factors involved in the adaptation of S. paramamosain to acute salinity decrease, and lipid metabolites played a supporting role.
The Hologenome of Haliclona fulva (Porifera, Demospongiae) Reveals an Abundant and Diverse Viral Community
Authors: García-Bonilla Erika , Chaves-Moreno Diego , Riaño-Pachón Diego , Terán Wilson , Acosta Alberto , Junca Howard
Published: November 2021

Viruses are among the most abundant biological entities in the ocean, largely responsible of modulating nutrients fluxes and influencing microbial composition and functioning. In marine invertebrate holobionts like sponges and their associated microbiomes, little is known about virome composition. Here, we characterized the Haliclona fulva hologenome, an encrusting low-microbial abundance sponge found across the Western Mediterranean Sea (35–40 m of depth) producer of a large metabolic repertoire of bioactive compounds and harboring a distinct and stable associated microbiome. Assembled contigs from shotgun metagenome sequences obtained from H. fulva specimens were comprehensively analyzed regarding taxonomic and functional content revealing its remarkable and abundant viral community dominated by single-stranded DNA (ssDNA) virus. Viral families consistently detected in contigs are Circoviridae, Phycodnaviridae, Poxviridae, Herelleviridae, Mimiviridae, Microviridae, and notably the first reported encounter of Nanoviridae and Genomoviridae in Porifera, expanding their known host range. The relative abundance of inferred bacteriophages/prophages was low, suggesting that the prokaryotic community in this sponge has a limited host range and susceptibility. H. fulva showed a distinct viral composition supporting the general proposition of specific and coevolving viromes in marine holobionts.
Modeling Marsh Dynamics Using a 3-D Coupled Wave-Flow-Sediment Model
Authors: Kalra Tarandeep S. , Ganju Neil K. , Aretxabaleta Alfredo L. , Carr Joel A. , Defne Zafer , Moriarty Julia M.
Published: November 2021

Salt marshes are dynamic biogeomorphic systems that respond to external physical factors, including tides, sediment transport, and waves, as well as internal processes such as autochthonous soil formation. Predicting the fate of marshes requires a modeling framework that accounts for these processes in a coupled fashion. In this study, we implement two new marsh dynamic processes in the 3-D COAWST (coupled-ocean-atmosphere-wave sediment transport) model. The processes added are the erosion of the marsh edge scarp caused by lateral wave thrust from surface waves and vertical accretion driven by biomass production on the marsh platform. The sediment released from the marsh during edge erosion causes a change in bathymetry, thereby modifying the wave-energy reaching the marsh edge. Marsh vertical accretion due to biomass production is considered for a single vegetation species and is determined by the hydroperiod parameters (tidal datums) and the elevation of the marsh cells. Tidal datums are stored at user-defined intervals as a hindcast (on the order of days) and used to update the vertical growth formulation. Idealized domains are utilized to verify the lateral wave thrust formulation and show the dynamics of lateral wave erosion leading to horizontal retreat of marsh edge. The simulations of Reedy and Dinner Creeks within the Barnegat Bay estuary system demonstrate the model capability to account for both lateral wave erosion and vertical accretion due to biomass production in a realistic marsh complex. The simulations show that vertical accretion is dominated by organic deposition in the marsh interior, whereas deposition of mineral estuarine sediments occurs predominantly along the channel edges. The ability of the model to capture the fate of the sediment can be extended to model to simulate the impacts of future storms and relative sea-level rise (RSLR) scenarios on salt-marsh ecomorphodynamics.
Phylogenetic Implications and Functional Disparity in the Chalcone synthase Gene Family of Common Seagrass Zostera marina
Authors: Ma Mingyu , Zhong Mingyu , Zhang Quansheng , Zhao Wei , Wang Mengxin , Luo Chengying
Published: November 2021

Chalcone synthase (CHS) family are plant type III polyketide synthases that participate in the flavonoid synthesis pathway to induce plant resistance to various biotic and abiotic stresses. Zostera marina, a common seagrass, migrated to terrestrial conditions and returned to the sea, achieving the most severe habitat shift of flowering plants. Given the special evolutionary process, we conducted genome-wide, expression and enzyme activity analyses of the ZosmaCHS family to understand its phylogenetic implications. Various duplication modes led to the expansion of 11 CHS homologs in Z. marina. Based on the phylogenetic relationships, ZosmaCHSs were classified into three clades. Further quantitative real time-PCR analyses of the ZosmaCHS homologs showed different light responses and tissue-specific expression, indicating functional diversification of the ZosmaCHSs. Moreover, the ZosmaCHS proteins clustering with the validated chalcone synthases were recombined into prokaryotic expression systems. All the recombinant proteins showed CHS activity to generate naringenin chalcone with varying catalytic efficiencies. ZosmaCHS07 was regarded as the dominant CHS because of its significant light response and the higher catalytic efficiency. Taken together, the disparity of the expression and enzyme activity indicated that sub-functionalization is the primary mechanism of the expansion of the ZosmaCHSs family.
Circulating Immunosuppressive Regulatory T Cells Predict Risk of Incident Cutaneous Squamous Cell Carcinoma
Authors: Rollison Dana E. , Messina Jane L. , Cherpelis Basil S. , Fenske Neil A. , Schell Michael J. , Adeegbe Dennis O. , Zhao Yayi , Amorrortu Rossybelle P. , Akuffo Afua A. , Hesterberg Rebecca S. , Epling-Burnette Pearlie K.
Published: November 2021

Ultraviolet radiation exposure (UVR) is a risk factor for cutaneous squamous cell carcinoma (cuSCC) and has been shown to be positively associated with circulating immunosuppressive regulatory T cells (“Tregs”). However, the risk of cuSCC in association with circulating Tregs has not been studied. The aim of this study was to determine whether circulating Treg levels are associated with cuSCC development, particularly in the context of high UVR. Blood and spectrophotometer-based UVR measurements were obtained on 327 immunocompetent individuals undergoing routine skin cancer screenings at baseline and followed for up to 4 years for incident cuSCC development within a prospective cohort study. Proportions of phenotypically distinct Tregs, especially CCR4hi and CLA+ cells which are associated with activation and homing, respectively, were measured by flow cytometry. Tregs in cuSCC tumors were assessed using immunohistochemistry and graded for solar elastosis, a measure of cumulative UVR damage. Of several Treg phenotypes examined, higher levels of circulating CCR4hi Tregs at baseline were significantly associated with increased risk of subsequent cuSCC; those with higher levels of both CCR4hi and UVR were four times more likely to develop cuSCC compared to those with lower levels of both (Hazard Ratio = 4.11, 95% CI = 1.22–13.90). Within cuSCC tumors, CCR4hi Tregs were positively associated with solar elastosis. Results show that a higher proportion of CCR4hi peripheral Tregs predicts incident cuSCC up to 4 years, especially among highly UV-exposed individuals. Research of the underpinning biology of Tregs in UVR-associated skin damage may possibly reveal novel opportunities for screening, prevention, and treatment.
A Nomogram for Predicting Non-Rebound in HBV-Infected Pregnant Women With Mother-to-Child Transmission Prevention
Authors: Wang Chun-Rui , Zhong Guo-Chao , Chen Zhi-Wei , Hu Peng
Published: November 2021

Background: Current guidelines recommend that pregnancies with mother-to-child transmission (MTCT) prevention can cease antiviral treatment after delivery. We aimed to develop a nomogram for predicting non-rebound in HBV-infected pregnant women with MTCT prevention after post-partum nucleos(t)ide analogs (NAs) withdrawal based on parameters before treatment cessation.

Methods: Pregnant women receiving antiviral therapy for MTCT prevention and who withdrew from taking NAs after delivery were included in this study. We used the least absolute shrinkage and selection operator (LASSO) logistics and a two-way stepwise regression to select prognostic factors for the risk model, and the concordance index (C-index) was used to assess its discrimination. Internal validation was performed through bootstrapping.

Results: Of 92 included patients, 16 and 76 experienced non-rebound and virologic rebound within 48 weeks of post-partum NAs cessation, respectively. Platelet to lymphocyte ratio (PLR) at 34 ± 2 weeks of gestation, a reduction in hepatitis B surface antigen (HBsAg) from baseline to 34 ± 2 weeks of gestation, and hepatitis B virus (HBV) DNA declining from baseline to the end of treatment (EOT) were entered into the final risk model. Its C-index was 0.91 (95% CI, 0.82–0.99), and it reached as high as 0.88 after bootstrapping validation. The decision curve and decision tree were further developed to facilitate the application of this model.

Conclusions: We developed a nomogram for predicting non-rebound in pregnant women with MTCT prevention after the withdrawal of antiviral agents, which facilitates physicians in making appropriate treatment recommendations.
A Prospective Multicenter Study of the Chinese Scoring System for Hepatitis B Liver Failure
Authors: Zhe-bin Wu , Bing-liang Lin , Liang Peng , Zhi Chen , Xin-xin Zhang , De-ming Tan , Wan-hua Ren , Kai Wang , Xue-bin Yan , Wei-min Ke , Yu-bao Zheng , Zhi-liang Gao
Published: November 2021

Objective: To evaluate the clinical utility of a Chinese scoring system for hepatitis B liver failure in a prospective and multicenter study.

Methods: Clinical data for 1,143 patients with hepatitis B liver failure who had been followed up for a minimum of 6 months were collected from seven liver disease centers across China. The disease severity and prognosis for the patients were predicted using the Chinese scoring system and compared to those predicted with the model for end-stage liver disease (MELD) score, MELD-Na score, and Child-Turcotte-Pugh (CTP) score.

Results: The Chinese scoring system was more effective at predicting the outcomes of survival and mortality than the MELD score. In the peak disease stage, the area under the receiver operating characteristic curve for the Chinese scoring system was 0.954, significantly higher than that (0.896) for the MELD scoring system (P < 0.001). The positive prediction at 30, 90, and 180 days with the Chinese scoring system was 0.764 (95% CI: 0.714–0.808), 0.731 (95% CI: 0.694–0.769), and 0.724 (95% CI: 0.679–0.765), also significantly higher than that with the MELD, MELD-Na, and CTP scores (P < 0.001). In addition, the Chinese scoring system was superior to the MELD, MELD-Na, and CTP scores (P < 0.001) at predicting the prognosis of patients with hepatitis B liver failure at both 30 and 180 days.

Conclusion: The Chinese scoring system demonstrated superior performance to the three established scoring systems in assessing the severity and outcomes of hepatitis B liver failure in this cohort.
Whole Genome Sequencing Provides an Added Value to the Investigation of Staphylococcal Food Poisoning Outbreaks
Authors: Nouws Stéphanie , Bogaerts Bert , Verhaegen Bavo , Denayer Sarah , Laeremans Lasse , Marchal Kathleen , Roosens Nancy H. C. , Vanneste Kevin , De Keersmaecker Sigrid C. J.
Published: November 2021

Through staphylococcal enterotoxin (SE) production, Staphylococcus aureus is a common cause of food poisoning. Detection of staphylococcal food poisoning (SFP) is mostly performed using immunoassays, which, however, only detect five of 27 SEs described to date. Polymerase chain reactions are, therefore, frequently used in complement to identify a bigger arsenal of SE at the gene level (se) but are labor-intensive. Complete se profiling of isolates from different sources, i.e., food and human cases, is, however, important to provide an indication of their potential link within foodborne outbreak investigation. In addition to complete se gene profiling, relatedness between isolates is determined with more certainty using pulsed-field gel electrophoresis, Staphylococcus protein A gene typing and other methods, but these are shown to lack resolution. We evaluated how whole genome sequencing (WGS) can offer a solution to these shortcomings. By WGS analysis of a selection of S. aureus isolates, including some belonging to a confirmed foodborne outbreak, its added value as the ultimate multiplexing method was demonstrated. In contrast to PCR-based se gene detection for which primers are sometimes shown to be non-specific, WGS enabled complete se gene profiling with high performance, provided that a database containing reference sequences for all se genes was constructed and employed. The custom compiled database and applied parameters were made publicly available in an online user-friendly interface. As an all-in-one approach with high resolution, WGS additionally allowed inferring correct isolate relationships. The different DNA extraction kits that were tested affected neither se gene profiling nor relatedness determination, which is interesting for data sharing during SFP outbreak investigation. Although confirming the production of enterotoxins remains important for SFP investigation, we delivered a proof-of-concept that WGS is a valid alternative and/or complementary tool for outbreak investigation.
The Fate Status of Stem Cells in Diabetes and its Role in the Occurrence of Diabetic Complications
Authors: Xu Jinyi , Zuo Chengguo
Published: November 2021

Diabetes mellitus (DM) is becoming a growing risk factor for public health worldwide. It is a very common disease and is widely known for its susceptibility to multiple complications which do great harm to the life and health of patients, some even lead to death. To date, there are many mechanisms for the complications of diabetes, including the generation of reactive oxygen species (ROS) and the abnormal changes of gas transmitters, which ultimately lead to injuries of cells, tissues and organs. Normally, even if injured, the body can quickly repair and maintain its homeostasis. This is closely associated with the repair and regeneration ability of stem cells. However, many studies have demonstrated that stem cells happen to be damaged under DM, which may be a nonnegligible factor in the occurrence and progression of diabetic complications. Therefore, this review summarizes how diabetes causes the corresponding complications by affecting stem cells from two aspects: stem cells dysfunctions and stem cells quantity alteration. In addition, since mesenchymal stem cells (MSCs), especially bone marrow mesenchymal stem cells (BMMSCs), have the advantages of strong differentiation ability, large quantity and wide application, we mainly focus on the impact of diabetes on them. The review also puts forward the basis of using exogenous stem cells to treat diabetic complications. It is hoped that through this review, researchers can have a clearer understanding of the roles of stem cells in diabetic complications, thus promoting the process of using stem cells to treat diabetic complications.
Recent Advances in Fluorescence Imaging of Pulmonary Fibrosis in Animal Models
Authors: Liu Zongwei , Tang Xiaofang , Zhu Zongling , Ma Xunxun , Zhou Wenjuan , Guan Weijiang
Published: November 2021

Pulmonary fibrosis (PF) is a lung disease that may cause impaired gas exchange and respiratory failure while being difficult to treat. Rapid, sensitive, and accurate detection of lung tissue and cell changes is essential for the effective diagnosis and treatment of PF. Currently, the commonly-used high-resolution computed tomography (HRCT) imaging has been challenging to distinguish early PF from other pathological processes in the lung structure. Magnetic resonance imaging (MRI) using hyperpolarized gases is hampered by the higher cost to become a routine diagnostic tool. As a result, the development of new PF imaging technologies may be a promising solution. Here, we summarize and discuss recent advances in fluorescence imaging as a talented optical technique for the diagnosis and evaluation of PF, including collagen imaging, oxidative stress, inflammation, and PF-related biomarkers. The design strategies of the probes for fluorescence imaging (including multimodal imaging) of PF are briefly described, which can provide new ideas for the future PF-related imaging research. It is hoped that this review will promote the translation of fluorescence imaging into a clinically usable assay in PF.
RF Coil Setup for 31P MRSI in Tongue Cancer in vivo at 7 T
Authors: Forner Ria , Nam Kyungmin , de Koning Klijs J. , van der Velden Tijl , van der Kemp Wybe , Raaijmakers Alexander , Klomp Dennis W. J.
Published: November 2021

Surgery for tongue cancer often results in a major loss in quality of life. While MRI may be used to minimise the volume of excised tissue, often the full tumour extent is missed. This tumour extent may be detected with metabolic imaging. One of the main reasons for the lack of metabolic information on tongue cancer would be the absence of an x-nuclear coil with the tongue as a focus target. Metabolic MRI through 31P MRSI is known as a powerful tool to non-invasively study elevated cell proliferation and disturbed energy metabolism in tumours. Severe magnetic field non-uniformities are inherently caused by the substantial difference in magnetic susceptibilities of tissue and air in the mouth and its environs. Despite this, the wide chemical shift dispersion of 31P could still facilitate precise detection of the cell proliferation biomarkers, phospomonoesters and diesters, as well as energy metabolites ATP, inorganic phosphate, and phosphocreatine potentially mapped over the tongue or tumour in vivo. In this study, we present the first 31P MRSI data of the human tongue in vivo from healthy volunteers and a patient with a tongue tumour at 7 T MRI using a 1H 8-channel transceiver setup placed inside a body 31P transmitter, which is able to get a uniform excitation from the tongue while providing comfortable access to the patient. In addition, a user-friendly external 31P receiver array is used to provide high sensitivity (80%) comparable to an uncomfortable inner mouth loop coil positioned on the tongue. The primary aim is the demonstration of 31P metabolite profiles in the tongue and the differences between healthy and malignant tissue. Indeed, clear elevated cell proliferation expressed as enhanced phosphomonoesters is observed in the tumour vs. the healthy part of the tongue. This can be performed within a total scan duration of 30 min, comparable to clinical scans, with a spatial resolution of 1.5 cm for the 10-min 31P MRSI scan.
Altered Gut Microbial Load and Immune Activation in a Drosophila Model of Human Tauopathy
Authors: Rydbom Jerrik , Kohl Halea , Hyde Vanesa R. , Lohr Kelly M.
Published: November 2021

Tau is a microtubule-associated protein that stabilizes the neuronal cytoskeleton. In the family of neurodegenerative diseases known as tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE), abnormal tau aggregation destabilizes microtubule structure, contributing to a cascade of cellular processes leading to neuronal cell death. The gut microbiome has increasingly become a target of neurodegenerative disease research since gut microbiome imbalances have been linked to protein aggregation and inflammation through a bidirectional axis linking the gut and brain. Accordingly, the present study examined tau-mediated changes to gut microbiome composition and immune activation in a Drosophila melanogaster model of human mutant tauopathy. Fecal deposit quantification and gastric emptying time courses suggested an abnormal food distribution and reduced gut motility in tau transgenic flies compared to controls. Tau transgenic flies also showed an increase in gut bacteria colony forming units (CFUs) from diluted fly homogenate, indicating an increased bacterial load. Finally, we showed that tau transgenic flies have a trend towards elevated systemic levels of antimicrobial peptides targeting gram-negative bacteria using qPCR, suggesting an enhanced innate immune response to bacterial insult. These data demonstrate qualifiable and quantifiable gut microbial and innate immune responses to tauopathy. Furthermore, these results provide a framework for future studies targeting the gut microbiome as a modifier of neurodegenerative disease.
Irx3 and Irx5 - Novel Regulatory Factors of Postnatal Hypothalamic Neurogenesis
Authors: Dou Zhengchao , Son Joe Eun , Hui Chi-chung
Published: November 2021

The hypothalamus is a brain region that exhibits highly conserved anatomy across vertebrate species and functions as a central regulatory hub for many physiological processes such as energy homeostasis and circadian rhythm. Neurons in the arcuate nucleus of the hypothalamus are largely responsible for sensing of peripheral signals such as leptin and insulin, and are critical for the regulation of food intake and energy expenditure. While these neurons are mainly born during embryogenesis, accumulating evidence have demonstrated that neurogenesis also occurs in postnatal-adult mouse hypothalamus, particularly in the first two postnatal weeks. This second wave of active neurogenesis contributes to the remodeling of hypothalamic neuronal populations and regulation of energy homeostasis including hypothalamic leptin sensing. Radial glia cell types, such as tanycytes, are known to act as neuronal progenitors in the postnatal mouse hypothalamus. Our recent study unveiled a previously unreported radial glia-like neural stem cell (RGL-NSC) population that actively contributes to neurogenesis in the postnatal mouse hypothalamus. We also identified Irx3 and Irx5, which encode Iroquois homeodomain-containing transcription factors, as genetic determinants regulating the neurogenic property of these RGL-NSCs. These findings are significant as IRX3 and IRX5 have been implicated in FTO-associated obesity in humans, illustrating the importance of postnatal hypothalamic neurogenesis in energy homeostasis and obesity. In this review, we summarize current knowledge regarding postnatal-adult hypothalamic neurogenesis and highlight recent findings on the radial glia-like cells that contribute to the remodeling of postnatal mouse hypothalamus. We will discuss characteristics of the RGL-NSCs and potential actions of Irx3 and Irx5 in the regulation of neural stem cells in the postnatal-adult mouse brain. Understanding the behavior and regulation of neural stem cells in the postnatal-adult hypothalamus will provide novel mechanistic insights in the control of hypothalamic remodeling and energy homeostasis.
SUMOylation of the Kv4.2 Ternary Complex Increases Surface Expression and Current Amplitude by Reducing Internalization in HEK 293 Cells
Authors: Welch Meghyn A. , Jansen Leslie-Anne R. , Baro Deborah J.
Published: November 2021

Kv4 α-subunits exist as ternary complexes (TC) with potassium channel interacting proteins (KChIP) and dipeptidyl peptidase-like proteins (DPLP); multiple ancillary proteins also interact with the α-subunits throughout the channel’s lifetime. Dynamic regulation of Kv4.2 protein interactions adapts the transient potassium current, IA, mediated by Kv4 α-subunits. Small ubiquitin-like modifier (SUMO) is an 11 kD peptide post-translationally added to lysine (K) residues to regulate protein–protein interactions. We previously demonstrated that when expressed in human embryonic kidney (HEK) cells, Kv4.2 can be SUMOylated at two K residues, K437 and K579. SUMOylation at K437 increased surface expression of electrically silent channels while SUMOylation at K579 reduced IA maximal conductance (Gmax) without altering surface expression. KChIP and DPLP subunits are known to modify the pattern of Kv4.2 post-translational decorations and/or their effects. In this study, co-expressing Kv4.2 with KChIP2a and DPP10c altered the effects of enhanced Kv4.2 SUMOylation. First, the effect of enhanced SUMOylation was the same for a TC containing either the wild-type Kv4.2 or the mutant K437R Kv4.2, suggesting that either the experimental manipulation no longer enhanced K437 SUMOylation or K437 SUMOylation no longer influenced Kv4.2 surface expression. Second, instead of decreasing IA Gmax, enhanced SUMOylation at K579 now produced a significant ∼37–70% increase in IA maximum conductance (Gmax) and a significant ∼30–50% increase in Kv4.2g surface expression that was accompanied by a 65% reduction in TC internalization. Blocking clathrin-mediated endocytosis (CME) in HEK cells expressing the Kv4.2 TC mimicked and occluded the effect of SUMO on IA Gmax; however, the amount of Kv4.2 associated with the major adaptor for constitutive CME, adaptor protein 2 (AP2), was not SUMO dependent. Thus, SUMOylation reduced Kv4.2 internalization by acting downstream of Kv4.2 recruitment into clathrin-coated pits. In sum, the two major findings of this study are: SUMOylation of Kv4.2 at K579 regulates TC internalization most likely by promoting channel recycling. Additionally, there is a reciprocity between Kv4.2 SUMOylation and the Kv4.2 interactome such that SUMOylation regulates the interactome and the interactome influences the pattern and effect of SUMOylation.
Translatomics Probes Into the Role of Lycopene on Improving Hepatic Steatosis Induced by High-Fat Diet
Authors: Huang Tengda , Yu Jingsu , Ma Zeqiang , Fu Qinghua , Liu Siqi , Luo Zupeng , Liu Kang , Yu Lin , Miao Weiwei , Yu Dongling , Song Ziyi , Li Yixing , Zhou Lei , Xu Gaoxiao
Published: November 2021

Liver is an important organ for fat metabolism. Excessive intake of a high-fat/energy diet is a major cause of hepatic steatosis and its complications such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Supplementation with lycopene, a natural compound, is effective in lowering triglyceride levels in the liver, although the underlying mechanism at the translational level is unclear. In this study, mice were fed a high-fat diet (HFD) to induce hepatic steatosis and treated with or without lycopene. Translation omics and transcriptome sequencing were performed on the liver to explore the regulatory mechanism of lycopene in liver steatosis induced by HFD, and identify differentially expressed genes (DEGs). We identified 1,358 DEGs at the translational level. Through transcriptomics and translatomics joint analysis, we narrowed the range of functional genes to 112 DEGs and found that lycopene may affect lipid metabolism by regulating the expression of LPIN1 at the transcriptional and translational levels. This study provides a powerful tool for translatome and transcriptome integration and a new strategy for the screening of candidate genes.
The Future of Moringa Foods: A Food Chemistry Perspective
Authors: Grosshagauer Silke , Pirkwieser Philip , Kraemer Klaus , Somoza Veronika
Published: November 2021

The tree Moringa oleifera Lam. provides its leaves, pods, flowers and seeds for human nutrition. The chemical profile of all these Moringa products varies substantially, not only among the different parts of the plants used. Cultivating, processing as well as storage conditions chiefly determine the contents of nutrients and anti-nutritive constituents. Anti-nutrients, e.g., phytic acid or tannins, are present in notable amounts and may affect micronutrient bioavailability. Although Moringa oleifera products have been promoted for several health benefits and are discussed as an alternative treatment in various diseases, risk assessment studies evaluating contamination levels are scarce. Recent investigations have demonstrated alarming contents of heavy metals, polycyclic aromatic hydrocarbons and mycotoxins in Moringa oleifera products, indicating the need for a comprehensive risk assessment and contingent legal regulation of these products. In this mini review, we briefly outline pivotal, food chemistry and nutrition related data on Moringa preparations in order to stimulate in-depth research to close the presented knowledge gaps.
Recent Progress on Protein-Polyphenol Complexes: Effect on Stability and Nutrients Delivery of Oil-in-Water Emulsion System
Authors: Li Minghui , Ritzoulis Christos , Du Qiwei , Liu Yefeng , Ding Yuting , Liu Weilin , Liu Jianhua
Published: November 2021

Oil-in-water emulsions are widely encountered in the food and health product industries. However, the unsaturated fatty acids in emulsions are easily affected by light, oxygen, and heat, which leads to oxidation, bringing forward difficulties in controlling emulsion quality during transportation, storage, and retail. Proteins are commonly used as emulsifiers that can enhance the shelf, thermal and oxidation stability of emulsions. Polyphenols are commonly found in plants and members of the family have been reported to possess antioxidant, anticancer, and antimicrobial activities. Numerous studies have shown that binding of polyphenols to proteins can change the structure and function of the latter. In this paper, the formation of protein–polyphenol complexes (PPCs) is reviewed in relation to the latters' use as emulsifiers, using the (covalent or non-covalent) interactions between the two as a starting point. In addition, the effects polyphenol binding on the structure and function of proteins are discussed. The effects of proteins from different sources interacting with polyphenols on the emulsification, antioxidation, nutrient delivery and digestibility of oil-in-water emulsion are also summarized. In conclusion, the interaction between proteins and polyphenols in emulsions is complicated and still understudied, thereby requiring further investigation. The present review results in a critical appraisal of the relevant state-of-the-art with a focus on complexes' application potential in the food industry, including digestion and bioavailability studies.
What Is the Numerical Nature of Pain Relief?
Authors: Vigotsky Andrew D. , Tiwari Siddharth R. , Griffith James W. , Apkarian A. Vania
Published: November 2021

Pain relief, or a decrease in self-reported pain intensity, is frequently the primary outcome of pain clinical trials. Investigators commonly report pain relief in one of two ways: using raw units (additive) or using percentage units (multiplicative). However, additive and multiplicative scales have different assumptions and are incompatible with one another. In this work, we describe the assumptions and corollaries of additive and multiplicative models of pain relief to illuminate the issue from statistical and clinical perspectives. First, we explain the math underlying each model and illustrate these points using simulations, for which readers are assumed to have an understanding of linear regression. Next, we connect this math to clinical interpretations, stressing the importance of statistical models that accurately represent the underlying data; for example, how using percent pain relief can mislead clinicians if the data are actually additive. These theoretical discussions are supported by empirical data from four longitudinal studies of patients with subacute and chronic pain. Finally, we discuss self-reported pain intensity as a measurement construct, including its philosophical limitations and how clinical pain differs from acute pain measured during psychophysics experiments. This work has broad implications for clinical pain research, ranging from statistical modeling of trial data to the use of minimal clinically important differences and patient-clinician communication.
Case Report: Two Cases of Pediatric Thrombotic Thrombocytopenic Purpura Treated With Combined Therapy
Authors: Tripiciano Costanza , Zangari Paola , Montanari Mauro , Leone Giovanna , Massella Laura , Garaboldi Lucia , Massoud Michela , Lancellotti Stefano , Strocchio Luisa , Manno Emma Concetta , Palma Paolo , Corsetti Tiziana , Luciani Matteo
Published: November 2021

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by a severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. Over 95% of TTPs are acquired, due to autoantibody inhibitors. In children, acquired TTP is a very rare, life-threatening disease. To date, no consensus exists on the treatment strategy of pediatric TTP. We report the cases of two pediatric patients with a diagnosis of TTP, successfully treated with a combination of various therapeutic approaches. Although the patients complained of different sets of symptoms, laboratory data showed Coombs negative hemolytic anemia, renal impairment, and low platelet count in both cases. The diagnosis of acquired TTP was supported by the PLASMIC score and confirmed by the reduction of the ADAMTS13 activity and the presence of anti-ADAMTS13 antibodies. Intravenous immunoglobulin, corticosteroids, and plasma exchange (PEX) were performed without delay. As soon as available, caplacizumab was added to the therapy, with a prompt normalization of platelet count. Nevertheless, ADAMTS13 activity was persistently low, and anti-ADAMTS13 antibodies level was high; thus, a course of rituximab was administered, with persistent normalization of laboratory findings. No adverse events were observed during the treatment. In our experience, the combined use of PEX, caplacizumab, and immunosuppressive therapy during the acute phase of the disease is safe and may have a significant impact on the prognosis with successful clinical outcome and decrease in life-threatening events.
Analysis of the Efficacy and Safety of Endoscopic Retrograde Cholangiopancreatography in Children With Symptomatic Pancreas Divisum
Authors: Pan Guixian , Yang Kaihua , Gong Biao , Deng Zhaohui
Published: November 2021

Background: Endoscopic retrograde cholangiopancreatography (ERCP) has been increasingly performed in children with symptomatic pancreas divisum (PD).

Aim: To investigate the safety and efficacy of ERCP in the treatment of children with symptomatic PD.

Methods: We performed a retrospective analysis on children with PD who were treated with ERCP at Shanghai Children's Medical Center between June 2015 and May 2020. Pertinent patient, clinical and procedural data were collected to assess the therapeutic effects and identify the risk factors for post-ERCP pancreatitis (PEP).

Results: Overall, 114 ERCPs were performed in 46 children with PD. With a median follow-up of 28.5 months (12–71 months), 40 (87.0%) children achieved clinical remission, the median number of acute pancreatitis episodes decreased from four times per year pre-operatively to once per year post-operatively (P < 0.001), and the nutritional score improved post-operatively (P = 0.004). The incidence of PEP was 7.9%, and female sex, stone extraction, and gene mutations were identified as possible risk factors for PEP on univariate analysis. However, there was no statistical significance on multivariate analysis (P > 0.05).

Conclusion: Therapeutic ERCP is an effective and safe intervention for children with symptomatic PD.
Attenuation and Structural Transformation of Crassicauline A During Sand Frying Process and Antiarrhythmic Effects of its Transformed Products
Authors: Tao Pei , Wang Yan , Wang Yujie
Published: November 2021

To ensure safety and efficacy, most Aconitum herbs should be processed before clinical application. The processing methods include boiling, steaming, and sand frying. Among these methods, the transformation pathways of diterpenoid alkaloids in the process of sand frying are more complicated. Therefore, crassicauline A, a natural product with two ester bonds, was chosen as the experimental object. Consequently, a known alkaloid, together with three new alkaloids, was derived from crassicauline A. Meanwhile, the cardiotoxicity of converted products was reduced compared with their parent compound. Interestingly, some diterpenoid alkaloids have similar structures but opposite effects, such as arrhythmia and antiarrhythmic. Considering the converted products are structural analogues of crassicauline A, herein, the antiarrhythmic activity of the transformed products was further investigated. In a rat aconitine-induced arrhythmia assay, the three transformed products, which could dose-dependently delay the ventricular premature beat (VPB) incubation period, reduce the incidence of ventricular tachycardia (VT), combined with the increasing arrhythmia inhibition rate, exhibited prominent antiarrhythmic activities. Our experiments speculated that there might be at least two transformation pathways of crassicauline A during sand frying. The structure-activity data established in this paper constructs the critical pharmacophore of diterpenoid alkaloids as antiarrhythmic agents, which could be helpful in searching for the potential drugs that are equal or more active and with lower toxicity, than currently clinical used antiarrhythmic drugs.
Neuroprotective and Anti-Inflammatory Effect of Pterostilbene Against Cerebral Ischemia/Reperfusion Injury via Suppression of COX-2
Authors: Yan Wenjun , Ren Dongqing , Feng Xiaoxue , Huang Jinwen , Wang Dabin , Li Ting , Zhang Dong
Published: November 2021

Background: The incidence of cerebral ischemia disease leading cause of death in human population worldwide. Treatment of cerebral ischemia remains a clinical challenge for researchers and mechanisms of cerebral ischemia remain unknown. During the cerebral ischemia, inflammatory reaction and oxidative stress plays an important role. The current investigation scrutinized the neuroprotective and anti-inflammatory role of pterostilbene against cerebral ischemia in middle cerebral artery occlusion (MCAO) rodent model and explore the underlying mechanism.

Methods: The rats were divided into following groups viz., normal, sham, MCAO and MCAO + pterostilbene (25 mg/kg) group, respectively. The groups received the oral administration of pterostilbene for 30 days followed by MCAO induction. The neurological score, brain water content, infarct volume and Evan blue leakage were estimated. Hepatic, renal, heart, inflammatory cytokines and inflammatory mediators were estimated.

Results: Pterostilbene treatment significantly (p < 0.001) improved the body weight and suppressed the glucose level and brain weight. Pterostilbene significantly (p < 0.001) reduced the hepatic, renal and heart parameters. Pterostilbene significantly (p < 0.001) decreased the level of glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and decreased the level of malonaldehyde (MDA), 8-Hydroxy-2′-deoxyguanosine (8-OHdG). Pterostilbene significantly (p < 0.001) inflammatory cytokines and inflammatory parameters such as cyclooxygenase-2 (COX-2), inducible nitric oxidase synthase (iNOS) and prostaglandin (PGE2). Pterostilbene significantly (p < 0.001) down-regulated the level of metalloproteinases (MMP) such as MMP-2 and MMP-9. Pterostilbene suppressed the cellular swelling, cellular disintegration, macrophage infiltration, monocyte infiltration and polymorphonuclear leucocyte degranulation in the brain.

Conclusion: In conclusion, Pterostilbene exhibited the neuroprotective effect against cerebral ischemia in rats via anti-inflammatory mechanism.