bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Glycerin Content in Sodium Alginate/Poly(vinyl alcohol)-Based Hydrogels for Wound Dressing Application
Authors: Bialik-Wąs Katarzyna , Pluta Klaudia , Malina Dagmara , Barczewski Mateusz , Malarz Katarzyna , Mrozek-Wilczkiewicz Anna
Published: November 2021

The impact of different amounts of glycerin, which was used in the system of sodium alginate/poly(vinyl alcohol) (SA/PVA) hydrogel materials on the properties, such as gel fraction, swelling ability, degradation in simulated body fluids, morphological analysis, and elongation tests were presented. The study shows a significant decrease in the gel fraction from 80.5 ± 2.1% to 45.0 ± 1.2% with the increase of glycerin content. The T5 values of the tested hydrogels were varied and range from 88.7 °C to 161.5 °C. The presence of glycerin in the matrices significantly decreased the thermal resistance, which was especially visible by T10 changes (273.9 to 163.5 °C). The degradation tests indicate that most of the tested materials do not degrade throughout the incubation period and maintain a constant ion level after 7-day incubation. The swelling abilities in distilled water and phosphate buffer solution are approximately 200–300%. However, we noticed that these values decrease with the increase in glycerin content. All tested matrices are characterized by the maximum elongation rate at break in a range of 37.6–69.5%. The FT-IR analysis exhibits glycerin changes in hydrogel structures, which is associated with the cross-linking reaction. Additionally, cytotoxicity results indicate good adhesion properties and no toxicity towards normal human dermal fibroblasts.
Development and Validation of Tumor Immunogenicity Based Gene Signature for Skin Cancer Risk Stratification
Authors: Yavartanoo Maryam , Yi Gwan-Su
Published: November 2021

Melanoma is one of the most aggressive types of skin cancer, with significant heterogeneity in overall survival. Currently, tumor-node-metastasis (TNM) staging is insufficient to provide accurate survival prediction and appropriate treatment decision making for several types of tumors, such as those in melanoma patients. Therefore, the identification of more reliable prognosis biomarkers is urgently essential. Recent studies have shown that low immune cells infiltration is significantly associated with unfavorable clinical outcome in melanoma patients. Here we constructed a prognostic-related gene signature for melanoma risk stratification by quantifying the levels of several cancer hallmarks and identify the Wnt/β-catenin activation pathway as a primary risk factor for low tumor immunity. A series of bioinformatics and statistical methods were combined and applied to construct a Wnt-immune-related prognosis gene signature. With this gene signature, we computed risk scores for individual patients that can predict overall survival. To evaluate the robustness of the result, we validated the signature in multiple independent GEO datasets. Finally, an overall survival-related nomogram was established based on the gene signature and clinicopathological features. The Wnt-immune-related prognostic risk score could better predict overall survival compared with standard clinicopathological features. Our results provide a comprehensive map of the oncogene-immune-related gene signature that can serve as valuable biomarkers for better clinical decision making.
PRDM12 in Health and Diseases
Authors: Rienzo Monica , Di Zazzo Erika , Casamassimi Amelia , Gazzerro Patrizia , Perini Giovanni , Bifulco Maurizio , Abbondanza Ciro
Published: November 2021

PRDM12 is a member of the PRDI-BF1 (positive regulatory domain I-binding factor 1) homologous domain (PRDM)-containing protein family, a subfamily of Kruppel-like zinc finger proteins, controlling key processes in the development of cancer. PRDM12 is expressed in a spatio-temporal manner in neuronal systems where it exerts multiple functions. PRDM12 is essential for the neurogenesis initiation and activation of a cascade of downstream pro-neuronal transcription factors in the nociceptive lineage. PRDM12 inactivation, indeed, results in a complete absence of the nociceptive lineage, which is essential for pain perception. Additionally, PRDM12 contributes to the early establishment of anorexigenic neuron identity and the maintenance of high expression levels of pro-opiomelanocortin, which impacts on the program bodyweight homeostasis. PRDMs are commonly involved in cancer, where they act as oncogenes/tumor suppressors in a “Yin and Yang” manner. PRDM12 is not usually expressed in adult normal tissues but its expression is re-activated in several cancer types. However, little information is currently available on PRDM12 expression in cancers and its mechanism of action has not been thoroughly described. In this review, we summarize the recent findings regarding PRDM12 by focusing on four main biological processes: neurogenesis, pain perception, oncogenesis and cell metabolism. Moreover, we wish to highlight the importance of future studies focusing on the PRDM12 signaling pathway(s) and its role in cancer onset and progression.
From Forensics to Clinical Research: Expanding the Variant Calling Pipeline for the Precision ID mtDNA Whole Genome Panel
Authors: Cortes-Figueiredo Filipe , Carvalho Filipa S. , Fonseca Ana Catarina , Paul Friedemann , Ferro José M. , Schönherr Sebastian , Weissensteiner Hansi , Morais Vanessa A.
Published: November 2021

Despite a multitude of methods for the sample preparation, sequencing, and data analysis of mitochondrial DNA (mtDNA), the demand for innovation remains, particularly in comparison with nuclear DNA (nDNA) research. The Applied Biosystems™ Precision ID mtDNA Whole Genome Panel (Thermo Fisher Scientific, USA) is an innovative library preparation kit suitable for degraded samples and low DNA input. However, its bioinformatic processing occurs in the enterprise Ion Torrent Suite™ Software (TSS), yielding BAM files aligned to an unorthodox version of the revised Cambridge Reference Sequence (rCRS), with a heteroplasmy threshold level of 10%. Here, we present an alternative customizable pipeline, the PrecisionCallerPipeline (PCP), for processing samples with the correct rCRS output after Ion Torrent sequencing with the Precision ID library kit. Using 18 samples (3 original samples and 15 mixtures) derived from the 1000 Genomes Project, we achieved overall improved performance metrics in comparison with the proprietary TSS, with optimal performance at a 2.5% heteroplasmy threshold. We further validated our findings with 50 samples from an ongoing independent cohort of stroke patients, with PCP finding 98.31% of TSS’s variants (TSS found 57.92% of PCP’s variants), with a significant correlation between the variant levels of variants found with both pipelines.
Crosstalk during the Carbon–Nitrogen Cycle That Interlinks the Biosynthesis, Mobilization and Accumulation of Seed Storage Reserves
Authors: Kaur Manpreet , Tak Yamini , Bhatia Surekha , Asthir Bavita , Lorenzo José M. , Amarowicz Ryszard
Published: November 2021

Carbohydrates are the major storage reserves in seeds, and they are produced and accumulated in specific tissues during the growth and development of a plant. The storage products are hydrolyzed into a mobile form, and they are then translocated to the developing tissue following seed germination, thereby ensuring new plant formation and seedling vigor. The utilization of seed reserves is an important characteristic of seed quality. This review focuses on the seed storage reserve composition, source–sink relations and partitioning of the major transported carbohydrate form, i.e., sucrose, into different reserves through sucrolytic processes, biosynthetic pathways, interchanging levels during mobilization and crosstalk based on vital biochemical pathways that interlink the carbon and nitrogen cycles. Seed storage reserves are important due to their nutritional value; therefore, novel approaches to augmenting the targeted storage reserve are also discussed.
Low-Coverage Whole Genome Sequencing Using Laser Capture Microscopy with Combined Digital Droplet PCR: An Effective Tool to Study Copy Number and Kras Mutations in Early Lung Adenocarcinoma Development
Authors: Mickler Elizabeth A. , Zhou Huaxin , Phang Tzu L. , Geraci Mark W. , Stearman Robert S. , Sears Catherine R.
Published: November 2021

Defining detailed genomic characterization of early tumor progression is critical to identifying key regulators and pathways in carcinogenesis as potentially druggable targets. In human lung cancer, work to characterize early cancer development has mainly focused on squamous cancer, as the earliest lesions are more proximal in the airways and often accessible by repeated bronchoscopy. Adenocarcinomas are typically located distally in the lung, limiting accessibility for biopsy of pre-malignant and early stages. Mouse lung cancer models recapitulate many human genomic features and provide a model for tumorigenesis with pre-malignant atypical adenomatous hyperplasia and in situ adenocarcinomas often developing contemporaneously within the same animal. Here, we combined tissue characterization and collection by laser capture microscopy (LCM) with digital droplet PCR (ddPCR) and low-coverage whole genome sequencing (LC-WGS). ddPCR can be used to identify specific missense mutations in Kras (Kirsten rat sarcoma viral oncogene homolog, here focused on Kras Q61) and estimate the percentage of mutation predominance. LC-WGS is a cost-effective method to infer localized copy number alterations (CNAs) across the genome using low-input DNA. Combining these methods, the histological stage of lung cancer can be correlated with appearance of Kras mutations and CNAs. The utility of this approach is adaptable to other mouse models of human cancer.
Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila
Authors: Yamazoe Tatsuki , Nakahara Yasuyuki , Katsube Hiroka , Inoue Yoshihiro H.
Published: November 2021

Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in Drosophila using its ectopic expression system and investigated the resultant responses in development. Expression of the wild-type preproinsulin in the insulin-producing cells (IPCs) throughout the larval stage led to a stimulation of the overall and wing growth. However, ectopic expression of human mutant preproinsulins, hINSC96Y and hINSLB15YB16delinsH, neither of which secreted from the β-cells, could not stimulate the Drosophila growth. Furthermore, neither of the mutant polypeptides induced caspase activation leading to apoptosis. Instead, they induced expression of several markers indicating the activation of unfolded protein response, such as ER stress-dependent Xbp1 mRNA splicing and ER chaperone induction. We newly found that the mutant polypeptides induced the expression of Growth arrest and DNA-damage-inducible 45 (Gadd45) in imaginal disc cells. ER stress induced by hINSC96Y also activated the JAK-STAT signaling, involved in inflammatory responses. Collectively, we speculate that the diabetes-like growth defects appeared as a consequence of the human mutant preproinsulin expression was involved in dysfunction of the IPCs, rather than apoptosis.
MALDI-MS Analysis of Peptide Libraries Expands the Scope of Substrates for Farnesyltransferase
Authors: Schey Garrett L. , Buttery Peter H. , Hildebrandt Emily R. , Novak Sadie X. , Schmidt Walter K. , Hougland James L. , Distefano Mark D.
Published: November 2021

Protein farnesylation is a post-translational modification where a 15-carbon farnesyl isoprenoid is appended to the C-terminal end of a protein by farnesyltransferase (FTase). This modification typically causes proteins to associate with the membrane and allows them to participate in signaling pathways. In the canonical understanding of FTase, the isoprenoids are attached to the cysteine residue of a four-amino-acid CaaX box sequence. However, recent work has shown that five-amino-acid sequences can be recognized, including the pentapeptide CMIIM. This paper describes a new systematic approach to discover novel peptide substrates for FTase by combining the combinatorial power of solid-phase peptide synthesis (SPPS) with the ease of matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS). The workflow consists of synthesizing focused libraries containing 10–20 sequences obtained by randomizing a synthetic peptide at a single position. Incubation of the library with FTase and farnesyl pyrophosphate (FPP) followed by mass spectrometric analysis allows the enzymatic products to be clearly resolved from starting peptides due to the increase in mass that occurs upon farnesylation. Using this method, 30 hits were obtained from a series of libraries containing a total of 80 members. Eight of the above peptides were selected for further evaluation, reflecting a mixture that represented a sampling of diverse substrate space. Six of these sequences were found to be bona fide substrates for FTase, with several meeting or surpassing the in vitro efficiency of the benchmark sequence CMIIM. Experiments in yeast demonstrated that proteins bearing these sequences can be efficiently farnesylated within live cells. Additionally, a bioinformatics search showed that a variety of pentapeptide CaaaX sequences can be found in the mammalian genome, and several of these sequences display excellent farnesylation in vitro and in yeast cells, suggesting that the number of farnesylated proteins within mammalian cells may be larger than previously thought.
An Association between Diet and MC4R Genetic Polymorphism, in Relation to Obesity and Metabolic Parameters—A Cross Sectional Population-Based Study
Authors: Adamska-Patruno Edyta , Bauer Witold , Bielska Dorota , Fiedorczuk Joanna , Moroz Monika , Krasowska Urszula , Czajkowski Przemyslaw , Wielogorska Marta , Maliszewska Katarzyna , Puckowska Sylwia , Szczerbinski Lukasz , Lipinska Danuta , Gorska Maria , Kretowski Adam
Published: November 2021

The melanocortin-4 receptor (MC4R) gene harbours one of the strongest susceptibility loci for obesity and obesity-related metabolic consequences. We analysed whether dietary factors may attenuate the associations between MC4R genotypes and obesity and metabolic parameters. In 819 participants genotyped for common MC4R polymorphisms (rs17782313, rs12970134, rs633265, and rs135034), the anthropometric measurements, body fat content and distribution (visceral and subcutaneous adipose tissue, VAT and SAT, respectively), and blood glucose, insulin, total-, LDL-, HDL-cholesterol, triglycerides concentrations, and daily macronutrient intake were assessed. ANOVA or Kruskal–Wallis tests were used, and multivariate linear regression models were developed. We observed that the CC genotype carriers (rs17782313) presented higher VAT, VAT/SAT ratio, fasting blood glucose and triglyceride concentrations when they were stratified to the upper quantiles of protein intake. An increase in energy derived from proteins was associated with higher BMI (Est. 5.74, R2 = 0.12), body fat content (Est. 8.44, R2 = 0.82), VAT (Est. 32.59, R2 = 0.06), and VAT/SAT ratio (Est. 0.96, R2 = 0.05). The AA genotype carriers (rs12970134) presented higher BMI, body fat, SAT and VAT, fasting blood glucose, triglycerides and total cholesterol concentrations. An increase in energy derived from proteins by AA carriers was associated with higher VAT (Est.19.95, R2 = 0.06) and VAT/SAT ratio (Est. 0.64, R2 = 0.05). Our findings suggest that associations of the common MC4R SNPs with obesity and its metabolic complications may be dependent on the daily dietary intake, which may open new areas for developing personalised diets for preventing and treating obesity and obesity-related comorbidities.
Electrochemical Performance of Na3V2(PO4)2F3 Electrode Material in a Symmetric Cell
Authors: James Abraham Jeffin , Moossa Buzaina , Tariq Hanan Abdurehman , Kahraman Ramazan , Al-Qaradawi Siham , Shakoor R. A.
Published: November 2021

A NASICON-based Na3V2(PO4)2F3 (NVPF) cathode material is reported herein as a potential symmetric cell electrode material. The symmetric cell was active from 0 to 3.5 V and showed a capacity of 85 mAh/g at 0.1 C. With cycling, the NVPF symmetric cell showed a very long and stable cycle life, having a capacity retention of 61% after 1000 cycles at 1 C. The diffusion coefficient calculated from cyclic voltammetry (CV) and the galvanostatic intermittent titration technique (GITT) was found to be ~10−9–10−11, suggesting a smooth diffusion of Na+ in the NVPF symmetric cell. The electrochemical impedance spectroscopy (EIS) carried out during cycling showed increases in bulk resistance, solid electrolyte interphase (SEI) resistance, and charge transfer resistance with the number of cycles, explaining the origin of capacity fade in the NVPF symmetric cell. Finally, the postmortem analysis of the symmetric cell after 1000 cycles at a 1 C rate indicated that the intercalation/de-intercalation of sodium into/from the host structure occurred without any major structural destabilization in both the cathode and anode. However, there was slight distortion in the cathode structure observed, which resulted in capacity loss of the symmetric cell. The promising electrochemical performance of NVPF in the symmetric cell makes it attractive for developing long-life and cost-effective batteries.
B6 Mouse Strain: The Best Fit for LPS-Induced Interstitial Cystitis Model
Authors: Chen Ching-Hao , Liao Chun-Hou , Chen Kuo-Chiang , Wang Kuan-Lin , Tseng Xiao-Wen , Tsai Wei-Kung , Chiang Han-Sun , Wu Yi-No
Published: November 2021

Interstitial cystitis (IC) is a chronic inflammatory disease characterized by bladder pain and increased urinary frequency. Although the C57BL/6J (B6) and FVB/NJ (FVB) mouse strains are commonly used as animal models for studies involving the urinary system, few reports have compared their lower urinary tract anatomy, despite the importance of such data. Our study aimed to characterize bladder function changes in FVB and B6 mouse strains with lipopolysaccharide (LPS)-induced IC, to understand mouse model-based bladder research. The bladder function parameters were measured by cystometrogram. Histological assay was examined by hematoxylin and eosin stain, Masson’s trichrome stain, and immunofluorescence staining. Results indicated that the two strains in the control group exhibited different bladder structures and functions, with significant anatomical differences, including a larger bladder size in the FVB than in the B6 strain. Furthermore, cystometry tests revealed differences in bladder function pressure. LPS-treated B6 mice presented significant changes in peak pressure, with decreased intercontraction intervals; these results were similar to symptoms of IC in humans. Each strain displayed distinct characteristics, emphasizing the care required in choosing the appropriate strain for bladder-model studies. The results suggested that the B6 mouse strain is more suitable for IC models.
A Systematic Review on Nanoencapsulation Natural Antimicrobials in Foods: In Vitro versus In Situ Evaluation, Mechanisms of Action and Implications on Physical-Chemical Quality
Authors: Lelis Carini Aparecida , de Carvalho Anna Paula Azevedo , Conte Junior Carlos Adam
Published: November 2021

Natural antimicrobials (NA) have stood out in the last decade due to the growing demand for reducing chemical preservatives in food. Once solubility, stability, and changes in sensory attributes could limit their applications in foods, several studies were published suggesting micro-/nanoencapsulation to overcome such challenges. Thus, for our systematic review the Science Direct, Web of Science, Scopus, and Pub Med databases were chosen to recover papers published from 2010 to 2020. After reviewing all titles/abstracts and keywords for the full-text papers, key data were extracted and synthesized. The systematic review proposed to compare the antimicrobial efficacy between nanoencapsulated NA (nNA) and its free form in vitro and in situ studies, since although in vitro studies are often used in studies, they present characteristics and properties that are different from those found in foods; providing a comprehensive understanding of primary mechanisms of action of the nNA in foods; and analyzing the effects on quality parameters of foods. Essential oils and nanoemulsions (10.9–100 nm) have received significant attention and showed higher antimicrobial efficacy without sensory impairments compared to free NA. Regarding nNA mechanisms: (i) nanoencapsulation provides a slow-prolonged release to promote antimicrobial action over time, and (ii) prevents interactions with food constituents that in turn impair antimicrobial action. Besides in vitro antifungal and antibacterial, nNA also demonstrated antioxidant activity—potential to shelf life extension in food. However, of the studies involving nanoencapsulated natural antimicrobials used in this review, little attention was placed on proximate composition, sensory, and rheological evaluation. We encourage further in situ studies once data differ from in vitro assay, suggesting food matrix greatly influences NA mechanisms.
The Roles of Carbohydrate Response Element Binding Protein in the Relationship between Carbohydrate Intake and Diseases
Authors: Iizuka Katsumi
Published: November 2021

Carbohydrates are macronutrients that serve as energy sources. Many studies have shown that carbohydrate intake is nonlinearly associated with mortality. Moreover, high-fructose corn syrup (HFCS) consumption is positively associated with obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). Accordingly, products with equal amounts of glucose and fructose have the worst effects on caloric intake, body weight gain, and glucose intolerance, suggesting that carbohydrate amount, kind, and form determine mortality. Understanding the role of carbohydrate response element binding protein (ChREBP) in glucose and lipid metabolism will be beneficial for elucidating the harmful effects of high-fructose corn syrup (HFCS), as this glucose-activated transcription factor regulates glycolytic and lipogenic gene expression. Glucose and fructose coordinately supply the metabolites necessary for ChREBP activation and de novo lipogenesis. Chrebp overexpression causes fatty liver and lower plasma glucose levels, and ChREBP deletion prevents obesity and fatty liver. Intestinal ChREBP regulates fructose absorption and catabolism, and adipose-specific Chrebp-knockout mice show insulin resistance. ChREBP also regulates the appetite for sweets by controlling fibroblast growth factor 21, which promotes energy expenditure. Thus, ChREBP partly mimics the effects of carbohydrate, especially HFCS. The relationship between carbohydrate intake and diseases partly resembles those between ChREBP activity and diseases.
Bacillus subtilis ANSB168 Producing d-alanyl-d-alanine Carboxypeptidase Could Alleviate the Immune Injury and Inflammation Induced by Ochratoxin A
Authors: Qing Hanrui , Huo Xueting , Huang Shimeng , Zhao Lihong , Zhang Jianyun , Ji Cheng , Ma Qiugang
Published: November 2021

Ochratoxin A (OTA) is toxic to animals and threatens food safety through residues in animal tissues. A novel degrading strain Bacillus subtilis ANSB168 was isolated and further investigated. We cloned d-alanyl-d-alanine carboxypeptidase DacA and DacB from ANSB168 and over-expressed them in Escherichia coli Rosetta (DE3). Then, we characterized the OTA degradation mechanism of DacA and DacB, which was degrading OTA into OTα. A total of 45 laying hens were divided into three equal groups. The control group was fed basal feed, and other groups were administered with OTA (250 μg/kg of feed). A freeze-dried culture powder of ANSB168 (3 × 107 CFU/g, 2 kg/T of feed) was added to one of the OTA-fed groups for 28 days from day one of the experiment. We found that OTA significantly damaged the kidney and liver, inducing inflammation and activating the humoral immune system, causing oxidative stress in the layers. The ANSB168 bioproduct was able to alleviate OTA-induced kidney and liver damage, relieving OTA-induced inflammation and oxidative stress. Overall, DacA and DacB derived from ANSB168 degraded OTA into OTα, while the ANSB168 bioproduct was able to alleviate damages induced by OTA in laying hens.
Hetero/Homo-Complexes of Sucrose Transporters May Be a Subtle Mode to Regulate Sucrose Transportation in Grape Berries
Authors: Cai Yumeng , Yin Ling , Wang Jie , Dong Wenjie , Gao Han , Xu Jinxu , Deng Zhefang , Tu Wenrui , Yan Jing , Meng Qingyong , Zhang Yali
Published: November 2021

The sugar distribution mechanism in fruits has been the focus of research worldwide; however, it remains unclear. In order to elucidate the relevant mechanisms in grape berries, the expression, localization, function, and regulation of three sucrose transporters were studied in three representative Vitis varieties. Both SUC11 and SUC12 expression levels were positively correlated with sugar accumulation in grape berries, whereas SUC27 showed a negative relationship. The alignment analysis and sucrose transport ability of isolated SUCs were determined to reflect coding region variations among V. vinifera, V. amurensis Ruper, and V. riparia, indicating that functional variation existed in one SUT from different varieties. Furthermore, potentially oligomerized abilities of VvSUCs colocalized in the sieve elements of the phloem as plasma membrane proteins were verified. The effects of oligomerization on transport properties were characterized in yeast. VvSUC11 and VvSUC12 are high-affinity/low-capacity types of SUTs that stimulate each other by upregulating Vmax and Km, inhibiting sucrose transport, and downregulating the Km of VvSUC27. Thus, changes in the distribution of different SUTs in the same cell govern functional regulation. The activation and inhibition of sucrose transport could be achieved in different stages and tissues of grape development to achieve an effective distribution of sugar.
Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein
Authors: Lin Gaoping , Zhu Feiyan , Kanaan Nicholas M. , Asano Rei , Shirafuji Norimichi , Sasaki Hirohito , Yamaguchi Tomohisa , Enomoto Soichi , Endo Yoshinori , Ueno Asako , Ikawa Masamichi , Hayashi Kouji , Yamamura Osamu , Yen Shu-Hui , Nakamoto Yasunari , Hamano Tadanori
Published: November 2021

The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 μM CQ had no effect on cell viability; however, 100 μM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.
Hydrogen Sulfide in Plants: Crosstalk with Other Signal Molecules in Response to Abiotic Stresses
Authors: Wang Chunlei , Deng Yuzheng , Liu Zesheng , Liao Weibiao
Published: November 2021

Hydrogen sulfide (H2S) has recently been considered as a crucial gaseous transmitter occupying extensive roles in physiological and biochemical processes throughout the life of plant species. Furthermore, plenty of achievements have been announced regarding H2S working in combination with other signal molecules to mitigate environmental damage, such as nitric oxide (NO), abscisic acid (ABA), calcium ion (Ca2+), hydrogen peroxide (H2O2), salicylic acid (SA), ethylene (ETH), jasmonic acid (JA), proline (Pro), and melatonin (MT). This review summarizes the current knowledge within the mechanism of H2S and the above signal compounds in response to abiotic stresses in plants, including maintaining cellular redox homeostasis, exchanging metal ion transport, regulating stomatal aperture, and altering gene expression and enzyme activities. The potential relationship between H2S and other signal transmitters is also proposed and discussed.
Bioprospecting Antimicrobials from Lactiplantibacillus plantarum: Key Factors Underlying Its Probiotic Action
Authors: Rocchetti Maria Teresa , Russo Pasquale , Capozzi Vittorio , Drider Djamel , Spano Giuseppe , Fiocco Daniela
Published: November 2021

Lactiplantibacillus plantarum (L. plantarum) is a well-studied and versatile species of lactobacilli. It is found in several niches, including human mucosal surfaces, and it is largely employed in the food industry and boasts a millenary tradition of safe use, sharing a long-lasting relationship with humans. L. plantarum is generally recognised as safe and exhibits a strong probiotic character, so that several strains are commercialised as health-promoting supplements and functional food products. For these reasons, L. plantarum represents a valuable model to gain insight into the nature and mechanisms of antimicrobials as key factors underlying the probiotic action of health-promoting microbes. Probiotic antimicrobials can inhibit the growth of pathogens in the gut ensuring the intestinal homeostasis and contributing to the host health. Furthermore, they may be attractive alternatives to conventional antibiotics, holding potential in several biomedical applications. The aim of this review is to investigate the most relevant papers published in the last ten years, bioprospecting the antimicrobial activity of characterised probiotic L. plantarum strains. Specifically, it focuses on the different chemical nature, the action spectra and the mechanisms underlying the bioactivity of their antibacterial and antiviral agents. Emerging trends in postbiotics, some in vivo applications of L. plantarum antimicrobials, including strengths and limitations of their therapeutic potential, are addressed and discussed.
Prediction of Peptide Detectability Based on CapsNet and Convolutional Block Attention Module
Authors: Yu Minzhe , Duan Yushuai , Li Zhong , Zhang Yang
Published: November 2021

According to proteomics technology, as impacted by the complexity of sampling in the experimental process, several problems remain with the reproducibility of mass spectrometry experiments, and the peptide identification and quantitative results continue to be random. Predicting the detectability exhibited by peptides can optimize the mentioned results to be more accurate, so such a prediction is of high research significance. This study builds a novel method to predict the detectability of peptides by complying with the capsule network (CapsNet) and the convolutional block attention module (CBAM). First, the residue conical coordinate (RCC), the amino acid composition (AAC), the dipeptide composition (DPC), and the sequence embedding code (SEC) are extracted as the peptide chain features. Subsequently, these features are divided into the biological feature and sequence feature, and separately inputted into the neural network of CapsNet. Moreover, the attention module CBAM is added to the network to assign weights to channels and spaces, as an attempt to enhance the feature learning and improve the network training effect. To verify the effectiveness of the proposed method, it is compared with some other popular methods. As revealed from the experimentally achieved results, the proposed method outperforms those methods in most performance assessments.
Pathogenic Basis of Thromboinflammation and Endothelial Injury in COVID-19: Current Findings and Therapeutic Implications
Authors: Higashikuni Yasutomi , Liu Wenhao , Obana Takumi , Sata Masataka
Published: November 2021

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic with a great impact on social and economic activities, as well as public health. In most patients, the symptoms of COVID-19 are a high-grade fever and a dry cough, and spontaneously resolve within ten days. However, in severe cases, COVID-19 leads to atypical bilateral interstitial pneumonia, acute respiratory distress syndrome, and systemic thromboembolism, resulting in multiple organ failure with high mortality and morbidity. SARS-CoV-2 has immune evasion mechanisms, including inhibition of interferon signaling and suppression of T cell and B cell responses. SARS-CoV-2 infection directly and indirectly causes dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction, which interact with each other and are exacerbated by cardiovascular risk factors. In this review, we summarize current knowledge on the pathogenic basis of thromboinflammation and endothelial injury in COVID-19. We highlight the distinct contributions of dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction to the pathogenesis of COVID-19. In addition, we discuss potential therapeutic strategies targeting these mechanisms.
Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson’s Disease
Authors: Martínez-Menárguez José Ángel , Martínez-Alonso Emma , Cara-Esteban Mireia , Tomás Mónica
Published: November 2021

Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroautophagy from yeast to humans. It is also involved in signaling, carcinogenesis, and infection for some pathogens. It has been shown that it is directly linked to the pathogenesis of PD and other neurodegenerative diseases. It has a protective effect against α–σψν toxicity and has recently been shown to be a substrate of LRRK2, which is the most common cause of familial PD and the risk of sporadic disease. In this review, we analyze the key aspects of Rab1 function in dopamine neurons and its implications in PD neurodegeneration/restauration. The results of the current and former research support the notion that this GTPase is a good candidate for therapeutic strategies.
New Drug Targets to Prevent Death Due to Stroke: A Review Based on Results of Protein-Protein Interaction Network, Enrichment, and Annotation Analyses
Authors: Maes Michael , Nikiforov Nikita G. , Plaimas Kitiporn , Suratanee Apichat , Alfieri Daniela Frizon , Vissoci Reiche Edna Maria
Published: November 2021

This study used established biomarkers of death from ischemic stroke (IS) versus stroke survival to perform network, enrichment, and annotation analyses. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-β1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due to IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell-surface interactions, and the proteoglycan-integrin extracellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: (a) that NFKB1, RELA and SP1 were the major regulating actors of the PPI network; and (b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, the proteoglycan-integrin-ECM complex, TGF-β1/SMAD, NF-κB/RELA and SP1.
Phosphoproteomic Comparison of Four Eimeria tenella Life Cycle Stages
Authors: Ma Xueting , Liu Baohong , Gong Zhenxing , Qu Zigang , Cai Jianping
Published: November 2021

Protein phosphorylation is an important post-translational modification (PTM) involved in diverse cellular functions. It is the most prevalent PTM in both Toxoplasma gondii and Plasmodium falciparum, but its status in Eimeria tenella has not been reported. Herein, we performed a comprehensive, quantitative phosphoproteomic profile analysis of four stages of the E. tenella life cycle: unsporulated oocysts (USO), partially sporulated (7 h) oocysts (SO7h), sporulated oocysts (SO), and sporozoites (S). A total of 15,247 phosphorylation sites on 9514 phosphopeptides corresponding to 2897 phosphoproteins were identified across the four stages. In addition, 456, 479, and 198 differentially expressed phosphoproteins (DEPPs) were identified in the comparisons SO7h vs. USO, SO vs. SO7h, and S vs. SO, respectively. Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEPPs suggested that they were involved in diverse functions. For SO7h vs. USO, DEPPs were mainly involved in cell division, actin cytoskeleton organization, positive regulation of transport, and pyruvate metabolism. For SO vs. SO7h, they were related to the peptide metabolic process, translation, and RNA transport. DEPPs in the S vs. SO comparison were associated with the tricarboxylic acid metabolic process, positive regulation of ATPase activity, and calcium ion binding. Time course sequencing data analysis (TCseq) identified six clusters with similar expression change characteristics related to carbohydrate metabolism, cytoskeleton organization, and calcium ion transport, demonstrating different regulatory profiles across the life cycle of E. tenella. The results revealed significant changes in the abundance of phosphoproteins during E. tenella development. The findings shed light on the key roles of protein phosphorylation and dephosphorylation in the E. tenella life cycle.
Form and Function of the Vertebrate and Invertebrate Blood-Brain Barriers
Authors: Dunton Alicia D. , Göpel Torben , Ho Dao H. , Burggren Warren
Published: November 2021

The need to protect neural tissue from toxins or other substances is as old as neural tissue itself. Early recognition of this need has led to more than a century of investigation of the blood-brain barrier (BBB). Many aspects of this important neuroprotective barrier have now been well established, including its cellular architecture and barrier and transport functions. Unsurprisingly, most research has had a human orientation, using mammalian and other animal models to develop translational research findings. However, cell layers forming a barrier between vascular spaces and neural tissues are found broadly throughout the invertebrates as well as in all vertebrates. Unfortunately, previous scenarios for the evolution of the BBB typically adopt a classic, now discredited ‘scala naturae’ approach, which inaccurately describes a putative evolutionary progression of the mammalian BBB from simple invertebrates to mammals. In fact, BBB-like structures have evolved independently numerous times, complicating simplistic views of the evolution of the BBB as a linear process. Here, we review BBBs in their various forms in both invertebrates and vertebrates, with an emphasis on the function, evolution, and conditional relevance of popular animal models such as the fruit fly and the zebrafish to mammalian BBB research.
SARS-CoV-2 Variants, RBD Mutations, Binding Affinity, and Antibody Escape
Authors: Yang Lin , Li Jiacheng , Guo Shuai , Hou Chengyu , Liao Chenchen , Shi Liping , Ma Xiaoliang , Jiang Shenda , Zheng Bing , Fang Yi , Ye Lin , He Xiaodong
Published: November 2021

Since 2020, the receptor-binding domain (RBD) of the spike protein of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been constantly mutating, producing most of the notable missense mutations in the context of “variants of concern”, probably in response to the vaccine-driven alteration of immune profiles of the human population. The Delta variant, in particular, has become the most prevalent variant of the epidemic, and it is spreading in countries with the highest vaccination rates, causing the world to face the risk of a new wave of the contagion. Understanding the physical mechanism responsible for the mutation-induced changes in the RBD’s binding affinity, its transmissibility, and its capacity to escape vaccine-induced immunity is the “urgent challenge” in the development of preventive measures, vaccines, and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. In this study, entropy–enthalpy compensation and the Gibbs free energy change were used to analyze the impact of the RBD mutations on the binding affinity of SARS-CoV-2 variants with the receptor angiotensin converting enzyme 2 (ACE2) and existing antibodies. Through the analysis, we found that the existing mutations have already covered almost all possible detrimental mutations that could result in an increase of transmissibility, and that a possible mutation in amino-acid position 498 of the RBD can potentially enhance its binding affinity. A new calculation method for the binding energies of protein–protein complexes is proposed based on the entropy–enthalpy compensation rule. All known structures of RBD–antibody complexes and the RBD–ACE2 complex comply with the entropy–enthalpy compensation rule in providing the driving force behind the spontaneous protein–protein docking. The variant-induced risk of breakthrough infections in vaccinated people is attributed to the L452R mutation’s reduction of the binding affinity of many antibodies. Mutations reversing the hydrophobic or hydrophilic performance of residues in the spike RBD potentially cause breakthrough infections of coronaviruses due to the changes in geometric complementarity in the entropy–enthalpy compensations between antibodies and the virus at the binding sites.
Urocortin Role in Ischemia Cardioprotection and the Adverse Cardiac Remodeling
Authors: Calderón-Sánchez Eva M. , Falcón Débora , Martín-Bórnez Marta , Ordoñez Antonio , Smani Tarik
Published: November 2021

Despite the considerable progress in strategies of myocardial protection, ischemic heart diseases (IHD) and consequent heart failure (HF) remain the main cause of mortality worldwide. Several procedures are used routinely to guarantee the prompt and successful reestablishment of blood flow to preserve the myocardial viability of infarcted hearts from ischemia injuries. However, ischemic heart reperfusion/revascularization triggers additional damages that occur when oxygen-rich blood re-enters the vulnerable myocardial tissue, which is a phenomenon known as ischemia and reperfusion (I/R) syndrome. Complications of I/R injuries provoke the adverse cardiac remodeling, involving inflammation, mishandling of Ca2+ homeostasis, apoptotic genes activation, cardiac myocytes loss, etc., which often progress toward HF. Therefore, there is an urgent need to develop new cardioprotective therapies for IHD and HF. Compelling evidence from animal studies and pilot clinical trials in HF patients suggest that urocortin (Ucn) isoforms, which are peptides associated with stress and belonging to the corticotropin releasing factor family, have promising potential to improve cardiovascular functions by targeting many signaling pathways at different molecular levels. This review highlights the current knowledge on the role of urocortin isoforms in cardioprotection, focusing on its acute and long-term effects.
Estrogens Regulate Placental Angiogenesis in Horses
Authors: Haneda Shingo , Dini Pouya , Esteller-Vico Alejandro , Scoggin Kirsten E. , Squires Edward L. , Troedsson Mats H. , Daels Peter , Nambo Yasuo , Ball Barry A.
Published: November 2021

A sufficient vascular network within the feto-maternal interface is necessary for placental function. Several pregnancy abnormalities have been associated with abnormal vascular formations in the placenta. We hypothesized that growth and expansion of the placental vascular network in the equine (Equus caballus) placenta is regulated by estrogens (estrogen family hormones), a hormone with a high circulating concentration during equine gestation. Administration of letrozole, a potent and specific inhibitor of aromatase, during the first trimester (D30 to D118), decreased circulatory estrone sulfate concentrations, increased circulatory testosterone and androstenedione concentrations, and tended to reduce the weight of the fetus (p < 0.1). Moreover, the gene expression of CYP17A1 was increased, and the expression of androgen receptor was decreased in the D120 chorioallantois (CA) of letrozole-treated mares in comparison to that of the control mares. We also found that at D120, the number of vessels tended to decrease in the CAs with letrozole treatment (p = 0.07). In addition, expression of a subset of angiogenic genes, such as ANGPT1, VEGF, and NOS2, were altered in the CAs of letrozole-treated mares. We further demonstrated that 17β-estradiol increases the expression of ANGPT1 and VEGF and increases the angiogenic activity of equine endothelial cells in vitro. Our results from the estrogen-suppressed group demonstrated an impaired placental vascular network, suggesting an estrogen-dependent vasculogenesis in the equine CA during the first trimester.