bluuebunny/crossref_metadata_2025 huggingface dataset:
Printable Hydrogels Based on Alginate and Halloysite Nanotubes
Authors: Cavallaro Giuseppe , Lisuzzo Lorenzo , Lazzara Giuseppe , Milioto Stefana
Published: March 2022

The design of hydrogels for the controlled release of active species is an attractive challenge. In this work, we prepared hybrid hydrogels composed of halloysite nanotubes as the inorganic component, and alginate as the organic counterpart. The reported procedure allowed us to provide the resulting materials with a peculiar wire-like shape. Both optical and scanning electron microscopy were used to characterize the morphological properties of the hydrogel wires, whose diameters were ca. 0.19 and 0.47 mm, respectively. The possibility to be exploited as drug delivery systems was carried out by loading the nanoclay with salicylic acid and by studying the release profiles. Thermogravimetric experiments showed that the amount of encapsulated drug was 4.35 wt%, and the salicylic acid was thermally stabilized after the loading into the nanotubes, as observed by the shift of the degradation peak in the differential thermograms from 193 to 267 °C. The kinetics investigation was conducted using UV–Vis spectrophotometry, and it exhibited the profound effects of both the morphology and dimensions on the release of the drugs. In particular, the release of 50% of the payload occurred in 6 and 10 h for the filiform hydrogels, and it was slower compared to the bare drug-loaded halloysite, which occurred in 2 h. Finally, an induction period of 2 h was observed in the release profile from the thicker sample.
The Human Induced Pluripotent Stem Cell Test as an Alternative Method for Embryotoxicity Testing
Authors: Galanjuk Saskia , Zühr Etta , Dönmez Arif , Bartsch Deniz , Kurian Leo , Tigges Julia , Fritsche Ellen
Published: March 2022

The evaluation of substances for their potency to induce embryotoxicity is controlled by safety regulations. Test guidelines for reproductive and developmental toxicity rely mainly on animal studies, which make up the majority of animal usage in regulatory toxicology. Therefore, there is an urgent need for alternative in vitro methods to follow the 3R principles. To improve human safety, cell models based on human cells are of great interest to overcome species differences. Here, human induced pluripotent stem cells (hiPSCs) are an ideal cell source as they largely recapitulate embryonic stem cells without bearing ethical concerns and they are able to differentiate into most cell types of the human body. Here, we set up and characterized a fetal bovine serum (FBS)-free hiPSC-based in vitro test method, called the human induced pluripotent stem cell test (hiPS Test), to evaluate the embryotoxic potential of substances. After 10 days in culture, hiPSCs develop into beating cardiomyocytes. As terminal endpoint evaluations, cell viability, qPCR analyses as well as beating frequency and area of beating cardiomyocytes by video analyses are measured. The embryotoxic positive and non-embryotoxic negative controls, 5-Fluorouracil (5-FU) and Penicillin G (PenG), respectively, were correctly assessed in the hiPS Test. More compounds need to be screened in the future for defining the assay’s applicability domain, which will inform us of the suitability of the hiPS Test for detecting adverse effects of substances on embryonic development.
Differences and Interactions in Placental Manganese and Iron Transfer across an In Vitro Model of Human Villous Trophoblasts
Authors: Michaelis Vivien , Aengenheister Leonie , Tuchtenhagen Max , Rinklebe Jörg , Ebert Franziska , Schwerdtle Tanja , Buerki-Thurnherr Tina , Bornhorst Julia
Published: March 2022

Manganese (Mn) as well as iron (Fe) are essential trace elements (TE) important for the maintenance of physiological functions including fetal development. However, in the case of Mn, evidence suggests that excess levels of intrauterine Mn are associated with adverse pregnancy outcomes. Although Mn is known to cross the placenta, the fundamentals of Mn transfer kinetics and mechanisms are largely unknown. Moreover, exposure to combinations of TEs should be considered in mechanistic transfer studies, in particular for TEs expected to share similar transfer pathways. Here, we performed a mechanistic in vitro study on the placental transfer of Mn across a BeWo b30 trophoblast layer. Our data revealed distinct differences in the placental transfer of Mn and Fe. While placental permeability to Fe showed a clear inverse dose-dependency, Mn transfer was largely independent of the applied doses. Concurrent exposure of Mn and Fe revealed transfer interactions of Fe and Mn, indicating that they share common transfer mechanisms. In general, mRNA and protein expression of discussed transporters like DMT1, TfR, or FPN were only marginally altered in BeWo cells despite the different exposure scenarios highlighting that Mn transfer across the trophoblast layer likely involves a combination of active and passive transport processes.
A Mixture of Valine and Isoleucine Restores the Growth of Protein-Restricted Pigs Likely through Improved Gut Development, Hepatic IGF-1 Pathway, and Plasma Metabolomic Profile
Authors: Habibi Mohammad , Goodarzi Parniyan , Shili Cedrick Ndhumba , Sutton Julia , Wileman Caitlyn Marie , Kim Dohyung Markus , Lin Dingbo , Pezeshki Adel
Published: March 2022

Valine (Val) alone or in combination with isoleucine (Ile) improves the growth under severe protein restriction; however, the underlying mechanisms remain unknown. In this study, we assessed whether Val/Ile-induced growth in protein-restricted pigs is associated with changes in gut development, hepatic insulin-like growth factor 1 (IGF-1) production, and blood metabolomics. Forty piglets were assigned to five dietary groups: positive control (PC) with standard protein content; low protein (LP) with very low protein content; and LP supplemented with Val (LPV), Ile (LPI), and Val and Ile (LPVI). LPVI reversed the negative effects of VLP diets on growth and gut morphology. Both LPV and LPVI restored the reduced transcript of IGF-1 while decreasing the transcript of insulin-like growth factor binding protein 1 (IGFBP1) in the liver. LPV and LPVI recovered the reduced plasma Val, glycine, and leucine concentrations, which were positively correlated with improved gut morphology and the hepatic IGF-1 gene expression and negatively correlated with hepatic IGFBP1 mRNA abundance. In conclusion, supplementation with a combination of Val and Ile into the VLP diets restored the decreased growth performance of pigs fed with these diets likely through improved gut development, hepatic IGF-1 expression and bioavailability, and plasma metabolomics profile.
Factors Associated with Platelet Activation-Recent Pharmaceutical Approaches
Authors: Theofilis Panagiotis , Sagris Marios , Oikonomou Evangelos , Antonopoulos Alexios S. , Tsioufis Konstantinos , Tousoulis Dimitris
Published: March 2022

Platelets are at the forefront of human health and disease following the advances in their research presented in past decades. Platelet activation, their most crucial function, although beneficial in the case of vascular injury, may represent the initial step for thrombotic complications characterizing various pathologic states, primarily atherosclerotic cardiovascular diseases. In this review, we initially summarize the structural and functional characteristics of platelets. Next, we focus on the process of platelet activation and its associated factors, indicating the potential molecular mechanisms involving inflammation, endothelial dysfunction, and miRs. Finally, an overview of the available antiplatelet agents is being portrayed, together with agents possessing off-set platelet-inhibitory actions, while an extensive presentation of drugs under investigation is being given.
Peptidomic Analysis on Mouse Lung Tissue Reveals AGDP as a Potential Bioactive Peptide against Pseudorabies Virus Infection
Authors: Ma Yijie , Tian Shimao , Wan Qianhui , Kong Yingying , Liu Chang , Tian Ke , Ning Hongya , Xu Xiaodong , Qi Baomin , Yang Guihong
Published: March 2022

Pseudorabies virus (PRV) infection could cause severe histopathological damage via releasing multiple factors, including cytokines, peptides, etc. Here, peptidomic results showed that 129 peptides were identified in PRV-infected mouse lungs and were highly involved in the process of PRV infection. The role of one down-regulated biological peptide (designated as AGDP) during PRV infection was investigated. To verify the expression profiles of AGDP in response to PRV infection, the expression level of the precursor protein of AGDP mRNA was significantly decreased in PRV-infected mouse lungs and cells. The synthesized AGDP-treating cells were less susceptible to PRV challenges than the controls, as demonstrated by the decreased virus production and gE expression. AGDP not only inhibited the expression of TNF-α and IL-8 but also appeared to suppress the extracellular release of high-mobility group box 1 (HMGB1) by inhibiting the output of nuclear HMGB1 in cells. AGDP could also inhibit the degradation of IκBα and the phosphorylation levels of P65 after PRV infection. In total, our results revealed many meaningful peptides involved in PRV infection, thereby enhancing the current understanding of the host response to PRV infection, and how AGDP may serve as a promising candidate for developing novel anti-PRV drugs.
miRNAs in Cardiac Myxoma: New Pathologic Findings for Potential Therapeutic Opportunities
Authors: Nenna Antonio , Loreni Francesco , Giacinto Omar , Chello Camilla , Nappi Pierluigi , Chello Massimo , Nappi Francesco
Published: March 2022

MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, contributing to all major cellular processes. The importance of miRNAs in cardiac development, heart function, and valvular heart disease has been shown in recent years, and aberrant expression of miRNA has been reported in various malignancies, such as gastric cancer and breast cancer. Different from other fields of investigation, the role of miRNAs in cardiac tumors still remains difficult to interpret due to the scarcity publications and a lack of narrative focus on this topic. In this article, we summarize the available evidence on miRNAs and cardiac myxomas and propose new pathways for future research. miRNAs play a part in modifying the expression of cardiac transcription factors (miR-335-5p), increasing cell cycle trigger factors (miR-126-3p), interfering with ceramide synthesis (miR-320a), inducing apoptosis (miR-634 and miR-122), suppressing production of interleukins (miR-217), and reducing cell proliferation (miR-218). As such, they have complex and interconnected roles. At present, the study of the complete mechanistic control of miRNA remains a crucial issue, as proper understanding of signaling pathways is essential for the forecasting of therapeutic implications. Other types of cardiac tumors still lack adequate investigation with regard to miRNA. Further research should aim at investigating the causal relationship between different miRNAs and cell overgrowth, considering both myxoma and other histological types of cardiac tumors. We hope that this review will help in understanding this fascinating molecular approach.
Mitochondria as the Target of Hepatotoxicity and Drug-Induced Liver Injury: Molecular Mechanisms and Detection Methods
Authors: Mihajlovic Milos , Vinken Mathieu
Published: March 2022

One of the major mechanisms of drug-induced liver injury includes mitochondrial perturbation and dysfunction. This is not a surprise, given that mitochondria are essential organelles in most cells, which are responsible for energy homeostasis and the regulation of cellular metabolism. Drug-induced mitochondrial dysfunction can be influenced by various factors and conditions, such as genetic predisposition, the presence of metabolic disorders and obesity, viral infections, as well as drugs. Despite the fact that many methods have been developed for studying mitochondrial function, there is still a need for advanced and integrative models and approaches more closely resembling liver physiology, which would take into account predisposing factors. This could reduce the costs of drug development by the early prediction of potential mitochondrial toxicity during pre-clinical tests and, especially, prevent serious complications observed in clinical settings.
Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts
Authors: Komatsu Satoshi , Fan Liang , Idell Steven , Shetty Sreerama , Ikebe Mitsuo
Published: March 2022

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by an excess deposition of extracellular matrix in the pulmonary interstitium. Caveolin-1 scaffolding domain peptide (CSP) has been found to mitigate pulmonary fibrosis in several animal models. However, its pathophysiological role in IPF is obscure, and it remains critical to understand the mechanism by which CSP protects against pulmonary fibrosis. We first studied the delivery of CSP into cells and found that it is internalized and accumulated in the Endoplasmic Reticulum (ER). Furthermore, CSP reduced ER stress via suppression of inositol requiring enzyme1α (IRE1α) in transforming growth factor β (TGFβ)-treated human IPF lung fibroblasts (hIPF-Lfs). Moreover, we found that CSP enhanced the gelatinolytic activity of TGFβ-treated hIPF-Lfs. The IRE1α inhibitor; 4µ8C also augmented the gelatinolytic activity of TGFβ-treated hIPF-Lfs, supporting the concept that CSP induced inhibition of the IRE1α pathway. Furthermore, CSP significantly elevated expression of MMPs in TGFβ-treated hIPF-Lfs, but conversely decreased the secretion of collagen 1. Similar results were observed in two preclinical murine models of PF, bleomycin (BLM)- and adenovirus expressing constitutively active TGFβ (Ad-TGFβ)-induced PF. Our findings provide new insights into the mechanism by which lung fibroblasts contribute to CSP dependent protection against lung fibrosis.
Insight into the Molecular Basis Underlying Chromothripsis
Authors: Ostapińska Katarzyna , Styka Borys , Lejman Monika
Published: March 2022

Chromoanagenesis constitutes a group of events that arise from single cellular events during early development. This particular class of complex rearrangements is a newfound occurrence that may lead to chaotic and complex genomic realignments. By that, chromoanagenesis is thought to be a crucial factor regarding macroevolution of the genome, and consequently is affecting the karyotype revolution together with genomic plasticity. One of chromoanagenesis-type of events is chromothripsis. It is characterised by the breakage of the chromosomal structure and its reassembling in random order and orientation which results in the establishment of derivative forms of chromosomes. Molecular mechanisms that underlie this phenomenon are mostly related to chromosomal sequestration throughout the micronuclei formation process. Chromothripsis is linked both to congenital and cancer diseases, moreover, it might be detected in subjects characterised by a normal phenotype. Chromothripsis, as well as the other chromoanagenetic variations, may be confined to one or more chromosomes, which makes up a non-uniform variety of karyotypes among chromothriptic patients. The detection of chromothripsis is enabled via tools like microarray-based comparative genomic hybridisation, next generation sequencing or authorial protocols aimed for the recognition of structural variations.
Effect of Paper-Bagging on Apple Skin Patterning Associated with MdMYB10 Promoter Methylation
Authors: Cho Hye Jeong , Han A Reum , Choi Cheol
Published: March 2022

Paper-bagging is an efficient method to maximize apple skin color, but a relationship between this technique and fruit skin patterning has not been demonstrated. Here, the ‘Fuji’ fruit with red-striped skin changed to red-blushed skin under re-exposure to light after bag treatment. Higher expression of MdMYB10, a transcription factor that regulates anthocyanin biosynthesis in apples, correlated with increased anthocyanin concentration in bag removal fruit. At the mature stage, a comparison of methylation status in the MdMYB10 promoter revealed that the methylation level in the region from −2585 to −2117 bp was reduced in bag removal fruit, especially for CHG context. It can be regulated by the downregulated expression of DNA methyltransferases such as MdMET, MdCMT, and MdDRM. Our results suggest that the bag removal treatment in this cultivar causes a change in skin patterning from striped to blushed pigmentation by inducing DNA demethylation of MdMYB10.
Fluorescence-Based Binding Characterization of Small Molecule Ligands Targeting CUG RNA Repeats
Authors: Chang Zhihua , Zheng Ya Ying , Mathivanan Johnsi , Valsangkar Vibhav A. , Du Jinxi , Abou-Elkhair Reham A. I. , Hassan Abdalla E. A. , Sheng Jia
Published: March 2022

Pathogenic CUG and CCUG RNA repeats have been associated with myotonic dystrophy type 1 and 2 (DM1 and DM2), respectively. Identifying small molecules that can bind these RNA repeats is of great significance to develop potential therapeutics to treat these neurodegenerative diseases. Some studies have shown that aminoglycosides and their derivatives could work as potential lead compounds targeting these RNA repeats. In this work, sisomicin, previously known to bind HIV-1 TAR, is investigated as a possible ligand for CUG RNA repeats. We designed a novel fluorescence-labeled RNA sequence of r(CUG)10 to mimic cellular RNA repeats and improve the detecting sensitivity. The interaction of sisomicin with CUG RNA repeats is characterized by the change of fluorescent signal, which is initially minimized by covalently incorporating the fluorescein into the RNA bases and later increased upon ligand binding. The results show that sisomicin can bind and stabilize the folded RNA structure. We demonstrate that this new fluorescence-based binding characterization assay is consistent with the classic UV Tm technique, indicating its feasibility for high-throughput screening of ligand-RNA binding interactions and wide applications to measure the thermodynamic parameters in addition to binding constants and kinetics when probing such interactions.
Crosstalk between p38 MAPK and GR Signaling
Authors: Zeyen Lisa , Seternes Ole Morten , Mikkola Ingvild
Published: March 2022

The p38 MAPK is a signaling pathway important for cells to respond to environmental and intracellular stress. Upon activation, the p38 kinase phosphorylates downstream effectors, which control the inflammatory response and coordinate fundamental cellular processes such as proliferation, apoptosis, and differentiation. Dysregulation of this signaling pathway has been linked to inflammatory diseases and cancer. Secretion of glucocorticoids (GCs) is a classical endocrine response to stress. The glucocorticoid receptor (GR) is the primary effector of GCs and plays an important role in the regulation of cell metabolism and immune response by influencing gene expression in response to hormone-dependent activation. Its ligands, the GCs or steroids, in natural or synthetic variation, are used as standard therapy for anti-inflammatory treatment, severe asthma, autoimmune diseases, and several types of cancer. Several years ago, the GR was identified as one of the downstream targets of p38, and, at the same time, it was shown that glucocorticoids could influence p38 signaling. In this review, we discuss the role of the crosstalk between the p38 and GR in the regulation of gene expression in response to steroids and comprehend the importance and potential of this interplay in future clinical applications.
Regulatory miRNAs in Cardiovascular and Alzheimer’s Disease: A Focus on Copper
Authors: Sacco Anna , Martelli Fabio , Pal Amit , Saraceno Claudia , Benussi Luisa , Ghidoni Roberta , Rongioletti Mauro , Squitti Rosanna
Published: March 2022

Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are key regulators of differentiation and development. In the cell, transcription factors regulate the production of miRNA in response to different external stimuli. Copper (Cu) is a heavy metal and an essential micronutrient with widespread industrial applications. It is involved in a number of vital biological processes encompassing respiration, blood cell line maturation, and immune responses. In recent years, the link between deregulation of miRNAs’ functionality and the development of various pathologies as well as cardiovascular diseases (CVDs) has been extensively studied. Alzheimer’s disease (AD) is the most common cause of dementia in the elderly with a complex disease etiology, and its link with Cu abnormalities is being increasingly studied. A direct interaction between COMMD1, a regulator of the Cu pathway, and hypoxia-inducible factor (HIF) HIF-1a does exist in ischemic injury, but little information has been collected on the role of Cu in hypoxia associated with AD thus far. The current review deals with this matter in an attempt to structurally discuss the link between miRNA expression and Cu dysregulation in AD and CVDs.
Intracerebral but Not Peripheral Infection of Live Porphyromonas gingivalis Exacerbates Alzheimer’s Disease Like Amyloid Pathology in APP-TgCRND8 Mice
Authors: Aravindraja Chairmandurai , Sakthivel Ravi , Liu Xuefei , Goodwin Marshall , Veena Patnam , Godovikova Valentina , Fenno J. Christopher , Levites Yona , Golde Todd E. , Kesavalu Lakshmyya
Published: March 2022

The impact of oral microbial dysbiosis on Alzheimer’s disease (AD) remains controversial. Building off recent studies reporting that various microbes might directly seed or promote amyloid β (Aβ) deposition, we evaluated the effects of periodontal bacteria (Porphyromonas gingivalis, Treponema denticola) and supragingival commensal (Streptococcus gordonii) oral bacterial infection in the APP-transgenic CRND8 (Tg) mice model of AD. We tracked bacterial colonization and dissemination, and monitored effects on gliosis and amyloid deposition. Chronic oral infection did not accelerate Aβ deposition in Tg mice but did induce alveolar bone resorption, IgG immune response, and an intracerebral astrogliosis (GFAP: glial fibrillary acidic protein). In contrast, intracerebral inoculation of live but not heat-killed P. gingivalis increased Aβ deposition and Iba-1 (ionized calcium-binding adaptor-1) microgliosis after 8 weeks of bacterial infection but not at 4 days. These data show that there may be differential effects of infectious microbes on glial activation and amyloid deposition depending on the species and route of inoculation, and thereby provide an important framework for future studies. Indeed, these studies demonstrate marked effects on amyloid β deposition only in a fairly non-physiologic setting where live bacteria is injected directly into the brain.
Nimodipine Exerts Time-Dependent Neuroprotective Effect after Excitotoxical Damage in Organotypic Slice Cultures
Authors: Hohmann Urszula , Ghadban Chalid , Hohmann Tim , Kleine Joshua , Schmidt Miriam , Scheller Christian , Strauss Christian , Dehghani Faramarz
Published: March 2022

During injuries in the central nervous system, intrinsic protective processes become activated. However, cellular reactions, especially those of glia cells, are frequently unsatisfactory, and further exogenous protective mechanisms are necessary. Nimodipine, a lipophilic L-type calcium channel blocking agent is clinically used in the treatment of aneurysmal subarachnoid haemorrhage with neuroprotective effects in different models. Direct effects of nimodipine on neurons amongst others were observed in the hippocampus as well as its influence on both microglia and astrocytes. Earlier studies proposed that nimodipine protective actions occur not only via calcium channel-mediated vasodilatation but also via further time-dependent mechanisms. In this study, the effect of nimodipine application was investigated in different time frames on neuronal damage in excitotoxically lesioned organotypic hippocampal slice cultures. Nimodipine, but not nifedipine if pre-incubated for 4 h or co-applied with NMDA, was protective, indicating time dependency. Since blood vessels play no significant role in our model, intrinsic brain cell-dependent mechanisms seems to strongly be involved. We also examined the effect of nimodipine and nifedipine on microglia survival. Nimodipine seem to be a promising agent to reduce secondary damage and reduce excitotoxic damage.
Identification and Characterization of Salt- and Drought-Responsive AQP Family Genes in Medicagosativa L.
Authors: Luo Yijing , Ma Lin , Du Wenxuan , Yan Su , Wang Zengyu , Pang Yongzhen
Published: March 2022

Aquaporins (AQP) are distributed ubiquitously in plants, and they play important roles in multiple aspects of plant growth and development, as well as in plant resistance to various environmental stresses. In this study, 43 MsAQP genes were identified in the forage crop Medicago sativa. All the MsAQP proteins were clustered into four subfamilies based on sequence similarity and phylogenetic relationship, including 17 TIPs, 14 NIPs, 9 PIPs and 3 SIPs. Analyses of gene structure and conserved domains indicated that the majority of the deduced MsAQP proteins contained the signature transmembrane domains and the NPA motifs. Analyses on cis-acting elements in the promoter region of MsAQP genes revealed the presence of multiple and diverse stress-responsive and hormone-responsive cis-acting elements. In addition, by analyzing the available and comprehensive gene expression data of M. truncatula, we screened ten representative MtAQP genes that were responsive to NaCl or drought stress. By analyzing the sequence similarity and phylogenetic relationship, we finally identified the corresponding ten salt- or drought-responsive AQP genes in M. sativa, including three MsTIPs, three MsPIPs and four MsNIPs. The qPCRs showed that the relative expression levels of these ten selected MsAQP genes responded differently to NaCl or drought treatment in M. sativa. Gene expression patterns showed that most MsAQP genes were preferentially expressed in roots or in leaves, which may reflect their tissue-specific functions associated with development. Our results lay an important foundation for the future characterization of the functions of MsAQP genes, and provide candidate genes for stress resistance improvement through genetic breeding in M. sativa.
Characterization of Chromosomal Breakpoints in 12 Cases with 8p Rearrangements Defines a Continuum of Fragility of the Region
Authors: Redaelli Serena , Conconi Donatella , Sala Elena , Villa Nicoletta , Crosti Francesca , Roversi Gaia , Catusi Ilaria , Valtorta Chiara , Recalcati Maria Paola , Dalprà Leda , Lavitrano Marialuisa , Bentivegna Angela
Published: March 2022

Improvements in microarray-based comparative genomic hybridization technology have allowed for high-resolution detection of genome wide copy number alterations, leading to a better definition of rearrangements and supporting the study of pathogenesis mechanisms. In this study, we focused our attention on chromosome 8p. We report 12 cases of 8p rearrangements, analyzed by molecular karyotype, evidencing a continuum of fragility that involves the entire short arm. The breakpoints seem more concentrated in three intervals: one at the telomeric end, the others at 8p23.1, close to the beta-defensin gene cluster and olfactory receptor low-copy repeats. Hypothetical mechanisms for all cases are described. Our data extend the cohort of published patients with 8p aberrations and highlight the need to pay special attention to these sequences due to the risk of formation of new chromosomal aberrations with pathological effects.
Inferring Time-Lagged Causality Using the Derivative of Single-Cell Expression
Authors: Wei Huanhuan , Lu Hui , Zhao Hongyu
Published: March 2022

Many computational methods have been developed to infer causality among genes using cross-sectional gene expression data, such as single-cell RNA sequencing (scRNA-seq) data. However, due to the limitations of scRNA-seq technologies, time-lagged causal relationships may be missed by existing methods. In this work, we propose a method, called causal inference with time-lagged information (CITL), to infer time-lagged causal relationships from scRNA-seq data by assessing the conditional independence between the changing and current expression levels of genes. CITL estimates the changing expression levels of genes by “RNA velocity”. We demonstrate the accuracy and stability of CITL for inferring time-lagged causality on simulation data against other leading approaches. We have applied CITL to real scRNA data and inferred 878 pairs of time-lagged causal relationships. Furthermore, we showed that the number of regulatory relationships identified by CITL was significantly more than that expected by chance. We provide an R package and a command-line tool of CITL for different usage scenarios.
Scent of a Symbiont: The Personalized Genetic Relationships of Rhizobium—Plant Interaction
Authors: Cangioli Lisa , Vaccaro Francesca , Fini Margherita , Mengoni Alessio , Fagorzi Camilla
Published: March 2022

Many molecular signals are exchanged between rhizobia and host legume plants, some of which are crucial for symbiosis to take place, while others are modifiers of the interaction, which have great importance in the competition with the soil microbiota and in the genotype-specific perception of host plants. Here, we review recent findings on strain-specific and host genotype-specific interactions between rhizobia and legumes, discussing the molecular actors (genes, gene products and metabolites) which play a role in the establishment of symbiosis, and highlighting the need for research including the other components of the soil (micro)biota, which could be crucial in developing rational-based strategies for bioinoculants and synthetic communities’ assemblage.
Natural Compounds as Promising Adjuvant Agents in The Treatment of Gliomas
Authors: Persano Francesca , Gigli Giuseppe , Leporatti Stefano
Published: March 2022

In humans, glioblastoma is the most prevalent primary malignant brain tumor. Usually, glioblastoma has specific characteristics, such as aggressive cell proliferation and rapid invasion of surrounding brain tissue, leading to a poor patient prognosis. The current therapy—which provides a multidisciplinary approach with surgery followed by radiotherapy and chemotherapy with temozolomide—is not very efficient since it faces clinical challenges such as tumor heterogeneity, invasiveness, and chemoresistance. In this respect, natural substances in the diet, integral components in the lifestyle medicine approach, can be seen as potential chemotherapeutics. There are several epidemiological studies that have shown the chemopreventive role of natural dietary compounds in cancer progression and development. These heterogeneous compounds can produce anti-glioblastoma effects through upregulation of apoptosis and autophagy; allowing the promotion of cell cycle arrest; interfering with tumor metabolism; and permitting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis inhibition. Although these beneficial effects are promising, the efficacy of natural compounds in glioblastoma is limited due to their bioavailability and blood–brain barrier permeability. Thereby, further clinical trials are necessary to confirm the in vitro and in vivo anticancer properties of natural compounds. In this article, we overview the role of several natural substances in the treatment of glioblastoma by considering the challenges to be overcome and future prospects.
Long-Term Effect of Porcine Brain Enzyme Hydrolysate Intake on Scopolamine-Induced Memory Impairment in Rats
Authors: Zhang Ting , Kim Min Jung , Kim Min Ju , Wu Xuangao , Yang Hye Jeong , Yuan Heng , Huang Shaokai , Yoon Sun Myung , Kim Keun-Nam , Park Sunmin
Published: March 2022

No study has revealed the effect of porcine brain enzyme hydrolysate (PBEH) on memory impairment. We aimed to examine the hypothesis that PBEH intake modulates memory deficits and cognitive behavior in scopolamine (SC)-induced amnesia rats, and its mechanism, including gut microbiota changes, was determined. Sprague–Dawley male rats had intraperitoneal injections of SC (2 mg/kg body weight/day) at 30 min after daily feeding of casein (MD-control), PBEH (7 mg total nitrogen/mL) at 0.053 mL (Low-PBEH), 0.159 mL (Medium-PBEH), 0.478 mL (High-PBEH), or 10 mg donepezil (Positive-control) per kilogram body weight per day through a feeding needle for six weeks. The Normal-control rats had casein feeding without SC injection. PBEH dose-dependently protected against memory deficits determined by passive avoidance test, Y-maze, water-maze, and novel object recognition test in SC-induced rats compared to the MD-control. The High-PBEH group had a similar memory function to the Positive-control group. Systemic insulin resistance determined by HOMA-IR was lower in the PBEH groups than in the Normal-control but not the Positive-control. In parallel with systemic insulin resistance, decreased cholesterol and increased glycogen contents in the hippocampus in the Medium-PBEH and High-PBEH represented reduced brain insulin resistance. PBEH intake prevented the increment of serum TNF-α and IL-1β concentrations in the SC-injected rats. Hippocampal lipid peroxide and TNF-α contents and mRNA TNF-α and IL-1β expression were dose-dependently reduced in PBEH and Positive-control. PBEH decreased the hippocampal acetylcholinesterase activity compared to the MD-control, but not as much as the Positive-control. PBEH intake increased the α-diversity of the gut microbiota compared to the MD-control, and the gut microbiota community was separated from MD-control. In metagenome function analysis, PBEH increased the energy metabolism-related pathways of the gut microbiota, including citric acid cycle, oxidative phosphorylation, glycolysis, and amino acid metabolism, which were lower in the MD-control than the Normal-control. In conclusion, alleviated memory deficit by PBEH was associated potentially with not only reducing acetylcholinesterase activity but also improving brain insulin resistance and neuroinflammation potentially through modulating gut microbiota. PBEH intake (1.5–4.5 mL of 7 mg total nitrogen/mL for human equivalent) can be a potential therapeutic agent for improving memory impairment.
The In Vitro Cytotoxicity of Eremothecium oil and Its Components—Aromatic and Acyclic Monoterpene Alcohols
Authors: Semenova Elena , Presniakova Victoria , Kozlovskaya Vera , Markelova Natalia , Gusev Alexey , Linert Wolfgang , Kurakov Alexander , Shpichka Anastasia
Published: March 2022

The microscopic fungi Eremothecium ashbyi and E. gossypii are known for their ability to synthetize essential oil, which has a composition similar to that of rose oil. The development of Eremothecium oil technology enables the production of rose-scented products, which are demanded by pharmaceutical, food, and perfumery industries. This study focuses on assessing the in vitro cytotoxicity of Eremothecium oil, in comparison with that of rose oil, using a combination of methods and two cell types (3T3 mouse fibroblast cell line and bone-marrow-derived mesenchymal stromal cells (BM-MSCs)). The Eremothecium oil samples possessed cytotoxic effects that varied among strains and batches. The revealed cytotoxicity level may be used to tailor the qualitative and quantitative composition of Eremothecium oil to achieve a particular quality in its end products. These results require further analysis using other cell types and assays based on measuring other cell functions.
Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy
Authors: Moghaddasi Leyla , Reid Paul , Bezak Eva , Marcu Loredana G.
Published: March 2022

The continuously evolving field of radiotherapy aims to devise and implement techniques that allow for greater tumour control and better sparing of critical organs. Investigations into the complexity of tumour radiobiology confirmed the high heterogeneity of tumours as being responsible for the often poor treatment outcome. Hypoxic subvolumes, a subpopulation of cancer stem cells, as well as the inherent or acquired radioresistance define tumour aggressiveness and metastatic potential, which remain a therapeutic challenge. Non-conventional irradiation techniques, such as spatially fractionated radiotherapy, have been developed to tackle some of these challenges and to offer a high therapeutic index when treating radioresistant tumours. The goal of this article was to highlight the current knowledge on the molecular and radiobiological mechanisms behind spatially fractionated radiotherapy and to present the up-to-date preclinical and clinical evidence towards the therapeutic potential of this technique involving both photon and proton beams.
Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients
Authors: Alkowari Moza , Espino-Guarch Meritxell , Daas Sahar , Abdelrahman Doua , Hasan Waseem , Krishnamoorthy Navaneethakrishnan , Sathappan Abbirami , Sheehan Patrick , Panhuys Nicholas ,   The Qatar Genome Program Research Consortium, Estivill Xavier
Published: March 2022

Hereditary hearing loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children, of which 70% is inherited in an autosomal recessive pattern. The long tradition of consanguinity among the Qatari population has increased the prevalence of HHL, which negatively impacts the quality of life. Here, we functionally validated the pathogenicity of the c.178G>C, p.E60Q mutation in the MYO6 gene, which was detected previously in a Qatari HHL family, using cellular and animal models. In vitro analysis was conducted in HeLa cells transiently transfected with plasmids carrying MYO6WT or MYO6p.E60Q, and a zebrafish model was generated to characterize the in vivo phenotype. Cells transfected with MYO6WT showed higher expression of MYO6 in the plasma membrane and increased ATPase activity. Modeling the human MYO6 variants in zebrafish resulted in severe otic defects. At 72 h post-injection, MYO6p.E60Q embryos demonstrated alterations in the sizes of the saccule and utricle. Additionally, zebrafish with MYO6p.E60Q displayed super-coiled and bent hair bundles in otic hair cells when compared to control and MYO6WT embryos. In conclusion, our cellular and animal models add support to the in silico prediction that the p.E60Q missense variant is pathogenic and damaging to the protein. Since the c.178G>C MYO6 variant has a 0.5% allele frequency in the Qatari population, about 400 times higher than in other populations, it could contribute to explaining the high prevalence of hearing impairment in Qatar.
Marginal Zone B-Cell Populations and Their Regulatory Potential in the Context of HIV and Other Chronic Inflammatory Conditions
Authors: Doyon-Laliberté Kim , Aranguren Matheus , Poudrier Johanne , Roger Michel
Published: March 2022

Inflammation in the context of Human Immunodeficiency Virus (HIV) establishes early and persists beyond antiretroviral therapy (ART). As such, we have shown excess B-cell activating factor (BAFF) in the blood of HIV-infected progressors, as soon as in the acute phase, and despite successful ART. Excess BAFF was associated with deregulation of the B-cell compartment; notably, with increased frequencies of a population sharing features of both transitional immature (TI) and marginal zone (MZ) B-cells, we termed Marginal Zone precursor-like (MZp). We have reported similar observations with HIV-transgenic mice, Simian Immunodeficiency Virus (SIV)-infected macaques, and more recently, with HIV-infected Beninese commercial sex workers, which suggests that excess BAFF and increased frequencies of MZp B-cells are reliable markers of inflammation in the context of HIV. Importantly, we have recently shown that in healthy individuals, MZps present an important regulatory B-cell (Breg) profile and function. Herein, we wish to review our current knowledge on MZ B-cell populations, especially their Breg status, and that of other B-cell populations sharing similar features. BAFF and its analog A Proliferation-Inducing Ligand (APRIL) are important in shaping the MZ B-cell pool; moreover, the impact that excess BAFF—encountered in the context of HIV and several chronic inflammatory conditions—may exert on MZ B-cell populations, Breg and antibody producing capacities is a threat to the self-integrity of their antibody responses and immune surveillance functions. As such, deregulations of MZ B-cell populations contribute to autoimmune manifestations and the development of MZ lymphomas (MZLs) in the context of HIV and other inflammatory diseases. Therefore, further comprehending the mechanisms regulating MZ B-cell populations and their functions could be beneficial to innovative therapeutic avenues that could be deployed to restore MZ B-cell immune competence in the context of chronic inflammation involving excess BAFF.
Two Male-Specific Antimicrobial Peptides SCY2 and Scyreprocin as Crucial Molecules Participated in the Sperm Acrosome Reaction of Mud Crab Scylla paramamosain
Authors: Yang Ying , Chen Fangyi , Qiao Kun , Zhang Hua , Chen Hui-Yun , Wang Ke-Jian
Published: March 2022

Antimicrobial peptides (AMPs) identified in the reproductive system of animals have been widely studied for their antimicrobial activity, but only a few studies have focused on their physiological roles. Our previous studies have revealed the in vitro antimicrobial activity of two male gonadal AMPs, SCY2 and scyreprocin, from mud crab Scylla paramamosain. Their physiological functions, however, remain a mystery. In this study, the two AMPs were found co-localized on the sperm apical cap. Meanwhile, progesterone was confirmed to induce acrosome reaction (AR) of mud crab sperm in vitro, which intrigued us to explore the roles of the AMPs and progesterone in AR. Results showed that the specific antibody blockade of scyreprocin inhibited the progesterone-induced AR without affecting intracellular Ca2+ homeostasis, while the blockade of SCY2 hindered the influx of Ca2+. We further showed that SCY2 could directly bind to Ca2+. Moreover, progesterone failed to induce AR when either scyreprocin or SCY2 function was deprived. Taken together, scyreprocin and SCY2 played a dual role in reproductive immunity and sperm AR. To our knowledge, this is the first report on the direct involvement of AMPs in sperm AR, which would expand the current understanding of the roles of AMPs in reproduction.
Two Triacylglycerol Lipases Are Negative Regulators of Chilling Stress Tolerance in Arabidopsis
Authors: Wang Ling , Qian Bilian , Zhao Lei , Liang Ming-Hua , Zhan Xiangqiang , Zhu Jianhua
Published: March 2022

Cold stress is one of the abiotic stress conditions that severely limit plant growth and development and productivity. Triacylglycerol lipases are important metabolic enzymes for the catabolism of triacylglycerols and, therefore, play important roles in cellular activities including seed germination and early seedling establishment. However, whether they play a role in cold stress responses remains unknown. In this study, we characterized two Arabidopsis triacylglycerol lipases, MPL1 and LIP1 and defined their role in cold stress. The expression of MPL1 and LIP1 is reduced by cold stress, suggesting that they may be negative factors related to cold stress. Indeed, we found that loss-of-function of MPL1 and LIP1 resulted in increased cold tolerance and that the mpl1lip1 double mutant displayed an additive effect on cold tolerance. We performed RNA-seq analysis to reveal the global effect of the mpl1 and lip1 mutations on gene expression under cold stress. The mpl1 mutation had a small effect on gene expression under both under control and cold stress conditions whereas the lip1 mutation caused a much stronger effect on gene expression under control and cold stress conditions. The mpl1lip1 double mutant had a moderate effect on gene expression under control and cold stress conditions. Together, our results indicate that MPL1 and LIP1 triacylglycerol lipases are negative regulators of cold tolerance without any side effects on growth in Arabidopsis and that they might be ideal candidates for breeding cold-tolerant crops through genome editing technology.
Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: A Focus on Neurofilaments and Therapeutic Considerations
Authors: Biernacki Tamás , Kokas Zsófia , Sandi Dániel , Füvesi Judit , Fricska-Nagy Zsanett , Faragó Péter , Kincses Tamás Zsigmond , Klivényi Péter , Bencsik Krisztina , Vécsei László
Published: March 2022

Introduction: Multiple Sclerosis (MS) is the most common immune-mediated chronic neurodegenerative disease of the central nervous system (CNS) affecting young people. This is due to the permanent disability, cognitive impairment, and the enormous detrimental impact MS can exert on a patient’s health-related quality of life. It is of great importance to recognise it in time and commence adequate treatment at an early stage. The currently used disease-modifying therapies (DMT) aim to reduce disease activity and thus halt disability development, which in current clinical practice are monitored by clinical and imaging parameters but not by biomarkers found in blood and/or the cerebrospinal fluid (CSF). Both clinical and radiological measures routinely used to monitor disease activity lack information on the fundamental pathophysiological features and mechanisms of MS. Furthermore, they lag behind the disease process itself. By the time a clinical relapse becomes evident or a new lesion appears on the MRI scan, potentially irreversible damage has already occurred in the CNS. In recent years, several biomarkers that previously have been linked to other neurological and immunological diseases have received increased attention in MS. Additionally, other novel, potential biomarkers with prognostic and diagnostic properties have been detected in the CSF and blood of MS patients. Areas covered: In this review, we summarise the most up-to-date knowledge and research conducted on the already known and most promising new biomarker candidates found in the CSF and blood of MS patients. Discussion: the current diagnostic criteria of MS relies on three pillars: MRI imaging, clinical events, and the presence of oligoclonal bands in the CSF (which was reinstated into the diagnostic criteria by the most recent revision). Even though the most recent McDonald criteria made the diagnosis of MS faster than the prior iteration, it is still not an infallible diagnostic toolset, especially at the very early stage of the clinically isolated syndrome. Together with the gold standard MRI and clinical measures, ancillary blood and CSF biomarkers may not just improve diagnostic accuracy and speed but very well may become agents to monitor therapeutic efficacy and make even more personalised treatment in MS a reality in the near future. The major disadvantage of these biomarkers in the past has been the need to obtain CSF to measure them. However, the recent advances in extremely sensitive immunoassays made their measurement possible from peripheral blood even when present only in minuscule concentrations. This should mark the beginning of a new biomarker research and utilisation era in MS.