bluuebunny/crossref_metadata_2025 huggingface dataset:
Epichloë Endophyte-Promoted Seed Pathogen Increases Host Grass Resistance Against Insect Herbivory
Authors: Laihonen Miika , Saikkonen Kari , Helander Marjo , Vázquez de Aldana Beatriz R. , Zabalgogeazcoa Iñigo , Fuchs Benjamin
Published: January 2022

Plants host taxonomically and functionally complex communities of microbes. However, ecological studies on plant–microbe interactions rarely address the role of multiple co-occurring plant-associated microbes. Here, we contend that plant-associated microbes interact with each other and can have joint consequences for higher trophic levels. In this study we recorded the occurrence of the plant seed pathogenic fungusClaviceps purpureaand aphids (Sitobionsp.) on an established field experiment with red fescue (Festuca rubra) plants symbiotic to a seed transmitted endophytic fungusEpichloë festucae(E+) or non-symbiotic (E–). Both fungi are known to produce animal-toxic alkaloids. The study was conducted in a semi-natural setting, where E+ and E– plants from different origins (Spain and Northern Finland) were planted in a randomized design in a fenced common garden at Kevo Subarctic Research Station in Northern Finland. The results reveal that 45% of E+ plants were infected withClavicepscompared to 31% of E– plants. Uninfected plants had 4.5 times more aphids thanClavicepsinfected plants. By contrast, aphid infestation was unaffected byEpichloësymbiosis.Clavicepsalkaloid concentrations correlated with a decrease in aphid numbers, which indicates their insect deterring features. These results show that plant mutualistic fungi can increase the infection probability of a pathogenic fungus, which then becomes beneficial to the plant by controlling herbivorous insects. Our study highlights the complexity and context dependency of species–species and multi-trophic interactions, thus challenging the labeling of species as plant mutualists or pathogens.
Natural Shifts in Endosymbionts' Occurrence and Relative Frequency in Their Ciliate Host Population
Authors: Flemming Felicitas E. , Grosser Katrin , Schrallhammer Martina
Published: January 2022

The role of bacterial endosymbionts harbored by heterotrophic Paramecium species is complex. Obligate intracellular bacteria supposedly always inflict costs as the host is the only possible provider of resources. However, several experimental studies have shown that paramecia carrying bacterial endosymbionts can benefit from their infection. Here, we address the question which endosymbionts occur in natural paramecia populations isolated from a small lake over a period of 5 years and which factors might explain observed shifts and persistence in the symbionts occurrence. One hundred and nineteen monoclonal strains were investigated and approximately two-third harbored intracellular bacteria. The majority of infected paramecia carried the obligate endosymbiotic “Candidatus Megaira polyxenophila”, followed by Caedimonas varicaedens, and Holospora undulata. The latter was only detected in a single strain. While “Ca. M. polyxenophila” was observed in seven out of 13 samplings, C. varicaedens presence was limited to a single sampling occasion. After the appearance of C. varicaedens, “Ca. M. polyxenophila” prevalence dramatically dropped with some delay but recovered to original levels at the end of our study. Potential mechanisms explaining these observations include differences in infectivity, host range, and impact on host fitness as well as host competitive capacities. Growth experiments revealed fitness advantages for infected paramecia harboring “Ca. M. polyxenophila” as well as C. varicaedens. Furthermore, we showed that cells carrying C. varicaedens gain a competitive advantage from the symbiosis-derived killer trait. Other characteristics like infectivity and overlapping host range were taken into consideration, but the observed temporal persistence of “Ca. M. polyxenophila” is most likely explained by the positive effect this symbiont provides to its host.
Metformin Alters the Chemotaxis and Flagellar Motility of Escherichia coli
Authors: Ye Yingxiang , Jiang Panmei , Huang Chengyun , Li Jingyun , Chen Juan , Wang Lu , Lin Yan , Wang Fangbin , Liu Jian
Published: January 2022

Metformin is a biguanide molecule that is widely prescribed to treat type 2 diabetes and metabolic syndrome. Although it is known that metformin promotes the lifespan by altering intestinal microorganism metabolism, how metformin influences and alters the physiological behavior of microorganisms remains unclear. Here we studied the effect of metformin on the behavior alterations of the model organism Escherichia coli (E. coli), including changes in chemotaxis and flagellar motility that plays an important role in bacterial life. It was found that metformin was sensed as a repellent to E. coli by tsr chemoreceptors. Moreover, we investigated the chemotactic response of E. coli cultured with metformin to two typical attractants, glucose and α-methyl-DL-aspartate (MeAsp), finding that metformin prolonged the chemotactic recovery time to the attractants, followed by the recovery time increasing with the concentration of stimulus. Metformin also inhibited the flagellar motility of E. coli including the flagellar motor rotation and cell swimming. The inhibition was due to the reduction of torque generated by the flagellar motor. Our discovery that metformin alters the behavior of chemotaxis and flagellar motility of E. coli could provide potential implications for the effect of metformin on other microorganisms.
CRISPR Technology in Gene-Editing-Based Detection and Treatment of SARS-CoV-2
Authors: Shademan Behrouz , Nourazarian Alireza , Hajazimian Saba , Isazadeh Alireza , Biray Avci Cigir , Oskouee Mahin Ahangar
Published: January 2022

Outbreak and rapid spread of coronavirus disease (COVID-19) caused by coronavirus acute respiratory syndrome (SARS-CoV-2) caused severe acute respiratory syndrome (SARS-CoV-2) that started in Wuhan, and has become a global problem because of the high rate of human-to-human transmission and severe respiratory infections. Because of high prevalence of SARS-CoV-2, which threatens many people worldwide, rapid diagnosis and simple treatment are needed. Genome editing is a nucleic acid-based approach to altering the genome by artificially changes in genetic information and induce irreversible changes in the function of target gene. Clustered, regularly interspaced short palindromic repeats (CRISPR/Cas) could be a practical and straightforward approach to this disease. CRISPR/Cas system contains Cas protein, which is controlled by a small RNA molecule to create a double-stranded DNA gap. Evidence suggested that CRISPR/Cas was also usable for diagnosis and treatment of SARS-CoV-2 infection. In this review study, we discoursed on application of CRISPR technology in detection and treatment of SARS-CoV-2 infection. Another aspect of this study was to introduce potential future problems in use of CRISPR/Cas technology.
A Minireview of Microfluidic Scaffold Materials in Tissue Engineering
Authors: Tong Anh , Voronov Roman
Published: January 2022

In 2020, nearly 107,000 people in the U.S needed a lifesaving organ transplant, but due to a limited number of donors, only ∼35% of them have actually received it. Thus, successful bio-manufacturing of artificial tissues and organs is central to satisfying the ever-growing demand for transplants. However, despite decades of tremendous investments in regenerative medicine research and development conventional scaffold technologies have failed to yield viable tissues and organs. Luckily, microfluidic scaffolds hold the promise of overcoming the major challenges associated with generating complex 3D cultures: 1) cell death due to poor metabolite distribution/clearing of waste in thick cultures; 2) sacrificial analysis due to inability to sample the culture non-invasively; 3) product variability due to lack of control over the cell action post-seeding, and 4) adoption barriers associated with having to learn a different culturing protocol for each new product. Namely, their active pore networks provide the ability to perform automated fluid and cell manipulations (e.g., seeding, feeding, probing, clearing waste, delivering drugs, etc.) at targeted locations in-situ. However, challenges remain in developing a biomaterial that would have the appropriate characteristics for such scaffolds. Specifically, it should ideally be: 1) biocompatible—to support cell attachment and growth, 2) biodegradable—to give way to newly formed tissue, 3) flexible—to create microfluidic valves, 4) photo-crosslinkable—to manufacture using light-based 3D printing and 5) transparent—for optical microscopy validation. To that end, this minireview summarizes the latest progress of the biomaterial design, and of the corresponding fabrication method development, for making the microfluidic scaffolds.
Aging-Related Changes in Cortical Sources of Sleep Oscillatory Neural Activity Following Motor Learning Reflect Contributions of Cortical Thickness and Pre-sleep Functional Activity
Authors: Fitzroy Ahren B. , Jones Bethany J. , Kainec Kyle A. , Seo Jeehye , Spencer Rebecca M. C.
Published: January 2022

Oscillatory neural activity during sleep, such as that in the delta and sigma bands, is important for motor learning consolidation. This activity is reduced with typical aging, and this reduction may contribute to aging-related declines in motor learning consolidation. Evidence suggests that brain regions involved in motor learning contribute to oscillatory neural activity during subsequent sleep. However, aging-related differences in regional contributions to sleep oscillatory activity following motor learning are unclear. To characterize these differences, we estimated the cortical sources of consolidation-related oscillatory activity using individual anatomical information in young and older adults during non-rapid eye movement sleep after motor learning and analyzed them in light of cortical thickness and pre-sleep functional brain activation. High-density electroencephalogram was recorded from young and older adults during a midday nap, following completion of a functional magnetic resonance imaged serial reaction time task as part of a larger experimental protocol. Sleep delta activity was reduced with age in a left-weighted motor cortical network, including premotor cortex, primary motor cortex, supplementary motor area, and pre-supplementary motor area, as well as non-motor regions in parietal, temporal, occipital, and cingulate cortices. Sleep theta activity was reduced with age in a similar left-weighted motor network, and in non-motor prefrontal and middle cingulate regions. Sleep sigma activity was reduced with age in left primary motor cortex, in a non-motor right-weighted prefrontal-temporal network, and in cingulate regions. Cortical thinning mediated aging-related sigma reductions in lateral orbitofrontal cortex and frontal pole, and partially mediated delta reductions in parahippocampal, fusiform, and lingual gyri. Putamen, caudate, and inferior parietal cortex activation prior to sleep predicted frontal and motor cortical contributions to sleep delta and theta activity in an age-moderated fashion, reflecting negative relationships in young adults and positive or absent relationships in older adults. Overall, these results support the local sleep hypothesis that brain regions active during learning contribute to consolidation-related neural activity during subsequent sleep and demonstrate that sleep oscillatory activity in these regions is reduced with aging.
GABAA Receptors in Astrocytes Are Targets for Commonly Used Intravenous and Inhalational General Anesthetic Drugs
Authors: Chung Woosuk , Wang Dian-Shi , Khodaei Shahin , Pinguelo Arsene , Orser Beverley A.
Published: January 2022

Background: Perioperative neurocognitive disorders (PNDs) occur commonly in older patients after anesthesia and surgery. Treating astrocytes with general anesthetic drugs stimulates the release of soluble factors that increase the cell-surface expression and function of GABAA receptors in neurons. Such crosstalk may contribute to PNDs; however, the receptor targets in astrocytes for anesthetic drugs have not been identified. GABAA receptors, which are the major targets of general anesthetic drugs in neurons, are also expressed in astrocytes, raising the possibility that these drugs act on GABAA receptors in astrocytes to trigger the release of soluble factors. To date, no study has directly examined the sensitivity of GABAA receptors in astrocytes to general anesthetic drugs that are frequently used in clinical practice. Thus, the goal of this study was to determine whether the function of GABAA receptors in astrocytes was modulated by the intravenous anesthetic etomidate and the inhaled anesthetic sevoflurane.

Methods: Whole-cell voltage-clamp recordings were performed in astrocytes in the stratum radiatum of the CA1 region of hippocampal slices isolated from C57BL/6 male mice. Astrocytes were identified by their morphologic and electrophysiologic properties. Focal puff application of GABA (300 μM) was applied with a Picospritzer system to evoke GABA responses. Currents were studied before and during the application of the non-competitive GABAA receptor antagonist picrotoxin (0.5 mM), or etomidate (100 μM) or sevoflurane (532 μM).

Results: GABA consistently evoked inward currents that were inhibited by picrotoxin. Etomidate increased the amplitude of the peak current by 35.0 ± 24.4% and prolonged the decay time by 27.2 ± 24.3% (n = 7, P < 0.05). Sevoflurane prolonged current decay by 28.3 ± 23.1% (n = 7, P < 0.05) but did not alter the peak amplitude. Etomidate and sevoflurane increased charge transfer (area) by 71.2 ± 45.9% and 51.8 ± 48.9% (n = 7, P < 0.05), respectively.

Conclusion: The function of astrocytic GABAA receptors in the hippocampus was increased by etomidate and sevoflurane. Future studies will determine whether these general anesthetic drugs act on astrocytic GABAA receptors to stimulate the release of soluble factors that may contribute to PNDs.
The Association Between Loneliness and Inflammation: Findings From an Older Adult Sample
Authors: Van Bogart Karina , Engeland Christopher G. , Sliwinski Martin J. , Harrington Karra D. , Knight Erik L. , Zhaoyang Ruixue , Scott Stacey B. , Graham-Engeland Jennifer E.
Published: January 2022

Loneliness has been linked to poor mental and physical health outcomes. Past research suggests that inflammation is a potential pathway linking loneliness and health, but little is known about how loneliness assessed in daily life links with inflammation, or about linkages between loneliness and inflammation among older adults specifically. As part of a larger investigation, we examined the cross-sectional associations between loneliness and a panel of both basal and LPS-stimulated inflammatory markers. Participants were 222 socioeconomically and racially diverse older adults (aged 70–90 years; 38% Black; 13% Hispanic) systematically recruited from the Bronx, NY. Loneliness was measured in two ways, with a retrospective trait measure (the UCLA Three Item Loneliness Scale) and an aggregated momentary measure assessed via ecological momentary assessment (EMA) across 14 days. Inflammatory markers included both basal levels of C-reactive protein (CRP) and cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10, TNF-α) and LPS-stimulated levels of the same cytokines. Multiple regression analyses controlled for age, body-mass index, race, and depressive symptoms. Moderation by gender and race were also explored. Both higher trait loneliness and aggregated momentary measures of loneliness were associated with higher levels of CRP (β = 0.16, p = 0.02; β = 0.15, p = 0.03, respectively). There were no significant associations between loneliness and basal or stimulated cytokines and neither gender nor race were significant moderators. Results extend prior research linking loneliness with systemic inflammation in several ways, including by examining this connection among a sample of older adults and using a measure of aggregated momentary loneliness.
Subjective and Objective Quality Assessment of Swimming Pool Images
Authors: Lei Fei , Li Shuhan , Xie Shuangyi , Liu Jing
Published: January 2022

As the research basis of image processing and computer vision research, image quality evaluation (IQA) has been widely used in different visual task fields. As far as we know, limited efforts have been made to date to gather swimming pool image databases and benchmark reliable objective quality models, so far. To filled this gap, in this paper we reported a new database of underwater swimming pool images for the first time, which is composed of 1500 images and associated subjective ratings recorded by 16 inexperienced observers. In addition, we proposed a main target area extraction and multi-feature fusion image quality assessment (MM-IQA) for a swimming pool environment, which performs pixel-level fusion for multiple features of the image on the premise of highlighting important detection objects. Meanwhile, a variety of well-established full-reference (FR) quality evaluation methods and partial no-reference (NR) quality evaluation algorithms are selected to verify the database we created. Extensive experimental results show that the proposed algorithm is superior to the most advanced image quality models in performance evaluation and the outcomes of subjective and objective quality assessment of most methods involved in the comparison have good correlation and consistency, which further indicating indicates that the establishment of a large-scale pool image quality assessment database is of wide applicability and importance.
Cerebellar Coordination of Neuronal Communication in Cerebral Cortex
Authors: McAfee Samuel S. , Liu Yu , Sillitoe Roy V. , Heck Detlef H.
Published: January 2022

Cognitive processes involve precisely coordinated neuronal communications between multiple cerebral cortical structures in a task specific manner. Rich new evidence now implicates the cerebellum in cognitive functions. There is general agreement that cerebellar cognitive function involves interactions between the cerebellum and cerebral cortical association areas. Traditional views assume reciprocal interactions between one cerebellar and one cerebral cortical site, via closed-loop connections. We offer evidence supporting a new perspective that assigns the cerebellum the role of a coordinator of communication. We propose that the cerebellum participates in cognitive function by modulating the coherence of neuronal oscillations to optimize communications between multiple cortical structures in a task specific manner.
Effects of M/G Ratios of Sodium Alginate on Physicochemical Stability and Calcium Release Behavior of Pickering Emulsion Stabilized by Calcium Carbonate
Authors: Yang Xiaotong , Sui Haomin , Liang Hongshan , Li Jing , Li Bin
Published: January 2022

The gel properties of sodium alginate (SA) have been revealed to be strongly correlated with its ratio of D-mannuronate to L-guluronate (M/G ratio). Herein, we focused on SA with different M/G ratios to conduct an in-depth study on the effect of the M/G ratio difference on physicochemical stability and calcium release behavior of the Pickering emulsion stabilized by calcium carbonate (CaCO3). The oil phase was added to the aqueous phase, prepared by SA with different M/G ratios (2.23, 0.89, and 0.56) and CaCO3, for one-step shearing to obtain the E1, E2, and E3 emulsions, respectively. The results of the particle size, microstructure, long-term stability, rheological, and microrheological properties of the emulsions showed that the E3 emulsion, prepared by SA with a smaller M/G ratio, had a smaller particle size and has remained in a flow condition during the long-term storage, while the E1 and E2 emulsions had a gelation behavior and a stronger viscoelasticity. Moreover, the emulsion, as a liquid calcium supplement, is not only convenient for oral intake while meeting the calcium needs of the body, but also controls the release of Ca2+. The calcium release of the emulsions in a simulated gastric environment demonstrated that the calcium release ratio increased with the decrease of SA concentration, with the increase of M/G ratio, and with the decrease of oil phase volume.
Investigation of PALB2 Mutation and Correlation With Immunotherapy Biomarker in Chinese Non-Small Cell Lung Cancer Patients
Authors: Zhang Jiexia , Tang Shuangfeng , Zhang Chunning , Li Mingyao , Zheng Yating , Hu Xue , Huang Mengli , Cheng Xiangyang
Published: January 2022

Background

PALB2, a gene in the homologous recombination repair (HRR) pathway of the DNA damage response (DDR), is associated with the efficacy of platinum-based chemotherapy, immunotherapy, and PARP inhibitor therapy in several tumors. However, the PALB2 characteristics, its correlation with immunotherapy biomarker, and the prognostic effect of immunotherapy in non-small cell lung cancer (NSCLC) were unknown.

Methods

Tumor tissue samples from advanced Chinese NSCLC patients were analyzed by next-generation sequencing (NGS) (panel on 381/733-gene). Tumor mutation burden (TMB) is defined as the total number of somatic non-synonymous mutations in the coding region. Microsatellite instability (MSI) was evaluated by NGS of 500 known MSI loci. Programmed Cell Death-Ligand 1 (PD-L1) expression was evaluated using immunohistochemistry (Dako 22C3 or SP263). One independent cohort (Rizvi2018.NSCLC.240.NGS cohort) containing genomic and clinical data from 240 patients with advanced NSCLC and two cohorts (the OAK and POPLAR study cohort) containing genomic and clinical data from 429 patients with advanced NSCLC were used to analyze the prognostic effect of PALB2 on immunotherapy.

Results

Genetic mutation of 5,227 NSCLC patients were analyzed using NGS, of which 162 (3.1%) harbored germline PALB2 mutation (PALB2gmut) and 87 (1.66%) harbored somatic PALB2 mutation (PALB2smut). In NSCLC patients with PALB2gmut and PALB2smut, the most frequently mutated gene was TP53 (65%, 64%). PALB2smut (14.52 Muts/Mb) was associated with higher TMB (p < 0.001) than PALB wild-type (PALB2wt) (6.15 Muts/Mb). However, there was no significant difference in TMB between PALB2gmut (6.45 Muts/Mb) and PALB2wt (6.15 Muts/Mb) (p = 0.64). There was no difference in PD-L1 expression among PALB2gmut, PALB2smut, and PALB2wt. In the Rizvi2018.NSCLC.240.NGS cohort, there was no difference in progression-free survival (PFS) (HR =1.06, p = 0.93) between PALB2 mutation (3.15 months) and PALB2wt (3.17 months). The OAK and POPLAR study cohort of NSCLC patients showed that there was no difference in overall survival (OS) (HR =1.1, p = 0.75) between PALB2 mutation (10.38 months) and PALB2wt (11.07 months).

Conclusions

These findings suggest that PALB2 may not be used as a biomarker for determining prognosis on immunotherapy in NSCLC.
Adaptive MR-Guided Stereotactic Radiotherapy is Beneficial for Ablative Treatment of Lung Tumors in High-Risk Locations
Authors: Regnery Sebastian , Buchele Carolin , Weykamp Fabian , Pohl Moritz , Hoegen Philipp , Eichkorn Tanja , Held Thomas , Ristau Jonas , Rippke Carolin , König Laila , Thomas Michael , Winter Hauke , Adeberg Sebastian , Debus Jürgen , Klüter Sebastian , Hörner-Rieber Juliane
Published: January 2022

Purpose

To explore the benefit of adaptive magnetic resonance-guided stereotactic body radiotherapy (MRgSBRT) for treatment of lung tumors in different locations with a focus on ultracentral lung tumors (ULT).

Patients & Methods

A prospective cohort of 21 patients with 23 primary and secondary lung tumors was analyzed. Tumors were located peripherally (N = 10), centrally (N = 2) and ultracentrally (N = 11, planning target volume (PTV) overlap with proximal bronchi, esophagus and/or pulmonary artery). All patients received MRgSBRT with gated dose delivery and risk-adapted fractionation. Before each fraction, the baseline plan was recalculated on the anatomy of the day (predicted plan). Plan adaptation was performed in 154/165 fractions (93.3%). Comparison of dose characteristics between predicted and adapted plans employed descriptive statistics and Bayesian linear multilevel models. The posterior distributions resulting from the Bayesian models are presented by the mean together with the corresponding 95% compatibility interval (CI).

Results

Plan adaptation decreased the proportion of fractions with violated planning objectives from 94% (predicted plans) to 17% (adapted plans). In most cases, inadequate PTV coverage was remedied (predicted: 86%, adapted: 13%), corresponding to a moderate increase of PTV coverage (mean +6.3%, 95% CI: [5.3–7.4%]) and biologically effective PTV doses (BED10) (BEDmin: +9.0 Gy [6.7–11.3 Gy], BEDmean: +1.4 Gy [0.8–2.1 Gy]). This benefit was smaller in larger tumors (−0.1%/10 cm³ PTV [−0.2 to −0.02%/10 cm³ PTV]) and ULT (−2.0% [−3.1 to −0.9%]). Occurrence of exceeded maximum doses inside the PTV (predicted: 21%, adapted: 4%) and violations of OAR constraints (predicted: 12%, adapted: 1%, OR: 0.14 [0.04–0.44]) was effectively reduced. OAR constraint violations almost exclusively occurred if the PTV had touched the corresponding OAR in the baseline plan (18/19, 95%).

Conclusion

Adaptive MRgSBRT is highly recommendable for ablative treatment of lung tumors whose PTV initially contacts a sensitive OAR, such as ULT. Here, plan adaptation protects the OAR while maintaining best-possible PTV coverage.
Identification of Novel Prognostic Markers Associated With Laryngeal Squamous Cell Carcinoma Using Comprehensive Analysis
Authors: Huang Chao , He Jun , Dong Yi , Huang Li , Chen Yichao , Peng Anquan , Huang Hao
Published: January 2022

Background

Laryngeal squamous cell carcinoma (LSCC) is a leading malignant cancer of the head and neck. Patients with LSCC, in which the cancer has infiltrated and metastasized, have a poor prognosis. Therefore, there is an urgent need to identify more potential targets for drugs and biomarkers for early diagnosis.

Methods

RNA sequence data from LSCC and patients’ clinical traits were obtained from the Gene Expression Omnibus (GEO) (GSE142083) and The Cancer Genome Atlas (TCGA) database. Differentially expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify hub genes. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, prognostic value analysis, receiver operating characteristic (ROC) curve analysis, gene mutation analysis, tumor-infiltrating immune cell abundance profile estimation, gene set variation analysis (GSVA), and gene set enrichment analysis (GSEA) were performed. Single-gene RNA sequencing data were obtained from the GSE150321 dataset. Cell proliferation and viability were confirmed by the CCK-8 assay and real-time PCR.

Results

A total of 701 DEGs, including 329 upregulated and 372 downregulated genes, were screened in the GSE142083 dataset. Using WGCNA, three modules were identified to be closely related to LSCC. After intersecting the DEGs and performing univariate and multivariate Cox analyses, a novel prognostic model based on three genes (SLC35C1, HOXB7, and TEDC2) for LSCC was established. Interfering TEDC2 expression inhibited tumor cell proliferation and migration.

Conclusions

Our results show that SLC35C1, HOXB7, and TEDC2 have the potential to become new therapeutic targets and prognostic biomarkers for LSCC.
A Novel 2-Carbon-Linked Dimeric Artemisinin With Potent Antileukemic Activity and Favorable Pharmacology
Authors: Kagan Amanda B. , Moses Blake S. , Mott Bryan T. , Rai Ganesha , Anders Nicole M. , Rudek Michelle A. , Civin Curt I.
Published: January 2022

Acute myeloid leukemia (AML) remains a devastating disease, with low cure rates despite intensive standard chemotherapy regimens. In the past decade, targeted antileukemic drugs have emerged from research efforts. Nevertheless, targeted therapies are often effective for only a subset of patients whose leukemias harbor a distinct mutational or gene expression profile and provide only transient antileukemic responses as monotherapies. We previously presented single agent and combination preclinical data for a novel 3-carbon-linked artemisinin-derived dimer (3C-ART), diphenylphosphate analog 838 (ART838), that indicates a promising approach to treat AML, given its demonstrated synergy with targeted antileukemic drugs and large therapeutic window. We now report new data from our initial evaluation of a structurally distinct class of 2-carbon-linked dimeric artemisinin-derived analogs (2C-ARTs) with prior documented in vivo antimalarial activity. These 2C-ARTs have antileukemic activity at low (nM) concentrations, have similar cooperativity with other antineoplastic drugs and comparable physicochemical properties to ART838, and provide a viable path to clinical development.
Aberrant GATA2 Activation in Pediatric B-Cell Acute Lymphoblastic Leukemia
Authors: Wang Han , Cui Bowen , Sun Huiying , Zhang Fang , Rao Jianan , Wang Ronghua , Zhao Shuang , Shen Shuhong , Liu Yu
Published: January 2022

GATA2 is a transcription factor that is critical for the generation and survival of hematopoietic stem cells (HSCs). It also plays an important role in the regulation of myeloid differentiation. Accordingly, GATA2 expression is restricted to HSCs and hematopoietic progenitors as well as early erythroid cells and megakaryocytic cells. Here we identified aberrant GATA2 expression in B-cell acute lymphoblastic leukemia (B-ALL) by analyzing transcriptome sequencing data obtained from St. Jude Cloud. Differentially expressed genes upon GATA2 activation showed significantly myeloid-like transcription signature. Further analysis identified several tumor-associated genes as targets of GATA2 activation including BAG3 and EPOR. In addition, the correlation between KMT2A-USP2 fusion and GATA2 activation not only indicates a potential trans-activating mechanism of GATA2 but also suggests that GATA2 is a target of KMT2A-USP2. Furthermore, by integrating whole-genome and transcriptome sequencing data, we showed that GATA2 is also cis activated. A somatic focal deletion located in the GATA2 neighborhood that disrupts the boundaries of topologically associating domains was identified in one B-ALL patient with GATA2 activation. These evidences support the hypothesis that GATA2 could be involved in leukemogenesis of B-ALL and can be transcriptionally activated through multiple mechanisms. The findings of aberrant activation of GATA2 and its molecular function extend our understanding of transcriptional factor dysregulation in B-ALL.
Analytical Challenges and Metrological Approaches to Ensuring Dietary Supplement Quality: International Perspectives
Authors: Durazzo Alessandra , Sorkin Barbara C. , Lucarini Massimo , Gusev Pavel A. , Kuszak Adam J. , Crawford Cindy , Boyd Courtney , Deuster Patricia A. , Saldanha Leila G. , Gurley Bill J. , Pehrsson Pamela R. , Harnly James M. , Turrini Aida , Andrews Karen W. , Lindsey Andrea T. , Heinrich Michael , Dwyer Johanna T.
Published: January 2022

The increased utilization of metrology resources and expanded application of its’ approaches in the development of internationally agreed upon measurements can lay the basis for regulatory harmonization, support reproducible research, and advance scientific understanding, especially of dietary supplements and herbal medicines. Yet, metrology is often underappreciated and underutilized in dealing with the many challenges presented by these chemically complex preparations. This article discusses the utility of applying rigorous analytical techniques and adopting metrological principles more widely in studying dietary supplement products and ingredients, particularly medicinal plants and other botanicals. An assessment of current and emerging dietary supplement characterization methods is provided, including targeted and non-targeted techniques, as well as data analysis and evaluation approaches, with a focus on chemometrics, toxicity, dosage form performance, and data management. Quality assessment, statistical methods, and optimized methods for data management are also discussed. Case studies provide examples of applying metrological principles in thorough analytical characterization of supplement composition to clarify their health effects. A new frontier for metrology in dietary supplement science is described, including opportunities to improve methods for analysis and data management, development of relevant standards and good practices, and communication of these developments to researchers and analysts, as well as to regulatory and policy decision makers in the public and private sectors. The promotion of closer interactions between analytical, clinical, and pharmaceutical scientists who are involved in research and product development with metrologists who develop standards and methodological guidelines is critical to advance research on dietary supplement characterization and health effects.
Nanocarriers-Assisted Needle-Free Vaccine Delivery Through Oral and Intranasal Transmucosal Routes: A Novel Therapeutic Conduit
Authors: Mangla Bharti , Javed Shamama , Sultan Muhammad H. , Ahsan Waquar , Aggarwal Geeta , Kohli Kanchan
Published: January 2022

Drug delivery using oral route is the most popular, convenient, safest and least expensive approach. It includes oral transmucosal delivery of bioactive compounds as the mucosal cavity offers an intriguing approach for systemic drug distribution. Owing to the dense vascular architecture and high blood flow, oral mucosal layers are easily permeable and can be an ideal site for drug administration. Recently, the transmucosal route is being investigated for other therapeutic candidates such as vaccines for their efficient delivery. Vaccines have the potential to trigger immune reactions and can act as both prophylactic and therapeutic conduit to a variety of diseases. Administration of vaccines using transmucosal route offers multiple advantages, the most important one being the needle-free (non-invasive) delivery. Development of needle-free devices are the most recent and pioneering breakthrough in the delivery of drugs and vaccines, enabling patients to avoid needles, reducing anxiety, pain and fear as well as improving compliance. Oral, nasal and aerosol vaccination is a novel immunization approach that utilizes a nanocarrier to administer the vaccine. Nanocarriers improve the bioavailability and serve as adjuvants to elicit a stronger immune response, resulting in increased effectiveness of vaccination. Drugs and vaccines with lower penetration abilities can also be delivered transmucosally while maintaining their biological function. The development of micro/nanocarriers for transmucosal delivery of macromolecules, vaccines and other substances is currently drawing much attention and a number of studies were performed recently. This comprehensive review is aimed to summarize the most recent investigations on needle-free and non-invasive approaches for the delivery of vaccines using oral transmucosal route, their strengths and associated challenges. The oral transmucosal vaccine delivery by nanocarriers is the most upcoming advancement in efficient vaccine delivery and this review would help further research and trials in this field.
Accentuating CircRNA-miRNA-Transcription Factors Axis: A Conundrum in Cancer Research
Authors: Singh Deepti , Kesharwani Prashant , Alhakamy Nabil A. , Siddique Hifzur R.
Published: January 2022

Circular RNAs (circRNAs) are the newly uncovered class of non-coding RNAs being cognized as profound regulators of gene expression in developmental and disease biology. These are the covalently closed RNAs synthesized when the pre-mRNA transcripts undergo a back-splicing event. In recent years, circRNAs are gaining special attention in the scientific world and are no longer considered as “splicing noise” but rather structurally stable molecules having multiple biological functions including acting as miRNA sponges, protein decoys/scaffolds, and regulators of transcription and translation. Further, emerging evidence suggests that circRNAs are also differentially expressed in multiple cancers where they play oncogenic roles. In addition, circRNAs in association with miRNAs change the expression patterns of multiple transcription factors (TFs), which play important roles in cancer. Thus, the circRNA-miRNA-TFs axis is implicated in the progression or suppression of various cancer types and plays a role in cell proliferation, invasion, and metastasis. In this review article, we provide an outline of the biogenesis, localization, and functions of circRNAs specifically in cancer. Also, we highlight the regulatory function of the circRNA-miRNA-TFs axis in the progression or suppression of cancer and the targeting of this axis as a potential therapeutic approach for cancer management. We anticipate that our review will contribute to expanding the knowledge of the research community about this recent and rapidly growing field of circRNAs for further thorough investigation which will surely help in the management of deadly disease cancer.
Anti-Gout Effects of the Medicinal Fungus Phellinus igniarius in Hyperuricaemia and Acute Gouty Arthritis Rat Models
Authors: Li Hongxing , Zhang Xinyue , Gu Lili , Li Qín , Ju Yue , Zhou Xuebin , Hu Min , Li Qīn
Published: January 2022

Background:Phellinus igniarius (P. igniarius) is an important medicinal and edible fungus in China and other Southeast Asian countries and has diverse biological activities. This study was performed to comparatively investigate the therapeutic effects of wild and cultivated P. igniarius on hyperuricaemia and gouty arthritis in rat models.

Methods: UPLC-ESI-qTOF-MS was used to identify the chemical constituents of polyphenols from wild P. igniarius (WPP) and cultivated P. igniarius (CPP). Furthermore, WPP and CPP were evaluated in an improved hyperuricaemia rat model induced by yeast extract, adenine and potassium oxonate, which was used to examine xanthine oxidase (XO) activity inhibition and anti-hyperuricemia activity. WPP and CPP therapies for acute gouty arthritis were also investigated in a monosodium urate (MSU)-induced ankle swelling model. UHPLC-QE-MS was used to explore the underlying metabolic mechanisms of P. igniarius in the treatment of gout.

Results: The main active components of WPP and CPP included protocatechuic aldehyde, hispidin, davallialactone, phelligridimer A, hypholomine B and inoscavin A as identified by UPLC-ESI-qTOF-MS. Wild P. igniarius and cultivated P. igniarius showed similar activities in reducing uric acid levels through inhibiting XO activity and down-regulating the levels of UA, Cr and UN, and they had anti-inflammatory activities through down-regulating the secretions of ICAM-1, IL-1β and IL-6 in the hyperuricaemia rat model. The pathological progression of kidney damage was also reversed. The polyphenols from wild and cultivated P. igniarius also showed significant anti-inflammatory activity by suppressing the expression of ICAM-1, IL-1β and IL-6 and by reducing the ankle joint swelling degree in an MSU-induced acute gouty arthritis rat model. The results of metabolic pathway enrichment indicated that the anti-hyperuricemia effect of WPP was mainly related to the metabolic pathways of valine, leucine and isoleucine biosynthesis and histidine metabolism. Additionally, the anti-hyperuricemia effect of CPP was mainly related to nicotinate and nicotinamide metabolism and beta-alanine metabolism.

Conclusions: Wild P. igniarius and cultivated P. igniarius both significantly affected the treatment of hyperuricaemia and acute gouty arthritis models in vivo and therefore may be used as potential active agents for the treatment of hyperuricaemia and acute gouty arthritis.
The Role of Exercise-Induced Molecular Processes and Vitamin D in Improving Cardiorespiratory Fitness and Cardiac Rehabilitation in Patients With Heart Failure
Authors: Aleksova Aneta , Janjusevic Milijana , Gagno Giulia , Pierri Alessandro , Padoan Laura , Fluca Alessandra Lucia , Carriere Cosimo , Beltrami Antonio Paolo , Sinagra Gianfranco
Published: January 2022

Heart failure (HF) still affects millions of people worldwide despite great advances in therapeutic approaches in the cardiovascular field. Remarkably, unlike pathological hypertrophy, exercise leads to beneficial cardiac hypertrophy characterized by normal or enhanced contractile function. Exercise-based cardiac rehabilitation improves cardiorespiratory fitness and, as a consequence, ameliorates the quality of life of patients with HF. Particularly, multiple studies demonstrated the improvement in left ventricular ejection fraction (LVEF) among patients with HF due to the various processes in the myocardium triggered by exercise. Exercise stimulates IGF-1/PI3K/Akt pathway activation involved in muscle growth in both the myocardium and skeletal muscle by regulating protein synthesis and catabolism. Also, physical activity stimulates the activation of the mitogen-activated protein kinase (MAPK) pathway which regulates cellular proliferation, differentiation and apoptosis. In addition, emerging data pointed out the anti-inflammatory effects of exercises as well. Therefore, it is of utmost importance for clinicians to accurately evaluate the patient’s condition by performing a cardiopulmonary exercise test and/or a 6-min walking test. Portable devices with the possibility to measure exercise capacity proved to be very useful in this setting as well. The aim of this review is to gather together the molecular processes triggered by the exercise and available therapies in HF settings that could ameliorate heart performance, with a special focus on strategies such as exercise-based cardiac rehabilitation.
Fractal-Based Analysis of fMRI BOLD Signal During Naturalistic Viewing Conditions
Authors: Campbell Olivia , Vanderwal Tamara , Weber Alexander Mark
Published: January 2022

Background: Temporal fractals are characterized by prominent scale-invariance and self-similarity across time scales. Monofractal analysis quantifies this scaling behavior in a single parameter, the Hurst exponent (H). Higher H reflects greater correlation in the signal structure, which is taken as being more fractal. Previous fMRI studies have observed lower H during conventional tasks relative to resting state conditions, and shown that H is negatively correlated with task difficulty and novelty. To date, no study has investigated the fractal dynamics of BOLD signal during naturalistic conditions.

Methods: We performed fractal analysis on Human Connectome Project 7T fMRI data (n = 72, 41 females, mean age 29.46 ± 3.76 years) to compare H across movie-watching and rest.

Results: In contrast to previous work using conventional tasks, we found higher H values for movie relative to rest (mean difference = 0.014; p = 5.279 × 10−7; 95% CI [0.009, 0.019]). H was significantly higher in movie than rest in the visual, somatomotor and dorsal attention networks, but was significantly lower during movie in the frontoparietal and default networks. We found no cross-condition differences in test-retest reliability of H. Finally, we found that H of movie-derived stimulus properties (e.g., luminance changes) were fractal whereas H of head motion estimates were non-fractal.

Conclusions: Overall, our findings suggest that movie-watching induces fractal signal dynamics. In line with recent work characterizing connectivity-based brain state dynamics during movie-watching, we speculate that these fractal dynamics reflect the configuring and reconfiguring of brain states that occurs during naturalistic processing, and are markedly different than dynamics observed during conventional tasks.
Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives
Authors: Beard Elidie , Lengacher Sylvain , Dias Sara , Magistretti Pierre J. , Finsterwald Charles
Published: January 2022

Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.
Ethephon Reduces Maize Nitrogen Uptake but Improves Nitrogen Utilization in Zea mays L.
Authors: Zhang Yushi , Wang Yubin , Liu Churong , Ye Delian , Ren Danyang , Li Zhaohu , Zhang Mingcai
Published: January 2022

Increasing use of plant density or/and nitrogen (N) application has been introduced to maize production in the past few decades. However, excessive planting density or/and use of fertilizer may cause reduced N use efficiency (NUE) and increased lodging risks. Ethephon application improves maize lodging resistance and has been an essential measure in maize intensive production systems associated with high plant density and N input in China. Limited information is available about the effect of ethephon on maize N use and the response to plant density under different N rates in the field. A three-year field study was conducted with two ethephon applications (0 and 90 g ha−1), four N application rates (0, 75, 150, and 225 kg N ha−1), and two plant densities (6.75 plants m−2and 7.5 plants m−2) to evaluate the effects of ethephon on maize NUE indices (N agronomic efficiency, NAE; N recovery efficiency, NRE; N uptake efficiency, NUpE; N utilization efficiency, NUtE; partial factor productivity of N, PFPN), biomass, N concentration, grain yield and N uptake, and translocation properties. The results suggest that the application of ethephon decreased the grain yield by 1.83–5.74% due to the decrease of grain numbers and grain weight during the three experimental seasons. Meanwhile, lower biomass,NO3-andNH4+fluxes in xylem bleeding sap, and total N uptake were observed under ethephon treatments. These resulted in lower NAE and NUpE under the ethephon treatment at a corresponding N application rate and plant density. The ethephon treatment had no significant effects on the N concentration in grains, and it decreased the N concentration in stover at the harvesting stage, while increasing the plant N concentration at the silking stage. Consequently, post-silking N remobilization was significantly increased by 14.10–32.64% under the ethephon treatment during the experimental periods. Meanwhile, NUtE significantly increased by ethephon.