bluuebunny/crossref_metadata_2025 huggingface dataset:
Tacrolimus Intrapatient Variability After Switching From Immediate or Prolonged-Release to Extended-Release Formulation, After an Organ Transplantation
Authors: Del Bello Arnaud , Gaible Clotilde , Longlune Nathalie , Hebral Anne-Laure , Esposito Laure , Gandia Peggy , Kamar Nassim
Published: October 2021

Background and Purpose: Several formulations of tacrolimus are available, but evidence of the benefit of changing to the most recent formulations is lacking. Tacrolimus intra-patient variability (tacrolimus IPV) is an emerging risk factor associated with poor graft outcomes after solid organ transplantations. Here, we examined the modifications of tacrolimus IPV after switching to a different formulation of tacrolimus.

Experimental Approach: We identified 353 solid organ transplant recipients that were switched in our center from immediate-release (IR-tacrolimus) or prolonged-release tacrolimus (PR-tacrolimus) to extended-release, LCP-tacrolimus (LCP-tacrolimus). Among them, 54 patients underwent at least 3 available tacrolimus blood concentrations before and after the switch, allowing us to investigate tacrolimus IPV.

Key Results: The switch was considered as a safe procedure since only four of the 353 patients presented a graft rejection after the switch, and no patient was hospitalized for tacrolimus overdose. The tacrolimus IPV estimated by the coefficient of variation (CV-IPV) was stable before and after the switch to LCP-tacrolimus (CV-IPV: 29.0% (IQR 25–75 (15.5; 38.5) before and 24.0% (15.8; 36.5) after the switch, p = 0.65).

Conclusion and Implications: Switching from IR- or PR-tacrolimus to LCP-tacrolimus is a safe procedure. However, the CV-tacrolimus IPV was not impacted by the change of formulation.
Systematic Review of Polyherbal Combinations Used in Metabolic Syndrome
Authors: Palla Amber Hanif , Amin Faridah , Fatima Bilqees , Shafiq Arooj , Rehman Najeeb Ur , Haq Ikram ul , Gilani Anwar-ul-Hassan
Published: October 2021

Background: Metabolic syndrome (MetS) is a multifactorial disease, whose main stay of prevention and management is life-style modification which is difficult to attain. Combination of herbs have proven more efficacious in multi-targeted diseases, as compared to individual herbs owing to the “effect enhancing and side-effect neutralizing” properties of herbs, which forms the basis of polyherbal therapies This led us to review literature on the efficacy of herbal combinations in MetS.

Methods: Electronic search of literature was conducted by using Cinnahl, Pubmed central, Cochrane and Web of Science, whereas, Google scholar was used as secondary search tool. The key words used were “metabolic syndrome, herbal/poly herbal,” metabolic syndrome, clinical trial” and the timings were limited between 2005–2020.

Results: After filtering and removing duplications by using PRISMA guidelines, search results were limited to 41 studies, out of which 24 studies were evaluated for combinations used in animal models and 15 in clinical trials related to metabolic syndrome. SPICE and SPIDER models were used to assess the clinical trials, whereas, a checklist and a qualitative and a semi-quantitative questionnaire was formulated to report the findings for animal based studies. Taxonomic classification of Poly herbal combinations used in animal and clinical studies was designed.

Conclusion: With this study we have identified the potential polyherbal combinations along with a proposed method to validate animal studies through systematic qualitative and quantitative review. This will help researchers to study various herbal combinations in MetS, in the drug development process and will give a future direction to research on prevention and management of MetS through polyherbal combinations.
Beyond Sperm and Male Accessory Gland Proteins: Exploring Insect Reproductive Metabolomes
Authors: Scolari Francesca , Khamis Fathiya M. , Pérez-Staples Diana
Published: October 2021

Insect seminal fluid, the non-sperm component of the ejaculate, comprises a variegated set of molecules, including, but not limited to, lipids, proteins, carbohydrates, salts, hormones, nucleic acids, and vitamins. The identity and functional role of seminal fluid proteins (SFPs) have been widely investigated, in multiple species. However, most of the other small molecules in insect ejaculates remain uncharacterized. Metabolomics is currently adopted to deepen our understanding of complex biological processes and in the last 15years has been applied to answer different physiological questions. Technological advances in high-throughput methods for metabolite identification such as mass spectrometry and nuclear magnetic resonance (NMR) are now coupled to an expanded bioinformatics toolbox for large-scale data analysis. These improvements allow for the processing of smaller-sized samples and for the identification of hundreds to thousands of metabolites, not only inDrosophila melanogasterbut also in disease vectors, animal, and agricultural pests. In this review, we provide an overview of the studies that adopted metabolomics-based approaches in insects, with a particular focus on the reproductive tract (RT) of both sexes and the ejaculate. Progress in the field of metabolomics will contribute not only to achieve a deeper understanding of the composition of insect ejaculates and how they are affected by endogenous and exogenous factors, but also to provide increasingly powerful tools to decipher the identity and molecular interactions between males and females during and after mating.
Genome-Wide Identification and Comparative Analysis of the Teosinte Branched 1/Cycloidea/Proliferating Cell Factors 1/2 Transcription Factors Related to Anti-cancer Drug Camptothecin Biosynthesis in Ophiorrhiza pumila
Authors: Wang Can , Hao Xiaolong , Wang Yao , Shi Min , Zhou Zhi-Gang , Kai Guoyin
Published: October 2021

Ophiorrhiza pumila (O. pumila; Op) is a medicinal herbaceous plant, which can accumulate camptothecin (CPT). CPT and its derivatives are widely used as chemotherapeutic drugs for treating malignant tumors. Its biosynthesis pathway has been attracted significant attention. Teosinte branched 1/cycloidea/proliferating cell factors 1/2 (TCP) transcription factors (TFs) regulate a variety of physiological processes, while TCP TFs are involved in the regulation of CPT biosynthesis remain unclear. In this study, a systematic analysis of the TCP TFs family in O. pumila was performed. A total of 16 O. pumila TCP (OpTCP) genes were identified and categorized into two subgroups based on their phylogenetic relationships with those in Arabidopsis thaliana. Tissue-specific expression patterns revealed that nine OpTCP genes showed the highest expression levels in leaves, while the other seven OpTCPs showed a higher expression level in the stems. Co-expression, phylogeny analysis, and dual-luciferase (Dual-LUC) assay revealed that OpTCP15 potentially plays important role in CPT and its precursor biosynthesis. In addition, the subcellular localization experiment of candidate OpTCP genes showed that they are all localized in the nucleus. Our study lays a foundation for further functional characterization of the candidate OpTCP genes involved in CPT biosynthesis regulation and provides new strategies for increasing CPT production.
The Impact of Cross-Cultural Adaptation on the Psychology and Entrepreneurial Intention of Venture Entrepreneurs
Authors: Ye Long , Dong Xu-Yang
Published: October 2021

The purpose was to integrate cultural psychology into cross-cultural adaptation and analyze the factors of entrepreneurial psychology and entrepreneurial intention of venture entrepreneurs. The research framework of cross-cultural adaptation is constructed, and four hypotheses are put forward, and 100 venture entrepreneurs in multinational enterprises are randomly recruited and investigated through the QS (Questionnaire Survey) design. Finally, the results are analyzed through statistical software. The results show that among the basic information of venture entrepreneurs, the proportion of gender is balanced, and the educational level is generally high, with the majority of young entrepreneurs aged 20–35. Meanwhile, there are significant differences in the four dimensions of cross-cultural competence, cross-cultural adaptation, entrepreneurial intention, and psychological adaptation of venture entrepreneurs (p<0.05). Length of service influences cross-cultural competence, cross-cultural adaptation, and entrepreneurial intention but does not affect psychological adaptation. Hence, cross-cultural adaptation has a great impact on the entrepreneurial intention and psychological adaptation of venture entrepreneurs and provides a practical basis for the entrepreneurial optimization of venture entrepreneurs.
White Matter Correlates of Hostility and Aggression in the Visuospatial Function Network in Patients With Schizophrenia
Authors: An Iseul , Choi Tai Kiu , Bang Minji , Lee Sang-Hyuk
Published: October 2021

Background: Violent acts in patients with schizophrenia are often associated with their hostility and aggression levels. Poor visuospatial processing has been suggested as a possible risk factor of violence in schizophrenia. However, studies investigating the relationship between hostility, aggression, and the visuospatial function have been lacking. Here, we aimed to investigate brain dysconnectivity associated with hostility and aggression in schizophrenia, particularly focusing on the visuospatial function network.

Methods: Eighty-eight participants with schizophrenia and 42 healthy controls were enrolled. The visuospatial function network regions of interest were analyzed using Tract-Based Spatial Statistics. The hostility item from the Positive and Negative Syndrome Scale (PANSS), aggressive, and agitated behavior item from the Scale for the Assessment of Positive Symptoms (SAPS), and the Rey Complex Figure Test (R-CFT) were measured.

Results: Among the participants with schizophrenia, the SAPS aggressive and agitated behavior scores were significantly correlated with fractional anisotropies (FAs) of the white matter regions in the splenium of the corpus callosum (CC), left posterior thalamic radiations (PTR), and left posterior corona radiata (PCR). Exploratory correlational analysis revealed significant negative correlations between FAs of the splenium of the CC and R-CFT copy and immediate recall scores. In addition, three regions including CC, PTR, and PCR that significantly correlated with the aggression scores showed significant correlations with the total PANSS scores.

Conclusion: Our main finding suggests that aggression of patients with schizophrenia may be associated with poor visuospatial ability and underlying white matter dysconnectivity. These may help enhance understanding aggression in patients with schizophrenia.
Subjective Symptoms in Magnetic Resonance Imaging Personnel: A Multi-Center Study in Italy
Authors: Bravo Giulia , Modenese Alberto , Arcangeli Giulio , Bertoldi Chiara , Camisa Vincenzo , Corona Gianluca , Giglioli Senio , Ligabue Guido , Moccaldi Roberto , Mucci Nicola , Muscatello Martina , Venturelli Irene , Vimercati Luigi , Zaffina Salvatore , Zanotti Giulio , Gobba Fabriziomaria
Published: October 2021

Introduction: Magnetic Resonance Imaging (MRI) personnel have significant exposure to static and low-frequency time-varying magnetic fields. In these workers an increased prevalence of different subjective symptoms has been observed. The aim of our study was to investigate the prevalence of non-specific subjective symptoms and of “core symptoms” in a group of MRI personnel working in different centers in Italy, and of possible relationships with personal and occupational characteristics.

Methods: The occurrence of 11 subjective symptoms was evaluated using a specific questionnaire with 240 subjects working in 6 different Italian hospitals and research centers, 177 MRI health care and research personnel and 63 unexposed subjects employed in the same departments. Exposure was subjectively investigated according to the type of MRI scanner (≤1.5 vs. ≥3 T) and to the number of MRI procedures attended and/or performed by the personnel, even if no information on how frequently the personnel entered the scanner room was collected. The possible associations among symptoms and estimated EMF exposure, the main characteristics of the population, and job stress perception were analyzed.

Results: Eighty-six percent of the personnel reported at least one symptom; drowsiness, headache, and sleep disorders were the most frequent. The total number of symptoms did not differ between exposed persons and controls. Considering the total number of annual MRI procedures reported by the personnel, no significant associations were found nor with the total number of symptoms, nor with “core symptoms.” Only subjects complaining of drowsiness also reported a significantly higher mean annual number of MRI procedures with ≤ 1.5 T scanners when compared with exposed subjects without drowsiness. In a multivariate model, subjects with a high level of perceived stress complained of more symptoms (p = 0.0002).

Conclusions: Our study did not show any association between the occurrence of reversible subjective symptoms, including the more specific “core symptoms,” and the occupational exposure of MRI personnel to static and low-frequency time-varying magnetic fields. On the other hand, the role played by occupational stress appears to be not negligible. In further research in this field, measurements of EMF exposure should be considered.
Waist-To-Height Ratio Is a More Accurate Tool for Predicting Hypertension Than Waist-To-Hip Circumference and BMI in Patients With Type 2 Diabetes: A Prospective Study
Authors: Moosaie Fatemeh , Fatemi Abhari Seyede Marzie , Deravi Niloofar , Karimi Behnagh Arman , Esteghamati Sadaf , Dehghani Firouzabadi Fatemeh , Rabizadeh Soghra , Nakhjavani Manouchehr , Esteghamati Alireza
Published: October 2021

Background: Anthropometric measures [i.e., body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR)] have been used as prediction factors for incident hypertension. However, whether any of these measures is superior to another in the matter of accuracy in predicting hypertension in diabetic patients has been controversial. The present prospective study aimed to determine whether WHtR is a more accurate tool for predicting hypertension than WHR and BMI in patients with type 2 diabetes.

Methods: The study population consisted of 1,685 normotensive patients with type 2 diabetes. BMI, WHR, and WHtR were assessed at baseline and followed up for hypertension incidence for a mean of 4.8 years. A cox regression analysis was performed to assess the association between anthropometric measures (i.e., BMI, WHR, and WHtR) and incident hypertension during the follow-up period. The area under the ROC curve analysis was performed and optimal cutoff values were calculated for each anthropometric measure for hypertension prediction.

Results: WHtR and BMI were significantly associated with an increased incidence of hypertension (HR = 3.296 (0.936–12.857), P < 0.001, and HR = 1.050 (1.030–1.070), P < 0.001, respectively). The discriminative powers for each anthropometric index for hypertension were 0.571 (0.540–0.602) for BMI, 0.518 (0.486–0.550) for WHR, and 0.609 (0.578–0.639) for WHtR. The optimal cutoff points for predicting hypertension in patients with type 2 diabetes were 26.94 (sensitivity = 0.739, specificity = 0.380) for BMI, 0.90 (sensitivity = 0.718, specificity = 0.279) for WHR, and 0.59 (sensitivity = 0.676, specificity = 0.517) for WHtR.

Conclusion: WHtR was a more accurate tool for predicting hypertension compared to WHR and BMI in patients with type 2 diabetes.
An Empirical Perception of Economic Resilience Responded to the COVID-19 Epidemic Outbreak in Beijing–Tianjin–Hebei Urban Agglomeration, China: Characterization and Interaction
Authors: Zhang Yaping , Zhang Jianjun , Wang Ke , Wu Xia
Published: October 2021

The COVID-19 has caused a serious impact on the global economy, and all countries are in a predicament of fighting the epidemic and recovering their economies. Aiming to discuss the impact of the COVID-19 on the economic resilience of urban agglomerations, the economic data of each quarter from June 2019 to September 2020 of the Beijing–Tianjin–Hebei Urban Agglomeration are selected, and the economic development index (EDI) is calculated based on the entropy method. Combining the fundamental conditions of urban agglomerations and industrial policies during the COVID-19, urban economic resilience is discussed by the changing trend of the economic development index (EDI) and dividing into resistance and restoration. The results show that: (1) The economic development level of the urban agglomeration has been affected by the epidemic and has changed significantly. The change of endogenous power is the main cause of change; (2) During the outbreak of the COVID-19, the economic resilience of the Beijing–Tianjin–Hebei urban agglomeration shows four different development types: high resistance and restoration, high resistance but low restoration, low resistance but high restoration, low resistance and restoration cities; (3) High resistance but low restoration, low resistance but high restoration, and low resistance and restoration cities influence each other, but the relationship between cities is mainly dependent; (4) The economic restoration within the urban agglomeration forms a synergy, which promotes the economic recovery and development of the urban agglomeration during the recovery period of the COVID-19. Urban agglomerations should enhance the combined effect of resistance and increase the impact of high resistance and restoration cities on surrounding cities in the future.
ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control
Authors: Poltronieri Palmiro , Miwa Masanao , Masutani Mitsuko
Published: October 2021

Among the post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, and a large set of functions, including DNA repair, transcription, and cell signaling, have been assigned to this post-translational modification (PTM). This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing monoADP-ribosylation/polyADP-ribosylation (MAR/PAR) cycling in cancers. Of note, there is potential for the application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, the suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.
Feeding Rhythm-Induced Hypothalamic Agouti-Related Protein Elevation via Glucocorticoids Leads to Insulin Resistance in Skeletal Muscle
Authors: Shiuchi Tetsuya , Otsuka Airi , Shimizu Noriyuki , Chikahisa Sachiko , Séi Hiroyoshi
Published: October 2021

Circadian phase shifts in peripheral clocks induced by changes in feeding rhythm often result in insulin resistance. However, whether the hypothalamic control system for energy metabolism is involved in the feeding rhythm-related development of insulin resistance is unknown. Here, we show the physiological significance and mechanism of the involvement of the agouti-related protein (AgRP) in evening feeding-associated alterations in insulin sensitivity. Evening feeding during the active dark period increased hypothalamic AgRP expression and skeletal muscle insulin resistance in mice. Inhibiting AgRP expression by administering an antisense oligo or a glucocorticoid receptor antagonist mitigated these effects. AgRP-producing neuron-specific glucocorticoid receptor-knockout (AgRP-GR-KO) mice had normal skeletal muscle insulin sensitivity even under evening feeding schedules. Hepatic vagotomy enhanced AgRP expression in the hypothalamus even during ad-lib feeding in wild-type mice but not in AgRP-GR-KO mice. The findings of this study indicate that feeding in the late active period may affect hypothalamic AgRP expression via glucocorticoids and induce skeletal muscle insulin resistance.
Identification of Rare LRP5 Variants in a Cohort of Males with Impaired Bone Mass
Authors: Rocca Maria Santa , Minervini Giovanni , Di Nisio Andrea , Merico Maurizio , Bueno Marinas Maria , De Toni Luca , Pilichou Kalliopi , Garolla Andrea , Foresta Carlo , Ferlin Alberto
Published: October 2021

Osteoporosis is the most common bone disease characterized by reduced bone mass and increased bone fragility. Genetic contribution is one of the main causes of primary osteoporosis; therefore, both genders are affected by this skeletal disorder. Nonetheless, osteoporosis in men has received little attention, thus being underestimated and undertreated. The aim of this study was to identify novel genetic variants in a cohort of 128 males with idiopathic low bone mass using a next-generation sequencing (NGS) panel including genes whose mutations could result in reduced bone mineral density (BMD). Genetic analysis detected in eleven patients ten rare heterozygous variants within the LRP5 gene, which were categorized as VUS (variant of uncertain significance), likely pathogenic and benign variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. Protein structural and Bayesian analysis performed on identified LRP5 variants pointed out p.R1036Q and p.R1135C as pathogenic, therefore suggesting the likely association of these two variants with the low bone mass phenotype. In conclusion, this study expands our understanding on the importance of a functional LRP5 protein in bone formation and highlights the necessity to sequence this gene in subjects with idiopathic low BMD.
Inflammatory Mechanisms in the Pathophysiology of Diabetic Peripheral Neuropathy (DN)—New Aspects
Authors: Baum Petra , Toyka Klaus V. , Blüher Matthias , Kosacka Joanna , Nowicki Marcin
Published: October 2021

The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.
Insights into Cadmium-Induced Carcinogenesis through an In Vitro Study Using C3H10T1/2Cl8 Cells: The Multifaceted Role of Mitochondria
Authors: Oldani Monica , Villa Anna Maria , Manzoni Marta , Melchioretto Pasquale , Parenti Paolo , Monti Eugenio , Fusi Paola , Forcella Matilde , Urani Chiara
Published: October 2021

In this paper, we report the metabolic characterization of two foci, F1 and F3, obtained at the end of Cell Transformation Assay (CTA), performed by treating C3H10T1/2Cl8 mouse embryo fibroblasts with 1 μM CdCl2 for 24 h. The elucidation of the cadmium action mechanism can be useful both to improve the in vitro CTA and to yield insights into carcinogenesis. The metabolism of the two foci was investigated through Seahorse and enzyme activity assays; mitochondria were studied in confocal microscopy and reactive oxygen species were detected by flow cytometry. The results showed that F1 focus has higher glycolytic and TCA fluxes compared to F3 focus, and a more negative mitochondrial membrane potential, so that most ATP synthesis is performed through oxidative phosphorylation. Confocal microscopy showed mitochondria crowded in the perinuclear region. On the other hand, F3 focus showed lower metabolic rates, with ATP mainly produced by glycolysis and damaged mitochondria. Overall, our results showed that cadmium treatment induced lasting metabolic alterations in both foci. Triggered by the loss of the Pasteur effect in F1 focus and by mitochondrial impairment in F3 focus, these alterations lead to a loss of coordination among glycolysis, TCA and oxidative phosphorylation, which leads to malignant transformation.
Roles of Non-Canonical Wnt Signalling Pathways in Bone Biology
Authors: Lojk Jasna , Marc Janja
Published: October 2021

The Wnt signalling pathway is one of the central signalling pathways in bone development, homeostasis and regulation of bone mineral density. It consists of numerous Wnt ligands, receptors and co-receptors, which ensure tight spatiotemporal regulation of Wnt signalling pathway activity and thus tight regulation of bone tissue homeostasis. This enables maintenance of optimal mineral density, tissue healing and adaptation to changes in bone loading. While the role of the canonical/β-catenin Wnt signalling pathway in bone homeostasis is relatively well researched, Wnt ligands can also activate several non-canonical, β-catenin independent signalling pathways with important effects on bone tissue. In this review, we will provide a thorough overview of the current knowledge on different non-canonical Wnt signalling pathways involved in bone biology, focusing especially on the pathways that affect bone cell differentiation, maturation and function, processes involved in bone tissue structure regulation. We will describe the role of the two most known non-canonical pathways (Wnt/planar cell polarity pathways and Wnt/Ca2+ pathway), as well as other signalling pathways with a strong role in bone biology that communicate with the Wnt signalling pathway through non-canonical Wnt signalling. Our goal is to bring additional attention to these still not well researched but important pathways in the regulation of bone biology in the hope of prompting additional research in the area of non-canonical Wnt signalling pathways.
Skin Barrier Dysregulation in Psoriasis
Authors: Orsmond Andreas , Bereza-Malcolm Lara , Lynch Tom , March Lyn , Xue Meilang
Published: October 2021

The skin barrier is broadly composed of two elements—a physical barrier mostly localised in the epidermis, and an immune barrier localised in both the dermis and epidermis. These two systems interact cooperatively to maintain skin homeostasis and overall human health. However, if dysregulated, several skin diseases may arise. Psoriasis is one of the most prevalent skin diseases associated with disrupted barrier function. It is characterised by the formation of psoriatic lesions, the aberrant differentiation and proliferation of keratinocytes, and excessive inflammation. In this review, we summarize recent discoveries in disease pathogenesis, including the contribution of keratinocytes, immune cells, genetic and environmental factors, and how they advance current and future treatments.
Empagliflozin Relaxes Resistance Mesenteric Arteries by Stimulating Multiple Smooth Muscle Cell Voltage-Gated K+ (KV) Channels
Authors: Hasan Ahasanul , Hasan Raquibul
Published: October 2021

The antidiabetic drug empagliflozin is reported to produce a range of cardiovascular effects, including a reduction in systemic blood pressure. However, whether empagliflozin directly modulates the contractility of resistance-size mesenteric arteries remains unclear. Here, we sought to investigate if empagliflozin could relax resistance-size rat mesenteric arteries and the associated underlying molecular mechanisms. We found that acute empagliflozin application produces a concentration-dependent vasodilation in myogenic, depolarized and phenylephrine (PE)-preconstricted mesenteric arteries. Selective inhibition of smooth muscle cell voltage-gated K+ channels KV1.5 and KV7 abolished empagliflozin-induced vasodilation. In contrast, pharmacological inhibition of large-conductance Ca2+-activated K+ (BKCa) channels and ATP-sensitive (KATP) channels did not abolish vasodilation. Inhibition of the vasodilatory signaling axis involving endothelial nitric oxide (NO), smooth muscle cell soluble guanylyl cyclase (sGC) and protein kinase G (PKG) did not abolish empagliflozin-evoked vasodilation. Inhibition of the endothelium-derived vasodilatory molecule prostacyclin (PGI2) had no effect on the vasodilation. Consistently, empagliflozin-evoked vasodilation remained unaltered by endothelium denudation. Overall, our data suggest that empagliflozin stimulates smooth muscle cell KV channels KV1.5 and KV7, resulting in vasodilation in resistance-size mesenteric arteries. This study demonstrates for the first time a novel mechanism whereby empagliflozin regulates arterial contractility, resulting in vasodilation. Due to known antihypertensive properties, treatment with empagliflozin may complement conventional antihypertensive therapy.
GPNMB Extracellular Fragment Protects Melanocytes from Oxidative Stress by Inhibiting AKT Phosphorylation Independent of CD44
Authors: Wang Qianqian , Kuroda Yasutaka , Yang Lingli , Lai Sylvia , Mizutani Yukiko , Iddamalgoda Arunasiri , Guo Jiao , Yamamoto Asako , Murase Daiki , Takahashi Yoshito , Xiang Leihong , Inoue Shintaro , Tsuruta Daisuke , Katayama Ichiro
Published: October 2021

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein that plays an important role in cancer metastasis and osteoblast differentiation. In the skin epidermis, GPNMB is mainly expressed in melanocytes and plays a critical role in melanosome formation. In our previous study, GPNMB was also found to be expressed in skin epidermal keratinocytes. In addition, decreased GPNMB expression was observed in the epidermis of lesional skin of patients with vitiligo. However, the exact role of keratinocyte-derived GPNMB and its effect on vitiligo is still unknown. In this study, we demonstrated that GPNMB expression was also decreased in rhododendrol-induced leukoderma, as seen in vitiligo. The extracellular soluble form of GPNMB (sGPNMB) was found to protect melanocytes from cytotoxicity and the impairment of melanogenesis induced by oxidative stress. Furthermore, the effect of rGPNMB was not altered by the knockdown of CD44, which is a well-known receptor of GPNMB, but accompanied by the suppressed phosphorylation of AKT but not ERK, p38, or JNK. In addition, we found that oxidative stress decreased both transcriptional GPNMB expression and sGPNMB protein expression in human keratinocytes. Our results suggest that GPNMB might provide novel insights into the mechanisms related to the pathogenesis of vitiligo and leukoderma.
Optical Fibre-Enabled Photoswitching for Localised Activation of an Anti-Cancer Therapeutic Drug
Authors: Palasis Kathryn A. , Lokman Noor A. , Quirk Bryden C. , Adwal Alaknanda , Scolaro Loretta , Huang Weikun , Ricciardelli Carmela , Oehler Martin K. , McLaughlin Robert A. , Abell Andrew D.
Published: October 2021

Local activation of an anti-cancer drug when and where needed can improve selectivity and reduce undesirable side effects. Photoswitchable drugs can be selectively switched between active and inactive states by illumination with light; however, the clinical development of these drugs has been restricted by the difficulty in delivering light deep into tissue where needed. Optical fibres have great potential for light delivery in vivo, but their use in facilitating photoswitching in anti-cancer compounds has not yet been explored. In this paper, a photoswitchable chemotherapeutic is switched using an optical fibre, and the cytotoxicity of each state is measured against HCT-116 colorectal cancer cells. The performance of optical-fibre-enabled photoswitching is characterised through its dose response. The UV–Vis spectra confirm light delivered by an optical fibre effectively enables photoswitching. The activated drug is shown to be twice as effective as the inactive drug in causing cancer cell death, characterised using an MTT assay and fluorescent microscopy. This is the first study in which a photoswitchable anti-cancer compound is switched using an optical fibre and demonstrates the feasibility of using optical fibres to activate photoswitchable drugs for potential future clinical applications.
Galanin(1-15) Potentiates the Antidepressant-like Effects Induced by Escitalopram in a Rat Model of Depression
Authors: García-Durán Laura , Flores-Burgess Antonio , Cantero-García Noelia , Puigcerver Araceli , Narváez José Ángel , Fuxe Kjell , Santín Luis , Millón Carmelo , Díaz-Cabiale Zaida
Published: October 2021

Selective 5-HT reuptake inhibitor antidepressants (SSRIs) are the first choice in major depressive disorder (MDD), but 50% of affected patients do not show improvement. Galanin(1-15) [GAL(1-15)] enhanced Fluoxetine antidepressant-like effects in an animal model of depression, the olfactory bulbectomy (OBX); however, further detailed analysis of GAL(1-15) effects as augmentation treatment in OBX rats are needed. In OBX rats, we analysed the effect of GAL(1–15) on Escitalopram (ESC)-mediated responses in behavioural tests related to despair. We studied whether GAL(1–15) effects involved 5-HT1AR using an in vivo model siRNA 5-HT1A knockdown rats. Moreover, we analysed by immunohistochemistry the expression of the immediate-early gene c-Fos (c-Fos IR) after the administration of GAL(1-15)+ESC in OBX rats in several nuclei involved in MDD. GAL(1-15) enhances the antidepressant-like effects of ESC, and the GALR2 antagonist M871 blocked GAL(1-15) mediated actions. The downregulation of 5-HT1AR by siRNA was sufficient to block GAL(1-15) effects. Our immunohistochemistry and principal component analysis (PCA) analysis suggest that two functional networks are involved in these effects; one includes the lateral (LHb) and medial (mHb) habenula, dorsal raphe (DR) and ventral tegmental area (VTA), and the other consists of the dentate gyrus (DG), and prefrontal cortex (PFC). The results open up the possibility of using GAL(1-15) in combination with SSRIs as a novel strategy for treating MDD.
Saussurea involucrata (Snow Lotus) ICE1 and ICE2 Orthologues Involved in Regulating Cold Stress Tolerance in Transgenic Arabidopsis
Authors: Wu Chia-Ling , Lin Lee-Fong , Hsu Hsiao-Chun , Huang Li-Fen , Hsiao Chung-Der , Chou Ming-Lun
Published: October 2021

As with other environmental stresses, cold stress limits plant growth, geographical distribution, and agricultural productivity. CBF/DREB (CRT-binding factors/DRE-binding proteins) regulate tolerance to cold/freezing stress across plant species. ICE (inducer of CBF expression) is regarded as the upstream inducer of CBF expression and plays a crucial role as a main regulator of cold acclimation. Snow lotus (Saussurea involucrata) is a well-known traditional Chinese herb. This herb is known to have greater tolerance to cold/freezing stress compared to other plants. According to transcriptome datasets, two putative ICE homologous genes, SiICE1 and SiICE2, were identified in snow lotus. The predicted SiICE1 cDNA contains an ORF of 1506 bp, encoding a protein of 501 amino acids, whereas SiICE2 cDNA has an ORF of 1482 bp, coding for a protein of 493 amino acids. Sequence alignment and structure analysis show SiICE1 and SiICE2 possess a S-rich motif at the N-terminal region, while the conserved ZIP-bHLH domain and ACT domain are at the C-terminus. Both SiICE1 and SiICE2 transcripts were cold-inducible. Subcellular localization and yeast one-hybrid assays revealed that SiICE1 and SiICE2 are transcriptional regulators. Overexpression of SiICE1 (35S::SiICE1) and SiICE2 (35S::SiICE2) in transgenic Arabidopsis increased the cold tolerance. In addition, the expression patterns of downstream stress-related genes, CBF1, CBF2, CBF3, COR15A, COR47, and KIN1, were up-regulated when compared to the wild type. These results thus provide evidence that SiICE1 and SiICE2 function in cold acclimation and this cold/freezing tolerance may be regulated through a CBF-controlling pathway.
Contributing to Understand the Crosstalk between Brain and Periphery in Methylmercury Intoxication: Neurotoxicity and Extracellular Vesicles
Authors: Arrifano Gabriela de Paula , Augusto-Oliveira Marcus , Sealey-Bright Megan , Zainal Jaezah , Imbiriba Luciana , Fernandes Luanna Melo Pereira , Maia Cristiane Socorro Ferraz , Anthony Daniel , Crespo-Lopez Maria Elena
Published: October 2021

Human exposure to methylmercury (MeHg) is currently high in regions such as the Amazon. Understanding the molecular changes associated with MeHg-induced neurotoxicity and the crosstalk with the periphery is essential to support early diagnoses. This work aimed to evaluate cellular and molecular changes associated with behavioral alterations in MeHg acute exposure and the possible changes in extracellular vesicles (EVs) number and S100β content. Adults male Wistar rats were orally treated with 5 mg/kg for four days. Behavioral performance, molecular and histological changes in the cerebellum, and plasma EVs were assessed. MeHg-intoxicated animals performed significantly worse in behavioral tests. MeHg increased the number of GFAP+ cells and GFAP and S100β mRNA expression in the cerebellum but no change in NeuN+ or IBA-1+ cells number was detected. The number of exosomes isolated from plasma were decreased by the metal. S100B mRNA was detected in circulating plasma EVs cargo in MeHg exposure. Though preliminary, our results suggest astrocytic reactivity is displaying a protective role once there was no neuronal death. Interestingly, the reduction in exosomes number could be a new mechanism associated with MeHg-induced neurotoxicity and plasma EVs could represent a source of future biomarkers in MeHg intoxication.
A Semiautomatic Multi-Label Color Image Segmentation Coupling Dirichlet Problem and Colour Distances
Authors: Aletti Giacomo , Benfenati Alessandro , Naldi Giovanni
Published: October 2021

Image segmentation is an essential but critical component in low level vision, image analysis, pattern recognition, and now in robotic systems. In addition, it is one of the most challenging tasks in image processing and determines the quality of the final results of the image analysis. Colour based segmentation could hence offer more significant extraction of information as compared to intensity or texture based segmentation. In this work, we propose a new local or global method for multi-label segmentation that combines a random walk based model with a direct label assignment computed using a suitable colour distance. Our approach is a semi-automatic image segmentation technique, since it requires user interaction for the initialisation of the segmentation process. The random walk part involves a combinatorial Dirichlet problem for a weighted graph, where the nodes are the pixel of the image, and the positive weights are related to the distances between pixels: in this work we propose a novel colour distance for computing such weights. In the random walker model we assign to each pixel of the image a probability quantifying the likelihood that the node belongs to some subregion. The computation of the colour distance is pursued by employing the coordinates in a colour space (e.g., RGB, XYZ, YCbCr) of a pixel and of the ones in its neighbourhood (e.g., in a 8–neighbourhood). The segmentation process is, therefore, reduced to an optimisation problem coupling the probabilities from the random walker approach, and the similarity with respect the labelled pixels. A further investigation involves an adaptive preprocess strategy using a regression tree for learning suitable weights to be used in the computation of the colour distance. We discuss the properties of the new method also by comparing with standard random walk and k−means approaches. The experimental results carried on the White Blood Cell (WBC) dataset and GrabCut datasets show the remarkable performance of the proposed method in comparison with state-of-the-art methods, such as normalised random walk and normalised lazy random walk, with respect to segmentation quality and computational time. Moreover, it reveals to be very robust with respect to the presence of noise and to the choice of the colourspace.
Upper-Bound General Circulation of the Ocean: A Theoretical Exposition
Authors: Ou Hsien-Wang
Published: October 2021

This paper considers the general ocean circulation (GOC) within the thermodynamical closure of our climate theory, which aims to deduce the generic climate state from first principles. The preceding papers of this theory have reduced planetary fluids to warm/cold masses and determined their bulk properties, which provide prior constraints for the derivation of the upper-bound circulation when the potential vorticity (PV) is homogenized in moving masses. In a companion paper on the general atmosphere circulation (GAC), this upper bound is seen to reproduce the observed prevailing wind, therefore forsaking discordant explanations of the easterly trade winds and the polar jet stream. In this paper on the ocean, we again show that this upper bound may replicate broad features of the observed circulation, including a western-intensified subtropical gyre and a counter-rotating tropical gyre feeding the equatorial undercurrent. Since PV homogenization has short-circuited the wind curl, the Sverdrup dynamics does not need to be the sole progenitor of the western intensification, as commonly perceived. Together with GAC, we posit that PV homogenization provides a unifying dynamical principle of the large-scale planetary circulation, which may be interpreted as the maximum macroscopic motion extractable by microscopic stirring, within the confines of thermal differentiation.
Liquid–Solid Flow Characteristics in Vertical Swirling Hydraulic Transportation with Tangential Jet Inlet
Authors: Qi Jiyang , Yin Jie , Yan Fei , Liu Ping , Wang Tieli , Chen Chen
Published: October 2021

In order to improve the efficiency and safety of vertical hydraulic transport systems for non-spherical particles, a new pipeline transport system with a tangential jet inlet is adopted in this study, and a modified non-spherical drag coefficient model is used to analyze the liquid–solid flow characteristics based on the CFD-DEM (Computational Fluid Dynamics-Discrete Element Method) coupling method. The focus of the study is on the influence of different tangential flow proportions in terms of the velocity distribution, the vorticity, the total pressure, the concentration and drag force of particles of various shapes. The conveying efficiency is measured according to the fluid velocity distribution and the particle concentration, and the safety of conveying is evaluated according to the flow structure and drag force of the particles. The result shows that the velocity of the swirling pipes is significantly higher than the straight pipe. With the increase of the tangential flow proportion, the swirling number and the vorticity magnitude increase, and the vortex core is broken and merged more quickly. Furthermore, the concentration gap and axial drag force gap between particles of various shapes are reduced with the effect of swirling flow, the particle concentration increases, and the particles of each component are uniformly mixed and transported.
Detection and Analysis of the Causes of Intensive Harmful Algal Bloom in Kamchatka Based on Satellite Data
Authors: Bondur Valery , Zamshin Viktor , Chvertkova Olga , Matrosova Ekaterina , Khodaeva Vasilisa
Published: October 2021

In this paper, the causes of the anomalous harmful algal bloom which occurred in the fall of 2020 in Kamchatka have been detected and analyzed using a long-term time series of heterogeneous satellite and simulated data with respect to the sea surface height (HYCOM) and temperature (NOAA OISST), chlorophyll-a concentration (MODIS Ocean Color SMI), slick parameters (SENTINEL-1A/B), and suspended matter characteristics (SENTINEL-2A/B, C2RCC algorithm). It has been found that the harmful algal bloom was preceded by temperature anomalies (reaching 6 °C, exceeding the climatic norm by more than three standard deviation intervals) and intensive ocean level variability followed by the generation of vortices, mixing water masses and providing nutrients to the upper photic layer. The harmful algal bloom itself was manifested in an increase in the concentration of chlorophyll-a, its average monthly value for October 2020 (bloom peak) approached 15 mg/m3, exceeding the climatic norm almost four-fold for the region of interest (Avacha Gulf). The zones of accumulation of a large amount of biogenic surfactant films registered in radar satellite imagery correlate well with the local regions of the highest chlorophyll-a concentration. The harmful bloom was influenced by river runoff, which intensively brought mineral and biogenic suspensions into the marine environment (the concentration of total suspended matter within the plume of the Nalycheva River reached 10 mg/m3 and more in 2020), expanding food resources for microalgae.
Sea Level Rise Drivers and Projections from Coupled Model Intercomparison Project Phase 6 (CMIP6) under the Paris Climate Targets: Global and around the Korea Peninsula
Authors: Sung Hyun Min , Kim Jisun , Shim Sungbo , Ha Jong-Chul , Byun Young-Hwa , Kim Yeon-Hee
Published: October 2021

Estimating future sea level rise (SLR) projections is important for assessing coastal risks and planning of climate-resilient infrastructure. Therefore, in this study, we estimated the future projections of SLR from Coupled Model Intercomparison Project phase 6 (CMIP6) models for three climate targets (1.5 °C (T15), 2.0 °C (T20), and 3.0 °C (T30)) described by the Paris Agreement. The global SLR projections are 60, 140, and 320 mm for T15, T20, and T30, respectively, relative to the present-day levels. Similarly, around the Korean Peninsula, SLR projections become more intense with continuous global warming (20 mm (T15), 110 mm (T20), and 270 mm (T30)). Ocean variables show a slow response to climate change. Therefore, we developed the Emergence of Climate Change (EoC) index for determining the time when the variable is not following the present climate trend. The EoC of SLR appears after the EoC of sea-ice melting near the time of T15 warming. Moreover, the EoC of thermal expansion appears around the 2040s, which is similar to the time of the maximum of the T15 warming period and the median of the T20 warming period. Overall, our analysis suggests that the T15 warming may act as a trigger and SLR will accelerate after the T15 warming.