bluuebunny/crossref_metadata_2025 huggingface dataset:
Spirituality, Community Belonging, and Mental Health Outcomes of Indigenous Peoples during the COVID-19 Pandemic
Authors: Burnett Chantal , Purkey Eva , Davison Colleen M. , Watson Autumn , Kehoe Jennifer , Traviss Sheldon , Nolan Dionne , Bayoumi Imaan
Published: February 2022

We aimed to assess the association between community belonging, spirituality, and mental health outcomes among Indigenous Peoples during the COVID-19 pandemic. This cross-sectional observational study used online survey distribution and targeted outreach to the local Indigenous community to collect a convenience sample between 23 April 2020 and 20 November 2020. The surveys included demographic information, self-reported symptoms of depression (PHQ-2) and anxiety (GAD-2), and measures of the sense of community belonging and the importance of spirituality. Multivariate logistic regression was used to model the association between the sense of community belonging and spirituality, and symptoms of anxiety and depression. Of the 263 self-identified Indigenous people who participated, 246 participants had complete outcome data, including 99 (40%) who reported symptoms of depression and 110 (45%) who reported symptoms of anxiety. Compared to Indigenous participants with a strong sense of community belonging, those with weak community belonging had 2.42 (95% CI: 1.12–5.24)-times greater odds of reporting symptoms of anxiety, and 4.40 (95% CI: 1.95–9.89)-times greater odds of reporting symptoms of depression. While spirituality was not associated with anxiety or depression in the adjusted models, 76% of Indigenous participants agreed that spirituality was important to them pre-pandemic, and 56% agreed that it had become more important since the pandemic began. Community belonging was associated with positive mental health outcomes. Indigenous-led cultural programs that foster community belonging may promote the mental health of Indigenous Peoples.
An Atypical Case of Late-Onset Wolfram Syndrome 1 without Diabetes Insipidus
Authors: Rigoli Luciana , Caruso Valerio , Aloi Concetta , Salina Alessandro , Maghnie Mohamad , d'Annunzio Giuseppe , Lamacchia Olga , Salzano Giuseppina , Lombardo Fortunato , Picca Giuseppe
Published: February 2022

Wolfram syndrome 1, a rare autosomal recessive neurodegenerative disease, is caused by mutations in the WFS1 gene. It is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD), and other clinical manifestations such as urological and neurological disorders. Here we described the case of a patient with an atypical late-onset Wolfram syndrome 1 without DI. Our WS1 patient was a c.1620_1622delGTG (p.Trp540del)/c.124 C > T (p.Arg42*) heterozygous compound. The p.Arg42* nonsense mutation was also found in heterozygosity in his sister and niece, both suffering from psychiatric disorders. The p.Arg42* nonsense mutation has never been found in WS1 and its pathogenicity is unclear so far. Our study underlined the need to study a greater number of WS1 cases in order to better understand the clinical significance of many WFS1 variants.
“Well, I Signed Up to Be a Soldier; I Have Been Trained and Equipped Well”: Exploring Healthcare Workers’ Experiences during COVID-19 Organizational Changes in Singapore, from the First Wave to the Path towards Endemicity
Authors: Ting Celene , Chan Alyssa Yenyi , Chan Lai Gwen , Hildon Zoe Jane-Lara
Published: February 2022

(1) Background: As COVID-19 transmission continues despite vaccination programs, healthcare workers (HCWs) face an ongoing pandemic response. We explore the effects of this on (1) Heartware, by which we refer to morale and commitment of HCWs; and identify how to improve (2) Hardware, or ways of enabling operational safety and functioning. (2) Methods: Qualitative e-diary entries were shared by HCWs during the early phases of the outbreak in Singapore from June to August 2020. Data were collected via an online survey of n = 3616 HCWs of all cadres. Nine institutions—restructured hospitals (n = 5), affiliated primary partners (n = 2) and hospices (n = 2)—participated. Applied thematic analysis was undertaken and organized according to Heartware and Hardware. Major themes are in italics (3) Results: n = 663 (18%) HCWs submitted a qualitative entry. Dominant themes undermining (1) Heartware consisted of burnout from being overworked and emotional exhaustion and at times feeling a lack of appreciation or support at work. The most common themes overriding morale breakers were a stoic acceptance to fight, adjust and hold the line, coupled with motivation from engaging leadership and supportive colleagues. The biggest barrier in (2) Hardware analysis related to sub-optimal segregation strategies within wards and designing better protocols for case detection, triage, and admissions criteria. Overall, the most cited enabler was the timely and well-planned provision of Personal Protective Equipment (PPE) for front-liners, though scope for scale-up was called for by those not considered frontline. Analysis maps internal organizational functioning to wider external public and policy-related narratives. (4) Conclusions: COVID-19 surges are becoming endemic rather than exceptional events. System elasticity needs to build on known pillars coupling improving safety and care delivery with improving HCW morale. Accordingly, a model capturing such facets of Adaptive Pandemic Response derived from our data analyses is described. HCW burnout must be urgently addressed, and health systems moved away from reactive “wartime” response configurations.
The Use of the Bolk Model for Positive Health and Living Environment in the Development of an Integrated Health Promotion Approach: A Case Study in a Socioeconomically Deprived Neighborhood in The Netherlands
Authors: van Wietmarschen Herman A. , Staps Sjef , Meijer Judith , Flinterman J. Francisca , Jong Miek C.
Published: February 2022

Background. Despite considerable efforts, health disparities between people with high and low socioeconomic status (SES) have not changed over the past decades in The Netherlands. To create a culture of health and an environment in which all people can flourish, a shift in focus is needed from disease management towards health promotion. The Bolk model for Positive Health and Living Environment was used as a tool to guide this shift. This study aimed to describe how this model was used and perceived by stakeholders in a case study on an integrated health promotion approach for residents with low SES. Methods. An instrumental case study was undertaken in Venserpolder, a neighborhood in Amsterdam South East of approximately 8500 residents. A participatory action approach was used that allowed continuous interaction between the residents, health care professionals, researchers, and other stakeholders. The Bolk model is a tool, based on the conceptual framework of positive health, that was developed to guide health promotion practice. Its use in the case study was evaluated by means of semistructured interviews with stakeholders, using qualitative directed content analyses. Results. The Bolk model was found to be a useful tool to identify and map the needs and strengths of residents with low SES. The model facilitated the development and implementation of eight health promotion pilots by transforming the needs and strengths of residents into concrete actions carried out by responsible actors in the neighborhood. Although the Bolk model seemed to be accepted by all stakeholders, the shift towards positive health thinking appeared to be more embodied by local professionals than by residents. Adjustments were proposed to enhance the applicability of the model in a multicultural setting, to increase its cultural sensitivity and to use language more familiar to residents. Conclusions. The Bolk model for positive health and living environment seems to be promising in the guidance of health promotion practices in Amsterdam South East. Further research and development are needed to improve its cultural sensitivity and to investigate its applicability in a broader range of public health settings.
An Investigation on the Academic Burden of Chinese Students Ranging from Primary Schools to Universities Based on a Word Association Test in Guangdong Province
Authors: Gao Ruixiang , He Tingxin , Liao Yu , Liu Xiaoqin , Fan Yinqing , Su Yingting , Zuo Huang , Mo Lei
Published: February 2022

China’s basic education and higher education are currently facing policies aimed at reducing and increasing the academic burden, respectively. In this context, we first review and assess the methods of measuring students’ academic burden and then apply the implicit association test for the first time to the academic burden of Chinese students from primary school to university under a unified framework. The results demonstrates that students’ academic burden increases with the school stage, and thus university students face a greater burden than primary and high school students, and that learning attitude fully mediates the relationship between objective and subjective views of academic burden. These results suggest the three policy approaches of implementing a management system for classifying academic burden, considering how to improve students’ learning quality, and developing their mental health education, thus providing a reference and inspiration for research and practice in the field of academic burden.
Epidemiology of Fungal Colonization in Children Treated at the Department of Oncology and Hematology: Single-Center Experience
Authors: Klepacka Joanna , Zakrzewska Zuzanna , Czogała Małgorzata , Wojtaszek-Główka Magdalena , Krzysztofik Emil , Czogała Wojciech , Skoczeń Szymon
Published: February 2022

Oncological patients are especially predisposed to fungal infections due to multiple risk factors and immunocompromising treatment. Epidemiological research regarding pediatric oncologic patients is still insufficient, and existing data are difficult to generalize on different populations. Therefore, we aimed to analyze fungal infections and fungal epidemiology in the Department of Oncology and Hematology of the University Children’s Hospital in Krakow with help from the Clinical Microbiology Department. During the chosen period of 2005 and 2015–2020, 2342 tests were performed in our ward on 847 patients. Analyzed samples were divided into five source groups. The amount of patients with positive test results was 62.5%. The year with the highest detection level was 2005. The most frequent pathogen was Candida albicans, with a significant decrease in tendency. An increase in non-albicans species was observed. Candida parapsilosis was not frequently observed compared to similar studies. We noticed an increase in positive results from the urinary tract material. Our results confirmed that fungal infections are still an issue, and they may indicate the efficacy of prophylaxis. The majority of our results are consistent with the literature, yet we managed to emphasize data unique to our patients’ population. Our findings are helpful in clinical work and for further studies in our center.
Research on the Effect of Rural Inclusive Financial Ecological Environment on Rural Household Income in China
Authors: Ge Heping , Tang Lianzhen , Zhou Xiaojun , Tang Decai , Boamah Valentina
Published: February 2022

After a long struggle against poverty, the problem of absolute poverty among Chinese rural residents has been solved, but the problem of relative poverty still exists. With digitalization, the ecological environment of rural inclusive finance has been optimized. This paper empirically tests the individual fixed-effect model and finds that digital inclusive finance has a positive income-increasing effect on rural residents. Wage income, operating income, and transfer income among the income types undergo a certain degree of promotion, while property income is affected to the contrary. In addition, digital inclusive finance has the same effect on farmers’ income increases in the east and central regions of China. However, it has a slightly smaller impact on farmers in the west. This paper uses a spatial econometric model and finds that promoting the development of local digital inclusive finance will enhance the income level of local farmers and increase the income of neighboring farmers. Therefore, this paper proposes to speed up the development of digital inclusive finance, optimize the rural financial ecological environment, strengthen government supervision and other recommendations, further enhance farmers’ income, and achieve common prosperity.
Mental Health Status before and during the COVID-19 Pandemic in Patients First Visiting a Psychosomatic Internal Medicine Clinic in Tokyo, Japan
Authors: Shaku Fumio , Ishiburo Motoko , Miwa Masako , Maruoka Shuichiro
Published: February 2022

The coronavirus disease (COVID-19) pandemic has aggravated anxiety and depression worldwide, particularly in patients with chronic illnesses and mental disorders. Using validated questionnaires, in this paper, we examine the psychological effects of the pandemic in Japan in detail. The General Mental Health Scale (GHQ), the State–Trait Anxiety Inventory (STAI), and the Center for Epidemiologic Studies Depression Scale (CES-D) were used to assess mental health, state and trait anxiety, and depression, respectively. The survey was completed during the patients’ first visits to the clinic of Psychosomatic Internal Medicine from November 2018 to April 2021. The Mann–Whitney U test was used to compare data from 226 participants before and during the COVID-19 pandemic. The GHQ total, GHQ subscales of “social dysfunction” and “anxiety and dysphoria”, and state anxiety scores were significantly higher during than before the pandemic. The GHQ total, some GHQ subscales, and state anxiety scores were significantly higher among male than female participants during the pandemic. The GHQ total, some GHQ subscales, CES-D, and state anxiety scores in those aged 10–39 years were significantly higher. Thus, the COVID-19 pandemic may have caused mental health changes in many individuals based on their gender, age, and with time.
Interpretation of Map Symbols in the Context of Gamers’ Age and Experience
Authors: Horbiński Tymoteusz , Zagata Krzysztof
Published: February 2022

In this article researchers examined the differences that may characterise selected groups of gamers with regard to age and time spent on playing a survival game, Valheim, confronted with their interpretation of map symbols used in the game. The Valheim video game, which was released in early 2021, is a survival game set in a gameplay world inspired by Norse mythology. The authors of the article noted that the age factor and gaming experience may have different results in terms of the interpretation of cartographic products. The obtained data came from an online questionnaire. In the statistical analysis the authors employed the Pearson’s chi-squared test and the Benjamini–Hochberg procedure to find statistically significant differences between selected groups of respondents and their subjective interpretation of map symbols. Statistical analysis showed several differences and interesting relationships in the interpretation of symbols in relation to the age of the players and in the interpretation of symbols in relation to the time spent in the game. For future research, it is worth continuing towards researching new video games with existing cartographic products in order to investigate how games and players influence the culture in which they participate.
CRISPR-Cas9 Mediated Mutation in OsPUB43 Improves Grain Length and Weight in Rice by Promoting Cell Proliferation in Spikelet Hull
Authors: Wu Qi , Liu Yingfan , Huang Junli
Published: February 2022

Grain weight, a crucial trait that determines the grain yield in rice, is influenced by grain size. Although a series of regulators that control grain size have been identified in rice, the mechanisms underlying grain development are not yet well understood. In this study, we identified OsPUB43, a U-box E3 ubiquitin ligase, as an important negative regulator determining the gain size and grain weight in rice. Phenotypes of large grain are observed in ospub43 mutants, whereas overexpression of OsPUB43 results in short grains. Scanning electron microscopy analysis reveals that OsPUB43 modulates the grain size mainly by inhibiting cell proliferation in the spikelet hull. The OsPUB43 protein is localized in the cytoplasm and nucleus. The ospub43 mutants display high sensitivity to exogenous BR, while OsPUB43-OE lines are hyposensitive to BR. Furthermore, the transient transcriptional activity assay shows that OsBZR1 can activate the expression of OsPUB43. Collectively, our results indicate that OsPUB43 negatively controls the gain size by modulating the expression of BR-responsive genes as well as MADS-box genes that are required for lemma/palea specification, suggesting that OsPUB43 has a potential valuable application in the enlargement of grain size in rice.
The Biological Function of MicroRNAs in Bone Tumors
Authors: Scuderi Sarah Adriana , Calabrese Giovanna , Paterniti Irene , Campolo Michela , Lanza Marika , Capra Anna Paola , Pantaleo Luca , Munaò Stefania , Colarossi Lorenzo , Forte Stefano , Cuzzocrea Salvatore , Esposito Emanuela
Published: February 2022

Micro ribonucleic acids (miRNAs) are small endogenous noncoding RNAs molecules that regulate gene expression post-transcriptionally. A single miRNA is able to target hundreds of specific messenger RNA (mRNAs) by binding to the 3′-untranslated regions. miRNAs regulate different biological processes such as cell proliferation, differentiation and apoptosis. Altered miRNA expression is certainly related to the development of the most common human diseases, including tumors. Osteosarcoma (OS), Ewing’s Sarcoma (ES), and Chondrosarcoma (CS) are the most common primary bone tumors which affect mainly children and adolescents. A significant dysregulation of miRNA expression, in particular of mir-34, mir-21, mir-106, mir-143, and miR-100, has been revealed in OS, ES and CS. In this context, miRNAs can act as either tumor suppressor genes or oncogenes, contributing to the initiation and progression of bone tumors. The in-depth study of these small molecules can thus help to better understand their biological functions in bone tumors. Therefore, this review aims to examine the potential role of miRNAs in bone tumors, especially OS, ES and CS, and to suggest their possible use as potential therapeutic targets for the treatment of bone tumors and as biomarkers for early diagnosis.
Thalamic T-Type Calcium Channels as Targets for Hypnotics and General Anesthetics
Authors: Timic Stamenic Tamara , Todorovic Slobodan M.
Published: February 2022

General anesthetics mainly act by modulating synaptic inhibition on the one hand (the potentiation of GABA transmission) or synaptic excitation on the other (the inhibition of NMDA receptors), but they can also have effects on numerous other proteins, receptors, and channels. The effects of general anesthetics on ion channels have been the subject of research since the publication of reports of direct actions of these drugs on ion channel proteins. In particular, there is considerable interest in T-type voltage-gated calcium channels that are abundantly expressed in the thalamus, where they control patterns of cellular excitability and thalamocortical oscillations during awake and sleep states. Here, we summarized and discussed our recent studies focused on the CaV3.1 isoform of T-channels in the nonspecific thalamus (intralaminar and midline nuclei), which acts as a key hub through which natural sleep and general anesthesia are initiated. We used mouse genetics and in vivo and ex vivo electrophysiology to study the role of thalamic T-channels in hypnosis induced by a standard general anesthetic, isoflurane, as well as novel neuroactive steroids. From the results of this study, we conclude that CaV3.1 channels contribute to thalamocortical oscillations during anesthetic-induced hypnosis, particularly the slow-frequency range of δ oscillations (0.5–4 Hz), by generating “window current” that contributes to the resting membrane potential. We posit that the role of the thalamic CaV3.1 isoform of T-channels in the effects of various classes of general anesthetics warrants consideration.
Mechanistic Insights into Stereospecific Antifungal Activity of Chiral Fungicide Prothioconazole against Fusarium oxysporum F. sp. cubense
Authors: Yang Xiaofang , Gong Ronggao , Chu Yuanqi , Liu Siwen , Xiang Dandan , Li Chunyu
Published: February 2022

As a typical triazole fungicide, prothioconazole (Pro) has been used extensively due to its broad spectrum and high efficiency. However, as a racemic mixture of two enantiomers (R-Pro and S-Pro), the enantiomer-specific outcomes on the bioactivity have not been fully elucidated. Here, we investigate how chirality affects the activity and mechanism of action of Pro enantiomers on Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4), the notorious virulent strain causing Fusarium wilt of banana (FWB). The Pro enantiomers were evaluated in vivo and in vitro with the aid of three bioassay methods for their fungicidal activities against TR4 and the results suggested that the fungicidal activities of Pro enantiomers are stereoselective in a dose-dependent manner with R-Pro making a major contribution to the treatment outcomes. We found that R-Pro led to more severe morphological changes and impairment in membrane integrity than S-Pro. R-Pro also led to the increase of more MDA contents and the reduction of more SOD and CAT activities compared with the control and S-Pro groups. Furthermore, the expression of Cytochrome P450 14α-sterol demethylases (CYP51), the target for triazole fungicides, was significantly increased upon treatment with R-Pro rather than S-Pro, at both transcriptional and translational levels; so were the activities of the Cytochrome P450 enzymes. In addition, surface plasmon resonance (SPR) and molecular docking illuminated the stereoselective interactions between the Pro enantiomers and CYP51 of TR4 at the target site, and R-Pro showed a better binding affinity with CYP51 than S-Pro. These results suggested an enantioselective mechanism of Pro against TR4, which may rely on the enantioselective damages to the fungal cell membrane and the enantiospecific CYP51 binding affinity. Taken together, our study shed some light on the mechanisms underlying the differential activities of the Pro enantiomers against TR4 and demonstrated that Pro can be used as a potential candidate in the treatment of FWB.
Proline Dehydrogenase/Proline Oxidase (PRODH/POX) Is Involved in the Mechanism of Metformin-Induced Apoptosis in C32 Melanoma Cell Line
Authors: Oscilowska Ilona , Rolkowski Karol , Baszanowska Weronika , Huynh Thi Yen Ly , Lewoniewska Sylwia , Nizioł Magdalena , Sawicka Magdalena , Bielawska Katarzyna , Szoka Paweł , Miltyk Wojciech , Palka Jerzy
Published: February 2022

The role of proline dehydrogenase/proline oxidase (PRODH/POX) in the mechanism of antineoplastic activity of metformin (MET) was studied in C32 melanoma cells. PRODH/POX is a mitochondrial enzyme-degrading proline that is implicated in the regulation of cancer cell survival/apoptosis. The enzyme is activated by AMP kinase (AMPK). It has been found that MET induced a significant decrease in cell viability and DNA biosynthesis accompanied by an increase in the expressions of AMPK and PRODH/POX in C32 cells. The mechanism for MET-dependent cytotoxicity on C32 cells was found at the level of PRODH/POX-induced ROS generation and activation of Caspase-3 and Caspase-9 expressions in these cells. The effects were not observed in MET-treated PRODH/POX knock-out C32 cells. Of interest is an MET-dependent increase in the concentration of proline, which is a substrate for PRODH/POX. This phenomenon is due to the MET-dependent inhibition of collagen biosynthesis, which is the main proline-utilizing process. It has been found that the underlying mechanism of anticancer activity of MET involves the activation of AMPK, PRODH/POX, increase in the cytoplasmic concentration of proline, inhibition of collagen biosynthesis, and stimulation of PRODH/POX-dependent ROS generation, which initiate the apoptosis of melanoma cells.
ISSVA Classification of Vascular Anomalies and Molecular Biology
Authors: Kunimoto Kayo , Yamamoto Yuki , Jinnin Masatoshi
Published: February 2022

Vascular anomalies include various diseases, which are classified into two types according to the International Society for the Study of Vascular Anomalies (ISSVA) classification: vascular tumors with proliferative changes of endothelial cells, and vascular malformations primarily consisting of structural vascular abnormalities. The most recent ISSVA classifications, published in 2018, detail the causative genes involved in many lesions. Here, we summarize the latest findings on genetic abnormalities, with the presentation of the molecular pathology of vascular anomalies.
Maize Transcription Factor ZmARF4 Confers Phosphorus Tolerance by Promoting Root Morphological Development
Authors: Li Jing , Wu Fengkai , He Yafeng , He Bing , Gong Ying , Yahaya Baba Salifu , Xie Yuxin , Xie Wubing , Xu Jie , Wang Qingjun , Feng Xuanjun , Liu Yaxi , Lu Yanli
Published: February 2022

Plant growth and development are closely related to phosphate (Pi) and auxin. However, data regarding auxin response factors (ARFs) and their response to phosphate in maize are limited. Here, we isolated ZmARF4 in maize and dissected its biological function response to Pi stress. Overexpression of ZmARF4 in Arabidopsis confers tolerance of Pi deficiency with better root morphology than wild-type. Overexpressed ZmARF4 can partially restore the absence of lateral roots in mutant arf7 arf19. The ZmARF4 overexpression promoted Pi remobilization and up-regulated AtRNS1, under Pi limitation while it down-regulated the expression of the anthocyanin biosynthesis genes AtDFR and AtANS. A continuous detection revealed higher activity of promoter in the Pi-tolerant maize P178 line than in the sensitive 9782 line under low-Pi conditions. Meanwhile, GUS activity was specifically detected in new leaves and the stele of roots in transgenic offspring. ZmARF4 was localized to the nucleus and cytoplasm of the mesophyll protoplast and interacted with ZmILL4 and ZmChc5, which mediate lateral root initiation and defense response, respectively. ZmARF4 overexpression also conferred salinity and osmotic stress tolerance in Arabidopsis. Overall, our findings suggest that ZmARF4, a pleiotropic gene, modulates multiple stress signaling pathways, and thus, could be a candidate gene for engineering plants with multiple stress adaptation.
Metformin: Expanding the Scope of Application—Starting Earlier than Yesterday, Canceling Later
Authors: Kononova Yulia A. , Likhonosov Nikolai P. , Babenko Alina Yu.
Published: February 2022

Today the area of application of metformin is expanding, and a wealth of data point to its benefits in people without carbohydrate metabolism disorders. Already in the population of people leading an unhealthy lifestyle, before the formation of obesity and prediabetes metformin smooths out the adverse effects of a high-fat diet. Being prescribed at this stage, metformin will probably be able to, if not prevent, then significantly reduce the progression of all subsequent metabolic changes. To a large extent, this review will discuss the proofs of the evidence for this. Another recent important change is a removal of a number of restrictions on its use in patients with heart failure, acute coronary syndrome and chronic kidney disease. We will discuss the reasons for these changes and present a new perspective on the role of increasing lactate in metformin therapy.
Bioadhesive Nanoparticles for Local Drug Delivery
Authors: Yu Liu , Luo Zewen , Chen Tian , Ouyang Yaqi , Xiao Lingyun , Liang Shu , Peng Zhangwen , Liu Yang , Deng Yang
Published: February 2022

Local drug delivery is an effective strategy for achieving direct and instant therapeutic effects. Current clinical treatments have fallen short and are limited by traditional technologies. Bioadhesive nanoparticles (NPs), however, may be a promising carrier for optimized local drug delivery, offering prolonged drug retention time and steadily maintained therapeutic concentrations. In addition, the possibility of clinical applications of this platform are abundant, as most polymers used for bioadhesion are both biodegradable and biocompatible. This review highlights the major advances in the investigations of polymer-based bioadhesive nanoparticles and their innumerable applications in local drug delivery.
A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System
Authors: Confino Shir , Dor Talya , Tovin Adi , Wexler Yair , Ben-Moshe Livne Zohar , Kolker Michaela , Pisanty Odelia , Park Sohyun Kathy , Geyer Nathalie , Reiter Joel , Edvardson Shimon , Mor-Shaked Hagar , Elpeleg Orly , Vallone Daniela , Appelbaum Lior , Foulkes Nicholas S. , Gothilf Yoav
Published: February 2022

The circadian clock, which drives a wide range of bodily rhythms in synchrony with the day–night cycle, is based on a molecular oscillator that ticks with a period of approximately 24 h. Timed proteasomal degradation of clock components is central to the fine-tuning of the oscillator’s period. FBXL3 is a protein that functions as a substrate-recognition factor in the E3 ubiquitin ligase complex, and was originally shown in mice to mediate degradation of CRY proteins and thus contribute to the mammalian circadian clock mechanism. By exome sequencing, we have identified a FBXL3 mutation in patients with syndromic developmental delay accompanied by morphological abnormalities and intellectual disability, albeit with a normal sleep pattern. We have investigated the function of FBXL3 in the zebrafish, an excellent model to study both vertebrate development and circadian clock function and, like humans, a diurnal species. Loss of fbxl3a function in zebrafish led to disruption of circadian rhythms of promoter activity and mRNA expression as well as locomotor activity and sleep–wake cycles. However, unlike humans, no morphological effects were evident. These findings point to an evolutionary conserved role for FBXL3 in the circadian clock system across vertebrates and to the acquisition of developmental roles in humans.
The Role of Bone-Derived Hormones in Glucose Metabolism, Diabetic Kidney Disease, and Cardiovascular Disorders
Authors: Takashi Yuichi , Kawanami Daiji
Published: February 2022

Bone contributes to supporting the body, protecting the central nervous system and other organs, hematopoiesis, the regulation of mineral metabolism (mainly calcium and phosphate), and assists in respiration. Bone has many functions in the body. Recently, it was revealed that bone also works as an endocrine organ and secretes several systemic humoral factors, including fibroblast growth factor 23 (FGF23), osteocalcin (OC), sclerostin, and lipocalin 2. Bone can communicate with other organs via these hormones. In particular, it has been reported that these bone-derived hormones are involved in glucose metabolism and diabetic complications. Some functions of these bone-derived hormones can become useful biomarkers that predict the incidence of diabetes and the progression of diabetic complications. Furthermore, other functions are considered to be targets for the prevention or treatment of diabetes and its complications. As is well known, diabetes is now a worldwide health problem, and many efforts have been made to treat diabetes. Thus, further investigations of the endocrine system through bone-derived hormones may provide us with new perspectives on the prediction, prevention, and treatment of diabetes. In this review, we summarize the role of bone-derived hormones in glucose metabolism, diabetic kidney disease, and cardiovascular disorders.
Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease
Authors: Boag Matthew K. , Roberts Angus , Uversky Vladimir N. , Ma Linlin , Richardson Des R. , Pountney Dean L.
Published: February 2022

A major hallmark of Parkinson’s disease (PD) is the fatal destruction of dopaminergic neurons within the substantia nigra pars compacta. This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution of α-synuclein aggregation, iron accumulation, and mitochondrial dysfunction plague nigral neurons, yet the events underlying iron accumulation are poorly understood. Elevated intracellular iron concentrations up-regulate ferritin expression, an iron storage protein that provides cytoprotection against redox stress. The lysosomal degradation pathway, autophagy, can release iron from ferritin stores to facilitate its trafficking in a process termed ferritinophagy. Aggregated α-synuclein inhibits SNARE protein complexes and destabilizes microtubules to halt vesicular trafficking systems, including that of autophagy effectively. The scope of this review is to describe the physiological and pathological relationship between iron regulation and α-synuclein, providing a detailed understanding of iron metabolism within nigral neurons. The underlying mechanisms of autophagy and ferritinophagy are explored in the context of PD, identifying potential therapeutic targets for future investigation.
Premarin Reduces Neurodegeneration and Promotes Improvement of Function in an Animal Model of Spinal Cord Injury
Authors: Haque Azizul , Das Arabinda , Samantaray Supriti , Matzelle Denise , Capone Mollie , Wallace Gerald , Husarik Aarti N. , Taheri Saied , Reiter Russel J. , Varma Abhay , Ray Swapan K. , Banik Naren L.
Published: February 2022

Spinal cord injury (SCI) causes significant mortality and morbidity. Currently, no FDA-approved pharmacotherapy is available for treating SCI. Previously, low doses of estrogen (17β-estradiol, E2) were shown to improve the post-injury outcome in a rat SCI model. However, the range of associated side effects makes advocating its therapeutic use difficult. Therefore, this study aimed at investigating the therapeutic efficacy of Premarin (PRM) in SCI. PRM is an FDA-approved E2 (10%) formulation, which is used for hormone replacement therapy with minimal risk of serious side effects. The effects of PRM on SCI were examined by magnetic resonance imaging, immunofluorescent staining, and western blot analysis in a rat model. SCI animals treated with vehicle alone, PRM, E2 receptor antagonist (ICI), or PRM + ICI were graded in a blinded way for locomotor function by using the Basso–Beattie–Bresnahan (BBB) locomotor scale. PRM treatment for 7 days decreased post-SCI lesion volume and attenuated neuronal cell death, inflammation, and axonal damage. PRM also altered the balance of pro- and anti-apoptotic proteins in favor of cell survival and improved angiogenesis and microvascular growth. Increased expression of estrogen receptors (ERs) ERα and ERβ following PRM treatment and their inhibition by ER inhibitor indicated that the neuroprotection associated with PRM treatment might be E2-receptor mediated. The attenuation of glial activation with decreased inflammation and cell death, and increased angiogenesis by PRM led to improved functional outcome as determined by the BBB locomotor scale. These results suggest that PRM treatment has significant therapeutic implications for the improvement of post-SCI outcome.
Pro- and Anti-Inflammatory Cytokines in the Context of NK Cell–Trophoblast Interactions
Authors: Mikhailova Valentina , Grebenkina Polina , Khokhlova Evgeniia , Davydova Alina , Salloum Zeina , Tyshchuk Elizaveta , Zagainova Valeria , Markova Kseniia , Kogan Igor , Selkov Sergey , Sokolov Dmitry
Published: February 2022

During pregnancy, uterine NK cells interact with trophoblast cells. In addition to contact interactions, uterine NK cells are influenced by cytokines, which are secreted by the cells of the decidua microenvironment. Cytokines can affect the phenotypic characteristics of NK cells and change their functional activity. An imbalance of pro- and anti-inflammatory signals can lead to the development of reproductive pathology. The aim of this study was to assess the effects of cytokines on NK cells in the presence of trophoblast cells in an in vitro model. We used TNFα, IFNγ, TGFβ and IL-10; the NK-92 cell line; and peripheral blood NK cells (pNKs) from healthy, non-pregnant women. For trophoblast cells, the JEG-3 cell line was used. In the monoculture of NK-92 cells, TNFα caused a decrease in CD56 expression. In the coculture of NK cells with JEG-3 cells, TNFα increased the expression of NKG2C and NKG2A by NK-92 cells. Under the influence of TGFβ, the expression of CD56 increased and the expression of NKp30 decreased in the monoculture. After the preliminary cultivation of NK-92 cells in the presence of TGFβ, their cytotoxicity increased. In the case of adding TGFβ to the PBMC culture, as well as coculturing PBMCs and JEG-3 cells, the expression of CD56 and NKp44 by pNK cells was reduced. The differences in the effects of TGFβ in the model using NK-92 cells and pNK cells may be associated with the possible influence of monocytes or other lymphoid cells from the mononuclear fraction.
The Role of Natural Polymorphic Variants of DNA Polymerase β in DNA Repair
Authors: Kladova Olga A. , Fedorova Olga S. , Kuznetsov Nikita A.
Published: February 2022

DNA polymerase β (Polβ) is considered the main repair DNA polymerase involved in the base excision repair (BER) pathway, which plays an important part in the repair of damaged DNA bases usually resulting from alkylation or oxidation. In general, BER involves consecutive actions of DNA glycosylases, AP endonucleases, DNA polymerases, and DNA ligases. It is known that protein–protein interactions of Polβ with enzymes from the BER pathway increase the efficiency of damaged base repair in DNA. However natural single-nucleotide polymorphisms can lead to a substitution of functionally significant amino acid residues and therefore affect the catalytic activity of the enzyme and the accuracy of Polβ action. Up-to-date databases contain information about more than 8000 SNPs in the gene of Polβ. This review summarizes data on the in silico prediction of the effects of Polβ SNPs on DNA repair efficacy; available data on cancers associated with SNPs of Polβ; and experimentally tested variants of Polβ. Analysis of the literature indicates that amino acid substitutions could be important for the maintenance of the native structure of Polβ and contacts with DNA; others affect the catalytic activity of the enzyme or play a part in the precise and correct attachment of the required nucleotide triphosphate. Moreover, the amino acid substitutions in Polβ can disturb interactions with enzymes involved in BER, while the enzymatic activity of the polymorphic variant may not differ significantly from that of the wild-type enzyme. Therefore, investigation regarding the effect of Polβ natural variants occurring in the human population on enzymatic activity and protein–protein interactions is an urgent scientific task.
PTK7, a Catalytically Inactive Receptor Tyrosine Kinase, Increases Oncogenic Phenotypes in Xenograft Tumors of Esophageal Squamous Cell Carcinoma KYSE-30 Cells
Authors: Shin Won-Sik , Park Mi-Kyung , Kim Jae Hoon , Oh Si Won , Jang Ji-Yun , Lee Ho , Lee Seung-Taek
Published: February 2022

Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor protein tyrosine kinase, is upregulated in tumor tissues and cell lines of esophageal squamous cell carcinoma (ESCC). We showed that PTK7 plays an oncogenic role in various ESCC cell lines. However, its role as an oncogene has not been demonstrated in vivo. Here, we examined the influence of PTK7 on the tumorigenic potential of ESCC KYSE-30 cells, which are known to establish xenograft tumors. Overexpression of PTK7 enhanced the proliferation, adhesion, wound healing, and migration of KYSE-30 cells, and these effects were reversed by the knockdown of PTK7. PTK7 overexpression and knockdown, respectively, increased and decreased the tyrosine phosphorylation of cellular proteins and the phosphorylation of ERK, AKT, and FAK, which are important for cell proliferation, survival, adhesion, and migration. Additionally, PTK7 overexpression and silencing, respectively, increased and decreased the weight, volume, and number of Ki-67-positive proliferating cells in xenograft tumors of KYSE-30 cells. Therefore, we propose that PTK7 plays an important role in the tumorigenesis of ESCC cells in vivo and is a potential therapeutic target for ESCC.
Deficiency in RCAT-1 Function Causes Dopamine Metabolism Related Behavioral Disorders in Caenorhabditis elegans
Authors: Jeong Haelim , Park Jun Young , Lee Ji-Hyun , Baik Ja-Hyun , Kim Chae-Yeon , Cho Jin-Young , Driscoll Monica , Paik Young-Ki
Published: February 2022

When animals are faced with food depletion, food search-associated locomotion is crucial for their survival. Although food search-associated locomotion is known to be regulated by dopamine, it has yet to investigate the potential molecular mechanisms governing the regulation of genes involved in dopamine metabolism (e.g., cat-1, cat-2) and related behavioral disorders. During the studies of the pheromone ascaroside, a signal of starvation stress in C. elegans, we identified R02D3.7, renamed rcat-1 (regulator of cat genes-1), which had previously been shown to bind to regulatory sequences of both cat-1 and cat-2 genes. It was found that RCAT-1 (R02D3.7) is expressed in dopaminergic neurons and functions as a novel negative transcriptional regulator for cat-1 and cat-2 genes. When a food source becomes depleted, the null mutant, rcat-1(ok1745), exhibited an increased frequency of high-angled turns and intensified area restricted search behavior compared to the wild-type animals. Moreover, rcat-1(ok1745) also showed defects in state-dependent olfactory adaptation and basal slowing response, suggesting that the mutants are deficient in either sensing food or locomotion toward food. However, rcat-1(ok1745) has normal cuticular structures and locomotion genes. The discovery of rcat-1 not only identifies a new subtype of dopamine-related behaviors but also provides a potential therapeutic target in Parkinson’s disease.
Biological Determinants of Metabolic Syndrome in Visceral and Subcutaneous Adipose Tissue from Severely Obese Women
Authors: Osorio-Conles Óscar , Vega-Beyhart Arturo , Ibarzabal Ainitze , Balibrea José María , Vidal Josep , de Hollanda Ana
Published: February 2022

The metabolic syndrome (MetS) is a cluster of the most dangerous heart attack risk factors: diabetes or raised fasting plasma glucose, abdominal obesity, high cholesterol and high blood pressure. The goal of this study is to compare the state of the main features of obesity-associated white adipose tissue (WAT) dysfunction in 66 women with severe obesity without (MetS−) or with MetS (MetS+). Fat cell area, adipocyte size distribution and histological fibrosis were analysed in visceral (VAT) and abdominal subcutaneous WAT (SAT) in 33 age- and BMI-matched pairs of MetS− and MetS+ subjects. The mRNA expression of 93 genes implicated in obesity-associated WAT dysfunction was analysed by RT-qPCR in both fat depots. MetS+ females showed higher adipocyte hypertrophy in both fat depots and increased fibrosis and expression of macrophage and hypoxia markers in SAT. Transcriptional data suggest increased fatty acid oxidation in SAT and impaired thermogenesis and extracellular matrix remodelling in VAT from MetS+ subjects. A sPLS-DA model, including SAT expression of PPARA and LEPR genes identified MetS with an AUC = 0.87. Despite equal age, BMI and body composition, MetS+ females display morphological and transcriptional differences in both WAT depots, especially in SAT. These factors may contribute to the transition to MetS.
The Effects of a Meldonium Pre-Treatment on the Course of the LPS-Induced Sepsis in Rats
Authors: Đurašević Siniša , Ružičić Aleksandra , Lakić Iva , Tosti Tomislav , Đurović Saša , Glumac Sofija , Pejić Snežana , Todorović Ana , Drakulić Dunja , Stanković Sanja , Jasnić Nebojša , Đorđević Jelena , Todorović Zoran
Published: February 2022

A dysregulated and overwhelming response to an infection accompanied by the exaggerated pro-inflammatory state and metabolism disturbance leads to the fatal outcome in sepsis. Previously we showed that meldonium, an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia, strongly increases mortality in faecal-induced peritonitis (FIP) in rats. We postulated that the same mechanism that is responsible for the otherwise strong anti-inflammatory effects of meldonium could be the culprit of the increased mortality. In the present study, we applied the LPS-induced model of sepsis to explore the presence of any differences from and/or similarities to the FIP model. When it comes to energy production, despite some shared similarities, it is evident that LPS and FIP models of sepsis differ greatly. A different profile of sympathoadrenal activation may account for this observation, as it was lacking in the FIP model, whereas in the LPS model it was strong enough to overcome the effects of meldonium. Therefore, choosing the appropriate model of sepsis induction is of great importance, especially if energy homeostasis is the main focus of the study. Even when differences in the experimental design of the two models are acknowledged, the role of different patterns of energy production cannot be excluded. On that account, our results draw attention to the importance of uninterrupted energy production in sepsis but also call for much-needed revisions of the current recommendations for its treatment.
Chitosan Functionalized with Carboxyl Groups as a Recyclable Biomaterial for the Adsorption of Cu (II) and Zn (II) Ions in Aqueous Media
Authors: Abu El-Soad Asmaa , Lazzara Giuseppe , Abd El-Magied Mahmoud , Cavallaro Giuseppe , Al-Otaibi Jamelah , Sayyed M. , Kovaleva Elena
Published: February 2022

The modification of chitosan represents a challenging task in obtaining biopolymeric materials with enhanced removal capacity for heavy metals. In the present work, the adsorption characteristics of chitosan modified with carboxyl groups (CTS-CAA) towards copper (II) and zinc (II) ions have been tested. The efficacy of the synthesis of CTS-CAA has been evaluated by studying various properties of the modified chitosan. Specifically, the functionalized chitosan has been characterized by using several techniques, including thermal analyses (differential scanning calorimetry and thermogravimetry), spectroscopies (FT-IR, XRD), elemental analysis, and scanning electron microscopy. The kinetics and the adsorption isotherms of CTS-CAA towards both Cu (II) and Zn (II) have been determined in the aqueous solvent under variable pH. The obtained results have been analyzed by using different adsorption models. In addition, the experiments have been conducted at variable temperatures to explore the thermodynamics of the adsorption process. The regeneration of CTS-CAA has been investigated by studying the desorption process using different eluents. This paper reports an efficient protocol to synthesize chitosan-based material perspective as regenerative adsorbents for heavy metals.