bluuebunny/crossref_metadata_2025 huggingface dataset:
Gambling Problems Are Associated with Alcohol Misuse and Insomnia: Results from a Representative National Telephone Survey
Authors: Thorne Hannah Briony , Rockloff Matthew Justus , Ferguson Sally Anne , Vincent Grace Elizabeth , Browne Matthew
Published: June 2021

Gambling has significant costs to the community, with a health burden similar in scale to major depression. To reduce its impact, it is necessary to understand factors that may exacerbate harm from gambling. The gambling environment of late-night licensed venues and 24/7 online gambling has the potential to negatively impact sleep and increase alcohol consumption. This study explored gambling, alcohol, and sleep problems to understand whether there is a relationship between these three factors. Telephone interviews were conducted with a representative sample of Australian adults (n = 3760) combined across three waves of the National Social Survey. Participants completed screening measures for at-risk gambling, at-risk alcohol consumption, insomnia (2015 wave only), and sleep quality. There were small but significant positive correlations between problem gambling and alcohol misuse, problem gambling and insomnia, and problem gambling and poor sleep quality. A regression model showed that gambling problems and alcohol misuse were significant independent predictors of insomnia. A separate regression showed gambling problems (and not alcohol misuse) were a significant predictor of poor sleep quality, but only in one survey wave. Findings suggest that gambling, alcohol, and sleep problems are related within persons. Further research should examine the mechanisms through which this relationship exists.
Facing COVID-19 Pandemic in a Tertiary Hospital in Milan: Prevalence of Burnout in Nursing Staff Working in Sub-Intensive Care Units
Authors: Bisesti Alberto , Mallardo Andrea , Gambazza Simone , Binda Filippo , Galazzi Alessandro , Pazzaglia Silvia , Laquintana Dario
Published: June 2021

In early March 2020, Italy became the epicenter of the Coronavirus Disease 2019 (COVID-19) pandemic in Europe. A different organization of hospital units was required to take care of patients affected by acute respiratory failure caused by COVID-19. This study aimed to evaluate the prevalence of burnout in two sub-intensive care units (SICUs) of the COVID-19 hub center of the Lombardia region in Milan (Italy). All nurses and healthcare assistants working in the SICUs during June 2020 were included in the study. Burnout was assessed via the Maslach Burnout Inventory questionnaire. One hundred and five (84%) SICU staff participated in the study. The prevalence of high burnout for nurses and healthcare assistants was 61.9% for emotional exhaustion, 47.6% for depersonalization and 34.3% for personal accomplishment. Depersonalization was significantly more frequent in younger nurses (p = 0.009). Nurses were 4.5 times more likely to have burnout than healthcare assistants. Burnout was a common condition among healthcare workers operating in SICUs during the pandemic. Urgent actions are needed, especially for nurses, as well as preventive strategies for future pandemic scenarios.
Training Healthcare Professionals on How to Promote Physical Activity in the UK: A Scoping Review of Current Trends and Future Opportunities
Authors: Netherway Jake , Smith Brett , Monforte Javier
Published: June 2021

What physical activity (PA) training do current and future healthcare professionals (HCPs) receive in the UK? How is PA training delivered to them? The present scoping review looks at existing evidence to respond these questions. Seven databases were searched: Medline, SportDISCUS, PsycINFO, EMBASE, CINAHL, Cochrane Review Database, and Web of Science. Grey literature sources and key stakeholders were consulted. Studies were screened for inclusion, data were extracted and charted, and findings were synthesised according to the two research questions. Of the 3535 identified studies, 25 were included. The results show that no standardised approach was used to deliver PA promotion in HCPs training. PA training content was chiefly underpinned by an epidemiological approach. Online delivery of content predominated in continuing professional development training, whereas in undergraduate healthcare curriculum, delivery strategies varied. Overall, the process of embedding PA in HCPs’ curriculum and culture is ongoing. In addition to highlighting what is present within healthcare education, this study identifies further opportunities. Potential avenues include extending PA promotion into other workforces, including social workers.
Effect of Resisted Sprint and Plyometric Training on Lower Limb Functional Performance in Collegiate Male Football Players: A Randomised Control Trial
Authors: Hasan Shahnaz , Kandasamy Gokulakannan , Alyahya Danah , Alonazi Asma , Jamal Azfar , Unnikrishnan Radhakrishnan , Muthusamy Hariraja , Iqbal Amir
Published: June 2021

The main objectives of this study were to evaluate the short-term effects of resisted sprint and plyometric training on sprint performance together with lower limb physiological and functional performance in collegiate football players. Ninety collegiate football players participated in this three-arm, parallel group randomized controlled trial study. Participants were randomly divided into a control group and two experimental groups: resisted sprint training (RST) (n = 30), plyometric training (PT) (n = 30), and a control group (n = 30). Participants received their respective training program for six weeks on alternate days. The primary outcome measures were a knee extensor strength test (measured by an ISOMOVE dynamometer), a sprint test and a single leg triple hop test. Measurements were taken at baseline and after 6 weeks post-training. Participants, caregivers, and those assigning the outcomes were blinded to the group assignment. A mixed design analysis of variance was used to compare between groups, within-group and the interaction between time and group. A within-group analysis revealed a significant difference (p < 0.05) when compared to the baseline with the 6 weeks post-intervention scores for all the outcomes including STN (RST: d = 1.63; PT: d = 2.38; Control: d = 2.26), ST (RST: d = 1.21; PT: d = 1.36; Control: d = 0.38), and SLTHT (RST: d = 0.76; PT: d = 0.61; Control: d = 0.18). A sub-group analysis demonstrated an increase in strength in the plyometric training group (95% CI 14.73 to 15.09, p = 0.00), an increase in the single leg triple hop test in the resisted sprint training group (95% CI 516.41 to 538.4, p = 0.05), and the sprint test was also improved in both experimental groups (95% CI 8.54 to 8.82, p = 0.00). Our findings suggest that, during a short-term training period, RST or PT training are equally capable of enhancing the neuromechanical capacities of collegiate football players. No adverse events were reported by the participants.
Anti-TNF-Related Leukocytoclastic Vasculitis in Ulcerative Colitis: A Case Report
Authors: Giorgio Valentina , Blasi Elisa , Rigante Donato , Guerriero Cristina , De Simone Clara , Fedele Anna Laura , Stella Giuseppe , Gasbarrini Antonio , Scaldaferri Franco
Published: June 2021

Background: The development of drugs directed against tumor necrosis factor (TNF)-α has dramatically modified the therapeutic approach to inflammatory bowel diseases: a larger use of such drugs has also led to a major knowledge about their adverse effects, especially on skin. The aim of this report was to describe a rare steroid-dependent form of leukocytoclastic vasculitis induced by an anti-TNF-α agent in a young woman with ulcerative colitis. Case presentation: A young girl with ulcerative colitis developed a form of leukocytoclastic vasculitis induced by an anti-TNF-α agent. Recurrent palpable purpuric lesions on her legs were the main cutaneous manifestation. Skin lesions were steroid-dependent, but improved after withdrawal of the anti-TNF-α agent and second-line immunosuppressant therapy. Conclusions: The need to develop specific recommendations to guide the use of medications for managing skin reactions induced by anti-TNF-α drugs is herein emphasized.
Interactions between Personality and Types of Mindfulness Practice in Reducing Burnout in Mental Health Professionals
Authors: Ruiz-Íñiguez Raquel , Carralero Montero Ana , Burgos-Julián Francisco A. , Fabelo Roche Justo Reinaldo , Santed Miguel A.
Published: June 2021

Research on mindfulness-based interventions reports mainly on improvements at the group level. Thus, there is a need to elaborate on the individual differences in their effectiveness. The aim of this study was twofold: (1) to examine which personality factors could influence burnout reduction associated with different types of mindfulness practice and (2) to evaluate the interaction between personality factors and the amount of home practice; both aims were controlled for sociodemographic characteristics. A total of 104 Cuban mental health professionals, who participated in a crossover trial, were included. The effect of personality (Cattell’s 16 Personality Factors) was analyzed through regression analysis. First, the results revealed that Emotional Stability and Vigilance could negatively moderate the effectiveness of mindfulness-based interventions. Second, participants who scored low in Sensitivity or Vigilance could benefit more from the body-centered practices (i.e., body scan and Hatha yoga practices), but no significant results for the mind-centered practices (i.e., classical meditation) were found. Third, participants who scored high in Self-reliance could benefit more from informal practice. Other personality factors did not appear to moderate the effect of the interventions, though previous experience in related techniques must be considered. Recommendations and clinical implications are discussed. Trial registration number is NCT03296254 (clinicaltrials.gov).
The Impact of New Surgical Techniques on Geographical Unwarranted Variation: The Case of Benign Hysterectomy
Authors: Lungu Daniel Adrian , Foresi Elisa , Belardi Paolo , Nuti Sabina , Giannini Andrea , Simoncini Tommaso
Published: June 2021

Since the 1980s, the international literature has reported variations for healthcare services, especially for elective ones. Variations are positive if they reflect patient preferences, while if they do not, they are unwarranted, and thus avoidable. Benign hysterectomy is among the most frequent elective surgical procedures in developed countries, and, in recent years, it has been increasingly delivered through minimally invasive surgical techniques, namely laparoscopic or robotic. The question therefore arises over what the impact of these new surgical techniques on avoidable variation is. In this study we analyze the extent of unwarranted geographical variation of treatment rates and of the adoption of minimally invasive procedures for benign hysterectomy in an Italian regional healthcare system. We assess the impact of the surgical approach on the provision of benign hysterectomy, in terms of efficiency (by measuring the average length of stay) and efficacy (by measuring the post-operative complications). Geographical variation was observed among regional health districts for treatment rates and waiting times. At a provider level, we found differences for the minimally invasive approach. We found a positive and significant association between rates and the percentage of minimally invasive procedures. Providers that frequently adopt minimally invasive procedures have shorter average length of stay, and when they also perform open hysterectomies, fewer complications.
Building Public Health Capacity through Organizational Change in the Sport System: A Multiple-Case Study within Australian Gymnastics
Authors: Carrad Amy , Parrish Anne-Maree , Yeatman Heather
Published: June 2021

Sports clubs increasingly are settings for health promotion initiatives. This study explored organizational change processes and perceived facilitators and barriers relevant to implementing a health promotion initiative within gymnastics settings in New South Wales (NSW), Australia. A multiple-case design investigated the experiences of the state association (Gymnastics NSW) and five clubs from one region of NSW in a participatory Health-Promoting Gymnastics Clubs (HPGC) program. The program aimed to build the capacity of Gymnastics NSW to support affiliated clubs to become health-promoting settings. Interviews with organizational representatives explored their experiences of the program and identified factors that enabled or inhibited program adoption, implementation and sustainability. Facilitators and barriers identified included leadership and champions; organizational capacity and culture; priorities and timing; and characteristics of the HPGC framework. This multi-level, organizational change intervention demonstrated potential to create health-promoting gymnastics settings. Tailoring strategies in diverse club contexts required involvement of organizational leaders in program development and action planning. Despite positive impacts, pre-existing organizational culture inhibited integration of health promotion as a core value. Sustained organizational change may result from professional regulatory requirements (e.g., accreditation and affiliation), and policy directives and funding (for organizational change, not program delivery) from relevant government departments.
Identifying Predictors of University Students’ Wellbeing during the COVID-19 Pandemic—A Data-Driven Approach
Authors: Liu Chang , McCabe Melinda , Dawson Andrew , Cyrzon Chad , Shankar Shruthi , Gerges Nardin , Kellett-Renzella Sebastian , Chye Yann , Cornish Kim
Published: June 2021

Background: The COVID-19 pandemic has posed risks to public mental health worldwide. University students, who are already recognised as a vulnerable population, are at elevated risk of mental health issues given COVID-19-related disruptions to higher education. To assist universities in effectively allocating resources to the launch of targeted, population-level interventions, the current study aimed to uncover predictors of university students’ psychological wellbeing during the pandemic via a data-driven approach. Methods: Data were collected from 3973 Australian university students ((median age = 22, aged from 18 to 79); 70.6% female)) at five time points during 2020. Feature selection was conducted via least absolute shrinkage and selection operator (LASSO) to identify predictors from a comprehensive set of variables. Selected variables were then entered into an ordinary least squares (OLS) model to compare coefficients and assess statistical significance. Results: Six negative predictors of university students’ psychological wellbeing emerged: White/European ethnicity, restriction stress, perceived worry on mental health, dietary changes, perceived sufficiency of distancing communication, and social isolation. Physical health status, emotional support, and resilience were positively associated with students’ psychological wellbeing. Social isolation has the largest effect on students’ psychological wellbeing. Notably, age, gender, international status, and educational level did not emerge as predictors of wellbeing. Conclusion: To cost-effectively support student wellbeing through 2021 and beyond, universities should consider investing in internet- and tele- based interventions explicitly targeting perceived social isolation among students. Course-based online forums as well as internet- and tele-based logotherapy may be promising candidates for improving students’ psychological wellbeing.
Soybean (Glycine max) Is Able to Absorb, Metabolize and Accumulate Fenbendazole in All Organs Including Beans
Authors: Podlipná Radka , Navrátilová Martina , Raisová Stuchlíková Lucie , Moťková Kateřina , Langhansová Lenka , Skálová Lenka , Szotáková Barbora
Published: June 2021

Although manure is an important source of minerals and organic compounds it represents a certain risk of spreading the veterinary drugs in the farmland and their permeation to human food. We tested the uptake of the anthelmintic drug fenbendazole (FBZ) by soybean, a common crop plant, from the soil and its biotransformation and accumulation in different soybean organs, including beans. Soybeans were cultivated in vitro or grown in a greenhouse in pots. FBZ was extensively metabolized in roots of in vitro seedlings, where sixteen metabolites were identified, and less in leaves, where only two metabolites were found. The soybeans in greenhouse absorbed FBZ by roots and translocated it to the leaves, pods, and beans. In roots, leaves, and pods two metabolites were identified. In beans, FBZ and one metabolite was found. FBZ exposure did not affect the plant fitness or yield, but reduced activities of some antioxidant enzymes and isoflavonoids content in the beans. In conclusion, manure or biosolids containing FBZ and its metabolites represent a significant risk of these pharmaceuticals entering food consumed by humans or animal feed. In addition, the presence of these drugs in plants can affect plant metabolism, including the production of isoflavonoids.
Chemotaxis of Beneficial Rhizobacteria to Root Exudates: The First Step towards Root–Microbe Rhizosphere Interactions
Authors: Feng Haichao , Fu Ruixin , Hou Xueqin , Lv Yu , Zhang Nan , Liu Yunpeng , Xu Zhihui , Miao Youzhi , Krell Tino , Shen Qirong , Zhang Ruifu
Published: June 2021

Chemotaxis, the ability of motile bacteria to direct their movement in gradients of attractants and repellents, plays an important role during the rhizosphere colonization by rhizobacteria. The rhizosphere is a unique niche for plant–microbe interactions. Root exudates are highly complex mixtures of chemoeffectors composed of hundreds of different compounds. Chemotaxis towards root exudates initiates rhizobacteria recruitment and the establishment of bacteria–root interactions. Over the last years, important progress has been made in the identification of root exudate components that play key roles in the colonization process, as well as in the identification of the cognate chemoreceptors. In the first part of this review, we summarized the roles of representative chemoeffectors that induce chemotaxis in typical rhizobacteria and discussed the structure and function of rhizobacterial chemoreceptors. In the second part we reviewed findings on how rhizobacterial chemotaxis and other root–microbe interactions promote the establishment of beneficial rhizobacteria-plant interactions leading to plant growth promotion and protection of plant health. In the last part we identified the existing gaps in the knowledge and discussed future research efforts that are necessary to close them.
Photosensitizer-Functionalized Nanocomposites for Light-Activated Cancer Theranostics
Authors: Dash Banendu Sunder , Das Suprava , Chen Jyh-Ping
Published: June 2021

Photosensitizers (PSs) have received significant attention recently in cancer treatment due to its theranostic capability for imaging and phototherapy. These PSs are highly responsive to light source of a suitable wavelength for image-guided cancer therapy from generated singlet oxygen and/or thermal heat. Various organic dye PSs show tremendous attenuation of tumor cells during cancer treatment. Among them, porphyrin and chlorophyll-based ultraviolet-visible (UV-Vis) dyes are employed for photodynamic therapy (PDT) by reactive oxygen species (ROS) and free radicals generated with 400–700 nm laser lights, which have poor tissue penetration depth. To enhance the efficacy of PDT, other light sources such as red light laser and X-ray have been suggested; nonetheless, it is still a challenging task to improve the light penetration depth for deep tumor treatment. To overcome this deficiency, near infrared (NIR) (700–900 nm) PSs, indocyanine green (ICG), and its derivatives like IR780, IR806 and IR820, have been introduced for imaging and phototherapy. These NIR PSs have been used in various cancer treatment modality by combining photothermal therapy (PTT) and/or PDT with chemotherapy or immunotherapy. In this review, we will focus on the use of different PSs showing photothermal/photodynamic response to UV-Vis or NIR-Vis light. The emphasis is a comprehensive review of recent smart design of PS-loaded nanocomposites for targeted delivery of PSs in light-activated combination cancer therapy.
A pH-Sensitive Polymeric Micellar System Based on Chitosan Derivative for Efficient Delivery of Paclitaxel
Authors: Han Yang , Pan Jieyi , Liang Na , Gong Xianfeng , Sun Shaoping
Published: June 2021

In this study, an amphiphilic conjugate based on mPEG and cholesterol-modified chitosan with hydrazone bonds in the molecules (mPEG-CS-Hz-CH) was successfully synthesized. Using the polymer as the carrier, the paclitaxel (PTX)-loaded mPEG-CS-Hz-CH micelles were prepared by an ultrasonic probe method. The mean particle size and zeta potential of the optimized PTX-loaded micelles were 146 ± 4 nm and +21.7 ± 0.7 mV, respectively. An in vitro drug release study indicated that the PTX-loaded mPEG-CS-Hz-CH micelles were stable under normal physiological conditions (pH 7.4), whereas rapid drug release was observed in the simulated tumor intracellular microenvironment (pH 5.0). An in vitro cytotoxicity study demonstrated the non-toxicity of the polymer itself, and the PTX-loaded micelles exhibited superior cytotoxicity and significant selectivity on tumor cells. An in vivo antitumor efficacy study further confirmed that the PTX-loaded micelles could improve the therapeutic efficacy of PTX and reduce the side effects. All these results suggested that the mPEG-CS-Hz-CH micelles might be promising pH-sensitive nanocarriers for PTX delivery.
Reversible Lectin Binding to Glycan-Functionalized Graphene
Authors: Koukalová Tereza , Kovaříček Petr , Bojarová Pavla , Guerra Valentino L. P. , Vrkoslav Vladimír , Navara Lukáš , Jirka Ivan , Cebecauer Marek , Křen Vladimír , Kalbáč Martin
Published: June 2021

The monolayer character of two-dimensional materials predestines them for application as active layers of sensors. However, their inherent high sensitivity is always accompanied by a low selectivity. Chemical functionalization of two-dimensional materials has emerged as a promising way to overcome the selectivity issues. Here, we demonstrate efficient graphene functionalization with carbohydrate ligands—chitooligomers, which bind proteins of the lectin family with high selectivity. Successful grafting of a chitooligomer library was thoroughly characterized, and glycan binding to wheat germ agglutinin was studied by a series of methods. The results demonstrate that the protein quaternary structure remains intact after binding to the functionalized graphene, and that the lectin can be liberated from the surface by the addition of a binding competitor. The chemoenzymatic assay with a horseradish peroxidase conjugate also confirmed the intact catalytic properties of the enzyme. The present approach thus paves the way towards graphene-based sensors for carbohydrate–lectin binding.
Umbilical Cord Mesenchymal Stromal Cell-Derived Exosomes Rescue the Loss of Outer Hair Cells and Repair Cochlear Damage in Cisplatin-Injected Mice
Authors: Tsai Stella , Yang Kuender , Chang Kuang-Hsi , Lin Frank , Chou Ruey-Hwang , Li Min-Chih , Cheng Ching-Chang , Kao Chien-Yu , Chen Chie-Pein , Lin Hung-Ching , Hsu Yi-Chao
Published: June 2021

Umbilical cord-derived mesenchymal stromal cells (UCMSCs) have potential applications in regenerative medicine. UCMSCs have been demonstrated to repair tissue damage in many inflammatory and degenerative diseases. We have previously shown that UCMSC exosomes reduce nerve injury-induced pain in rats. In this study, we characterized UCMSC exosomes using RNA sequencing and proteomic analyses and investigated their protective effects on cisplatin-induced hearing loss in mice. Two independent experiments were designed to investigate the protective effects on cisplatin-induced hearing loss in mice: (i) chronic intraperitoneal cisplatin administration (4 mg/kg) once per day for 5 consecutive days and intraperitoneal UCMSC exosome (1.2 μg/μL) injection at the same time point; and (ii) UCMSC exosome (1.2 μg/μL) injection through a round window niche 3 days after chronic cisplatin administration. Our data suggest that UCMSC exosomes exert protective effects in vivo. The post-traumatic administration of UCMSC exosomes significantly improved hearing loss and rescued the loss of cochlear hair cells in mice receiving chronic cisplatin injection. Neuropathological gene panel analyses further revealed the UCMSC exosomes treatment led to beneficial changes in the expression levels of many genes in the cochlear tissues of cisplatin-injected mice. In conclusion, UCMSC exosomes exerted protective effects in treating ototoxicity-induced hearing loss by promoting tissue remodeling and repair.
NK Cells in Chronic Lymphocytic Leukemia and Their Therapeutic Implications
Authors: Sportoletti Paolo , De Falco Filomena , Del Papa Beatrice , Baldoni Stefano , Guarente Valerio , Marra Andrea , Dorillo Erica , Rompietti Chiara , Adamo Francesco Maria , Ruggeri Loredana , Di Ianni Mauro , Rosati Emanuela
Published: June 2021

Key features of chronic lymphocytic leukemia (CLL) are defects in the immune system and the ability of leukemic cells to evade immune defenses and induce immunosuppression, resulting in increased susceptibility to infections and disease progression. Several immune effectors are impaired in CLL, including T and natural killer (NK) cells. The role of T cells in defense against CLL and in CLL progression and immunotherapy has been extensively studied. Less is known about the role of NK cells in this leukemia, and data on NK cell alterations in CLL are contrasting. Besides studies showing that NK cells have intrinsic defects in CLL, there is a large body of evidence indicating that NK cell dysfunctions in CLL mainly depend on the escape mechanisms employed by leukemic cells. In keeping, it has been shown that NK cell functions, including antibody-dependent cellular cytotoxicity (ADCC), can be retained and/or restored after adequate stimulation. Therefore, due to their preserved ADCC function and the reversibility of CLL-related dysfunctions, NK cells are an attractive source for novel immunotherapeutic strategies in this disease, including chimeric antigen receptor (CAR) therapy. Recently, satisfying clinical responses have been obtained in CLL patients using cord blood-derived CAR-NK cells, opening new possibilities for further exploring NK cells in the immunotherapy of CLL. However, notwithstanding the promising results of this clinical trial, more evidence is needed to fully understand whether and in which CLL cases NK cell-based immunotherapy may represent a valid, alternative/additional therapeutic option for this leukemia. In this review, we provide an overview of the current knowledge about phenotypic and functional alterations of NK cells in CLL and the mechanisms by which CLL cells circumvent NK cell-mediated immunosurveillance. Additionally, we discuss the potential relevance of using NK cells in CLL immunotherapy.
Nonameric Peptide Orchestrates Signal Transduction in the Activating HLA-E/NKG2C/CD94 Immune Complex as Revealed by All-Atom Simulations
Authors: Prašnikar Eva , Perdih Andrej , Borišek Jure
Published: June 2021

The innate immune system’s natural killer (NK) cells exert their cytolytic function against a variety of pathological challenges, including tumors and virally infected cells. Their activation depends on net signaling mediated via inhibitory and activating receptors that interact with specific ligands displayed on the surfaces of target cells. The CD94/NKG2C heterodimer is one of the NK activating receptors and performs its function by interacting with the trimeric ligand comprised of the HLA-E/β2m/nonameric peptide complex. Here, simulations of the all-atom multi-microsecond molecular dynamics in five immune complexes provide atomistic insights into the receptor–ligand molecular recognition, as well as the molecular events that facilitate the NK cell activation. We identify NKG2C, the HLA-Eα2 domain, and the nonameric peptide as the key elements involved in the molecular machinery of signal transduction via an intertwined hydrogen bond network. Overall, the study addresses the complex intricacies that are necessary to understand the mechanisms of the innate immune system.
VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms
Authors: Subotički Tijana , Mitrović Ajtić Olivera , Živković Emilija , Diklić Miloš , Đikić Dragoslava , Tošić Milica , Beleslin-Čokić Bojana , Dragojević Teodora , Gotić Mirjana , Santibanez Juan F. , Čokić Vladan
Published: June 2021

Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. Results: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition.
Loss of Wnt16 Leads to Skeletal Deformities and Downregulation of Bone Developmental Pathway in Zebrafish
Authors: Qu Xiaochao , Liao Mei , Liu Weiwei , Cai Yisheng , Yi Qiaorong , Long Jianmei , Tan Lijun , Deng Yun , Deng Hongwen , Chen Xiangding
Published: June 2021

Wingless-type MMTV integration site family, member 16 (wnt16), is a wnt ligand that participates in the regulation of vertebrate skeletal development. Studies have shown that wnt16 can regulate bone metabolism, but its molecular mechanism remains largely undefined. We obtained the wnt16−/− zebrafish model using the CRISPR-Cas9-mediated gene knockout screen with 11 bp deletion in wnt16, which led to the premature termination of amino acid translation and significantly reduced wnt16 expression, thus obtaining the wnt16−/− zebrafish model. The expression of wnt16 in bone-related parts was detected via in situ hybridization. The head, spine, and tail exhibited significant deformities, and the bone mineral density and trabecular bone decreased in wnt16−/− using light microscopy and micro-CT analysis. RNA sequencing was performed to explore the differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the down-regulated DEGs are mainly concentrated in mTOR, FoxO, and VEGF pathways. Protein–protein interaction (PPI) network analysis was performed with the detected DEGs. Eight down-regulated DEGs including akt1, bnip4, ptena, vegfaa, twsg1b, prkab1a, prkab1b, and pla2g4f.2 were validated by qRT-PCR and the results were consistent with the RNA-seq data. Overall, our work provides key insights into the influence of wnt16 gene on skeletal development.
Liquid–Liquid Phase Separation in the Presence of Macromolecular Crowding and State-dependent Kinetics
Authors: Vweza Alick-O. , Song Chul-Gyu , Chong Kil-To
Published: June 2021

Biomolecular condensates formed via liquid–liquid phase separation (LLPS) are increasingly being shown to play major roles in cellular self-organization dynamics in health and disease. It is well established that macromolecular crowding has a profound impact on protein interactions, particularly those that lead to LLPS. Although synthetic crowding agents are used during in vitro LLPS experiments, they are considerably different from the highly crowded nucleo-/cytoplasm and the effects of in vivo crowding remain poorly understood. In this work, we applied computational modeling to investigate the effects of macromolecular crowding on LLPS. To include biologically relevant LLPS dynamics, we extended the conventional Cahn–Hilliard model for phase separation by coupling it to experimentally derived macromolecular crowding dynamics and state-dependent reaction kinetics. Through extensive field-theoretic computer simulations, we show that the inclusion of macromolecular crowding results in late-stage coarsening and the stabilization of relatively smaller condensates. At a high crowding concentration, there is an accelerated growth and late-stage arrest of droplet formation, effectively resulting in anomalous labyrinthine morphologies akin to protein gelation observed in experiments. These results not only elucidate the crowder effects observed in experiments, but also highlight the importance of including state-dependent kinetics in LLPS models, and may help in designing further experiments to probe the intricate roles played by LLPS in self-organization dynamics of cells.
The Role of ABCG2 in the Pathogenesis of Primary Hyperuricemia and Gout—An Update
Authors: Eckenstaler Robert , Benndorf Ralf A.
Published: June 2021

Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and extrarenal urate excretion. Importantly, disturbances in urate excretion are a common cause of hyperuricemia and gout. The majority of urate is eliminated by glomerular filtration in the kidney followed by an, as yet, not fully elucidated interplay of multiple transporters involved in the reabsorption or excretion of urate in the succeeding segments of the nephron. In this context, genome-wide association studies and subsequent functional analyses have identified the ATP-binding cassette (ABC) transporter ABCG2 as an important urate transporter and have highlighted the role of single nucleotide polymorphisms (SNPs) in the pathogenesis of reduced cellular urate efflux, hyperuricemia, and early-onset gout. Recent publications also suggest that ABCG2 is particularly involved in intestinal urate elimination and thus may represent an interesting new target for pharmacotherapeutic intervention in hyperuricemia and gout. In this review, we specifically address the involvement of ABCG2 in renal and extrarenal urate elimination. In addition, we will shed light on newly identified polymorphisms in ABCG2 associated with early-onset gout.
Lipidation of Temporin-1CEb Derivatives as a Tool for Activity Improvement, Pros and Cons of the Approach
Authors: Kosikowska-Adamus Paulina , Sikorska Emilia , Wyrzykowski Dariusz , Walewska Aleksandra , Golda Anna , Deptuła Milena , Obuchowski Michał , Prahl Adam , Pikuła Michał , Lesner Adam
Published: June 2021

The alarming raise of multi-drug resistance among human microbial pathogens makes the development of novel therapeutics a priority task. In contrast to conventional antibiotics, antimicrobial peptides (AMPs), besides evoking a broad spectrum of activity against microorganisms, could offer additional benefits, such as the ability to neutralize toxins, modulate inflammatory response, eradicate bacterial and fungal biofilms or prevent their development. The latter properties are of special interest, as most antibiotics available on the market have limited ability to diffuse through rigid structures of biofilms. Lipidation of AMPs is considered as an effective approach for enhancement of their antimicrobial potential and in vivo stability; however, it could also have undesired impact on selectivity, solubility or the aggregation state of the modified peptides. In the present work, we describe the results of structural modifications of compounds designed based on cationic antimicrobial peptides DK5 and CAR-PEG-DK5, derivatized at their N-terminal part with fatty acids with different lengths of carbon chain. The proposed modifications substantially improved antimicrobial properties of the final compounds and their effectiveness in inhibition of biofilm development as well as eradication of pre-formed 24 h old biofilms of Candida albicans and Staphylococcus aureus. The most active compounds (C5-DK5, C12-DK5 and C12-CAR-PEG-DK5) were also potent against multi-drug resistant Staphylococcus aureus USA300 strain and clinical isolates of Pseudomonas aeruginosa. Both experimental and in silico methods revealed strong correlation between the length of fatty acid attached to the peptides and their final membranolytic properties, tendency to self-assemble and cytotoxicity.
Treatment with the Probiotic Product Aviguard® Alleviates Inflammatory Responses during Campylobacter jejuni-Induced Acute Enterocolitis in Mice
Authors: Heimesaat Markus M. , Weschka Dennis , Mousavi Soraya , Bereswill Stefan
Published: June 2021

Prevalences of Campylobacter (C.) jejuni infections are progressively rising globally. Given that probiotic feed additives, such as the commercial product Aviguard®, have been shown to be effective in reducing enteropathogens, such as Salmonella, in vertebrates, including livestock, we assessed potential anti-pathogenic and immune-modulatory properties of Aviguard® during acute C. jejuni-induced murine enterocolitis. Therefore, microbiota-depleted IL-10−/− mice were infected with C. jejuni strain 81-176 by gavage and orally treated with Aviguard® or placebo from day 2 to 4 post-infection. The applied probiotic bacteria could be rescued from the intestinal tract of treated mice, but with lower obligate anaerobic bacterial counts in C. jejuni-infected as compared to non-infected mice. Whereas comparable gastrointestinal pathogen loads could be detected in both groups until day 6 post-infection, Aviguard® treatment resulted in improved clinical outcome and attenuated apoptotic cell responses in infected large intestines during acute campylobacteriosis. Furthermore, less distinct pro-inflammatory immune responses could be observed not only in the intestinal tract, but also in extra-intestinal compartments on day 6 post-infection. In conclusion, we show here for the first time that Aviguard® exerts potent disease-alleviating effects in acute C. jejuni-induced murine enterocolitis and might be a promising probiotic treatment option for severe campylobacteriosis in humans.
Highly Hydrophilic and Lipophilic Derivatives of Bile Salts
Authors: Vázquez-Tato M. Pilar , Seijas Julio A. , Meijide Francisco , Fraga Francisco , de Frutos Santiago , Miragaya Javier , Trillo Juan Ventura , Jover Aida , Soto Victor H. , Vázquez Tato José
Published: June 2021

Lipophilicity of 15 derivatives of sodium cholate, defined by the octan-1-ol/water partition coefficient (log P), has been theoretically determined by the Virtual log P method. These derivatives bear highly hydrophobic or highly hydrophilic substituents at the C3 position of the steroid nucleus, being linked to it through an amide bond. The difference between the maximum value of log P and the minimum one is enlarged to 3.5. The partition coefficient and the critical micelle concentration (cmc) are tightly related by a double-logarithm relationship (VirtuallogP=−(1.00±0.09)log(cmcmM)+(2.79±0.09)), meaning that the Gibbs free energies for the transfer of a bile anion from water to either a micelle or to octan-1-ol differ by a constant. The equation also means that cmc can be used as a measurement of lipophilicity. The demicellization of the aggregates formed by three derivatives of sodium cholate bearing bulky hydrophobic substituents has been studied by surface tension and isothermal titration calorimetry. Aggregation numbers, enthalpies, free energies, entropies, and heat capacities, ΔCP,demic, were obtained. ΔCP,demic, being positive, means that the interior of the aggregates is hydrophobic.
The Anticancer Effects of FDI-6, a FOXM1 Inhibitor, on Triple Negative Breast Cancer
Authors: Ulhaka Karan , Kanokwiroon Kanyanatt , Khongkow Mattaka , Bissanum Rassanee , Khunpitak Thanaporn , Khongkow Pasarat
Published: June 2021

Triple-negative breast cancer (TNBC) presents an important clinical challenge, as it does not respond to endocrine therapies or other available targeting agents. FOXM1, an oncogenic transcriptional factor, has reported to be upregulated and associated with poor clinical outcomes in TNBC patients. In this study, we investigated the anti-cancer effects of FDI-6, a FOXM1 inhibitor, as well as its molecular mechanisms, in TNBC cells. Two TNBC cell lines, MDA-MB-231 and HS578T, were used in this study. The anti-cancer activities of FDI-6 were evaluated using various 2D cell culture assays, including Sulforhodamine B (SRB), wound healing, and transwell invasion assays together with 3D spheroid assays, mimicking real tumour structural properties. After treatment with FDI-6, the TNBC cells displayed a significant inhibition in cell proliferation, migration, and invasion. Increased apoptosis was also observed in the treated cells. In addition, we found that FDI-6 lead to the downregulation of FOXM1 and its key oncogenic targets, including CyclinB1, Snail, and Slug. Interestingly, we also found that the FDI-6/Doxorubicin combination significantly enhanced the cytotoxicity and apoptotic properties, suggesting that FDI-6 might improve chemotherapy treatment efficacy and reduce unwanted side effects. Altogether, FDI-6 exhibited promising anti-tumour activities and could be developed as a newly effective treatment for TNBC.
Metformin and Vitamin D Modulate Inflammation and Autophagy during Adipose-Derived Stem Cell Differentiation
Authors: Cruciani Sara , Garroni Giuseppe , Pala Renzo , Cossu Maria Laura , Ginesu Giorgio Carlo , Ventura Carlo , Maioli Margherita
Published: June 2021

Adipose-derived stem cells (ADSCs) came out from the regenerative medicine landscape for their ability to differentiate into several phenotypes, contributing to tissue regeneration both in vitro and in vivo. Dysregulation in stem cell recruitment and differentiation during adipogenesis is linked to a chronic low-grade inflammation and macrophage infiltration inside the adipose tissue, insulin resistance, cardiovascular disease and obesity. In the present paper we aimed to evaluate the role of metformin and vitamin D, alone or in combination, in modulating inflammation and autophagy in ADSCs during adipogenic commitment. ADSCs were cultured for 21 days in the presence of a specific adipogenic differentiation medium, together with metformin, or vitamin D, or both. We then analyzed the expression of FoxO1 and Heat Shock Proteins (HSP) and the secretion of proinflammatory cytokines IL-6 and TNF-α by ELISA. Autophagy was also assessed by specific Western blot analysis of ATG12, LC3B I, and LC3B II expression. Our results showed the ability of the conditioned media to modulate adipogenic differentiation, finely tuning the inflammatory response and autophagy. We observed a modulation in HSP mRNA levels, and a significant downregulation in cytokine secretion. Taken together, our findings suggest the possible application of these molecules in clinical practice to counteract uncontrolled lipogenesis and prevent obesity and obesity-related metabolic disorders.
Functional Role of Non-Muscle Myosin II in Microglia: An Updated Review
Authors: Porro Chiara , Pennella Antonio , Panaro Maria Antonietta , Trotta Teresa
Published: June 2021

Myosins are a remarkable superfamily of actin-based motor proteins that use the energy derived from ATP hydrolysis to translocate actin filaments and to produce force. Myosins are abundant in different types of tissues and involved in a large variety of cellular functions. Several classes of the myosin superfamily are expressed in the nervous system; among them, non-muscle myosin II (NM II) is expressed in both neurons and non-neuronal brain cells, such as astrocytes, oligodendrocytes, endothelial cells, and microglia. In the nervous system, NM II modulates a variety of functions, such as vesicle transport, phagocytosis, cell migration, cell adhesion and morphology, secretion, transcription, and cytokinesis, as well as playing key roles during brain development, inflammation, repair, and myelination functions. In this review, we will provide a brief overview of recent emerging roles of NM II in resting and activated microglia cells, the principal regulators of immune processes in the central nervous system (CNS) in both physiological and pathological conditions. When stimulated, microglial cells react and produce a number of mediators, such as pro-inflammatory cytokines, free radicals, and nitric oxide, that enhance inflammation and contribute to neurodegenerative diseases. Inhibition of NM II could be a new therapeutic target to treat or to prevent CNS diseases.
A Novel Model for the RNase MRP-Induced Switch between the Formation of Different Forms of 5.8S rRNA
Authors: Li Xiao , Zengel Janice M. , Lindahl Lasse
Published: June 2021

Processing of the RNA polymerase I pre-rRNA transcript into the mature 18S, 5.8S, and 25S rRNAs requires removing the “spacer” sequences. The canonical pathway for the removal of the ITS1 spacer involves cleavages at the 3′ end of 18S rRNA and at two sites inside ITS1. The process can generate either a long or a short 5.8S rRNA that differs in the number of ITS1 nucleotides retained at the 5.8S 5′ end. Here we document a novel pathway to the long 5.8S, which bypasses cleavage within ITS1. Instead, the entire ITS1 is degraded from its 5′ end by exonuclease Xrn1. Mutations in RNase MRP increase the accumulation of long relative to short 5.8S rRNA. Traditionally this is attributed to a decreased rate of RNase MRP cleavage at its target in ITS1, called A3. However, results from this work show that the MRP-induced switch between long and short 5.8S rRNA formation occurs even when the A3 site is deleted. Based on this and our published data, we propose that the link between RNase MRP and 5.8S 5′ end formation involves RNase MRP cleavage at unknown sites elsewhere in pre-rRNA or in RNA molecules other than pre-rRNA.
Cytotoxic Activity against A549 Human Lung Cancer Cells and ADMET Analysis of New Pyrazole Derivatives
Authors: Czylkowska Agnieszka , Szczesio Małgorzata , Raducka Anita , Rogalewicz Bartłomiej , Kręcisz Paweł , Czarnecka Kamila , Szymański Paweł , Pitucha Monika , Pawlak Tomasz
Published: June 2021

Two new pyrazole derivatives, namely compound 1 and compound 2, have been synthesized, and their biological activity has been evaluated. Monocrystals of the obtained compounds were thoroughly investigated using single-crystal X-ray diffraction analysis, FTIR spectroscopy, and NMR spectroscopy. The results gathered from all three techniques are in good agreement, provide complete information about the structures of 1 and 2, and confirm their high purity. Thermal properties were studied using thermogravimetric analysis; both 1 and 2 are stable at room temperature. In order to better characterize 1 and 2, some physicochemical and biological properties have been evaluated using ADMET analysis. The cytotoxic activity of both compounds was determined using the MTT assay on the A549 cell line in comparison with etoposide. It was determined that compound 2 was effective in the inhibition of human lung adenocarcinoma cell growth and may be a promising compound for the treatment of lung cancer.