bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological Factors that Lessen the Impact of COVID-19 on the Self-Employment Intention of Business Administration and Economics’ Students from Latin America
Authors: Hernández-Sánchez Brizeida Raquel , Cardella Giuseppina Maria , Sánchez-García José Carlos
Published: July 2020

Background: The 2019 coronavirus disease epidemic (Covid-19) is a public health emergency of international concern and poses a challenge to the labor market. The pandemic has a devastating and disproportionate effect on young workers, their interest in entrepreneurship, and their mental health. Research is needed to develop evidence-based strategies to improve coping and reduce adverse psychological problems. The objective of this study was to analyze the impact that Covid-19 pandemic perception and psychological need satisfaction have on university students and their self-employment intention. In addition, we also analyzed the role of moderation played by psychological aspects. These psychological factors (i.e., Optimism and Proactiveness) can also improve young people’s mental health and well-being. Methods: An explorative study (online survey) was conducted in March 2020 934 university students from Latin America. Regression analysis models were built to examine the relationships between Covid-19 pandemic perception, personality variables, and entrepreneurial intention. Mediation models, through the bootstrapping method, were performed to analyze the mediating role of proactiveness and optimism. Results: Results indicate that students’ perception of Covid-19 and psychological need satisfaction are associated with entrepreneurial intention. Additionally, the present study argues that proactiveness and optimism mediate these relationships. Conclusions: This study identifies psychological factors associated with a lower level of Covid-19 impact and that can be used for psychological interventions that result in an improvement in the mental health of these vulnerable groups during and after the Covid-19 pandemic. Theoretical and practical implications are discussed.
Sleep Problems in Pregnancy—A Cross-Sectional Study in over 7000 Pregnant Women in Poland
Authors: Smyka Magdalena , Kosińska-Kaczyńska Katarzyna , Sochacki-Wójcicka Nicole , Zgliczyńska Magdalena , Wielgoś Mirosław
Published: July 2020

The aim was to characterize sleep patterns in pregnant women in Poland and to analyze the relation between sociodemographic factors, pregnancy-related physical symptoms and sleep problems. A self-composed questionnaire, containing questions in Polish language, was distributed online via web pages and Facebook groups designed for pregnant women. The questionnaire included questions regarding sociodemographic data and information on the current pregnancy and sleep patterns over the past four weeks. Exactly 7207 respondents were included to the study. 77.09% reported sleep problems: nocturnal awakening (52.77%), sleep onset insomnia (20.23%), awakening too early (18.56%) and believed their sleep was too shallow (9.82%). Sleep onset insomnia (26.38%) and frequent awakening (62.88%) were most often reported in 3rd trimester, while daytime drowsiness (86.35%) and naps impeding daytime function (27.18%) in the 1st trimester of pregnancy. The analyzed demographic, socioeconomic and psychological issues had a small but significant influence on sleep problems occurrence (aOR 0.81–1.24). Time to conceive from 6 to 12 months of trying increased the risk of developing sleep problems during pregnancy (aOR 1.31). Pregnancy ailments increased the risk of sleep disturbances (aOR 1.53–2.59). Sleep disorders are prevalent among pregnant women in Poland. The evaluation of risk factors is essential in proper screening for sleep disorders in pregnant women.
Social Inequalities and Loneliness as Predictors of Ageing Well: A Trend Analysis Using Mixed Models
Authors: Klein Jens , von dem Knesebeck Olaf , Lüdecke Daniel
Published: July 2020

Background: This study examines if education, income, and loneliness are associated with physical functioning and optimism in an ageing population in Germany. Furthermore, time trends of physical functioning and optimism as well as of associations with social inequality and loneliness are analyzed. Methods: The German Ageing Survey (DEAS), a longitudinal population-based survey of individuals aged 40 years and older, was used (four waves between 2008 and 2017, total sample size N = 23,572). Physical functioning and optimism were introduced as indicators of ageing well. Educational level, net equivalent income, and loneliness were used as predictors in linear mixed models for longitudinal data. Results: Time trends show that physical functioning decreases over time, while optimism slightly increases. Education and income are positively associated with physical functioning, while higher loneliness correlates with lower physical functioning. Higher optimism was associated with higher income and particularly with lower loneliness. Income and notable educational inequalities in physical functioning increase over time. Time trends of the associations with optimism show decreasing income inequalities and increasing disparities in loneliness. Conclusions: Increasing educational inequalities in physical functioning and a strong association of loneliness with optimism provide information for further interventions. Targeted health promotion among the aged and addressing maladaptive social cognition are options to tackle these issues. Key areas for action on healthy ageing include, for instance, the alignment of health systems to the needs of older populations or the creation of age-friendly environments.
Effect of Chronic Ankle Sprain on Pain, Range of Motion, Proprioception, and Balance among Athletes
Authors: Alghadir Ahmad , Iqbal Zaheen , Iqbal Amir , Ahmed Hashim , Ramteke Swapnil
Published: July 2020

Background: Ankle sprains are common among physically active individuals, especially among athletes. Majority of those who suffer ankle sprains have residual symptoms including pain, episodes of giving way, compromised proprioception and neuromuscular control, and re-injury leading to chronic ankle instability. The aim of this study was to see the effect of chronic ankle sprain on pain, range of motion, proprioception, and, static and dynamic balance among athletes. Methods: A total of 80 athletes, aged 18 to 25 years, involved in track-and-field sports were invited to participate in this study. They were divided in two groups. Athletes with history of grade 1 or 2 ankle sprain on either side requiring medical care who reported at least three episodes of ankle giving way in past 12 months were included in group A. An equal number of healthy athletes without any history of ankle sprain or injury in the lower limbs in the past one year matched by sex, age, height, weight, and limb dominance, were included in group B (control). Outcome measures: Participant’s pain, range of motion, proprioception and balance (static and dynamic) was measured using visual analog scale, half circle goniometer, degree of foot position sense, single leg stance time and Y-balance test respectively. Results: Although there were no differences in the active ankle joint range of motion (p > 0.05) in comparison to the control group, athletes with chronic ankle sprain reported mild pain and statistically significant (p < 0.05) deficits in foot proprioception, static and dynamic balance. Conclusions: Deficits in foot proprioception, static and dynamic balance even one year after the ankle sprain could be the reason for limitations in the dynamic defense system of the joint that predisposes to recurrent injury and instability. It is essential to understand the normal clinical course and risk factors for athletes who sustain sprain before devising a long term comprehensive rehabilitation program that focuses on mechanical and functional insufficiencies in order to improve their functional performance and prevent the risk of recurrent sprain.
Hyponatremia in Infectious Diseases—A Literature Review
Authors: Królicka Anna L. , Kruczkowska Adrianna , Krajewska Magdalena , Kusztal Mariusz A.
Published: July 2020

Hyponatremia is one of the most common water–electrolyte imbalances in the human organism. A serum sodium concentration threshold of less than 135 mmol/L is diagnostic for hyponatremia. The disorder is usually secondary to various diseases, including infections. Our review aims to summarize the diagnostic value and impact of hyponatremia on the prognosis, length of the hospitalization, and mortality among patients with active infection. The scientific literature regarding hyponatremia was reviewed using PubMed, ClinicalKey, and Web of Science databases. Studies published between 2011 and 2020 were screened and eligible studies were selected according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and specific inclusion criteria. The most common infections that were associated with hyponatremia were viral and bacterial infections, including COVID-19 (coronavirus disease 2019). The etiology varied according to the infection site, setting and patient cohort it concerned. In several studies, hyponatremia was associated with prolonged hospitalization, worse outcomes, and higher mortality rates. Hyponatremia can also play a diagnostic role in differentiating pathogens that cause a certain infection type, as it was observed in community-acquired pneumonia. Although many mechanisms leading to hyponatremia have already been described, it is impossible with any certainty to ascribe the etiology of hyponatremia to any of them.
Investigating the Vascular Toxicity Outcomes of the Irreversible Proteasome Inhibitor Carfilzomib
Authors: Efentakis Panagiotis , Doerschmann Hendrik , Witzler Claudius , Siemer Svenja , Nikolaou Panagiota-Efstathia , Kastritis Efstathios , Stauber Roland , Dimopoulos Meletios Athanasios , Wenzel Philip , Andreadou Ioanna , Terpos Evangelos
Published: July 2020

Background: Carfilzomib’s (Cfz) adverse events in myeloma patients include cardiovascular toxicity. Since carfilzomib’s vascular effects are elusive, we investigated the vascular outcomes of carfilzomib and metformin (Met) coadministration. Methods: Mice received: (i) saline; (ii) Cfz; (iii) Met; (iv) Cfz+Met for two consecutive (acute) or six alternate days (subacute protocol). Leucocyte-derived reactive oxygen species (ROS) and serum NOx levels were determined and aortas underwent vascular and molecular analyses. Mechanistic experiments were recapitulated in aged mice who received similar treatment to young animals. Primary murine (prmVSMCs) and aged human aortic smooth muscle cells (HAoSMCs) underwent Cfz, Met and Cfz+Met treatment and viability, metabolic flux and p53-LC3-B expression were measured. Experiments were recapitulated in AngII, CoCl2 and high-glucose stimulated HAoSMCs. Results: Acutely, carfilzomib alone led to vascular hypo-contraction and increased ROS release. Subacutely, carfilzomib increased ROS release without vascular manifestations. Cfz+Met increased PGF2α-vasoconstriction and LC3-B-dependent autophagy in both young and aged mice. In vitro, Cfz+Met led to cytotoxicity and autophagy, while Met and Cfz+Met shifted cellular metabolism. Conclusion: Carfilzomib induces a transient vascular impairment and oxidative burst. Cfz+Met increased vascular contractility and synergistically induced autophagy in all settings. Therefore, carfilzomib cannot be accredited for a permanent vascular dysfunction, while Cfz+Met exert vasoprotective potency.
A Genome-Wide View of Transcriptional Responses during Aphis glycines Infestation in Soybean
Authors: Yao Luming , Yang Biyun , Ma Xiaohong , Wang Shuangshuang , Guan Zhe , Wang Biao , Jiang Yina
Published: July 2020

Soybean aphid (Aphis glycines Matsumura) is one of the major limiting factors in soybean production. The mechanism of aphid resistance in soybean remains enigmatic as little information is available about the different mechanisms of antibiosis and antixenosis. Here, we used genome-wide gene expression profiling of aphid susceptible, antibiotic, and antixenotic genotypes to investigate the underlying aphid–plant interaction mechanisms. The high expression correlation between infested and non-infested genotypes indicated that the response to aphid was controlled by a small subset of genes. Plant response to aphid infestation was faster in antibiotic genotype and the interaction in antixenotic genotype was moderation. The expression patterns of transcription factor genes in susceptible and antixenotic genotypes clustered together and were distant from those of antibiotic genotypes. Among them APETALA 2/ethylene response factors (AP2/ERF), v-myb avian myeloblastosis viral oncogene homolog (MYB), and the transcription factor contained conserved WRKYGQK domain (WRKY) were proposed to play dominant roles. The jasmonic acid-responsive pathway was dominant in aphid–soybean interaction, and salicylic acid pathway played an important role in antibiotic genotype. Callose deposition was more rapid and efficient in antibiotic genotype, while reactive oxygen species were not involved in the response to aphid attack in resistant genotypes. Our study helps to uncover important genes associated with aphid-attack response in soybean genotypes expressing antibiosis and antixenosis.
Phage S144, a New Polyvalent Phage Infecting Salmonella spp. and Cronobacter sakazakii
Authors: Gambino Michela , Nørgaard Sørensen Anders , Ahern Stephen , Smyrlis Georgios , Gencay Yilmaz Emre , Hendrix Hanne , Neve Horst , Noben Jean-Paul , Lavigne Rob , Brøndsted Lone
Published: July 2020

Phages are generally considered species- or even strain-specific, yet polyvalent phages are able to infect bacteria from different genera. Here, we characterize the novel polyvalent phage S144, a member of the Loughboroughvirus genus. By screening 211 Enterobacteriaceae strains, we found that phage S144 forms plaques on specific serovars of Salmonella enterica subsp. enterica and on Cronobacter sakazakii. Analysis of phage resistant mutants suggests that the O-antigen of lipopolysaccharide is the phage receptor in both bacterial genera. The S144 genome consists of 53,628 bp and encodes 80 open reading frames (ORFs), but no tRNA genes. In total, 32 ORFs coding for structural proteins were confirmed by ESI-MS/MS analysis, whereas 45 gene products were functionally annotated within DNA metabolism, packaging, nucleotide biosynthesis and phage morphogenesis. Transmission electron microscopy showed that phage S144 is a myovirus, with a prolate head and short tail fibers. The putative S144 tail fiber structure is, overall, similar to the tail fiber of phage Mu and the C-terminus shows amino acid similarity to tail fibers of otherwise unrelated phages infecting Cronobacter. Since all phages in the Loughboroughvirus genus encode tail fibers similar to S144, we suggest that phages in this genus infect Cronobacter sakazakii and are polyvalent.
Amyloidogenic Propensities of Ribosomal S1 Proteins: Bioinformatics Screening and Experimental Checking
Authors: Grishin Sergei Y. , Deryusheva Evgeniya I. , Machulin Andrey V. , Selivanova Olga M. , Glyakina Anna V. , Gorbunova Elena Y. , Mustaeva Leila G. , Azev Vyacheslav N. , Rekstina Valentina V. , Kalebina Tatyana S. , Surin Alexey K. , Galzitskaya Oxana V.
Published: July 2020

Structural S1 domains belong to the superfamily of oligosaccharide/oligonucleotide-binding fold domains, which are highly conserved from prokaryotes to higher eukaryotes and able to function in RNA binding. An important feature of this family is the presence of several copies of the structural domain, the number of which is determined in a strictly limited range from one to six. Despite the strong tendency for the aggregation of several amyloidogenic regions in the family of the ribosomal S1 proteins, their fibril formation process is still poorly understood. Here, we combined computational and experimental approaches for studying some features of the amyloidogenic regions in this protein family. The FoldAmyloid, Waltz, PASTA 2.0 and Aggrescan programs were used to assess the amyloidogenic propensities in the ribosomal S1 proteins and to identify such regions in various structural domains. The thioflavin T fluorescence assay and electron microscopy were used to check the chosen amyloidogenic peptides’ ability to form fibrils. The bioinformatics tools were used to study the amyloidogenic propensities in 1331 ribosomal S1 proteins. We found that amyloidogenicity decreases with increasing sizes of proteins. Inside one domain, the amyloidogenicity is higher in the terminal parts. We selected and synthesized 11 amyloidogenic peptides from the Escherichia coli and Thermus thermophilus ribosomal S1 proteins and checked their ability to form amyloids using the thioflavin T fluorescence assay and electron microscopy. All 11 amyloidogenic peptides form amyloid-like fibrils. The described specific amyloidogenic regions are actually responsible for the fibrillogenesis process and may be potential targets for modulating the amyloid properties of bacterial ribosomal S1 proteins.
Diabetes Mellitus and Hypertension—A Case of Sugar and Salt?
Authors: Sondermann Marcus , Holecki Michał , Kirsch Andrea Marita , Bastian Manuela , Fischer Dagmar-Christiane , Willenberg Holger Sven
Published: July 2020

The majority of patients with diabetes mellitus (DM) have hypertension (HTN). A specific mechanism for the development of HTN in DM has not been described. In the Zucker, Endothel, und Salz (sugar, endothelium, and salt) study (ZEuS), indices of glucose metabolism and of volume regulation are recorded. An analysis of these parameters shows that glucose concentrations interfere with plasma osmolality and that changes in glycemic control have a significant impact on fluid status and blood pressure. The results of this study are discussed against the background of the striking similarities between the regulation of sugar and salt blood concentrations, introducing the view that DM is probably a sodium-retention disorder that leads to a state of hypervolemia.
Preliminary In Vitro Evaluation of Chitosan–Graphene Oxide Scaffolds on Osteoblastic Adhesion, Proliferation, and Early Differentiation
Authors: Wong Sonia How Ming , Lim Siew Shee , Tiong Timm Joyce , Show Pau Loke , Zaid Hayyiratul Fatimah Mohd , Loh Hwei-San
Published: July 2020

An ideal scaffold should be biocompatible, having appropriate microstructure, excellent mechanical strength yet degrades. Chitosan exhibits most of these exceptional properties, but it is always associated with sub-optimal cytocompatibility. This study aimed to incorporate graphene oxide at wt % of 0, 2, 4, and 6 into chitosan matrix via direct blending of chitosan solution and graphene oxide, freezing, and freeze drying. Cell fixation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, alkaline phosphatase colorimetric assays were conducted to assess cell adhesion, proliferation, and early differentiation of MG63 on chitosan–graphene oxide scaffolds respectively. The presence of alkaline phosphatase, an early osteoblast differentiation marker, was further detected in chitosan–graphene oxide scaffolds using western blot. These results strongly supported that chitosan scaffolds loaded with graphene oxide at 2 wt % mediated cell adhesion, proliferation, and early differentiation due to the presence of oxygen-containing functional groups of graphene oxide. Therefore, chitosan scaffolds loaded with graphene oxide at 2 wt % showed the potential to be developed into functional bone scaffolds.
HLA-B*44 and C*01 Prevalence Correlates with Covid19 Spreading across Italy
Authors: Correale Pierpaolo , Mutti Luciano , Pentimalli Francesca , Baglio Giovanni , Saladino Rita Emilena , Sileri Pierpaolo , Giordano Antonio
Published: July 2020

The spread of COVID-19 is showing huge, unexplained, differences between northern and southern Italy. We hypothesized that the regional prevalence of specific class I human leukocyte antigen (HLA) alleles, which shape the anti-viral immune response, might partly underlie these differences. Through an ecological approach, we analyzed whether a set of HLA alleles (A, B, C), known to be involved in the immune response against infections, correlates with COVID-19 incidence. COVID-19 data were provided by the National Civil Protection Department, whereas HLA allele prevalence was retrieved through the Italian Bone-Marrow Donors Registry. Among all the alleles, HLA-A*25, B*08, B*44, B*15:01, B*51, C*01, and C*03 showed a positive log-linear correlation with COVID-19 incidence rate fixed on 9 April 2020 in proximity of the national outbreak peak (Pearson’s coefficients between 0.50 and 0.70, p-value < 0.0001), whereas HLA-B*14, B*18, and B*49 showed an inverse log-linear correlation (Pearson’s coefficients between −0.47 and −0.59, p-value < 0.0001). When alleles were examined simultaneously using a multiple regression model to control for confounding factors, HLA-B*44 and C*01 were still positively and independently associated with COVID-19: a growth rate of 16% (95%CI: 0.1–35%) per 1% point increase in B*44 prevalence; and of 19% (95%CI: 1–41%) per 1% point increase in C*01 prevalence. Our epidemiologic analysis, despite the limits of the ecological approach, is strongly suggestive of a permissive role of HLA-C*01 and B*44 towards SARS-CoV-2 infection, which warrants further investigation in case-control studies. This study opens a new potential avenue for the identification of sub-populations at risk, which could provide Health Services with a tool to define more targeted clinical management strategies and priorities in vaccination campaigns.
Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy
Authors: Cersosimo Francesca , Lonardi Silvia , Bernardini Giulia , Telfer Brian , Mandelli Giulio Eugenio , Santucci Annalisa , Vermi William , Giurisato Emanuele
Published: July 2020

Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a more effective therapeutic management regimen, and hence patient survival, there is a need to identify more focused targeted therapies for OSs treatment in the clinical setting. The role of the OS tumor stroma microenvironment plays a significant part in the development and dissemination of this disease. Important components, and hence potential targets for treatment, are the tumor-infiltrating macrophages that are known to orchestrate many aspects of OS stromal signaling and disease progression. In particular, increased infiltration of M2-like tumor-associated macrophages (TAMs) has been associated with OS metastasis and poor patient prognosis despite currently used aggressive therapies regimens. This review aims to provide a summary update of current macrophage-centered knowledge and to discuss the possible roles that macrophages play in the process of OS metastasis development focusing on the potential influence of stromal cross-talk signaling between TAMs, cancer-stem cells and additional OSs tumoral microenvironment factors.
Unusual Occurrence of Two Bona-Fide CCA-Adding Enzymes in Dictyostelium discoideum
Authors: Erber Lieselotte , Hoffmann Anne , Fallmann Jörg , Hagedorn Monica , Hammann Christian , Stadler Peter F. , Betat Heike , Prohaska Sonja , Mörl Mario
Published: July 2020

Dictyostelium discoideum, the model organism for the evolutionary supergroup of Amoebozoa, is a social amoeba that, upon starvation, undergoes transition from a unicellular to a multicellular organism. In its genome, we identified two genes encoding for tRNA nucleotidyltransferases. Such pairs of tRNA nucleotidyltransferases usually represent collaborating partial activities catalyzing CC- and A-addition to the tRNA 3′-end, respectively. In D. discoideum, however, both enzymes exhibit identical activities, representing bona-fide CCA-adding enzymes. Detailed characterization of the corresponding activities revealed that both enzymes seem to be essential and are regulated inversely during different developmental stages of D. discoideum. Intriguingly, this is the first description of two functionally equivalent CCA-adding enzymes using the same set of tRNAs and showing a similar distribution within the cell. This situation seems to be a common feature in Dictyostelia, as other members of this phylum carry similar pairs of tRNA nucleotidyltransferase genes in their genome.
Cx43 in Neural Progenitors Promotes Glioma Invasion in a 3D Culture System
Authors: Khosla Kanika , Naus Christian C. , Sin Wun Chey
Published: July 2020

The environment that envelops the cancer cells intimately affects the malignancy of human cancers. In the case of glioma, an aggressive adult brain cancer, its high rate of recurrence after total resection is responsible for a poor prognosis. Connexin43 (Cx43) is a gap junction protein with a prominent presence in glioma-associated normal brain cells, specifically in the reactive astrocytes. We previously demonstrated that elimination of Cx43 in these astrocytes reduces glioma invasion in a syngeneic mouse model. To further our investigation in human glioma cells, we developed a scaffold-free 3D platform that takes into account both the tumor and its interaction with the surrounding tissue. Using cell-tracking dyes and 3D laser scanning confocal microscopy, we now report that the elimination of Cx43 protein in neural progenitor spheroids reduced the invasiveness of human brain tumor-initiating cells, confirming our earlier observation in an intact mouse brain. By investigating the glioma invasion in a defined multicellular system with a tumor boundary that mimics the intact brain environment, our findings strengthen Cx43 as a candidate target for glioma control.
lncRNA_Mdeep: An Alignment-Free Predictor for Distinguishing Long Non-Coding RNAs from Protein-Coding Transcripts by Multimodal Deep Learning
Authors: Fan Xiao-Nan , Zhang Shao-Wu , Zhang Song-Yao , Ni Jin-Jie
Published: July 2020

Long non-coding RNAs (lncRNAs) play crucial roles in diverse biological processes and human complex diseases. Distinguishing lncRNAs from protein-coding transcripts is a fundamental step for analyzing the lncRNA functional mechanism. However, the experimental identification of lncRNAs is expensive and time-consuming. In this study, we presented an alignment-free multimodal deep learning framework (namely lncRNA_Mdeep) to distinguish lncRNAs from protein-coding transcripts. LncRNA_Mdeep incorporated three different input modalities, then a multimodal deep learning framework was built for learning the high-level abstract representations and predicting the probability whether a transcript was lncRNA or not. LncRNA_Mdeep achieved 98.73% prediction accuracy in a 10-fold cross-validation test on humans. Compared with other eight state-of-the-art methods, lncRNA_Mdeep showed 93.12% prediction accuracy independent test on humans, which was 0.94%~15.41% higher than that of other eight methods. In addition, the results on 11 cross-species datasets showed that lncRNA_Mdeep was a powerful predictor for predicting lncRNAs.
Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials
Authors: Al-Horani Rami A. , Kar Srabani , Aliter Kholoud F.
Published: July 2020

The ongoing pandemic of coronavirus disease-2019 (COVID-19) is being caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease continues to present significant challenges to the health care systems around the world. This is primarily because of the lack of vaccines to protect against the infection and the lack of highly effective therapeutics to prevent and/or treat the illness. Nevertheless, researchers have swiftly responded to the pandemic by advancing old and new potential therapeutics into clinical trials. In this review, we summarize potential anti-COVID-19 therapeutics that block the early stage of the viral life cycle. The review presents the structures, mechanisms, and reported results of clinical trials of potential therapeutics that have been listed in clinicaltrials.gov. Given the fact that some of these therapeutics are multi-acting molecules, other relevant mechanisms will also be described. The reviewed therapeutics include small molecules and macromolecules of sulfated polysaccharides, polypeptides, and monoclonal antibodies. The potential therapeutics target viral and/or host proteins or processes that facilitate the early stage of the viral infection. Frequent targets are the viral spike protein, the host angiotensin converting enzyme 2, the host transmembrane protease serine 2, and clathrin-mediated endocytosis process. Overall, the review aims at presenting update-to-date details, so as to enhance awareness of potential therapeutics, and thus, to catalyze their appropriate use in combating the pandemic.
Loss of Caveolin-1 Is Associated with a Decrease in Beta Cell Death in Mice on a High Fat Diet
Authors: Lillo Urzúa Paloma , Núñez Murillo Olinda , Castro-Sepúlveda Mauricio , Torres-Quintana María A. , Lladser Caldera Álvaro , Quest Andrew F. G. , Espinoza Robles Carolina , Llanos Vidal Paola , Wehinger Sergio
Published: July 2020

Elevated free fatty acids (FFAs) impair beta cell function and reduce beta cell mass as a consequence of the lipotoxicity that occurs in type 2 diabetes (T2D). We previously reported that the membrane protein caveolin-1 (CAV1) sensitizes to palmitate-induced apoptosis in the beta pancreatic cell line MIN6. Thus, our hypothesis was that CAV1 knock-out (CAV1 KO) mice subjected to a high fat diet (HFD) should suffer less damage to beta cells than wild type (WT) mice. Here, we evaluated the in vivo response of beta cells in the pancreatic islets of 8-week-old C57Bl/6J CAV1 KO mice subjected to a control diet (CD, 14% kcal fat) or a HFD (60% kcal fat) for 12 weeks. We observed that CAV1 KO mice were resistant to weight gain when on HFD, although they had high serum cholesterol and FFA levels, impaired glucose tolerance and were insulin resistant. Some of these alterations were also observed in mice on CD. Interestingly, KO mice fed with HFD showed an adaptive response of the pancreatic beta cells and exhibited a significant decrease in beta cell apoptosis in their islets compared to WT mice. These in vivo results suggest that although the CAV1 KO mice are metabolically unhealthy, they adapt better to a HFD than WT mice. To shed light on the possible signaling pathway(s) involved, MIN6 murine beta cells expressing (MIN6 CAV) or not expressing (MIN6 Mock) CAV1 were incubated with the saturated fatty acid palmitate in the presence of mitogen-activated protein kinase inhibitors. Western blot analysis revealed that CAV1 enhanced palmitate-induced JNK, p38 and ERK phosphorylation in MIN6 CAV1 cells. Moreover, all the MAPK inhibitors partially restored MIN6 viability, but the effect was most notable with the ERK inhibitor. In conclusion, our results suggest that CAV1 KO mice adapted better to a HFD despite their altered metabolic state and that this may at least in part be due to reduced beta cell damage. Moreover, they indicate that the ability of CAV1 to increase sensitivity to FFAs may be mediated by MAPK and particularly ERK activation.
Extracellular Nucleotides Selectively Induce Migration of Chondrocytes and Expression of Type II Collagen
Authors: Szustak Marcin , Gendaszewska-Darmach Edyta
Published: July 2020

The migration of chondrocytes from healthy to injured tissues is one of the most important challenges during cartilage repair. Additionally, maintenance of the chondrogenic phenotype remains another limitation, especially during monolayer culture in vitro. Using both the differentiated and undifferentiated chondrogenic ATDC5 cell line, we showed that extracellular nucleotides are able to increase the migration rate of chondrocytes without affecting their chondrogenic phenotype. We checked the potency of natural nucleotides (ATP, ADP, UTP, and UDP) as well as their stable phosphorothioate analogs, containing a sulfur atom in the place of one nonbridging oxygen atom in a phosphate group. We also detected P2y1, P2y2, P2y4, P2y6, P2y12, P2y13, and P2y14 mRNA transcripts for nucleotide receptors, demonstrating that P2y1 and P2y13 are highly upregulated in differentiated ATDC5 cells. We showed that ADPβS, UDPβS, and ADP are the best stimulators of migration of differentiated chondrocytes. Additionally, ADP and ADPβS positively affected the expression of type II collagen, a structural component of the cartilage matrix.
Is the Retinol-Binding Protein 4 a Possible Risk Factor for Cardiovascular Diseases in Obesity?
Authors: Rychter Anna Maria , Skrzypczak-Zielińska Marzena , Zielińska Aleksandra , Eder Piotr , Souto Eliana B. , Zawada Agnieszka , Ratajczak Alicja Ewa , Dobrowolska Agnieszka , Krela-Kaźmierczak Iwona
Published: July 2020

Although many preventive and treatment approaches have been proposed, cardiovascular disease (CVD) remains one of the leading causes of deaths worldwide. Current epidemiological data require the specification of new causative factors, as well as the development of improved diagnostic tools to provide better cardiovascular management. Excessive accumulation of adipose tissue among patients suffering from obesity not only constitutes one of the main risk factors of CVD development but also alters adipokines. Increased attention is devoted to bioactive adipokines, which are also produced by the adipose tissue. The retinol-binding protein 4 (RBP4) has been associated with numerous CVDs and is presumably associated with an increased cardiovascular risk. With this in mind, exploring the role of RBP4, particularly among patients with obesity, could be a promising direction and could lead to better CVD prevention and management in this patient group. In our review, we summarized the current knowledge about RBP4 and its association with essential aspects of cardiovascular disease—lipid profile, intima-media thickness, atherosclerotic process, and diet. We also discussed the RBP4 gene polymorphisms essential from a cardiovascular perspective.
Genetic Biomarkers in Melanoma of the Ocular Region: What the Medical Oncologist Should Know
Authors: Bol Kalijn Fredrike , Donia Marco , Heegaard Steffen , Kiilgaard Jens Folke , Svane Inge Marie
Published: July 2020

Melanoma of the ocular region (ocular melanoma) comprises about 5% of all patients with melanoma and covers posterior uveal melanoma, iris melanoma, and conjunctival melanoma. The risk of metastasis is much higher in patients with ocular melanoma compared to a primary melanoma of the skin. The subtypes of ocular melanoma have distinct genetic features, which should be taken into consideration when making clinical decisions. Most relevant for current practice is the absence of BRAF mutations in posterior uveal melanoma, although present in some iris melanomas and conjunctival melanomas. In this review, we discuss the genetic biomarkers of the subtypes of ocular melanoma and their impacts on the clinical care of these patients.
Molecular Targets, Pathways, and Therapeutic Implications for Hepatocellular Carcinoma
Authors: Gong Jun , Chuang Jeremy , Cho May , Toomey Kyra , Hendifar Andrew , Li Daneng
Published: July 2020

Hepatocellular carcinoma (HCC) represents one of the leading causes of cancer mortality worldwide. While significant advances have been made for the treatment of advanced hepatocellular carcinoma in the past few years, the prognosis remains poor and effective biomarkers to guide selection of therapies remain noticeably absent. However, several targeted therapies have been approved in the past few years that have improved the outlook for this disease. In this review, we will highlight the recent therapies approved for the treatment of advanced HCC and discuss promising therapeutic options, targets, and pathways for drug development and consideration for future clinical trials.
The Biological and Clinical Role of the Long Non-Coding RNA LOC642852 in Ovarian Carcinoma
Authors: Filippov-Levy Natalie , Reich Reuven , Davidson Ben
Published: July 2020

The objective of the present study was to analyze the biological and clinical role of the long non-coding RNA LOC642852 in ovarian carcinoma (OC). LOC642852 expression was analyzed in seven OC cell lines (OVCAR-3, OVCAR-8, OVCA 433, OVCA 429, OC 238, DOV13, ES-2) and 139 high-grade serous carcinoma (HGSC) specimens (85 effusions, 54 surgical specimens). Following LOC642852 knockout (KO) using the CRISPR/Cas9 system, OVCAR-8 HGSC cells were analyzed for spheroid formation, migration, invasion, proliferation, matrix metalloproteinase (MMP) activity, and expression of cell signaling proteins. OVCAR-8 cells with LOC642852 KO were significantly less motile and less invasive compared to controls, with no differences in spheroid formation, proliferation, or matrix metalloproteinase (MMP) activity. Total Akt and Erk levels were comparable in controls and KO cells, but their phosphorylation was significantly increased in the latter. In clinical specimens, LOC642852 was overexpressed in ovarian tumors and omental/peritoneal metastases compared to effusion specimens (p = 0.013). A non-significant trend for shorter overall (p = 0.109) and progression-free (p = 0.056) survival was observed in patients with HGSC effusions with high LOC642852 levels. Bioinformatics analysis showed potential roles for LOC642852 as part of the TLE3/miR-221-3p ceRNA network and in relation to the FGFR3 protein. In conclusion, LOC642852 inactivation via CRISPR/Cas9 affects cell signaling, motility, and invasion in HGSC cells. LOC642852 is differentially expressed in HGSC cells at different anatomical sites. Its potential role in regulating the TLE3/miR-221-3p ceRNA network and FGFR3 merits further research.
Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways
Authors: Sabirzhanov Boris , Makarevich Oleg , Barrett James P. , Jackson Isabel L. , Glaser Ethan P. , Faden Alan I. , Stoica Bogdan A.
Published: July 2020

Radiotherapy for brain tumors induces neuronal DNA damage and may lead to neurodegeneration and cognitive deficits. We investigated the mechanisms of radiation-induced neuronal cell death and the role of miR-711 in the regulation of these pathways. We used in vitro and in vivo models of radiation-induced neuronal cell death. We showed that X-ray exposure in primary cortical neurons induced activation of p53-mediated mechanisms including intrinsic apoptotic pathways with sequential upregulation of BH3-only molecules, mitochondrial release of cytochrome c and AIF-1, as well as senescence pathways including upregulation of p21WAF1/Cip1. These pathways of irradiation-induced neuronal apoptosis may involve miR-711-dependent downregulation of pro-survival genes Akt and Ang-1. Accordingly, we demonstrated that inhibition of miR-711 attenuated degradation of Akt and Ang-1 mRNAs and reduced intrinsic apoptosis after neuronal irradiation; likewise, administration of Ang-1 was neuroprotective. Importantly, irradiation also downregulated two novel miR-711 targets, DNA-repair genes Rad50 and Rad54l2, which may impair DNA damage responses, amplifying the stimulation of apoptotic and senescence pathways and contributing to neurodegeneration. Inhibition of miR-711 rescued Rad50 and Rad54l2 expression after neuronal irradiation, enhancing DNA repair and reducing p53-dependent apoptotic and senescence pathways. Significantly, we showed that brain irradiation in vivo persistently elevated miR-711, downregulated its targets, including pro-survival and DNA-repair molecules, and is associated with markers of neurodegeneration, not only across the cortex and hippocampus but also specifically in neurons isolated from the irradiated brain. Our data suggest that irradiation-induced miR-711 negatively modulates multiple pro-survival and DNA-repair mechanisms that converge to activate neuronal intrinsic apoptosis and senescence. Using miR-711 inhibitors to block the development of these regulated neurodegenerative pathways, thus increasing neuronal survival, may be an effective neuroprotective strategy.
Insights into the Effects of Mesenchymal Stem Cell-Derived Secretome in Parkinson’s Disease
Authors: d’Angelo Michele , Cimini Annamaria , Castelli Vanessa
Published: July 2020

Mesenchymal stem cell (MSC)-derived secretome demonstrated therapeutic effects like those reported after MSCs transplantation. MSC-derived secretome may avoid various side effects of MSC-based therapy, comprising undesirable differentiation of engrafted MSCs and potential activation of the allogeneic immune response. MSC-derived secretome comprises soluble factors and encapsulated extravesicles (EVs). MSC-derived EVs comprise microvesicles, apoptotic bodies, and exosomes. In this review, we focus on the recent insights into the effects of MSC-derived secretome in Parkinson’s disease (PD). In particular, MSC-derived secretome and exosomal components counteracted neuroinflammation and enhanced antioxidant capacity and neurotrophic factors expression. In light of the insights reported in this review, MSC-derived secretome or their released exosomes may be used as a potential therapeutic approach or as adjuvant therapy to counteract the disease progression and improve PD symptoms. Also, MSC-derived secretome may be used as a vehicle in cell transplantation approaches to enhance the viability and survival of engrafted cells. Furthermore, since exosomes can cross the blood–brain barrier, they may be used as biomarkers of neural dysfunction. Further studies are necessary to fully characterize the bioactive molecules present in the secretome and to create a new, effective, cell-free therapeutic approach towards a robust clinical outcome for PD patients.
Trajectories of Short Physical Performance Battery Are Strongly Associated with Future Major Mobility Disability: Results from the LIFE Study
Authors: Brown Joshua D. , Lo-Ciganic Wei-Hsuan , Shao Hui , Pahor Marco , Manini Todd M.
Published: July 2020

Short Physical Performance Battery (SPPB) assessment is a widely used measure of lower extremity function, strength, and balance. In the Lifestyles Interventions and Independence for Elders (LIFE) Study, baseline SPPB and changes throughout the trial were strongly associated with major mobility disability (MMD). This study further investigated this association by identifying trajectories of SPPB and evaluating the predictive validity of SPPB trajectories for future MMD. Participants (n = 1635) aged 70–89 years were randomized to a physical activity or health education intervention and assessed every 6 months for MMD. We used group-based trajectory models (GBTMs) to identify trajectories of a binary outcome for a decrease from baseline SPPB of ≥1. Multinomial logistic regression explored baseline factors associated with group membership. Survival analyses evaluated the association between trajectories with MMD. The GBTM identified a 3-group model which included a “No Decline” group (46.0%), “Late Decline” group (27.7%), and an “Early Decline” group (26.3%). Adjusting for all other baseline characteristics, group assignment during the previous follow-up visit was strongly associated with MMD at the subsequent period. Comparisons between groups showed a 2-to-3-fold increase in MMD comparing the “Late” to “No” decline group and a 4-to-5-fold increase in MMD comparing the “Early” to “No” decline group. Group membership and impact on MMD was not different between intervention arms. Group-based trajectories of SPPB scores identified distinct subgroups in LIFE Study participants. Using these group assignments in outcome models were highly associated with MMD. GBTMs have potential to identify and improve prediction of aging-related decline to better design and identify patients for interventions.
Receptor-Associated Prorenin System in the Trabecular Meshwork of Patients with Primary Open-Angle Glaucoma and Neovascular Glaucoma
Authors: Ishizuka Erdal Tan , Kanda Atsuhiro , Shinmei Yasuhiro , Ohguchi Takeshi , Tagawa Yoshiaki , Hase Keitaro , Yamamoto Taku , Noda Kousuke , Chin Shinki , Ishida Susumu
Published: July 2020

The receptor-associated prorenin system (RAPS) is associated with several pathologic conditions, including diabetic retinopathy, age-related macular degeneration, and uveitis. Here, we show the involvement of RAPS in the trabecular meshwork (TM) from patients with primary open-angle glaucoma (POAG) and neovascular glaucoma (NVG) due to proliferative diabetic retinopathy. Anterior chamber (AC) levels of prorenin significantly increased in both POAG and NVG, as did those of angiotensin II in NVG alone, compared to cataract. In surgically excised TM tissues, (pro)renin receptor ((P)RR) and angiotensin II type 1 receptor (AT1R) co-localized with prorenin and angiotensinogen, respectively. In screening for various genes related to glaucoma, prorenin stimulation to human TM cells exclusively upregulated cell junction constituents connexin 43 and zona occludens 1, while downregulating an extracellular matrix-degrading enzyme tissue plasminogen activator, all of which were reversed by (P)RR blockade. In contrast, angiotensin II application upregulated a pro-angiogenic factor placental growth factor alone, which was abolished by AT1R blockade. Consistently, (P)RR and AT1R co-localized with these corresponding proteins in patient TM tissues. Oxidative stress, a known etiology for glaucoma, induced the expression of prorenin and angiotensinogen in human TM cells. These data suggest the contribution of RAPS to the molecular pathogenesis of POAG and NVG through TM tissue remodeling and AC angle angiogenesis.
Outcome of Recipient Surgery and 6-Month Follow-Up of the Swedish Live Donor Robotic Uterus Transplantation Trial
Authors: Brännström Mats , Dahm-Kähler Pernilla , Ekberg Jana , Akouri Randa , Groth Klaus , Enskog Anders , Broecker Verena , Mölne Johan , Ayoubi Jean-Marc , Kvarnström Niclas
Published: July 2020

Uterus transplantation has proved to be a feasible treatment for uterine factor infertility. Herein, we report on recipient outcome in the robotic uterus transplantation trial of 2017–2019. The eight recipients had congenital uterine aplasia. The donors were six mothers, one sister, and one family friend. Donor surgery was by robotic-assisted laparoscopy. Recipient surgery was by laparotomy and vascular anastomoses to the external iliacs. The duration (median (ranges)) of recipient surgery, blood loss, measured (left/right) uterine artery blood flow after reperfusion, and length of hospital stay were 5.15 h (4.5–6.6), 300 mL (150–600), 43.5 mL/min (20–125)/37.5 mL/min (10–98), and 6 days (5–9), respectively. Postoperative uterine perfusion evaluated by color Doppler showed open anastomoses but restricted blood distribution in two cases. Repeated cervical biopsies in these two cases initially showed ischemia and, later, necrosis. Endometrial growth was not seen, and hysterectomy was later performed, with pathology showing partly viable myometrium and fibrosis but necrosis towards the cavity. The other six patients acquired regular menstrual cyclicity. Surgery was performed in two patients to correct vaginal stenosis. Reversible rejection episodes were seen in two patients. In conclusion, the rate of viable uterine grafts during the initial 6-months of the present study (75%) leaves room for improvement in the inclusion/exclusion criteria of donors and in surgical techniques. Initial low blood flow may indicate subsequent graft failure.