bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of Soil Survey Estimates of Saturated Hydraulic Conductivity in Major Soils of Puerto Rico
Authors: Juliá Fernando E. , Snyder Victor A. , Vázquez Miguel A.
Published: June 2021

Ranges or “classes” of probable saturated hydraulic conductivity values (Ksat) are listed for all soil series in USDA-NRCS Soil Survey reports. Listed values are not measured, but rather estimated from other soil properties using a pedotransfer function (PTF). To validate the PTF, we compared estimated Ksat classes with measured values in various horizons of nine major soil series of Puerto Rico. For each horizon, a minimum of 9 and usually 16 Ksat measurements were made with Guelph permeameters near locations where soil pedons had been thoroughly described. In most horizons, Ksat was log-normally distributed. The ratios of Ksat values corresponding to one geometric standard deviation above and below the mean were usually less than 10, which is the ratio of upper and lower class boundaries in the Ksat classification system. For most horizons, measured Ksat values were distributed among the rated Ksat class and the next higher class, indicating that the PTF systematically underestimated the Ksat distributions, but by less than an order of magnitude. From the point of view of soil and water management decisions requiring conservative Ksat estimates, the PTF estimates appeared reasonably conservative without deviating from actual values so as to limit the usefulness of the estimates.
Evaluation of the Efficacy and Safety of an Exercise Program for Persons with Total Hip or Total Knee Replacement: Study Protocol for a Randomized Controlled Trial
Authors: Barone Giuseppe , Zinno Raffaele , Pinelli Erika ,   PAIR Study Group, Benvenuti Francesco , Bragonzoni Laura
Published: June 2021

Total hip replacement (THR) and total knee replacement (TKR) are among the most common elective surgical procedures. There is a large consensus on the importance of physical activity promotion for an active lifestyle in persons who underwent THR or TKR to prevent or mitigate disability and improve the quality of life (QoL) in the long term. However, there is no best practice in exercise and physical activity specifically designed for these persons. The present protocol aims to evaluate the efficacy and safety of an exercise program (6 month duration) designed for improving quality of life in people who had undergone THR or TKR. This paper describes a randomized controlled trial protocol that involves persons with THR or TKR. The participant will be randomly assigned to an intervention group or a control group. The intervention group will perform post-rehabilitation supervised training; the control group will be requested to follow the usual care. The primary outcome is QoL, measured with the Short-Form Health Survey (SF-36); Secondary outcomes are clinical, functional and lifestyle measures that may influence QoL. The results of this study could provide evidence for clinicians, exercise trainers, and policymakers toward a strategy that ensures safe and effective exercise physical activity after surgery.
The Psychological and Quality of Life Impacts on Women in Hong Kong during the COVID-19 Pandemic
Authors: Hung Maria Shuk Yu , Lam Stanley Kam Ki , Chan Liliane Chui King , Liu Sisi Pui Shan , Chow Meyrick Chum Ming
Published: June 2021

The coronavirus (COVID-19) pandemic has caused a global health crisis. The adverse impacts on Asian women, including those in Hong Kong, are substantial. This cross-sectional online study examined the impacts of COVID-19 on Hong Kong women, including psychological effects, self-belief in coping, and quality of life, and was conducted over 4 weeks from July to August 2020. Females aged over 18, living in Hong Kong, and that could read Chinese, were included. Among 417 participants, 50.8% were aged below 50, 66.7% were married, 57.1% were caregivers, 61.4% had a family income of <USD 2600, and 70.3% attained higher secondary education or above. The results show that 32.2%, 42.4%, and 44.9% of participants had negative emotions of stress, anxiety, and depression. There are significant negative correlations between emotional state and different aspects of quality of life, but positive correlations between general self-efficacy and different aspects of quality of life. COVID-19 induced significant psychological and quality of life impacts on females in Hong Kong. The policymakers, healthcare professionals, and social support organizations should establish appropriate strategies and policies to support women during the COVID-19 pandemic or similar future crises.
Ageist Attitudes Are Associated with Will-to-Live and Moderated by Age, Medical Conditions and Attitudes toward Aging
Authors: Gvili Racheli-Lital , Bodner Ehud
Published: June 2021

The extent to which older adults’ ageist attitudes associate with their will-to-live has barely been studied. Moreover, whether this effect is moderated by older adults’ age, medical conditions, and attitudes toward their own aging has not been investigated. These associations were examined by two studies. Study 1 examined the relationship between ageist attitudes and will-to-live among individuals aged 48–97, and the moderating roles of age and medical conditions on this connection. Study 2 reassessed this connection in a new sample of older adults (people aged 60–94 years) and examined the moderating role of their attitudes toward aging in this regard. In line with the hypothesis of the first study, ageist attitudes and will-to-live were negatively associated among older adults with more medical conditions. In accordance with the hypotheses of study 2, the ageist attitudes and will-to-live connection was reconstructed, and when regressed on the ageist attitudes × attitudes toward aging interaction, it remained significant only among those with increased ageist attitudes. These findings demonstrate the negative effect that ageist attitudes may have on will-to-live, especially among the very old, and particularly when their health deteriorates, and support the utility of interventions aimed at increasing their will-to-live.
The Impact of Different Types of Shift Work on Blood Pressure and Hypertension: A Systematic Review and Meta-Analysis
Authors: Gamboa Madeira Sara , Fernandes Carina , Paiva Teresa , Santos Moreira Carlos , Caldeira Daniel
Published: June 2021

Shift work (SW) encompasses 20% of the European workforce. Moreover, high blood pressure (BP) remains a leading cause of death globally. This review aimed to synthesize the magnitude of the potential impact of SW on systolic blood pressure (SBP), diastolic blood pressure (DBP) and hypertension (HTN). MEDLINE, EMBASE and CENTRAL databases were searched for epidemiological studies evaluating BP and/or HTN diagnosis among shift workers, compared with day workers. Random-effects meta-analyses were performed and the results were expressed as pooled mean differences or odds ratios and 95% confidence intervals (95% CI). The Newcastle–Ottawa Scale was used to assess the risk of bias. Forty-five studies were included, involving 117,252 workers. We found a significant increase in both SBD and DBP among permanent night workers (2.52 mmHg, 95% CI 0.75–4.29 and 1.76 mmHg, 95% CI 0.41–3.12, respectively). For rotational shift workers, both with and without night work, we found a significant increase but only for SBP (0.65 mmHg, 95% CI 0.07–1.22 and 1.28 mmHg, 95% CI 0.18–2.39, respectively). No differences were found for HTN. Our findings suggest that SW is associated with an increase of BP, mainly for permanent night workers and for SBP. This is of special interest given the large number of susceptible workers exposed over time.
Medical Cost of Cancer Care for Privately Insured Children in Chile
Authors: Borrescio-Higa Florencia , Valdés Nieves
Published: June 2021

Medical care for children with cancer is complex and expensive, and represents a large financial burden for families around the world. We estimated the medical cost of cancer care for children under the age of 18, using administrative records of the universe of children with private insurance in Chile in the period 2007–2018, based on a sample of 3853 observations. We analyzed total cost and out-of-pocket spending by patients’ characteristics, type of cancer, and by service. Children with cancer had high annual medical costs, USD 32,287 on average for 2018. Costs were higher for the younger children in the sample. The vast majority of the cost was driven by inpatient hospital care for all types of cancer. The average total cost increased 20% in real terms over the period of study, while out-of-pocket expenses increased almost 29%. Private insurance beneficiaries faced a significant economic burden associated with medical treatment of a child with cancer. Interventions that reduce hospitalizations, as well as systemwide reforms that incorporate maximum out-of-pocket payments and prevent catastrophic expenditures, can contribute to alleviating the financial burden of childhood cancer.
A Systematic Review and Meta-Analysis of Telemonitoring Interventions on Severe COPD Exacerbations
Authors: Jang Sujin , Kim Youngmee , Cho Won-Kyung
Published: June 2021

This systematic review and meta-analysis aimed to provide current evidence regarding the effectiveness of telemonitoring for preventing COPD exacerbations, focusing on severe exacerbations requiring hospitalisation or emergency room (ER) visits. We systematically searched for randomised controlled trials using nine databases from August to September 2020 following the Cochrane Collaboration Guidelines. Of 2159 records identified, 22 studies involving 2906 participants met the inclusion criteria. The participants in 55% and 59% of studies had severe airflow limitations and severe exacerbation histories in the preceding year, respectively. The most commonly telemonitored data were oxygen saturation (91%) and symptoms (73%). A meta-analysis showed that telemonitoring did not reduce the number of admissions (12 studies) but decreased the number of ER visits due to severe exacerbations [7 studies combined, standardised mean difference (SMD) = −0.14; 95% confidence interval (CI): −0.28, −0.01]. Most studies reported no benefit in mortality, quality of life, or cost-effectiveness. All eight studies that surveyed participant satisfaction reported high satisfaction levels. Our review suggested that adding telemonitoring to usual care reduced unnecessary ER visits but was unlikely to prevent hospitalisations due to COPD exacerbations and that telemonitoring was well-accepted by patients with COPD and could be easily integrated into their existing care.
Future Changes in Simulated Evapotranspiration across Continental Africa Based on CMIP6 CNRM-CM6
Authors: Nooni Isaac Kwesi , Hagan Daniel Fiifi T. , Wang Guojie , Ullah Waheed , Lu Jiao , Li Shijie , Dzakpasu Mawuli , Prempeh Nana Agyemang , Lim Kam Sian Kenny T. C.
Published: June 2021

The main goal of this study was to assess the interannual variations and spatial patterns of projected changes in simulated evapotranspiration (ET) in the 21st century over continental Africa based on the latest Shared Socioeconomic Pathways and the Representative Concentration Pathways (SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5) provided by the France Centre National de Recherches Météorologiques (CNRM-CM) model in the Sixth Phase of Coupled Model Intercomparison Project (CMIP6) framework. The projected spatial and temporal changes were computed for three time slices: 2020–2039 (near future), 2040–2069 (mid-century), and 2080–2099 (end-of-the-century), relative to the baseline period (1995–2014). The results show that the spatial pattern of the projected ET was not uniform and varied across the climate region and under the SSP-RCPs scenarios. Although the trends varied, they were statistically significant for all SSP-RCPs. The SSP5-8.5 and SSP3-7.0 projected higher ET seasonality than SSP1-2.6 and SSP2-4.5. In general, we suggest the need for modelers and forecasters to pay more attention to changes in the simulated ET and their impact on extreme events. The findings provide useful information for water resources managers to develop specific measures to mitigate extreme events in the regions most affected by possible changes in the region’s climate. However, readers are advised to treat the results with caution as they are based on a single GCM model. Further research on multi-model ensembles (as more models’ outputs become available) and possible key drivers may provide additional information on CMIP6 ET projections in the region.
Benefits in the Macrophage Response Due to Graphene Oxide Reduction by Thermal Treatment
Authors: Cicuéndez Mónica , Casarrubios Laura , Barroca Nathalie , Silva Daniela , Feito María José , Diez-Orejas Rosalía , Marques Paula A. A. P. , Portolés María Teresa
Published: June 2021

Graphene and its derivatives are very promising nanomaterials for biomedical applications and are proving to be very useful for the preparation of scaffolds for tissue repair. The response of immune cells to these graphene-based materials (GBM) appears to be critical in promoting regeneration, thus, the study of this response is essential before they are used to prepare any type of scaffold. Another relevant factor is the variability of the GBM surface chemistry, namely the type and quantity of oxygen functional groups, which may have an important effect on cell behavior. The response of RAW-264.7 macrophages to graphene oxide (GO) and two types of reduced GO, rGO15 and rGO30, obtained after vacuum-assisted thermal treatment of 15 and 30 min, respectively, was evaluated by analyzing the uptake of these nanostructures, the intracellular content of reactive oxygen species, and specific markers of the proinflammatory M1 phenotype, such as CD80 expression and secretion of inflammatory cytokines TNF-α and IL-6. Our results demonstrate that GO reduction resulted in a decrease of both oxidative stress and proinflammatory cytokine secretion, significantly improving its biocompatibility and potential for the preparation of 3D scaffolds able of triggering the appropriate immune response for tissue regeneration.
Renin-Angiotensin System in Pathogenesis of Atherosclerosis and Treatment of CVD
Authors: Poznyak Anastasia V. , Bharadwaj Dwaipayan , Prasad Gauri , Grechko Andrey V. , Sazonova Margarita A. , Orekhov Alexander N.
Published: June 2021

Atherosclerosis has complex pathogenesis, which involves at least three serious aspects: inflammation, lipid metabolism alterations, and endothelial injury. There are no effective treatment options, as well as preventive measures for atherosclerosis. However, this disease has various severe complications, the most severe of which is cardiovascular disease (CVD). It is important to note, that CVD is among the leading causes of death worldwide. The renin–angiotensin–aldosterone system (RAAS) is an important part of inflammatory response regulation. This system contributes to the recruitment of inflammatory cells to the injured site and stimulates the production of various cytokines, such as IL-6, TNF-a, and COX-2. There is also an association between RAAS and oxidative stress, which is also an important player in atherogenesis. Angiotensin-II induces plaque formation at early stages, and this is one of the most crucial impacts on atherogenesis from the RAAS. Importantly, while stimulating the production of ROS, Angiotensin-II at the same time decreases the generation of NO. The endothelium is known as a major contributor to vascular function. Oxidative stress is the main trigger of endothelial dysfunction, and, once again, links RAAS to the pathogenesis of atherosclerosis. All these implications of RAAS in atherogenesis lead to an explicable conclusion that elements of RAAS can be promising targets for atherosclerosis treatment. In this review, we also summarize the data on treatment approaches involving cytokine targeting in CVD, which can contribute to a better understanding of atherogenesis and even its prevention.
Do Changes in ACE-2 Expression Affect SARS-CoV-2 Virulence and Related Complications: A Closer Look into Membrane-Bound and Soluble Forms
Authors: Yalcin Huseyin C. , Sukumaran Vijayakumar , Al-Ruweidi Mahmoud Khatib A. A. , Shurbaji Samar
Published: June 2021

The SARS-CoV-2 virus utilizes angiotensin converting enzyme (ACE-2) for cell entry and infection. This enzyme has important functions in the renin-angiotensin aldosterone system to preserve cardiovascular function. In addition to the heart, it is expressed in many tissues including the lung, intestines, brain, and kidney, however, its functions in these organs are mostly unknown. ACE-2 has membrane-bound and soluble forms. Its expression levels are altered in disease states and by a variety of medications. Currently, it is not clear how altered ACE-2 levels influence ACE-2 virulence and relevant complications. In addition, membrane-bound and soluble forms are thought to have different effects. Most work on this topic in the literature is on the SARS-CoV virus that has a high genetic resemblance to SARS-Co-V-2 and also uses ACE-2 enzyme to enter the cell, but with much lower affinity. More recent studies on SARS-CoV-2 are mainly clinical studies aiming at relating the effect of medications that are thought to influence ACE-2 levels, with COVID-19 outcomes for patients under these medications. This review paper aims to summarize what is known about the relationship between ACE-2 levels and SARS-CoV/SARS-CoV-2 virulence under altered ACE-2 expression states.
The Adipose Tissue-Derived Secretome (ADS) in Obesity Uniquely Induces L-Type Amino Acid Transporter 1 (LAT1) and mTOR Signaling in Estrogen-Receptor-Positive Breast Cancer Cells
Authors: Thompson Chelsea , Rahman M Motiur , Singh Soudamani , Arthur Subha , Sierra-Bakhshi Cecilia , Russell Rebecca , Denning Krista , Sundaram Uma , Salisbury Travis
Published: June 2021

Obesity increases the risk of postmenopausal breast cancer (BC). This risk is mediated by obesity-induced changes in the adipose-derived secretome (ADS). The pathogenesis of BC in obesity is stimulated by mTOR hyperactivity. In obesity, leucine might support mTOR hyperactivity. Leucine uptake by BC cells is through L-Type Amino Acid Transporter 1 (LAT1). Our objective was to link obesity-ADS induction of LAT1 to the induction of mTOR signaling. Lean- and obese-ADS were obtained from lean and obese mice, respectively. Breast ADS was obtained from BC patients. Estrogen-receptor-positive BC cells were stimulated with ADS. LAT1 activity was determined by uptake of 3H-leucine. The LAT1/CD98 complex, and mTOR signaling were assayed by Western blot. The LAT1 antagonists, BCH and JPH203, were used to inhibit LAT1. Cell migration and invasion were measured by Transwell assays. The results showed obese-ADS-induced LAT1 activity by increasing transporter affinity for leucine. Consistent with this mechanism, LAT1 and CD98 expression were unchanged. Induction of mTOR by obese-ADS was inhibited by LAT1 antagonists. Breast ADS from patients with BMIs > 30 stimulated BC cell migration and invasiveness. Collectively, our findings show that obese-ADS induction of LAT1 supports mTOR hyperactivity in luminal BC cells.
CD163 as a Potential Biomarker of Monocyte Activation in Ischemic Stroke Patients
Authors: Greco Rosaria , Demartini Chiara , Zanaboni Anna Maria , Tumelero Elena , Persico Alessandra , Candeloro Elisa , Morotti Andrea , Amantea Diana , Tassorelli Cristina
Published: June 2021

In ischemic stroke patients, a higher monocyte count is associated with disease severity and worse prognosis. The complex correlation between subset phenotypes and functions underscores the importance of clarifying the role of monocyte subpopulations. We examined the subtype-specific distribution of the CD163+ and CD80+ circulating monocytes and evaluated their association with the inflammatory status in 26 ischemic stroke patients and 16 healthy controls. An increased percentage of CD163+/CD16+ and CD163+/CD14++ events occurred 24 and 48 h after a stroke compared to the controls. CD163+ expression was more pronounced in CD16+ non-classical and intermediate monocytes, as compared to CD14+ classical subtype, 24 h after stroke. Conversely, the percentage of CD80+/CD16+ events was unaffected in patients; meanwhile, the percentage of CD80+/CD14+ events significantly increased only 24 h after stroke. Interleukin (IL)-1beta, TNF-alpha, and IL-4 mRNA levels were higher, while IL-10 mRNA levels were reduced in total monocytes from patients versus controls, at either 24 h or 48 h after stroke. The percentage of CD163+/CD16+ events 24 h after stroke was positively associated with NIHSS score and mRS at admission, suggesting that stroke severity and disability are relevant triggers for CD163+ expression in circulating CD16+ monocytes.
NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas
Authors: Bohuslavova Romana , Smolik Ondrej , Malfatti Jessica , Berkova Zuzana , Novakova Zaneta , Saudek Frantisek , Pavlinkova Gabriela
Published: June 2021

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.
NOD-Like Receptors: Guards of Cellular Homeostasis Perturbation during Infection
Authors: Pei Gang , Dorhoi Anca
Published: June 2021

The innate immune system relies on families of pattern recognition receptors (PRRs) that detect distinct conserved molecular motifs from microbes to initiate antimicrobial responses. Activation of PRRs triggers a series of signaling cascades, leading to the release of pro-inflammatory cytokines, chemokines and antimicrobials, thereby contributing to the early host defense against microbes and regulating adaptive immunity. Additionally, PRRs can detect perturbation of cellular homeostasis caused by pathogens and fine-tune the immune responses. Among PRRs, nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) have attracted particular interest in the context of cellular stress-induced inflammation during infection. Recently, mechanistic insights into the monitoring of cellular homeostasis perturbation by NLRs have been provided. We summarize the current knowledge about the disruption of cellular homeostasis by pathogens and focus on NLRs as innate immune sensors for its detection. We highlight the mechanisms employed by various pathogens to elicit cytoskeleton disruption, organelle stress as well as protein translation block, point out exemplary NLRs that guard cellular homeostasis during infection and introduce the concept of stress-associated molecular patterns (SAMPs). We postulate that integration of information about microbial patterns, danger signals, and SAMPs enables the innate immune system with adequate plasticity and precision in elaborating responses to microbes of variable virulence.
Ultra-Low Dose Cytokines in Rheumatoid Arthritis, Three Birds with One Stone as the Rationale of the 2LARTH® Micro-Immunotherapy Treatment
Authors: Jacques Camille , Floris Ilaria , Lejeune Béatrice
Published: June 2021

Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are two cytokines involved in the perpetuation of the chronic inflammation state characterizing rheumatoid arthritis (RA). Significant advances in the treatment of this pathology have been made over the past ten years, partially through the development of anti-TNF and anti-IL-1 therapies. However, major side effects still persist and new alternative therapies should be considered. The formulation of the micro-immunotherapy medicine (MIM) 2LARTH® uses ultra-low doses (ULD) of TNF-α, IL-1β, and IL-2, in association with other immune factors, to gently restore the body’s homeostasis. The first part of this review aims at delineating the pivotal roles played by IL-1β and TNF-α in RA physiopathology, leading to the development of anti-TNF and anti-IL-1 therapeutic agents. In a second part, an emphasis will be made on explaining the rationale of using multiple therapeutic targets, including both IL-1β and TNF-α in 2LARTH® medicine. Particular attention will be paid to the ULD of those two main pro-inflammatory factors in order to counteract their overexpression through the lens of their molecular implication in RA pathogenesis.
Molecular Characterisation of Uterine Endometrial Proteins during Early Stages of Pregnancy in Pigs by MALDI TOF/TOF
Authors: Pierzchała Dorota , Liput Kamila , Korwin-Kossakowska Agnieszka , Ogłuszka Magdalena , Poławska Ewa , Nawrocka Agata , Urbański Paweł , Ciepłoch Aleksandra , Juszczuk-Kubiak Edyta , Lepczyński Adam , Ślaska Brygida , Kowal Krzysztof , te Pas Marinus F. W. , Śmiech Magdalena , Leszczyński Paweł , Taniguchi Hiroaki , Fraser Leyland , Sobiech Przemysław , Sachajko Mateusz , Herudzinska Magdalena , Pareek Chandra S. , Pierzchała Mariusz
Published: June 2021

The molecular mechanism underlying embryonic implantation is vital to understand the correct communications between endometrium and developing conceptus during early stages of pregnancy. This study’s objective was to determine molecular changes in the uterine endometrial proteome during the preimplantation and peri-implantation between 9 days (9D), 12 days (12D), and 16 days (16D) of pregnant Polish Large White (PLW) gilts. 2DE-MALDI-TOF/TOF and ClueGOTM approaches were employed to analyse the biological networks and molecular changes in porcine endometrial proteome during maternal recognition of pregnancy. A total of sixteen differentially expressed proteins (DEPs) were identified using 2-DE gels and MALDI-TOF/TOF mass spectrometry. Comparison between 9D and 12D of pregnancy identified APOA1, CAPZB, LDHB, CCT5, ANXA4, CFB, TTR upregulated DEPs, and ANXA5, SMS downregulated DEPs. Comparison between 9D and 16D of pregnancy identified HP, APOA1, ACTB, CCT5, ANXA4, CFB upregulated DEPs and ANXA5, SMS, LDHB, ACTR3, HP, ENO3, OAT downregulated DEPs. However, a comparison between 12D and 16D of pregnancy identified HP, ACTB upregulated DEPs, and CRYM, ANXA4, ANXA5, CAPZB, LDHB, ACTR3, CCT5, ENO3, OAT, TTR down-regulated DEPs. Outcomes of this study revealed key proteins and their interactions with metabolic pathways involved in the recognition and establishment of early pregnancy in PLW gilts.
MicroRNA 195-5p Targets Foxo3 Promoter Region to Regulate Its Expression in Granulosa Cells
Authors: Bai Yinshan , Pan Bo , Zhan Xiaoshu , Silver Hailey , Li Julang
Published: June 2021

Forkhead box O3 (Foxo3) is a member of the FOXO subfamily within the forkhead box (FOX) family, which has been shown to be essential for ovarian follicular development and maturation. Previous studies have shown the abundant expression of miR-195-5p in the nuclei of porcine granulosa cells (GCs), suggesting its potential role during ovarian follicle growth. In this study, a conditional immortalized porcine granulosa cell (CIPGC) line was used to determine whether the expression of Foxo3 could be regulated by the nuclear-enriched miR-195-5p. Through silico target prediction, we identified a potential binding site of miR-195-5p within the Foxo3 promoter. The over-expression of miR-195-5p increased Foxo3 expression at both mRNA and protein levels, while the knockdown of miR-195-5p decreased the expression of Foxo3. Furthermore, driven by the Foxo3 promoter, luciferase reporter activity was increased in response to miR-195-5p, while the mutation of the miR-195-5p binding site in the promoter region abolished this effect. In addition, the siRNA knockdown of Argonaute (AGO) 2, but not AGO1, significantly decreased Foxo3 transcript level. However, miR-195-5p failed to upregulate Foxo3 expression when AGO2 was knocked down. Moreover, chromatin immunoprecipitation (CHIP) assay showed that anti-AGO2 antibody pulled down both AGO2 and the Foxo3 promoter sequence, suggesting that AGO2 may be required for miR-195-5p to regulate Foxo3 expression in the nucleus. Additionally, Foxo3 expression was significantly increased by valproic acid (VPA), the inhibitor of deacetylase, as well as by methyltransferase inhibitor BIX-01294, indicating the involvement of histone modification. These effects were further enhanced in the presence of miR-195-5p and were decreased when miR-195-5p was knocked down. Overall, our results suggest that nuclear-enriched miR-195-5p regulates Foxo3 expression, which may be associated with AGO2 recruitment, as well as histone demethylation and acetylation in ovarian granulosa cells.
Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma
Authors: Mergener Svenja , Siveke Jens T. , Peña-Llopis Samuel
Published: June 2021

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.
Photochemical Properties and Stability of BODIPY Dyes
Authors: Rybczynski Patryk , Smolarkiewicz-Wyczachowski Aleksander , Piskorz Jaroslaw , Bocian Szymon , Ziegler-Borowska Marta , Kędziera Dariusz , Kaczmarek-Kędziera Anna
Published: June 2021

The present study is devoted to the combined experimental and theoretical description of the photophysical properties and photodegradation of the new boron-dipyrromethene (BODIPY) derivatives obtained recently for biomedical applications, such as bacteria photoinactivation (Piskorz et al., Dyes and Pigments 2020, 178, 108322). Absorption and emission spectra for a wide group of solvents of different properties for the analyzed BODIPY derivatives were investigated in order to verify their suitability for photopharmacological applications. Additionally, the photostability of the analyzed systems were thoroughly determined. The exposition to the UV light was found first to cause the decrease in the most intensive absorption band and the appearance of the hypsochromically shifted band of similar intensity. On the basis of the chromatographic and computational study, this effect was assigned to the detachment of the iodine atoms from the BODIPY core. After longer exposition to UV light, photodegradation occurred, leading to the disappearance of the intensive absorption bands and the emergence of small intensity signals in the strongly blue-shifted range of the spectrum. Since the most intensive bands in original dyes are ascribed to the molecular core bearing the BF2 moiety, this result can be attributed to the significant cleavage of the BF2 ring. In order to fully characterize the obtained molecules, the comprehensive computational chemistry study was performed. The influence of the intermolecular interactions for their absorption in solution was analyzed. The theoretical data entirely support the experimental outcomes.
The Footprint of Kynurenine Pathway in Neurodegeneration: Janus-Faced Role in Parkinson’s Disorder and Therapeutic Implications
Authors: Behl Tapan , Kaur Ishnoor , Sehgal Aayush , Singh Sukhbir , Bhatia Saurabh , Al-Harrasi Ahmed , Zengin Gokhan , Bumbu Adrian Gheorghe , Andronie-Cioara Felicia Liana , Nechifor Aurelia Cristina , Gitea Daniela , Bungau Alexa Florina , Toma Mirela Marioara , Bungau Simona Gabriela
Published: June 2021

Progressive degeneration of neurons and aggravation of dopaminergic neurons in the substantia nigra pars compacta results in the loss of dopamine in the brain of Parkinson’s disease (PD) patients. Numerous therapies, exhibiting transient efficacy have been developed; however, they are mostly accompanied by side effects and limited reliability, therefore instigating the need to develop novel optimistic treatment targets. Significant therapeutic targets have been identified, namely: chaperones, protein Abelson, glucocerebrosidase-1, calcium, neuromelanin, ubiquitin-proteasome system, neuroinflammation, mitochondrial dysfunction, and the kynurenine pathway (KP). The role of KP and its metabolites and enzymes in PD, namely quinolinic acid (QUIN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranillic acid (3-HAA), kunurenine-3-monooxygenase (KMO), etc. has been reported. The neurotoxic QUIN, N-methyl-D-aspartate (NMDA) receptor agonist, and neuroprotective KYNA—which antagonizes QUIN actions—primarily justify the Janus-faced role of KP in PD. Moreover, KP has been reported to play a biomarker role in PD detection. Therefore, the authors detail the neurotoxic, neuroprotective, and immunomodulatory neuroactive components, alongside the upstream and downstream metabolic pathways of KP, forming a basis for a therapeutic paradigm of the disease while recognizing KP as a potential biomarker in PD, thus facilitating the development of a suitable target in PD management.
Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes
Authors: Delaitre Céline , Boisbrun Michel , Lecat Sandra , Dupuis François
Published: June 2021

The physiological and pathophysiological relevance of the angiotensin II type 1 (AT1) G protein-coupled receptor no longer needs to be proven in the cardiovascular system. The renin–angiotensin system and the AT1 receptor are the targets of several classes of therapeutics (such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, ARBs) used as first-line treatments in cardiovascular diseases. The importance of AT1 in the regulation of the cerebrovascular system is also acknowledged. However, despite numerous beneficial effects in preclinical experiments, ARBs do not induce satisfactory curative results in clinical stroke studies. A better understanding of AT1 signaling and the development of biased AT1 agonists, able to selectively activate the β-arrestin transduction pathway rather than the Gq pathway, have led to new therapeutic strategies to target detrimental effects of AT1 activation. In this paper, we review the involvement of AT1 in cerebrovascular diseases as well as recent advances in the understanding of its molecular dynamics and biased or non-biased signaling. We also describe why these alternative signaling pathways induced by β-arrestin biased AT1 agonists could be considered as new therapeutic avenues for cerebrovascular diseases.
MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It
Authors: Shklovskaya Elena , Rizos Helen
Published: June 2021

It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells.
The Effect of DREADD Activation of Leptin Receptor Positive Neurons in the Nucleus of the Solitary Tract on Sleep Disordered Breathing
Authors: Amorim Mateus , Dergacheva Olga , Fleury-Curado Thomaz , Pho Huy , Freire Carla , Mendelowitz David , Branco Luiz , Polotsky Vsevolod
Published: June 2021

Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway due to the loss of upper airway muscle tone during sleep. OSA is highly prevalent, especially in obesity. There is no pharmacotherapy for OSA. Previous studies have demonstrated the role of leptin, an adipose-tissue-produced hormone, as a potent respiratory stimulant. Leptin signaling via a long functional isoform of leptin receptor, LEPRb, in the nucleus of the solitary tract (NTS), has been implicated in control of breathing. We hypothesized that leptin acts on LEPRb positive neurons in the NTS to increase ventilation and maintain upper airway patency during sleep in obese mice. We expressed designer receptors exclusively activated by designer drugs (DREADD) selectively in the LEPRb positive neurons of the NTS of Leprb-Cre-GFP mice with diet-induced obesity (DIO) and examined the effect of DREADD ligand, J60, on tongue muscle activity and breathing during sleep. J60 was a potent activator of LEPRb positive NTS neurons, but did not stimulate breathing or upper airway muscles during NREM and REM sleep. We conclude that, in DIO mice, the stimulating effects of leptin on breathing during sleep are independent of LEPRb signaling in the NTS.
Neutrophils in Tumorigenesis: Missing Targets for Successful Next Generation Cancer Therapies?
Authors: Tolle Fabrice , Umansky Viktor , Utikal Jochen , Kreis Stephanie , Bréchard Sabrina
Published: June 2021

Neutrophils—once considered as simple killers of pathogens and unexciting for cancer research—are now acknowledged for their role in the process of tumorigenesis. Neutrophils are recruited to the tumor microenvironment where they turn into tumor-associated neutrophils (TANs), and are able to initiate and promote tumor progression and metastasis. Conversely, anti-tumorigenic properties of neutrophils have been documented, highlighting the versatile nature and high pleiotropic plasticity of these polymorphonuclear leukocytes (PMN-L). Here, we dissect the ambivalent roles of TANs in cancer and focus on selected functional aspects that could be therapeutic targets. Indeed, the critical point of targeting TAN functions lies in the fact that an immunosuppressive state could be induced, resulting in unwanted side effects. A deeper knowledge of the mechanisms linked to diverse TAN functions in different cancer types is necessary to define appropriate therapeutic strategies that are able to induce and maintain an anti-tumor microenvironment.
DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer’s Disease
Authors: Wang Heling , Lautrup Sofie , Caponio Domenica , Zhang Jianying , Fang Evandro
Published: June 2021

DNA repair ensures genomic stability to achieve healthy ageing, including cognitive maintenance. Mutations on genes encoding key DNA repair proteins can lead to diseases with accelerated ageing phenotypes. Some of these diseases are xeroderma pigmentosum group A (XPA, caused by mutation of XPA), Cockayne syndrome group A and group B (CSA, CSB, and are caused by mutations of CSA and CSB, respectively), ataxia-telangiectasia (A-T, caused by mutation of ATM), and Werner syndrome (WS, with most cases caused by mutations in WRN). Except for WS, a common trait of the aforementioned progerias is neurodegeneration. Evidence from studies using animal models and patient tissues suggests that the associated DNA repair deficiencies lead to depletion of cellular nicotinamide adenine dinucleotide (NAD+), resulting in impaired mitophagy, accumulation of damaged mitochondria, metabolic derailment, energy deprivation, and finally leading to neuronal dysfunction and loss. Intriguingly, these features are also observed in Alzheimer’s disease (AD), the most common type of dementia affecting more than 50 million individuals worldwide. Further studies on the mechanisms of the DNA repair deficient premature ageing diseases will help to unveil the mystery of ageing and may provide novel therapeutic strategies for AD.
External dsRNA Downregulates Anthocyanin Biosynthesis-Related Genes and Affects Anthocyanin Accumulation in Arabidopsis thaliana
Authors: Kiselev Konstantin V. , Suprun Andrey R. , Aleynova Olga A. , Ogneva Zlata V. , Kalachev Alexander V. , Dubrovina Alexandra S.
Published: June 2021

Exogenous application of double-stranded RNAs (dsRNAs) and small-interfering RNAs (siRNAs) to plant surfaces has emerged as a promising method for regulation of essential genes in plant pathogens and for plant disease protection. Yet, regulation of plant endogenous genes via external RNA treatments has not been sufficiently investigated. In this study, we targeted the genes of chalcone synthase (CHS), the key enzyme in the flavonoid/anthocyanin biosynthesis pathway, and two transcriptional factors, MYBL2 and ANAC032, negatively regulating anthocyanin biosynthesis in Arabidopsis. Direct foliar application of AtCHS-specific dsRNAs and siRNAs resulted in an efficient downregulation of the AtCHS gene and suppressed anthocyanin accumulation in A. thaliana under anthocyanin biosynthesis-modulating conditions. Targeting the AtMYBL2 and AtANAC032 genes by foliar dsRNA treatments markedly reduced their mRNA levels and led to a pronounced upregulation of the AtCHS gene. The content of anthocyanins was increased after treatment with AtMYBL2-dsRNA. Laser scanning microscopy showed a passage of Cy3-labeled AtCHS-dsRNA into the A. thaliana leaf vessels, leaf parenchyma cells, and stomata, indicating the dsRNA uptake and spreading into leaf tissues and plant individual cells. Together, these data show that exogenous dsRNAs were capable of downregulating Arabidopsis genes and induced relevant biochemical changes, which may have applications in plant biotechnology and gene functional studies.
Investigating Immune Responses to the scAAV9-HEXM Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse Models
Authors: Kot Shalini , Karumuthil-Melethil Subha , Woodley Evan , Zaric Violeta , Thompson Patrick , Chen Zhilin , Lykken Erik , Keimel John G. , Kaemmerer William F. , Gray Steven J. , Walia Jagdeep S.
Published: June 2021

GM2 gangliosidosis disorders are a group of neurodegenerative diseases that result from a functional deficiency of the enzyme β-hexosaminidase A (HexA). HexA consists of an α- and β-subunit; a deficiency in either subunit results in Tay–Sachs Disease (TSD) or Sandhoff Disease (SD), respectively. Viral vector gene transfer is viewed as a potential method of treating these diseases. A recently constructed isoenzyme to HexA, called HexM, has the ability to effectively catabolize GM2 gangliosides in vivo. Previous gene transfer studies have revealed that the scAAV9-HEXM treatment can improve survival in the murine SD model. However, it is speculated that this treatment could elicit an immune response to the carrier capsid and “non-self”-expressed transgene. This study was designed to assess the immunocompetence of TSD and SD mice, and test the immune response to the scAAV9-HEXM gene transfer. HexM vector-treated mice developed a significant anti-HexM T cell response and antibody response. This study confirms that TSD and SD mouse models are immunocompetent, and that gene transfer expression can create an immune response in these mice. These mouse models could be utilized for investigating methods of mitigating immune responses to gene transfer-expressed “non-self” proteins, and potentially improve treatment efficacy.
Efficacy of a Three Drug-Based Therapy for Neuroblastoma in Mice
Authors: Garbati Patrizia , Barbieri Raffaella , Calderoni Matilde , Baldini Francesca , Nizzari Mario , Modesto Paola , Florio Tullio , Pagano Aldo
Published: June 2021

High-risk neuroblastoma (HR-NB) still remains the most dangerous tumor in early childhood. For this reason, the identification of new therapeutic approaches is of fundamental importance. Recently, we combined the conventional pharmacological approach to NB, represented by cisplatin, with fendiline hydrochloride, an inhibitor of several transporters involved in multidrug resistance of cancer cells, which demonstrated an enhancement of the ability of cisplatin to induce apoptosis. In this work, we co-administrated acetazolamide, a carbonic anhydrase isoform IX (CAIX) inhibitor which was reported to increase chemotherapy efficacy in various cancer types, to the cisplatin/fendiline approach in SKNBE2 xenografts in NOD-SCID mice with the aim of identifying a novel and more effective treatment. We observed that the combination of the three drugs increases more than twelvefold the differences in the cytotoxic activity of cisplatin alone, leading to a remarkable decrease of the expression of malignancy markers. Our conclusion is that this approach, based on three FDA-approved drugs, may constitute an appropriate improvement of the pharmacological approach to HR-NB.
Emerging Prospects for Combating Fungal Infections by Targeting Phosphatidylinositol Transfer Proteins
Authors: Khan Danish , Nile Aaron H. , Tripathi Ashutosh , Bankaitis Vytas A.
Published: June 2021

The emergence of fungal “superbugs” resistant to the limited cohort of anti-fungal agents available to clinicians is eroding our ability to effectively treat infections by these virulent pathogens. As the threat of fungal infection is escalating worldwide, this dwindling response capacity is fueling concerns of impending global health emergencies. These developments underscore the urgent need for new classes of anti-fungal drugs and, therefore, the identification of new targets. Phosphoinositide signaling does not immediately appear to offer attractive targets due to its evolutionary conservation across the Eukaryota. However, recent evidence argues otherwise. Herein, we discuss the evidence identifying Sec14-like phosphatidylinositol transfer proteins (PITPs) as unexplored portals through which phosphoinositide signaling in virulent fungi can be chemically disrupted with exquisite selectivity. Recent identification of lead compounds that target fungal Sec14 proteins, derived from several distinct chemical scaffolds, reveals exciting inroads into the rational design of next generation Sec14 inhibitors. Development of appropriately refined next generation Sec14-directed inhibitors promises to expand the chemical weaponry available for deployment in the shifting field of engagement between fungal pathogens and their human hosts.