bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparisons of Different Methods to Determine Starting Altitudes for Dry Air Atmosphere by GNSS-RO Data
Authors: Andrisani Andrea , Vespe Francesco
Published: October 2021

Boundary profile evaluation (BPV) is an approach proposed in order to estimate water vapor content in the atmosphere. It exploits radio occultation (RO) observations of the signals emitted by the satellites of global navigation systems (GNSS) which are eclipsing (rising) as viewed by a low earth orbit satellite (LEO). BPV requires, as a preliminary step, the estimation of the dry background atmosphere model of refractivity (i.e., obtained from bending angle profiles) to be subtracted from the real observations in order to extract water vapor profiles. The determination of the lowest layer of the atmosphere over which the concentration of water vapor can be deemed negligible is particularly crucial for a correct application of the BPV method. In this study, we have applied three methods to set the starting altitudes for the dry air layers of the atmosphere: (1) by air temperature below some threshold values (for example, 250 K); (2) by “smooth” bending angle profiles in ROs; (3) by saturated water vapor pressure. These methods were tested with thermodynamic and bending angle profiles from 912 radiosonde excursions colocated with RO observations. For every dry air starting altitude we determined the best estimator from each of the three methods. In particular, by comparing those estimators with the quantiles and momenta of the dry air starting altitude distributions, we achieved improvements of up to 50% of the humidity profiles.
Maximum, Minimum, and Daily Air Temperature Range in Orchards: What Do Observations Reveal?
Authors: Firanj Sremac Ana , Lalic Branislava , Cuxart Joan , Marcic Milena
Published: October 2021

This study was designed to better understand vegetation’s impact on air maximum (Tmax), minimum (Tmin), and daily temperature range (DTR), as well as seasonality and variability. We selected a flat, under synoptic-scale, northern Serbian region with an operational network of automated weather stations (AWS) for the study. Data were collected directly from the eighteen AWSs placed in the orchard canopy during 2013–2018. Meteorological data, plant phenological data in the form of the BBCH scale, and orchards’ soil characteristics data were collected. Environmental factors influencing the temperature were classified as static (slow or unchangeable) and dynamic (fast-changing). The impact of both factors on maximum, minimum, and daily temperature range and its variability were analyzed. Results show that static factors (like soil texture) affect the annual variation of Tmax, Tmin, and DTR rather than its variability over the season. The dynamic factors, mainly coming from the plant’s phenology, substantially affected the seasonal variability of these variables. Studies like this suffer from missing data and sparse spatial coverage by the AWS network. Therefore, the alternatives of orchard micrometeorological data, nearest climatological station, and ERA5-Land reanalysis data are tested. Both data sets showcased limitations in their applicability, while reanalysis data deviated more from the in-situ measurements, both seasonally and regionally.
Evolution, Transport Characteristics, and Potential Source Regions of PM2.5 and O3 Pollution in a Coastal City of China during 2015–2020
Authors: Lv Min , Hu Anyong , Chen Jun , Wan Bingcheng
Published: October 2021

The evolution, transport characteristics, and potential source regions of PM2.5 and O3 were investigated from 1 January 2015 to 31 December 2020 in the coastal city of Nantong. The annual mean PM2.5 concentration declined obviously over the entire study period, and was 34.7 μg/m3 in 2020. O3 had a relatively smooth decreasing trend, but rebounded greatly during 2017 when the most frequent extreme high-temperature events occurred. Similar trends were observed for PM2.5 and O3 polluted hours. No PM2.5-O3 complex air pollution happened in 2019 and 2020, likely suggesting the preliminary results from the implementation of emission controls. Notable differences in transport pathways and frequencies were observed from the backward trajectory clusters in four seasons in Nantong. Clusters with the largest percentage of polluted PM2.5 and O3 trajectories were transported mostly over short distances rather than long distances. Analysis involving the potential source contribution function (PSCF) and concentration weighted trajectory (CWT) showed that PM2.5 polluted sources were from the adjacent western and northwestern provinces, whereas the influence of eastern marine sources was relatively small. O3 had a greatly different spatial distribution of polluted source regions from PM2.5, mostly covering the North China Plain, the Bohai Sea, and the Yellow Sea.
Bioactive Scaffolds Integrated with Liposomal or Extracellular Vesicles for Bone Regeneration
Authors: Kang Minjee , Lee Chung-Sung , Lee Min
Published: October 2021

With population aging and increased life expectancy, an increasing number of people are facing musculoskeletal health problems that necessitate therapeutic intervention at defect sites. Bone tissue engineering (BTE) has become a promising approach for bone graft substitutes as traditional treatments using autografts or allografts involve clinical complications. Significant advancements have been made in developing ideal BTE scaffolds that can integrate bioactive molecules promoting robust bone repair. Herein, we review bioactive scaffolds tuned for local bone regenerative therapy, particularly through integrating synthetic liposomal vesicles or extracellular vesicles to the scaffolds. Liposomes offer an excellent drug delivery system providing sustained release of the loaded bioactive molecules. Extracellular vesicles, with their inherent capacity to carry bioactive molecules, are emerging as an advanced substitute of synthetic nanoparticles and a novel cell-free therapy for bone regeneration. We discuss the recent advance in the use of synthetic liposomes and extracellular vesicles as bioactive materials combined with scaffolds, highlighting major challenges and opportunities for their applications in bone regeneration. We put a particular focus on strategies to integrate vesicles to various biomaterial scaffolds and introduce the latest advances in achieving sustained release of bioactive molecules from the vesicle-loaded scaffolds at the bone defect site.
Inflammation in Duchenne Muscular Dystrophy–Exploring the Role of Neutrophils in Muscle Damage and Regeneration
Authors: Tulangekar Ankita , Sztal Tamar E.
Published: October 2021

Duchenne muscular dystrophy (DMD) is a severe and progressive, X-linked, neuromuscular disorder caused by mutations in the dystrophin gene. In DMD, the lack of functional dystrophin protein makes the muscle membrane fragile, leaving the muscle fibers prone to damage during contraction. Muscle degeneration in DMD patients is closely associated with a prolonged inflammatory response, and while this is important to stimulate regeneration, inflammation is also thought to exacerbate muscle damage. Neutrophils are one of the first immune cells to be recruited to the damaged muscle and are the first line of defense during tissue injury or infection. Neutrophils can promote inflammation by releasing pro-inflammatory cytokines and compounds, including myeloperoxidase (MPO) and neutrophil elastase (NE), that lead to oxidative stress and are thought to have a role in prolonging inflammation in DMD. In this review, we provide an overview of the roles of the innate immune response, with particular focus on mechanisms used by neutrophils to exacerbate muscle damage and impair regeneration in DMD.
Optical Biosensor Platforms Display Varying Sensitivity for the Direct Detection of Influenza RNA
Authors: Courtney Samantha , Stromberg Zachary , Myers y Gutiérrez Adán , Jacobsen Daniel , Stromberg Loreen , Lenz Kiersten , Theiler James , Foley Brian , Gans Jason , Yusim Karina , Kubicek-Sutherland Jessica
Published: October 2021

Detection methods that do not require nucleic acid amplification are advantageous for viral diagnostics due to their rapid results. These platforms could provide information for both accurate diagnoses and pandemic surveillance. Influenza virus is prone to pandemic-inducing genetic mutations, so there is a need to apply these detection platforms to influenza diagnostics. Here, we analyzed the Fast Evaluation of Viral Emerging Risks (FEVER) pipeline on ultrasensitive detection platforms, including a waveguide-based optical biosensor and a flow cytometry bead-based assay. The pipeline was also evaluated in silico for sequence coverage in comparison to the U.S. Centers for Disease Control and Prevention’s (CDC) influenza A and B diagnostic assays. The influenza FEVER probe design had a higher tolerance for mismatched bases than the CDC’s probes, and the FEVER probes altogether had a higher detection rate for influenza isolate sequences from GenBank. When formatted for use as molecular beacons, the FEVER probes detected influenza RNA as low as 50 nM on the waveguide-based optical biosensor and 1 nM on the flow cytometer. In addition to molecular beacons, which have an inherently high background signal we also developed an exonuclease selection method that could detect 500 pM of RNA. The combination of high-coverage probes developed using the FEVER pipeline coupled with ultrasensitive optical biosensors is a promising approach for future influenza diagnostic and biosurveillance applications.
From Affordances to Abstract Words: The Flexibility of Sensorimotor Grounding
Authors: Mazzuca Claudia , Fini Chiara , Michalland Arthur Henri , Falcinelli Ilenia , Da Rold Federico , Tummolini Luca , Borghi Anna M.
Published: October 2021

The sensorimotor system plays a critical role in several cognitive processes. Here, we review recent studies documenting this interplay at different levels. First, we concentrate on studies that have shown how the sensorimotor system is flexibly involved in interactions with objects. We report evidence demonstrating how social context and situations influence affordance activation, and then focus on tactile and kinesthetic components in body–object interactions. Then, we turn to word use, and review studies that have shown that not only concrete words, but also abstract words are grounded in the sensorimotor system. We report evidence that abstract concepts activate the mouth effector more than concrete concepts, and discuss this effect in light of studies on adults, children, and infants. Finally, we pinpoint possible sensorimotor mechanisms at play in the acquisition and use of abstract concepts. Overall, we show that the involvement of the sensorimotor system is flexibly modulated by context, and that its role can be integrated and flanked by that of other systems such as the linguistic system. We suggest that to unravel the role of the sensorimotor system in cognition, future research should fully explore the complexity of this intricate, and sometimes slippery, relation.
Optimization and Validation of a Novel Three-Dimensional Co-Culture System in Decellularized Human Liver Scaffold for the Study of Liver Fibrosis and Cancer
Authors: Thanapirom Kessarin , Caon Elisabetta , Papatheodoridi Margarita , Frenguelli Luca , Al-Akkad Walid , Zhenzhen Zhang , Vilia Maria Giovanna , Pinzani Massimo , Mazza Giuseppe , Rombouts Krista
Published: October 2021

The introduction of new preclinical models for in vitro drug discovery and testing based on 3D tissue-specific extracellular matrix (ECM) is very much awaited. This study was aimed at developing and validating a co-culture model using decellularized human liver 3D ECM scaffolds as a platform for anti-fibrotic and anti-cancer drug testing. Decellularized 3D scaffolds obtained from healthy and cirrhotic human livers were bioengineered with LX2 and HEPG2 as single and co-cultures for up to 13 days and validated as a new drug-testing platform. Pro-fibrogenic markers and cancer phenotypic gene/protein expression and secretion were differently affected when single and co-cultures were exposed to TGF-β1 with specific ECM-dependent effects. The anti-fibrotic efficacy of Sorafenib significantly reduced TGF-β1-induced pro-fibrogenic effects, which coincided with a downregulation of STAT3 phosphorylation. The anti-cancer efficacy of Regorafenib was significantly reduced in 3D bioengineered cells when compared to 2D cultures and dose-dependently associated with cell apoptosis by cleaved PARP-1 activation and P-STAT3 inhibition. Regorafenib reversed TGF-β1-induced P-STAT3 and SHP-1 through induction of epithelial mesenchymal marker E-cadherin and downregulation of vimentin protein expression in both co-cultures engrafting healthy and cirrhotic 3D scaffolds. In their complex, the results of the study suggest that this newly proposed 3D co-culture platform is able to reproduce the natural physio-pathological microenvironment and could be employed for anti-fibrotic and anti-HCC drug screening.
SSTR2 in Nasopharyngeal Carcinoma: Relationship with Latent EBV Infection and Potential as a Therapeutic Target
Authors: Emanuel Oscar , Liu Jacklyn , Schartinger Volker H. , Nei Wen Long , Chan Yuk Yu , Tsang Chi Man , Riechelmann Herbert , Masterson Liam , Haybaeck Johannes , Oppermann Udo , Willems Stefan M. , Ooft Marc L. , Wollmann Guido , Howard David , Vanhaesebroeck Bart , Lund Valerie J. , Royle Gary , Chua Melvin L. K. , Lo Kwok Wai , Busson Pierre , Lechner Matt
Published: October 2021

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor, most commonly located in the pharyngeal recess and endemic to parts of Asia. It is often detected at a late stage which is associated with poor prognosis (5-year survival rate of 63%). Treatment for this malignancy relies predominantly on radiotherapy and/or systemic chemotherapy, which can be associated with significant morbidity and impaired quality of life. In endemic regions NPC is associated with infection by Epstein–Barr virus (EBV) which was shown to upregulate the somatostatin receptor 2 (SSTR2) cell surface receptor. With recent advances in molecular techniques allowing for an improved understanding of the molecular aetiology of this disease and its relation to SSTR2 expression, we provide a comprehensive and up-to-date overview of this disease and highlight the emergence of SSTR2 as a key tumor biomarker and promising target for imaging and therapy.
Flow Cytometry Immunophenotyping for Diagnostic Orientation and Classification of Pediatric Cancer Based on the EuroFlow Solid Tumor Orientation Tube (STOT)
Authors: Ferreira-Facio Cristiane de Sá , Botafogo Vitor , Ferrão Patrícia Mello , Canellas Maria Clara , Milito Cristiane B. , Romano Sérgio , Lopes Daiana V. , Teixeira Lisandra C. , Oliveira Elen , Bruno-Riscarolli Enrico , Mello Fabiana V. , Siqueira Patrícia F. R. , Moura Patrícia , Macedo Francisco Nicanor , Forny Danielle N. , Simião Luíza , Pureza Ana Luíza , Land Marcelo Gerardin Poirot , Pedreira Carlos Eduardo , Dongen Jacques J. M. van , Orfao Alberto , Costa Elaine Sobral da
Published: October 2021

Early diagnosis of pediatric cancer is key for adequate patient management and improved outcome. Although multiparameter flow cytometry (MFC) has proven of great utility in the diagnosis and classification of hematologic malignancies, its application to non-hematopoietic pediatric tumors remains limited. Here we designed and prospectively validated a new single eight-color antibody combination—solid tumor orientation tube, STOT—for diagnostic screening of pediatric cancer by MFC. A total of 476 samples (139 tumor mass, 138 bone marrow, 86 lymph node, 58 peripheral blood, and 55 other body fluid samples) from 296 patients with diagnostic suspicion of pediatric cancer were analyzed by MFC vs. conventional diagnostic procedures. STOT was designed after several design–test–evaluate–redesign cycles based on a large panel of monoclonal antibody combinations tested on 301 samples. In its final version, STOT consists of a single 8-color/12-marker antibody combination (CD99-CD8/numyogenin/CD4-EpCAM/CD56/GD2/smCD3-CD19/cyCD3-CD271/CD45). Prospective validation of STOT in 149 samples showed concordant results with the patient WHO/ICCC-3 diagnosis in 138/149 cases (92.6%). These included: 63/63 (100%) reactive/disease-free samples, 43/44 (98%) malignant and 4/4 (100%) benign non-hematopoietic tumors together with 28/38 (74%) leukemia/lymphoma cases; the only exception was Hodgkin lymphoma that required additional markers to be stained. In addition, STOT allowed accurate discrimination among the four most common subtypes of malignant CD45− CD56++ non-hematopoietic solid tumors: 13/13 (GD2++ numyogenin− CD271−/+ nuMyoD1− CD99− EpCAM−) neuroblastoma samples, 5/5 (GD2− numyogenin++ CD271++ nuMyoD1++ CD99−/+ EpCAM−) rhabdomyosarcomas, 2/2 (GD2−/+ numyogenin− CD271+ nuMyoD1− CD99+ EpCAM−) Ewing sarcoma family of tumors, and 7/7 (GD2− numyogenin− CD271+ nuMyoD1− CD99− EpCAM+) Wilms tumors. In summary, here we designed and validated a new standardized antibody combination and MFC assay for diagnostic screening of pediatric solid tumors that might contribute to fast and accurate diagnostic orientation and classification of pediatric cancer in routine clinical practice.
Light Therapy for Cancer-Related Fatigue in (Non-)Hodgkin Lymphoma Survivors: Results of a Randomized Controlled Trial
Authors: Starreveld Daniëlle E. J. , Daniels Laurien A. , Kieffer Jacobien M. , Valdimarsdottir Heiddis B. , de Geus Jessie , Lanfermeijer Mirthe , van Someren Eus J. W. , Habers G. Esther A. , Bosch Jos A. , Janus Cécile P. M. , van Spronsen Dick Johan , de Weijer Roel J. , Marijt Erik W. A. , de Jongh Eva , Zijlstra Josée M. , Böhmer Lara H. , Houmes Margreet , Kersten Marie José , Korse Catharina M. , van Rossum Huub H. , Redd William H. , Lutgendorf Susan K , Ancoli-Israel Sonia , van Leeuwen Flora E. , Bleiker Eveline M. A.
Published: October 2021

Purpose: To evaluate the short- and long-term effects of light therapy on fatigue (primary outcome) and sleep quality, depression, anxiety, quality of life, and circadian rhythms (secondary outcomes) in survivors of (non-)Hodgkin lymphoma presenting with chronic cancer-related fatigue. Methods: We randomly assigned 166 survivors (mean survival 13 years) to a bright white light intervention (BWL) or dim white light comparison (DWL) group. Measurements were completed at baseline (T0), post-intervention (T1), at three (T2), and nine (T3) months follow-up. A mixed-effect modeling approach was used to compare linear and non-linear effects of time between groups. Results: There were no significant differences between BWL and DWL in the reduction in fatigue over time. Both BWL and DWL significantly (p < 0.001) improved fatigue levels during the intervention followed by a slight reduction in this effect during follow-up (EST0-T1 = −0.71; EST1-T3 = 0.15). Similar results were found for depression, sleep quality, and some aspects of quality of life. Light therapy had no effect on circadian rhythms. Conclusions: BWL was not superior in reducing fatigue compared to DWL in HL and DLBCL survivors. Remarkably, the total sample showed clinically relevant and persistent improvements on fatigue not commonly seen in longitudinal observational studies in these survivors.
Treatment Pattern and Outcomes with Systemic Therapy in Men with Metastatic Prostate Cancer in the Real-World Patients in the United States
Authors: Swami Umang , Sinnott Jennifer Anne , Haaland Benjamin , Sayegh Nicolas , McFarland Taylor Ryan , Tripathi Nishita , Maughan Benjamin L. , Rathi Nityam , Sirohi Deepika , Nussenzveig Roberto , Kohli Manish , Pal Sumanta K. , Agarwal Neeraj
Published: October 2021

Background: Both novel hormonal therapies and docetaxel are approved for treatment of metastatic prostate cancer (mPC; in castration sensitive or refractory settings). Present knowledge gaps include lack of real-world data on treatment patterns in patients with newly diagnosed mPC, and comparative effectiveness of novel hormonal therapies (NHT) versus docetaxel after treatment with a prior NHT. Methods: Herein we extracted patient-level data from a large real-world database of patients with mPC in United States. Utilization of NHT or docetaxel for mPC and comparative effectiveness of an alternate NHT versus docetaxel after one prior NHT was evaluated. Comparative effectiveness was examined via Cox proportional hazards model with propensity score matching weights. Each patient’s propensity for treatment was modeled via random forest based on 22 factors potentially driving treatment selection. Results: The majority of patients (54%) received only androgen deprivation therapy for mPC. In patients treated with an NHT, alternate NHT was the most common next therapy and was associated with improved median overall survival over docetaxel (abiraterone followed by docetaxel vs. enzalutamide (8.7 vs. 15.6 months; adjusted hazards ratio; aHR 1.32; p = 0.009; and enzalutamide followed by docetaxel vs. abiraterone (9.7 vs. 13.2 months aHR 1.40; p = 0.009). Limitations of the study include retrospective design.
Interaction between Microsatellite Instability (MSI) and Tumor DNA Methylation in the Pathogenesis of Colorectal Carcinoma
Authors: Jasmine Farzana , Haq Zahidul , Kamal Mohammed , Raza Maruf , da Silva Gustavo , Gorospe Katrina , Paul Rupash , Strzempek Patrick , Ahsan Habibul , Kibriya Muhammad G
Published: October 2021

In colorectal cancer (CRC), the role of microsatellite instability (MSI) is well known. In a genome-wide scale, for the first time, we explored whether differential methylation is associated with MSI. We analyzed 250 paired samples from 125 CRC patients (m = 72, f = 53) at different stages. Of them, 101 had left-sided CRC, 30 had MSI, 34 had somatic mutation in KRAS proto-oncogene (KRAS), and 6 had B-Raf proto-oncogene (BRAF) exon 15p.V600E mutation. MSI was more frequent in right-sided tumors (54% vs. 17%, p = 0.003). Among the microsatellite stable (MSS) CRC, a paired comparison revealed 1641 differentially methylated loci (DML) covering 686 genes at FDR 0.001 with delta beta ≥ 20%. Similar analysis in MSI revealed 6209 DML covering 2316 genes. ANOVA model including interaction (Tumor*MSI) revealed 23,322 loci, where the delta beta was different among MSI and MSS patients. Our study shows an association between MSI and tumor DNA methylation in the pathogenesis of CRC. Given the interaction seen in this study, it may be worth considering the MSI status while looking for methylation markers in CRC. The study also indicates an opportunity for potential use of certain immune checkpoint inhibitors (CTLA4 and HAVCR2 inhibitors) in CRC with MSI.
Nucleolin Aptamer N6L Reprograms the Translational Machinery and Acts Synergistically with mTORi to Inhibit Pancreatic Cancer Proliferation
Authors: Chalabi-Dchar Mounira , Cruz Elisabeth , Mertani Hichem C. , Diaz Jean-Jacques , Courty José , Cascone Ilaria , Bouvet Philippe
Published: October 2021

We previously showed that N6L, a pseudopeptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease in global protein synthesis. However, about 6% of the mRNAs were enriched in the polysomes. We identified a 5′TOP motif in many of these mRNAs and demonstrated that a chimeric RNA bearing a 5‘TOP motif was up-regulated by N6L. We demonstrated that N6L activates the mTOR pathway, which is required for the translation of these mRNAs. An inhibitory synergistic effect in PDAC cell lines, including patient-derived xenografts and tumor-derived organoids, was observed when N6L was combined with mTOR inhibitors. In conclusion, N6L reduces pancreatic cells proliferation, which then undergoes translational reprogramming through activation of the mTOR pathway. N6L and mTOR inhibitors act synergistically to inhibit the proliferation of PDAC and human PDX cell lines. This combotherapy of N6L and mTOR inhibitors could constitute a promising alternative to treat pancreatic cancer.
Mutation of the EPHA2 Tyrosine-Kinase Domain Dysregulates Cell Pattern Formation and Cytoskeletal Gene Expression in the Lens
Authors: Zhou Yuefang , Bennett Thomas M. , Ruzycki Philip A. , Shiels Alan
Published: October 2021

Genetic variations in ephrin type-A receptor 2 (EPHA2) have been associated with inherited and age-related forms of cataract in humans. Here, we have characterized the eye lens phenotype and transcript profile of germline Epha2 knock-in mutant mice homozygous for either a missense variant associated with age-related cataract in humans (Epha2-Q722) or a novel insertion-deletion mutation (Epha2-indel722) that were both located within the tyrosine-kinase domain of EPHA2. Confocal imaging of ex vivo lenses from Epha2-indel722 mice on a fluorescent reporter background revealed misalignment of epithelial-to-fiber cell meridional-rows at the lens equator and severe disturbance of Y-suture formation at the lens poles, whereas Epha2-Q722 lenses displayed mild disturbance of posterior sutures. Immunofluorescent labeling showed that EPHA2 was localized to radial columns of hexagonal fiber cell membranes in Epha2-Q722 lenses, whereas Epha2-indel722 lenses displayed disorganized radial cell columns and cytoplasmic retention of EPHA2. Immunoprecipitation/blotting studies indicated that EPHA2 formed strong complexes with Src kinase and was mostly serine phosphorylated in the lens. RNA sequencing analysis revealed differential expression of several cytoskeleton-associated genes in Epha2-mutant and Epha2-null lenses including shared downregulation of Lgsn and Clic5. Collectively, our data suggest that mutations within the tyrosine-kinase domain of EPHA2 result in lens cell patterning defects and dysregulated expression of several cytoskeleton-associated proteins.
Pathological AT1R-B2R Protein Aggregation and Preeclampsia
Authors: Quitterer Ursula , AbdAlla Said
Published: October 2021

Preeclampsia is one of the most frequent and severe complications of pregnancy. Symptoms of preeclampsia usually occur after 20 weeks of pregnancy and include hypertension and kidney dysfunction with proteinuria. Up to now, delivery of the infant has been the most effective and life-saving treatment to alleviate symptoms of preeclampsia because a causative treatment does not exist, which could prolong a pregnancy complicated with preeclampsia. Preeclampsia is a complex medical condition, which is attributed to a variety of different risk factors and causes. Risk factors account for insufficient placentation and impaired vasculogenesis and finally culminate in this life-threatening condition of pregnancy. Despite progress, many pathomechanisms and causes of preeclampsia are still incompletely understood. In recent years, it was found that excessive protein complex formation between G-protein-coupled receptors is a common sign of preeclampsia. Specifically, the aberrant heteromerization of two vasoactive G-protein-coupled receptors (GPCRs), the angiotensin II AT1 receptor and the bradykinin B2 receptor, is a causative factor of preeclampsia symptoms. Based on this knowledge, inhibition of abnormal GPCR protein complex formation is an experimental treatment approach of preeclampsia. This review summarizes the impact of pathological GPCR protein aggregation on symptoms of preeclampsia and delineates potential new therapeutic targets.
Eosinophils, beyond IL-5
Authors: Esnault Stephane , Johansson Mats W , Mathur Sameer K
Published: October 2021

New therapeutic monoclonal antibodies targeting the IL-5/IL-5 receptor pathway are extremely efficient in depleting blood eosinophils from subjects with asthma [...]
1,8-Cineole Affects Agonists-Induced Platelet Activation, Thrombus Formation and Haemostasis
Authors: Alatawi Kahdr A. , Ravishankar Divyashree , Patra Pabitra H. , Bye Alexander P. , Stainer Alexander R. , Patel Ketan , Widera Darius , Vaiyapuri Sakthivel
Published: October 2021

1,8-cineole, a monoterpenoid is a major component of eucalyptus oil and has been proven to possess numerous beneficial effects in humans. Notably, 1,8-cineole is the primary active ingredient of a clinically approved drug, Soledum® which is being mainly used for the maintenance of sinus and respiratory health. Due to its clinically valuable properties, 1,8-cineole has gained significant scientific interest over the recent years specifically to investigate its anti-inflammatory and antioxidant effects. However, the impact of 1,8-cineole on the modulation of platelet activation, thrombosis and haemostasis was not fully established. Therefore, in this study, we demonstrate the effects of 1,8-cineole on agonists-induced platelet activation, thrombus formation under arterial flow conditions and haemostasis in mice. 1,8-cineole largely inhibits platelet activation stimulated by glycoprotein VI (GPVI) agonists such as collagen and cross-linked collagen-related peptide (CRP-XL), while it displays minimal inhibitory effects on thrombin or ADP-induced platelet aggregation. It inhibited inside-out signalling to integrin αIIbβ3 and outside-in signalling triggered by the same integrin as well as granule secretion and intracellular calcium mobilisation in platelets. 1,8-cineole affected thrombus formation on collagen-coated surface under arterial flow conditions and displayed a minimal effect on haemostasis of mice at a lower concentration of 6.25 µM. Notably, 1,8-cineole was found to be non-toxic to platelets up to 50 µM concentration. The investigation on the molecular mechanisms through which 1,8-cineole inhibits platelet function suggests that this compound affects signalling mediated by various molecules such as AKT, Syk, LAT, and cAMP in platelets. Based on these results, we conclude that 1,8-cineole may act as a potential therapeutic agent to control unwarranted platelet reactivity under various pathophysiological settings.
Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner
Authors: Holtmann Theresa Maria , Inzaugarat Maria Eugenia , Knorr Jana , Geisler Lukas , Schulz Marten , Bieghs Veerle , Frissen Mick , Feldstein Ariel E. , Tacke Frank , Trautwein Christian , Wree Alexander
Published: October 2021

Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3−/− mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3−/− mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3−/− mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation.
Impaired Bile Acid Metabolism and Gut Dysbiosis in Mice Lacking Lysosomal Acid Lipase
Authors: Sachdev Vinay , Duta-Mare Madalina , Korbelius Melanie , Vujić Nemanja , Leopold Christina , Freark de Boer Jan , Rainer Silvia , Fickert Peter , Kolb Dagmar , Kuipers Folkert , Radovic Branislav , Gorkiewicz Gregor , Kratky Dagmar
Published: October 2021

Lysosomal acid lipase (LAL) is the sole enzyme known to be responsible for the hydrolysis of cholesteryl esters and triglycerides at an acidic pH in lysosomes, resulting in the release of unesterified cholesterol and free fatty acids. However, the role of LAL in diet-induced adaptations is largely unexplored. In this study, we demonstrate that feeding a Western-type diet to Lal-deficient (LAL-KO) mice triggers metabolic reprogramming that modulates gut-liver cholesterol homeostasis. Induction of ileal fibroblast growth factor 15 (three-fold), absence of hepatic cholesterol 7α-hydroxylase expression, and activation of the ERK phosphorylation cascade results in altered bile acid composition, substantial changes in the gut microbiome, reduced nutrient absorption by 40%, and two-fold increased fecal lipid excretion in LAL-KO mice. These metabolic adaptations lead to impaired bile acid synthesis, lipoprotein uptake, and cholesterol absorption and ultimately to the resistance of LAL-KO mice to diet-induced obesity. Our results indicate that LAL-derived lipolytic products might be important metabolic effectors in the maintenance of whole-body lipid homeostasis.
Proteomic Analysis of Exosomes during Cardiogenic Differentiation of Human Pluripotent Stem Cells
Authors: Ashok Preeti , Tzanakakis Emmanuel S.
Published: October 2021

Efforts to direct the specification of human pluripotent stem cells (hPSCs) to therapeutically important somatic cell types have focused on identifying proper combinations of soluble cues. Yet, whether exosomes, which mediate intercellular communication, play a role in the differentiation remains unexplored. We took a first step toward addressing this question by subjecting hPSCs to stage-wise specification toward cardiomyocytes (CMs) in scalable stirred-suspension cultures and collecting exosomes. Samples underwent liquid chromatography (LC)/mass spectrometry (MS) and subsequent proteomic analysis revealed over 300 unique proteins from four differentiation stages including proteins such as PPP2CA, AFM, MYH9, MYH10, TRA2B, CTNNA1, EHD1, ACTC1, LDHB, and GPC4, which are linked to cardiogenic commitment. There was a significant correlation of the protein composition of exosomes with the hPSC line and stage of commitment. Differentiating hPSCs treated with exosomes from hPSC-derived CMs displayed improved efficiency of CM formation compared to cells without exogenously added vesicles. Collectively, these results demonstrate that exosomes from hPSCs induced along the CM lineage contain proteins linked to the specification process with modulating effects and open avenues for enhancing the biomanufacturing of stem cell products for cardiac diseases.
Terc Gene Cluster Variants Predict Liver Telomere Length in Mice
Authors: Zeid Dana , Mooney-Leber Sean , Seemiller Laurel R. , Goldberg Lisa R. , Gould Thomas J.
Published: October 2021

Variants in a gene cluster upstream-adjacent to TERC on human chromosome 3, which includes genes APRM, LRRC31, LRRC34 and MYNN, have been associated with telomere length in several human populations. Currently, the mechanism by which variants in the TERC gene cluster influence telomere length in humans is unknown. Given the proximity between the TERC gene cluster and TERC (~0.05 Mb) in humans, it is speculated that cluster variants are in linkage disequilibrium with a TERC causal variant. In mice, the Terc gene/Terc gene cluster are also located on chromosome 3; however, the Terc gene cluster is located distantly downstream of Terc (~60 Mb). Here, we initially aim to investigate the interactions between genotype and nicotine exposure on absolute liver telomere length (aTL) in a panel of eight inbred mouse strains. Although we found no significant impact of nicotine on liver aTL, this first experiment identified candidate single nucleotide polymorphisms (SNPs) in the murine Terc gene cluster (within genes Lrrc31, Lrriq4 and Mynn) co-varying with aTL in our panel. In a second experiment, we tested the association of these Terc gene cluster variants with liver aTL in an independent panel of eight inbred mice selected based on candidate SNP genotype. This supported our initial finding that Terc gene cluster polymorphisms impact aTL in mice, consistent with data in human populations. This provides support for mice as a model for telomere dynamics, especially for studying mechanisms underlying the association between Terc cluster variants and telomere length. Finally, these data suggest that mechanisms independent of linkage disequilibrium between the Terc/TERC gene cluster and the Terc/TERC gene mediate the cluster’s regulation of telomere length.
Kir4.1 Dysfunction in the Pathophysiology of Depression: A Systematic Review
Authors: Della Vecchia Stefania , Marchese Maria , Santorelli Filippo Maria , Sicca Federico
Published: October 2021

A serotonergic dysfunction has been largely postulated as the main cause of depression, mainly due to its effective response to drugs that increase the serotonergic tone, still currently the first therapeutic line in this mood disorder. However, other dysfunctional pathomechanisms are likely involved in the disorder, and this may in part explain why some individuals with depression are resistant to serotonergic therapies. Among these, emerging evidence suggests a role for the astrocytic inward rectifier potassium channel 4.1 (Kir4.1) as an important modulator of neuronal excitability and glutamate metabolism. To discuss the relationship between Kir4.1 dysfunction and depression, a systematic review was performed according to the PRISMA statement. Searches were conducted across PubMed, Scopus, and Web of Science by two independent reviewers. Twelve studies met the inclusion criteria, analyzing Kir4.1 relationships with depression, through in vitro, in vivo, and post-mortem investigations. Increasing, yet not conclusive, evidence suggests a potential pathogenic role for Kir4.1 upregulation in depression. However, the actual contribution in the diverse subtypes of the disorder and in the comorbid conditions, for example, the epilepsy-depression comorbidity, remain elusive. Further studies are needed to better define the clinical phenotype associated with Kir4.1 dysfunction in humans and the molecular mechanisms by which it contributes to depression and implications for future treatments.
Analysis of Additives in Gypsum Coatings Based on Melamine, Polycarbonate Salts, Polycarboxylate, and Polycarboxylic Acids
Authors: Flores Yepes José Antonio , Serna Jara Luis Miguel , Gabarrón Antonio Martínez , Codes Alcaraz Ana María , Pastor Pérez Joaquín Julián
Published: October 2021

In this paper, we evaluate different gypsum coating additives that are available on the market, which are categorized by their chemical bases. The results will serve as a reference for future investigations of new additive bases in order to improve the properties of gypsum. As such, the objective of the this study is to assess the workability, mechanical behavior, and crystalline structure of calcium sulfate combined with different retarding and fluidifying bases, including melamine bases, which have a compressive strength of 19.32 N/mm2 and handling times with polycarbonate salts of up to 117.58 min. The following study presents the results of standard mechanical tests, analyzing semi-hydrated calcium sulfate (without additives) as a reference, along with the addition of melamines, synthetic melanin polymers, polycarbonate salts, polycarboxylates, and a polycarboxylic acid (citric acid). We already know that the addition of these additives will modify the mechanical properties of calcium sulfate, such as the Shore C surface hardness, flexural strength, modulus of elasticity, and compression resistance, which is the object of this study.
Gene Expression Analysis through Parallel Non-Negative Matrix Factorization
Authors: Serrano-Rubio Angelica Alejandra , Morales-Luna Guillermo B. , Meneses-Viveros Amilcar
Published: October 2021

Genetic expression analysis is a principal tool to explain the behavior of genes in an organism when exposed to different experimental conditions. In the state of art, many clustering algorithms have been proposed. It is overwhelming the amount of biological data whose high-dimensional structure exceeds mostly current computational architectures. The computational time and memory consumption optimization actually become decisive factors in choosing clustering algorithms. We propose a clustering algorithm based on Non-negative Matrix Factorization and K-means to reduce data dimensionality but whilst preserving the biological context and prioritizing gene selection, and it is implemented within parallel GPU-based environments through the CUDA library. A well-known dataset is used in our tests and the quality of the results is measured through the Rand and Accuracy Index. The results show an increase in the acceleration of 6.22× compared to the sequential version. The algorithm is competitive in the biological datasets analysis and it is invariant with respect to the classes number and the size of the gene expression matrix.
Wildlife Trade Influencing Natural Parrot Populations on a Biodiverse Indonesian Island
Authors: Nandika Dudi , Agustina Dwi , Heinsohn Robert , Olah George
Published: October 2021

Indonesia has been identified as the highest priority country for parrot conservation based on the number of species, endemics, and threats (trapping and smuggling). It is crucial to understand the current population status of parrots in the wild in relation to the illegal wildlife trade but the ecology and population dynamics of most parrot species in this region remain poorly understood. We conducted a parrot survey around an area of high biodiversity in the Manusela National Park, in Seram Island, Indonesia. We used a combination of fixed-radius point counts and fixed-width line transects to count multiple species of parrots. We recorded nearly 530 wild parrots from 10 species in and around Manusela National Park. The dominant parrot species were Eos bornea, Trichoglosus haematodus, and Geoffroyus geoffroyi. We applied the Savage selectivity index to evaluate poaching of parrot species in proportion to their abundance and which species had higher than expected poaching pressure. This study has important implications for the conservation status of endemic parrots (Cacatua moluccensis, Lorius domicella, and Eos semilarvata) and shows that parrots in the Manusela NP are largely threatened by poaching.
Rapid Automated Screening for SARS-CoV-2 B.1.617 Lineage Variants (Delta/Kappa) through a Versatile Toolset of qPCR-Based SNP Detection
Authors: Nörz Dominik , Grunwald Moritz , Tang Hui Ting , Olearo Flaminia , Günther Thomas , Robitaille Alexis , Fischer Nicole , Grundhoff Adam , Aepfelbacher Martin , Pfefferle Susanne , Lütgehetmann Marc
Published: October 2021

Background: The recent emergence of distinct and highly successful SARS-CoV-2 lineages has substantial implications for individual patients and public health measures. While next-generation-sequencing is routinely performed for surveillance purposes, RT-qPCR can be used to rapidly rule-in or rule-out relevant variants, e.g., in outbreak scenarios. The objective of this study was to create an adaptable and comprehensive toolset for multiplexed Spike-gene SNP detection, which was applied to screen for SARS-CoV-2 B.1.617 lineage variants. Methods: We created a broad set of single nucleotide polymorphism (SNP)-assays including del-Y144/145, E484K, E484Q, P681H, P681R, L452R, and V1176F based on a highly specific multi-LNA (locked nucleic acid)-probe design to maximize mismatch discrimination. As proof-of-concept, a multiplex-test was compiled and validated (SCOV2-617VOC-UCT) including SNP-detection for L452R, P681R, E484K, and E484Q to provide rapid screening capabilities for the novel B.1.617 lineages. Results: For the multiplex-test (SCOV2-617VOC-UCT), the analytic lower limit of detection was determined as 182 IU/mL for L452R, 144 IU/mL for P681R, and 79 IU/mL for E484Q. A total of 233 clinical samples were tested with the assay, including various on-target and off-target sequences. All SNPs (179/179 positive) were correctly identified as determined by SARS-CoV-2 whole genome sequencing. Conclusion: The recurrence of SNP locations and flexibility of methodology presented in this study allows for rapid adaptation to current and future variants. Furthermore, the ability to multiplex various SNP-assays into screening panels improves speed and efficiency for variant testing. We show 100% concordance with whole genome sequencing for a B.1.617.2 screening assay on the cobas6800 high-throughput system.
A New Strategy for Rapid Diagnosis of the Source of Low Back Pain in Patients Scheduled to Undergo Treatment with Cooled Radiofrequency Ablation
Authors: Chou Shih-Hsiang , Lu Cheng-Chang , Lin Sung-Yen , Shen Po-Chih , Liu Zi-Miao , Chih Wei-Hsing , Shih Chia-Lung
Published: October 2021

Objective: The objective of this study was to develop a new strategy for rapid diagnosis of the source of low back pain (LBP) for treatment with cooled radiofrequency ablation (RFA). Materials: Patients suffering from facet joint (FJ) or sacroiliac joint (SIJ) pain for more than 3 months were included. Two methods, Technetium Tc99m methylene diphosphonate single photon emission tomography/computed tomography (99mTc-MDP SPECT/CT) and a modified Fortin finger test were used to identify the source of LBP for treatment with cooled RFA. The visual analog scale (VAS) and Oswestry disability index (ODI) were used to assess the patients’ pain levels and disabilities respectively. These two measures were recorded at baseline and 1-week, 1-month, 3-month, and 6-month follow-up visits. Results: A total of 40 patients with LBP were included in this study. Our results demonstrated that the patients with LBP identified by our new strategy had significant improvements in VAS or ODI score at 1-week to 6-month follow-up visits (p < 0.001) after receiving cooled RFA. Similar results were also found in patients with FJ pain and those with FJ and SIJ pain respectively. Among all the patients, over 70% had greater than or equal to 50% reduction in VAS and ODI scores. No serious adverse events were observed after treatment. Conclusions: This new strategy could be successfully adopted for rapid diagnosis of the source of comprehensive LBP.
Needs Analysis of Psychosocial Module Development Based on Psychoeducation Approach for Public University Students in Malaysia
Authors: Amat Salleh , Samsudin Harizah Izyan , Bakar Abu Yazid Abu , Mahmud Mohd Izwan , Kamarulzaman Mohd Hasrul
Published: October 2021

This study is a needs analysis that aims to develop a psychosocial module based on a psychoeducation approach in order to strengthen the assertiveness, social skills, and psychological well-being of public university students in Malaysia. The specific objectives of this study were to identify the perceptions of university students on the need to design and build a psychosocial module, identify the constructs that should be included in the phase of designing and building of the psychosocial module as well as the support that has been received and the support that the students desire while on campus. This survey study utilized a questionnaire distributed to a total of 286 first year students studying at three public universities in Malaysia. The data obtained were analyzed by using descriptive statistics. The findings of the study showed a highly positive response from the students toward the development of a psychosocial module and the constructs listed in the questionnaire. Implications from this study can further solidify the constructs that should be included in the design and construction of the psychosocial module as well as identify the availability of the approaches, strategies, and support activities that have been received and desired by the students.