bluuebunny/crossref_metadata_2025 huggingface dataset:
Variable Induction of Pro-Inflammatory Cytokines by Commercial SARS CoV-2 Spike Protein Reagents: Potential Impacts of LPS on In Vitro Modeling and Pathogenic Mechanisms In Vivo
Authors: Ouyang Weiming , Xie Tao , Fang Hui , Gao Chunling , Stantchev Tzanko , Clouse Kathleen A. , Yuan Kun , Ju Tongzhong , Frucht David M.
Published: July 2021

Proinflammatory cytokine production following infection with severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is associated with poor clinical outcomes. Like SARS CoV-1, SARS CoV-2 enters host cells via its spike protein, which attaches to angiotensin-converting enzyme 2 (ACE2). As SARS CoV-1 spike protein is reported to induce cytokine production, we hypothesized that this pathway could be a shared mechanism underlying pathogenic immune responses. We herein compared the capabilities of Middle East Respiratory Syndrome (MERS), SARS CoV-1 and SARS CoV-2 spike proteins to induce cytokine expression in human peripheral blood mononuclear cells (PBMC). We observed that only specific commercial lots of SARS CoV-2 induce cytokine production. Surprisingly, recombinant SARS CoV-2 spike proteins from different vendors and batches exhibited different patterns of cytokine induction, and these activities were not inhibited by blockade of spike protein-ACE2 binding using either soluble ACE2 or neutralizing anti-S1 antibody. Moreover, commercial spike protein reagents contained varying levels of lipopolysaccharide (LPS), which correlated directly with their abilities to induce cytokine production. The LPS inhibitor, polymyxin B, blocked this cytokine induction activity. In addition, SARS CoV-2 spike protein avidly bound soluble LPS in vitro, rendering it a cytokine inducer. These results not only suggest caution in monitoring the purity of SARS CoV-2 spike protein reagents, but they indicate the possibility that interactions of SARS CoV-2 spike protein with LPS from commensal bacteria in virally infected mucosal tissues could promote pathogenic inflammatory cytokine production.
Combinatorial Virtual Library Screening Study of Transforming Growth Factor-β2–Chondroitin Sulfate System
Authors: Sankaranarayanan Nehru Viji , Nagarajan Balaji , Desai Umesh R.
Published: July 2021

Transforming growth factor-beta (TGF-β), a member of the TGF-β cytokine superfamily, is known to bind to sulfated glycosaminoglycans (GAGs), but the nature of this interaction remains unclear. In a recent study, we found that preterm human milk TGF-β2 is sequestered by chondroitin sulfate (CS) in its proteoglycan form. To understand the molecular basis of the TGF-β2–CS interaction, we utilized the computational combinatorial virtual library screening (CVLS) approach in tandem with molecular dynamics (MD) simulations. All possible CS oligosaccharides were generated in a combinatorial manner to give 24 di- (CS02), 192 tetra- (CS04), and 1536 hexa- (CS06) saccharides. This library of 1752 CS oligosaccharides was first screened against TGF-β2 using the dual filter CVLS algorithm in which the GOLDScore and root-mean-square-difference (RMSD) between the best bound poses were used as surrogate markers for in silico affinity and in silico specificity. CVLS predicted that both the chain length and level of sulfation are critical for the high affinity and high specificity recognition of TGF-β2. Interestingly, CVLS led to identification of two distinct sites of GAG binding on TGF-β2. CVLS also deduced the preferred composition of the high specificity hexasaccharides, which were further assessed in all-atom explicit solvent MD simulations. The MD results confirmed that both sites of binding form stable GAG–protein complexes. More specifically, the highly selective CS chains were found to engage the TGF-β2 monomer with high affinity. Overall, this work present key principles of recognition with regard to the TGF-β2–CS system. In the process, it led to the generation of the in silico library of all possible CS oligosaccharides, which can be used for advanced studies on other protein–CS systems. Finally, the study led to the identification of unique CS sequences that are predicted to selectively recognize TGF-β2 and may out-compete common natural CS biopolymers.
3,4-Dehydro-L-proline Induces Programmed Cell Death in the Roots of Brachypodium distachyon
Authors: Pinski Artur , Betekhtin Alexander , Kwasniewska Jolanta , Chajec Lukasz , Wolny Elzbieta , Hasterok Robert
Published: July 2021

As cell wall proteins, the hydroxyproline-rich glycoproteins (HRGPs) take part in plant growth and various developmental processes. To fulfil their functions, HRGPs, extensins (EXTs) in particular, undergo the hydroxylation of proline by the prolyl-4-hydroxylases. The activity of these enzymes can be inhibited with 3,4-dehydro-L-proline (3,4-DHP), which enables its application to reveal the functions of the HRGPs. Thus, to study the involvement of HRGPs in the development of root hairs and roots, we treated seedlings of Brachypodium distachyon with 250 µM, 500 µM, and 750 µM of 3,4-DHP. The histological observations showed that the root epidermis cells and the cortex cells beneath them ruptured. The immunostaining experiments using the JIM20 antibody, which recognizes the EXT epitopes, demonstrated the higher abundance of this epitope in the control compared to the treated samples. The transmission electron microscopy analyses revealed morphological and ultrastructural features that are typical for the vacuolar-type of cell death. Using the TUNEL test (terminal deoxynucleotidyl transferase dUTP nick end labelling), we showed an increase in the number of nuclei with damaged DNA in the roots that had been treated with 3,4-DHP compared to the control. Finally, an analysis of two metacaspases’ gene activity revealed an increase in their expression in the treated roots. Altogether, our results show that inhibiting the prolyl-4-hydroxylases with 3,4-DHP results in a vacuolar-type of cell death in roots, thereby highlighting the important role of HRGPs in root hair development and root growth.
N-Acetylcysteine Added to Local Anesthesia Reduces Scar Area and Width in Early Wound Healing—An Animal Model Study
Authors: Paskal Wiktor , Paskal Adriana M. , Pietruski Piotr , Stachura Albert , Pełka Kacper , Woessner Alan E. , Quinn Kyle P. , Kopka Michał , Galus Ryszard , Wejman Jarosław , Włodarski Paweł
Published: July 2021

The aim of the study was to evaluate if a pre-incisional N-acetylcysteine (NAC) treatment altered the process of wound healing in a rat model. The dorsal skin of 24 Sprague-Dawley rats was incised in six locations. Before the incisions were made, skin was injected either with lidocaine and epinephrine (one side) or with these agents supplemented with 0.015%, 0.03%, or 0.045% NAC (contralaterally). Photographic documentation of the wound healing process was made at 11 time points. Rats were sacrificed 3, 7, 14, or 60 days after incision to excise scars for histological analysis. They included: Abramov scale scoring, histomorphometry analysis, and collagen fiber arrangement assessment. Skin pretreated with 0.03% NAC produced the shortest scars at all analyzed time points, though this result was statistically insignificant. At this NAC concentration the scars had smaller areas on the third day and were narrower on the day 4 compared with all the other groups (p < 0.05). On day 7, at the same concentration of NAC, the scars had a higher superficial concentration index (p = 0.03) and larger dermal proliferation area (p = 0.04). NAC addition to pre-incisional anesthetic solution decreased wound size and width at an early stage of scar formation at all concentrations; however, with optimal results at 0.03% concentration.
Cysteine Proteome Reveals Response to Endogenous Oxidative Stress in Bacillus cereus
Authors: Hamitouche Fella , Armengaud Jean , Dedieu Luc , Duport Catherine
Published: July 2021

At the end of exponential growth, aerobic bacteria have to cope with the accumulation of endogenous reactive oxygen species (ROS). One of the main targets of these ROS is cysteine residues in proteins. This study uses liquid chromatography coupled to high-resolution tandem mass spectrometry to detect significant changes in protein abundance and thiol status for cysteine-containing proteins from Bacillus cereus during aerobic exponential growth. The proteomic profiles of cultures at early-, middle-, and late-exponential growth phases reveals that (i) enrichment in proteins dedicated to fighting ROS as growth progressed, (ii) a decrease in both overall proteome cysteine content and thiol proteome redox status, and (iii) changes to the reduced thiol status of some key proteins, such as the transition state transcriptional regulator AbrB. Taken together, our data indicate that growth under oxic conditions requires increased allocation of protein resources to attenuate the negative effects of ROS. Our data also provide a strong basis to understand the response mechanisms used by B. cereus to deal with endogenous oxidative stress.
Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling
Authors: Skoczek Dawid , Dulak Józef , Kachamakova-Trojanowska Neli
Published: July 2021

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous group of monogenic endocrine disorders that is characterised by autosomal dominant inheritance and pancreatic β-cell dysfunction. These patients are commonly misdiagnosed with type 1 or type 2 diabetes, as the clinical symptoms largely overlap. Even though several biomarkers have been tested none of which could be used as single clinical discriminator. The correct diagnosis for individuals with MODY is of utmost importance, as the applied treatment depends on the gene mutation or is subtype-specific. Moreover, in patients with HNF1A-MODY, additional clinical monitoring can be included due to the high incidence of vascular complications observed in these patients. Finally, stratification of MODY patients will enable better and newer treatment options for MODY patients, once the disease pathology for each patient group is better understood. In the current review the clinical characteristics and the known disease-related abnormalities of the most common MODY subtypes are discussed, together with the up-to-date applied diagnostic criteria and treatment options. Additionally, the usage of pluripotent stem cells together with CRISPR/Cas9 gene editing for disease modelling with the possibility to reveal new pathophysiological mechanisms in MODY is discussed.
Role of Dendritic Cell in Diabetic Nephropathy
Authors: Kim Hyunwoo , Kim Miyeon , Lee Hwa-Young , Park Ho-Young , Jhun Hyunjhung , Kim Soohyun
Published: July 2021

Diabetic nephropathy (DN) is one of the most significant microvascular complications in diabetic patients. DN is the leading cause of end-stage renal disease, accounting for approximately 50% of incident cases. The current treatment options, such as optimal control of hyperglycemia and elevated blood pressure, are insufficient to prevent its progression. DN has been considered as a nonimmune, metabolic, or hemodynamic glomerular disease initiated by hyperglycemia. However, recent studies suggest that DN is an inflammatory disease, and immune cells related with innate and adaptive immunity, such as macrophage and T cells, might be involved in its development and progression. Although it has been revealed that kidney dendritic cells (DCs) accumulation in the renal tissue of human and animal models of DN require activated T cells in the kidney disease, little is known about the function of DCs in DN. In this review, we describe kidney DCs and their subsets, and the role in the pathogenesis of DN. We also suggest how to improve the kidney outcomes by modulating kidney DCs optimally in the patients with DN.
Influence of the Rotor-Driven Perturbation on the Stator-Exit Flow within a High-Pressure Gas Turbine Stage
Authors: Gaetani Paolo , Persico Giacomo
Published: July 2021

In stator–rotor interaction studies on axial turbines, the attention is commonly focused on the unsteady rotor aerodynamics resulting from the periodic perturbations induced by the stator flow structures. Conversely, less interest has been historically attracted regarding the influence of the rotor on the flow released by the stator, correlated to propagation of the blade potential field upstream of the rotor leading edge. In this paper, experiments in the research high-pressure turbine of the Laboratory of Fluid-Machines of the Politecnico di Milano, performed by applying a fast-response aerodynamic pressure probe, alongside fully-3D time-accurate CFD simulations of the flow, are combined with the aim of discussing the rotor-to-stator interaction. While rotating, the rotor induces periodic perturbations on the pressure and velocity field in the stator–rotor gap, altering the evolution of the total quantities and the flow rate discharged by each stator channel and eventually triggering energy-separation effects which result in total pressure and total temperature oscillations in the stator-exit flow. Such oscillations were found to rise up to almost ±10% of the stage total temperature drop.
Mitochondrial DNA Variation in Peruvian Honey Bee (Apis mellifera L.) Populations Using the tRNAleu-cox2 Intergenic Region
Authors: Chávez-Galarza Julio , López-Montañez Ruth , Jiménez Alejandra , Ferro-Mauricio Rubén , Oré Juan , Medina Sergio , Rea Reyna , Vásquez Héctor
Published: July 2021

Mitochondrial DNA variations of Peruvian honey bee populations were surveyed by using the tRNAleu-cox2 intergenic region. Only two studies have characterized these populations, indicating the presence of Africanized honey bee colonies in different regions of Peru and varied levels of Africanization, but the current status of its genetic diversity is unknown. A total of 512 honey bee colonies were sampled from three regions to characterize them. Our results revealed the presence of European and African haplotypes: the African haplotypes identified belong to sub-lineage AI (13) and sub-lineage AIII (03), and the European haplotypes to lineages C (06) and M (02). Of 24 haplotypes identified, 15 new sequences are reported here (11 sub-lineage AI, 2 sub-lineage AIII, and 2 lineage M). Peruvian honey bee populations presented a higher proportion from African than European haplotypes. High proportions of African haplotype were reported for Piura and Junín, unlike Lima, which showed more European haplotypes from lineage C. Few colonies belonging to lineage M would represent accidental purchase or traces of the introduction into Peru in the 19th century.
Current Treatment of Juvenile Myelomonocytic Leukemia
Authors: Mayerhofer Christina , Niemeyer Charlotte M. , Flotho Christian
Published: July 2021

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric leukemia characterized by mutations in five canonical RAS pathway genes. The diagnosis is made by typical clinical and hematological findings associated with a compatible mutation. Although this is sufficient for clinical decision-making in most JMML cases, more in-depth analysis can include DNA methylation class and panel sequencing analysis for secondary mutations. NRAS-initiated JMML is heterogeneous and adequate management ranges from watchful waiting to allogeneic hematopoietic stem cell transplantation (HSCT). Upfront azacitidine in KRAS patients can achieve long-term remissions without HSCT; if HSCT is required, a less toxic preparative regimen is recommended. Germline CBL patients often experience spontaneous resolution of the leukemia or exhibit stable mixed chimerism after HSCT. JMML driven by PTPN11 or NF1 is often rapidly progressive, requires swift HSCT and may benefit from pretransplant therapy with azacitidine. Because graft-versus-leukemia alloimmunity is central to cure high risk patients, the immunosuppressive regimen should be discontinued early after HSCT.
Trends in Antibiotic Self-Medication for Dental Pathologies among Patients in the Dominican Republic: A Cross-Sectional Study
Authors: Aragoneses Juan Manuel , Aragoneses Javier , Rodríguez Cinthia , Algar Juan , Suárez Ana
Published: July 2021

The World Health Organisation has warned of the increase in antibiotic resistance, estimating that by 2050 it could become the leading cause of death worldwide. Several studies and literature reviews show a correlation between antibiotic use and bacterial resistance, with unnecessary broad-spectrum antibiotics, such as amoxicillin/clavulanic acid and azithromycin, being one of the main causative factors. An interview-based survey of 2160 participants was conducted to assess the prevalence in the practice of self-medication with antibiotics among dental patients in the Dominican Republic. A series of open-ended questions regarding self-medication and class of antibiotics were put to the patients. Over a third of the study population (39.7%) admitted to the practice of antibiotic self-medication. Most of the respondents (58.4%) who indulged in self-medication were females, and it was prevalent in the older adults between 32–42 years old (36%). There was a negative correlation between age and self-medication practice (p < 0.001) observed with point biserial correlation test. Binary logistic regression analysis found an odds ratio of 0.97 (p < 0.001). The most consumed antibiotics were amoxicillin/clavulanic acid (52%), amoxicillin (31.1%), and azithromycin (10.1%). It is imperative to educate patients about the harmful effects of self-medication and to stress the need for governments to implement stricter laws on non-prescription drug availability.
Superior Functional Outcome and Comparable Health-Related Quality of Life after Enhanced Recovery vs. Conventional THA: A Retrospective Matched Pair Analysis
Authors: Leiss Franziska , Schindler Melanie , Götz Julia Sabrina , Maderbacher Günther , Meyer Matthias , Reinhard Jan , Zeman Florian , Grifka Joachim , Greimel Felix
Published: July 2021

Background: The concept of enhanced recovery after total hip arthroplasty is gaining worldwide interest, as it shortens the length of hospital stay without an increase of complications. The aim of the study was to investigate the functional outcome and health-related quality of life 12 months after cementless total hip arthroplasty with the use of an enhanced recovery concept in comparison to a conventional rehabilitation. Material and Methods: 320 patients were retrospectively analyzed who underwent primary cementless total hip arthroplasty (THA). A total of 123 of the patients received an enhanced recovery program (ERAS) and 197 patients a conventional rehabilitation (Non-ERAS). Twelve months postoperatively, a clinical examination was performed regarding satisfaction, function and pain. Results were evaluated using WOMAC, EQ-5D-5L and EQ-VAS. A 1:1 matching was performed to correct for confounding variables, regarding age, sex and ASA score. Finally, 122 patients (n = 61, in each group) were analyzed and compared. Results: Patients showed a significant improvement of WOMAC total score, subscale pain, subscale stiffness and subscale function from preoperative to the follow up after 12 months in both groups, with significantly superior results for the WOMAC total score for the ERAS group (p = 0.042). EQ-5D and EQ-5D VAS showed a significant improvement from preoperative to 12 months postoperative (p < 0.001) for both groups, while no difference regarding the group-comparison was shown. Conclusion: Health-related quality of life and functional outcome increased to excellent values after total hip arthroplasty with the use of an enhanced recovery concept and a conventional rehabilitation, with a superior WOMAC total score for ERAS and a tendency to better results for health-related quality of life for patients with ERAS within the follow up after 12 months.
Effects of Weight Gain after 20 Years of Age and Incidence of Hyper-Low-Density Lipoprotein Cholesterolemia: The Iki Epidemiological Study of Atherosclerosis and Chronic Kidney Disease (ISSA-CKD)
Authors: Okutsu Shota , Kato Yoshifumi , Funakoshi Shunsuke , Maeda Toshiki , Yoshimura Chikara , Kawazoe Miki , Satoh Atsushi , Yokota Soichiro , Tada Kazuhiro , Takahashi Koji , Ito Kenji , Yasuno Tetsuhiko , Fujii Hideyuki , Mukoubara Shigeaki , Nakashima Hitoshi , Kawanami Daiji , Masutani Kosuke , Arima Hisatomi , Nabeshima Shigeki
Published: July 2021

The aim of this study was to investigate the effects of long-term weight gain from the age of 20 on incidence of hyper-low-density-lipoprotein (LDL) cholesterolemia in the general population of Japanese people. Methods: We conducted a population-based retrospective cohort study using annual health checkup data for residents of Iki City, Nagasaki Prefecture, Japan. A total of 3179 adult (≥30 years old) men and women without hyper-LDL cholesterolemia at baseline, who underwent two or more health checkups were included in the analysis. Information on weight gain (≥10 kg) after 20 years of age was obtained using questionnaire. The outcome of this study was development of hyper-LDL cholesterolemia defined as LDL-cholesterol level ≥3.62 mmol/L and/or initiation of lipid-lowering medications. Results: During a mean follow-up period of 4.53 years, 665 of the 3179 participants developed hyper-LDL cholesterolemia (46.5/1000 person-years). The incidence of hyper-LDL cholesterolemia was higher in participants with a weight gain of ≥10 kg (55.3/1000 person-years) than among those with a weight gain of <10 kg (41.8/1000 person-years). This association remained statistically significant even after adjustment for age, sex, smoking, daily drinking, exercise, obesity, hypertension, and diabetes (multivariable hazard ratio 1.31, 95% confidence interval 1.08–1.58, p = 0.006). Conclusion: A weight gain of ≥10 after 20 years of age affected the development of hyper-LDL cholesterol regardless of age, sex, and obesity in a general population of Japanese.
Long-Term Outcome with New Generation Prostheses in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Tamm Alexander R. , Geyer Martin , Kreidel Felix , Dausmann Lea , Jablonski Caroline , Hahad Omar , Schulz Eberhard , Münzel Thomas , Von Bardeleben Ralph Stephan
Published: July 2021

The aim of this study was to compare patients with transcatheter aortic valve replacement (TAVR) receiving new generation prostheses SAPIEN 3 (S3, Edwards Lifesc.) and Evolut R (ER, Medtronic Inc.) in terms of periprocedural and long-term outcome. Our retrospective, single-center analysis included 359 consecutive patients with severe aortic stenosis who underwent TAVR with S3 or ER from 2014–2016 (mean age 82 ± 7 years, 47% male, mean EuroSCORE II 8.0 ± 8%, mean follow-up 3.8 years). Device Success was equal (S3 93.0% vs. ER 92.4%, p = 0.812). We report a 30-day mortality of 2.8% in the S3 group, and 2.1% in the ER group (p = 0.674). There was no difference in stroke, conversion to open surgery, vascular and bleeding complications or myocardial infarction. While prosthesis mean gradients were higher with S3 (12.0 mmHg vs. 8.2 mmHg, p < 0.001), there was a trend to less paravalvular regurgitation (PVR moderate or severe: 1% vs. 3.6%, p = 0.088). All-cause mortality up to 5 years did not show a difference (mean survival S3 3.5 ± 0.24 years, ER 3.3 ± 0.29 years, p = 0.895). Independent predictors of long-term mortality were impaired LVEF, chronic kidney injury, peripheral artery disease, malignant tumor and periprocedural stroke. New generation TAVR valves offer an excellent implant and outcome success rate. Long-term survival was independent of prostheses choice and mainly attributed to comorbidities and complications.
A Feasibility Study on an Ultra-Brief Intervention for Improving Freshmen’s Emotional Intelligence
Authors: Puffer Keith A. , Pence Kris G. , Ferry Abigail E.
Published: July 2021

In 1990, Salovey and Mayer introduced emotional intelligence (EI). Thirty-one years later, a proliferation of interventions to improve people’s EI has taken place. A literature review of studies focused on enhancing the EI of college students revealed a notable gap. When educational material for training sessions included all of the skills in an EI model, researchers usually utilized lengthy durations (i.e., 11–56 h). Few successful investigations employed an ultra-brief (i.e., ≤1 h) approach. The present study examined the feasibility of training using a minimalistic timeframe and a sample of freshmen; their transitional challenges from high school to college mark them as an appropriate target population. Employing a quasi-experimental one-group pretest–posttest design, the recruited participants (n = 75) experienced an ultra-brief intervention highlighting the complete skill-set in the Ability Emotional Intelligence model. Findings from a one-way repeated measures MANOVA indicated improvement transpired in two of four MSCEIT scores (i.e., perception and facilitation). The merit of the present study is delineated using Orsmond and Cohn’s five objectives for feasibility investigations. In addition, implications of the results and possible applications are proposed.
Nitrogen Fixation in Subtropical Seagrass Sediments: Seasonal Patterns in Activity in Santa Rosa Sound, Florida, USA
Authors: Presley Rachel , Caffrey Jane M.
Published: July 2021

Seagrass beds are important coastal habitats that are diminishing globally. Nitrogen, a key nutrient, often limits seagrass growth. Nitrogen fixation provides new, bioavailable nitrogen to the plants. This study explores its importance and factors controlling rates in sediments colonized by two dominant taxa in Northwest Florida, Thalassia testudinum and Halodule wrightii, compared to unvegetated sediments. We hypothesized that nitrogen fixation rates would be greater in seagrass colonized sediments, particularly during high growth periods. We expected to observe a positive relationship between rates and porewater sulfide concentrations because sulfate reducers were the dominant diazotrophs in similar studies. Rates were higher in vegetated areas. In H. wrightii beds, nitrogen fixation was driven by the decreased availability of porewater ammonium relative to phosphorus. In T. testudinum beds, rates were highest during winter. Organic matter may be a controlling factor in all substrate types albeit the exact mechanism driving nitrogen fixation differs slightly. During the summer and fall, nitrogen fixation provided between 1–15% of T. testudinum nitrogen demand. Annually, nitrogen fixation provided 4% and 1% of T. testudinum and H. wrightii nitrogen demand, respectively. Nitrogen fixation was an important source of nitrogen during periods of senescence and dormancy when organic matter content was high.
Kernel Function Definition Completion for Time–Domain State–Space Representations of Radiation Forces: Application to the Hankel Singular Value Decomposition
Authors: Lecuyer-Le Bris Romain , Le Boulluec Marc , Charpentier Jean-Frédéric , Benbouzid Mohamed
Published: July 2021

This paper focuses on the formulation of state–space representations of radiation forces for marine structures using Hankel Singular Value Decomposition (HSVD), a method used to obtain a state–space realization from a Hankel matrix, with the classical definition of the kernel function and its new definition given in this paper. The first part shows the influence of a term commonly neglected and the resulting improvement by taking this term into account. The second part will focus on the feedthrough matrix to understand why some models have none and why some others, such as HSVD, have one. An exact definition of the kernel function will be given underlying its discontinuity and its causality. This study also shows the interest of extrapolating hydrodynamic coefficients before approaching radiation forces by a state–space model.
Epidemiology of Systemic Mycoses in the COVID-19 Pandemic
Authors: Frías-De-León María Guadalupe , Pinto-Almazán Rodolfo , Hernández-Castro Rigoberto , García-Salazar Eduardo , Meza-Meneses Patricia , Rodríguez-Cerdeira Carmen , Arenas Roberto , Conde-Cuevas Esther , Acosta-Altamirano Gustavo , Martínez-Herrera Erick
Published: July 2021

The physiopathologic characteristics of COVID-19 (high levels of inflammatory cytokines and T-cell reduction) promote fungal colonization and infection, which can go unnoticed because the symptoms in both diseases are very similar. The objective of this work was to study the current epidemiology of systemic mycosis in COVID-19 times. A literature search on the subject (January 2020–February 2021) was performed in PubMed, Embase, Cochrane Library, and LILACS without language restrictions. Demographic data, etiological agent, risk factors, diagnostic methods, antifungal treatment, and fatality rate were considered. Eighty nine publications were found on co-infection by COVID-19 and pneumocystosis, candidiasis, aspergillosis, mucormycosis, coccidioidomycosis, or histoplasmosis. In general, the co-infections occurred in males over the age of 40 with immunosuppression caused by various conditions. Several species were identified in candidiasis and aspergillosis co-infections. For diagnosis, diverse methods were used, from microbiological to molecular. Most patients received antifungals; however, the fatality rates were 11–100%. The latter may result because the clinical picture is usually attributed exclusively to SARS-CoV-2, preventing a clinical suspicion for mycosis. Diagnostic tests also have limitations beginning with sampling. Therefore, in the remainder of the pandemic, these diagnostic limitations must be overcome to achieve a better patient prognosis.
Antifungal Siderophore Conjugates for Theranostic Applications in Invasive Pulmonary Aspergillosis Using Low-Molecular TAFC Scaffolds
Authors: Pfister Joachim , Petrik Milos , Bendova Katerina , Matuszczak Barbara , Binder Ulrike , Misslinger Matthias , Kühbacher Alexander , Gsaller Fabio , Haas Hubertus , Decristoforo Clemens
Published: July 2021

Invasive pulmonary aspergillosis (IPA) is a life-threatening form of fungal infection, primarily in immunocompromised patients and associated with significant mortality. Diagnostic procedures are often invasive and/or time consuming and existing antifungals can be constrained by dose-limiting toxicity and drug interaction. In this study, we modified triacetylfusarinine C (TAFC), the main siderophore produced by the opportunistic pathogen Aspergillus fumigatus (A. fumigatus), with antifungal molecules to perform antifungal susceptibility tests and molecular imaging. A variation of small organic molecules (eflornithine, fludioxonil, thiomersal, fluoroorotic acid (FOA), cyanine 5 (Cy5) with antifungal activity were coupled to diacetylfusarinine C (DAFC), resulting in a “Trojan horse” to deliver antifungal compounds specifically into A. fumigatus hyphae by the major facilitator transporter MirB. Radioactive labeling with gallium-68 allowed us to perform in vitro characterization (distribution coefficient, stability, uptake assay) as well as biodistribution experiments and PET/CT imaging in an IPA rat infection model. Compounds chelated with stable gallium were used for antifungal susceptibility tests. [Ga]DAFC-fludioxonil, -FOA, and -Cy5 revealed a MirB-dependent active uptake with fungal growth inhibition at 16 µg/mL after 24 h. Visualization of an A. fumigatus infection in lungs of a rat was possible with gallium-68-labeled compounds using PET/CT. Heterogeneous biodistribution patterns revealed the immense influence of the antifungal moiety conjugated to DAFC. Overall, novel antifungal siderophore conjugates with promising fungal growth inhibition and the possibility to perform PET imaging combine both therapeutic and diagnostic potential in a theranostic compound for IPA caused by A. fumigatus.
Longitudinal Characterization of the Gut Bacterial and Fungal Communities in Yaks
Authors: Wang Yaping , Fu Yuhang , He Yuanyuan , Kulyar Muhammad Fakhar-e-Alam , Iqbal Mudassar , Li Kun , Liu Jiaguo
Published: July 2021

Development phases are important in maturing immune systems, intestinal functions, and metabolism for the construction, structure, and diversity of microbiome in the intestine during the entire life. Characterizing the gut microbiota colonization and succession based on age-dependent effects might be crucial if a microbiota-based therapeutic or disease prevention strategy is adopted. The purpose of this study was to reveal the dynamic distribution of intestinal bacterial and fungal communities across all development stages in yaks. Dynamic changes (a substantial difference) in the structure and composition ratio of the microbial community were observed in yaks that matched the natural aging process from juvenile to natural aging. This study included a significant shift in the abundance and proportion of bacterial phyla (Planctomycetes, Firmicutes, Bacteroidetes, Spirochaetes, Tenericutes, Proteobacteria, and Cyanobacteria) and fungal phyla (Chytridiomycota, Mortierellomycota, Neocallimastigomycota, Ascomycota, and Basidiomycota) across all development stages in yaks. As yaks grew older, variation reduced, and diversity increased as compared to young yaks. In addition, the intestine was colonized by a succession of microbiomes that coalesced into a more mature adult, including Ruminococcaceae_UCG-005, Romboutsia, Prevotellaceae_UCG-004, Blautia, Clostridium_sensu_stricto_1, Ruminococcus_1, Ruminiclostridium_5, Rikenellaceae_RC9_gut_group, Alloprevotella, Acetitomaculum, Lachnospiraceae_NK3A20_group, Bacteroides, Treponema_2, Olsenella, Escherichia-Shigella, Candidatus_Saccharimonas, and fungal communities Mortierella, Lomentospora, Orpinomyces, and Saccharomyces. In addition, microorganisms that threaten health, such as Escherichia-Shigella, Mortierella, Lomentospora and Hydrogenoanaerobacterium, Corynebacterium_1, Trichosporon, and Coprinellus, were enriched in young and old yaks, respectively, although all yaks were healthy. The significant shifts in microflora composition and structure might reflect adaptation of gut microbiome, which is associated with physicochemical conditions changes and substrate availability in the gut across all development periods of yaks.
Profile of Membrane Cargo Trafficking Proteins and Transporters Expressed under N Source Derepressing Conditions in Aspergillus nidulans
Authors: Dimou Sofia , Georgiou Xenia , Sarantidi Eleana , Diallinas George , Anagnostopoulos Athanasios K.
Published: July 2021

Solute and ion transporters are proteins essential for cell nutrition, detoxification, signaling, homeostasis and drug resistance. Being polytopic transmembrane proteins, they are co-translationally inserted and folded into the endoplasmic reticulum (ER) of eukaryotic cells and subsequently sorted to their final membrane destination via vesicular secretion. During their trafficking and in response to physiological/stress signals or prolonged activity, transporters undergo multiple quality control processes and regulated turnover. Consequently, transporters interact dynamically and transiently with multiple proteins. To further dissect the trafficking and turnover mechanisms underlying transporter subcellular biology, we herein describe a novel mass spectrometry-based proteomic protocol adapted to conditions allowing for maximal identification of proteins related to N source uptake in A. nidulans. Our analysis led to identification of 5690 proteins, which to our knowledge constitutes the largest protein dataset identified by omics-based approaches in Aspergilli. Importantly, we detected possibly all major proteins involved in basic cellular functions, giving particular emphasis to factors essential for membrane cargo trafficking and turnover. Our protocol is easily reproducible and highly efficient for unearthing the full A. nidulans proteome. The protein list delivered herein will form the basis for downstream systematic approaches and identification of protein–protein interactions in living fungal cells.
mRNA Inventory of Extracellular Vesicles from Ustilago maydis
Authors: Kwon Seomun , Rupp Oliver , Brachmann Andreas , Blum Christopher Frederik , Kraege Anton , Goesmann Alexander , Feldbrügge Michael
Published: July 2021

Extracellular vesicles (EVs) can transfer diverse RNA cargo for intercellular communication. EV-associated RNAs have been found in diverse fungi and were proposed to be relevant for pathogenesis in animal hosts. In plant-pathogen interactions, small RNAs are exchanged in a cross-kingdom RNAi warfare and EVs were considered to be a delivery mechanism. To extend the search for EV-associated molecules involved in plant-pathogen communication, we have characterised the repertoire of EV-associated mRNAs secreted by the maize smut pathogen, Ustilago maydis. For this initial survey, we examined EV-enriched fractions from axenic filamentous cultures that mimic infectious hyphae. EV-associated RNAs were resistant to degradation by RNases and the presence of intact mRNAs was evident. The set of mRNAs enriched inside EVs relative to the fungal cells are functionally distinct from those that are depleted from EVs. mRNAs encoding metabolic enzymes are particularly enriched. Intriguingly, mRNAs of some known effectors and other proteins linked to virulence were also found in EVs. Furthermore, several mRNAs enriched in EVs are also upregulated during infection, suggesting that EV-associated mRNAs may participate in plant-pathogen interactions.
β-Aminobutyric Acid Induced Resistance against Alternaria Fruit Rot in Apple Fruits
Authors: Gur Lior , Reuveni Moshe , Cohen Yigal
Published: July 2021

Fruit body rot and calyx rot caused by Alternaria alternata f. sp. mali is an important disease of apple worldwide. The disease has recently become severe in cv. Pink Lady apple in Israel to an extent that has never been reported elsewhere in the world. No alternative control measures of the disease except fungicides are known. Here, we show for the first time that dl-β-aminobutyric acid (BABA) induces resistance against Alternaria fruit rot (AFR) in apple fruits in the laboratory and in the orchard. AFR was inhibited in fruits treated with BABA of 1000 μg/mL. BABA did not inhibit spore germination or mycelial growth of the pathogen in vitro (up to 2000 μg/mL). It was most inhibitory when applied 4 days prior to inoculation of detached fruits. BABA inhibited AFR also curatively when applied at 24 h post inoculation. Five other isomers of aminobutyric acid failed to protect the fruits from rot formation. Three field trials in commercial apple orchards proved that BABA was as protective against AFR as the commercial standard fungicidal mixture of azoxystrobin and difenoconazole. This research suggests that BABA may serve as a resistance inducer in apple against AFR. It can be used as an adequate alternative to the currently used fungicides or integrated in disease management programs to reduce fungicide load and buildup of fungicide resistance.
RNF8–CDH1 Co-Expression Predicts Clinical Benefit of Chemoradiotherapy in Triple-Negative Breast Cancer
Authors: Kao Chieh-Ni , Moi Sin-Hua , Hou Ming-Feng , Luo Chi-Wen , Chen Fang-Ming , Pan Mei-Ren
Published: July 2021

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and exhibits an overall poor outcome. Due to the lack of targeted therapy, conventional systemic chemotherapy has been the main strategy for the treatment of TNBC. Further evidence has shown that combining radiation with chemotherapy is also a suitable treatment based on DNA repair deficiencies in patients with TNBC. However, the preferred treatment for metastatic TNBC remains unclear. Therefore, identification of biomarkers is an unmet need in personalized therapy for TNBC. RNF8 (ring finger protein 8) is a ubiquitin ligase implicated in TNBC metastasis; however, its role in TNBC pathogenesis is unclear. The purpose of the present study was to investigate the roles of the RNF8–CDH1(Cadherin 1) axis in node-positive TNBC patients. We found that the RNF8high/CDH1low index was significantly higher in patients with TNBC than in patients without TNBC. Furthermore, patients with an RNF8high/CDH1low index displayed poorer outcomes than those with an RNF8low-medium/CDH1medium-high index. Notably, as compared to patients with an RNF8low-medium/CDH1medium-high index, those with an RNF8high/CDH1low index had a poorer survival rate with chemotherapy treatment alone. The combination of radiation and chemotherapy resulted in a better survival rate than chemotherapy alone in patients with an RNF8high/CDH1low index. Taken together, the RNF8high/CDH1low index not only functions as a prognostic and therapeutic marker but may also act as a target in the development of anti-cancer agents for patients with TNBC.
The Ability to Run in Young People with Cerebral Palsy before and after Single Event Multi-Level Surgery
Authors: Rethwilm Roman , Böhm Harald , Döderlein Leonhard , Federolf Peter A. , Dussa Chakravarthy U.
Published: July 2021

The objective of the study is to identify and evaluate possible factors that influence the ability to run before and after single event multi-level surgery (SEMLS). Young patients (6–25 years) with spastic cerebral palsy (GMFCSI-II) were retrospectively included. Type and number of surgical procedures, time for recovery and 3D gait analysis variables were analyzed with respect to the ability to run. In total, 98 patients (38 females; 60 males) who received SEMLS (12 years, SD 3.4) were included and compared to a control group of 71 conservatively treated patients. Of 60 runners pre-surgery, 17 (28%) lost the ability, while gained in 8 of 38 (21%) non-runners. The number of surgical procedures was a significant predictor and those who lost their ability to run had significantly more (mean = 5.9, SD = 1.7), compared to the patients who gained the ability (mean = 3.5, SD = 0.9). Further, pre-surgical function (e.g., gait speed) was significantly different (p < 0.001). Pre-surgical function and the number of surgical procedures seem to play an important role for the gain or loss of the ability to run after surgery. Caution is warranted in patients with lower pre-surgical function and the ability to run, as they seem at a higher risk to lose the ability.
‘My Sport Won’t Pay the Bills Forever’: High-Performance Athletes’ Need for Financial Literacy and Self-Management
Authors: Hong Hee Jung , Fraser Ian
Published: July 2021

This paper investigates high-performance athletes’ development of their financial literacy and self-management skills and the related organisational support available to them during their athletic careers. The data were collected from 20 retired high-performance athletes (10 male and 10 female) representing six different countries (Japan, Mexico, Portugal, Singapore, South Korea, and the UK). Thematic analysis was applied to the processing of the data and five themes emerged: (1) Funding battles: financial challenges and misjudgements; (2) Coping Strategies; (3) Support from sponsors, parents, and sport organisations; (4) Development of Financial Literacy; and (5) Life After Sport. The data indicates that athletes experienced financial challenges due to a lack of organisational support, reduced or terminated funding, and limited opportunities to access sponsorship. Typically, athletes developed their financial literacy and self-management skills by ‘self-help’ or ‘trial and error’. The findings contribute to both literature and practice by providing empirical evidence on the coping strategies adopted by athletes in order to overcome financial challenges and on the methods used in order to develop their financial literacy and self-management skills. These findings inform sport organisations and governing bodies to develop support schemes for high-performance athletes as well as deepen our knowledge of athletes’ career development and transitions focusing on the financial aspect.
Storming the Beachhead: An Examination of Developed and Emerging Market Multinational Strategic Location Decisions in the U.S.
Authors: Dunlap Denise R. , Santos Roberto S.
Published: July 2021

Entering a foreign market is challenging given the fierce competition posed by local incumbents. The literature suggests that when entering a foreign market, it is advantageous to locate where there are agglomeration benefits. Given the dynamic nature of regional development, foreign firms have multiple location options. While the literature has primarily focused on developed country multinationals’ (DMNEs) location decisions, emerging market multinationals (EMNEs) are increasingly becoming influential in high-tech industries. Due to differences in DMNE and EMNE resource endowments, they may consider alternative options when locating abroad and, thus, we examine these nuances. Using multinomial logistic regression, we investigate domestic and foreign location patterns of firms within the U.S. biopharmaceutical industry as of 2018. We constructed a unique dataset of 19,962 U.S. locations and examined the location patterns of DMNEs and EMNEs from 61 countries and territories. Given the heterogeneity of regional development in the U.S., we developed a typology that stratifies regions into four categories (developed, growth, transitioning, and nascent). Counterintuitively, we find that foreign multinationals are more likely to be attracted to less developed regions than domestic firms and have different location patterns, not only compared to domestic firms, but also with respect to each other.
Does Pastoral Land-Use Legacy Influence Topsoil Carbon and Nitrogen Accrual Rates in Tallgrass Prairie Restorations?
Authors: Glass Nicholas , Molano-Flores Brenda , Dias de Oliveira Eduardo , Meraz Erika , Umar Samira , Whelan Christopher J. , Gonzalez-Meler Miquel A.
Published: July 2021

Restoration can recover degraded ecosystems and ecosystem services. However, effects of restoration on soil nutrient accrual are difficult to predict, partly because prior land use affects rates of soil nutrient recovery. In tallgrass prairie restorations, land-use legacy effects have not yet been quantified. We investigated topsoil carbon and nitrogen accrual within seven land-use histories: (1) row crop agriculture, (2) pasture, (3) pasture converted from row crops, (4) prairie restored from row crop, (5) prairie restored from old pasture, (6) bison prairie restored from pasture and row crops, and (7) remnant prairie. Soil samples were collected in 2008 and again in 2018 at Midewin National Tallgrass Prairie in Will County, IL. Soil samples were analyzed for bulk density, root chemistry, macro- and micronutrients, and carbon. Restored prairies contained similar soil bulk densities and rates of topsoil carbon accrual compared to each other in 2018. However, restorations from row cropping accrued nitrogen more slowly than restorations from pastures. Additionally, pastures converted from crop fields exhibited fewer legacy effects than restorations converted from crop fields. This research illustrates land-use legacy effects on soil and nutrients during grassland restorations, with implications for potential restoration trajectories and their role in carbon sequestration and ecosystem functioning.