bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the Learning Process During Covid-19 Pandemic
Authors: Rahayu Sri , Hariyanto Tanto , Wulandari Lisa , Finisia Hirdayanti
Published: February 2021

After Covid-19 was declared as Pandemic by the WHO, all activities are lingered over barriers including teaching and learning activities. Learning methods are transformed into online learning to minimize the spread of Covid-19 virus. But in its implementation there are obstacles and shortcomings so that the learning process is disrupted. This research aimed to analyze the online learning process during the Covid-19 pandemic in Poltekkes Kemenkes Malang. Research method used in this study was qualitative description and used total sampling method in collecting respondent. The results showed that online learning was still not maximal at its implementation. The result analysis used Respondent Achievement Level (RAL). On the topic of learning process and learning atmosphere was at vulnerable 55% - 69% with the category "less good", the topic of learning methods RAL results showed at vulnerable 43.2% - 44.3% which fall into the category "not good". For academic guidance, guidance activities of final exam/thesis and the implementation of final exam got a "pretty good" predicate with vulnerable RAL scores of 70%-79% and in research and community service activities got RAL results of 1%-54% which fall into the category of "not good".

Keywords: the covid-19 pandemic; online learning; higher education
The Effect of Service Quality and Maternal Satisfaction of Children Under Five on the Behavior of Mothers Visiting “Posyandu”
Authors: Suharto Agung , Santosa Budi Joko , Kasiati K
Published: February 2021

Background: “Posyandu” is a means for the community to obtain basic health services which includes five main “posyandu” activities, including: maternal and child health, family planning, nutrition, immunization and overcoming diarrhea. In terms of quantity, the development of the number of posyandu is very encouraging, because the ratio of posyandu to village is 3.51 “posyandu”. This study aims to determine the effect of service quality and maternal satisfaction of children under five on the behavior of mothers visiting “posyandu”. Methods: The design of this research was cross sectional. Population was 100 and sample was 80 people. Independent variable were the quality of service and satisfaction and dependent variable was the behavior (frequency) of visiting the “posyandu”. Data analysis was done by: descriptive analysis, and logistic regression. Results: The most of respondents said the quality of service was good as many as 56.3% and a small proportion of respondents said the quality of service was sufficient as much as 8.8%. Most of the respondents said that the level of satisfaction was satisfied as much as 55% and a small proportion of respondents said the level of satisfaction was satisfied as much as 6.3%. Most of the h good behavior was 71.3% and a small proportion of: less than 2.5%. Obtained a significant effect of service quality on the behavior of mothers under five visiting “posyandu” (p-value = 0.005) and there was a significant effect of satisfaction with the behavior of mothers under five visiting “posyandu” (p-value = 0.011). Conclusion: the quality of service and satisfaction of mothers under five have an effect on the behavior of mothers visiting “posyandu”.

Keywords: quality; satisfaction; behavior; “posyandu”
The Effect of Side Effects Tuberculosis Treatment in the Early Stage Towards Compliance with Tuberculosis Patients
Authors: Pramono Joko Sapto , Noorma Nilam , Gandini Andi Lis Arming , Fitriani Sopia
Published: February 2021

Pulmonary tuberculosis treatment causes various side effects including nausea and vomiting, itching, vision problems, and anemia. Drug side effects in the early stages are one of the causes of non-adherence to complete treatment. The purpose of this study was to analyze the effect of the side effects Tuberculosis treatment in the early stages on treatment compliance for tuberculosis patients. This study used a cross sectional design. Samples were taken as many as 71 respondents, the instruments used were side effects of early-stage tuberculosis treatment and compliance with tuberculosis treatment in tuberculosis patients from the Morisky Medication Adherence Scale (MMAS). The results of the study found 97.7% adherent and 2.3% non-adherent, 39.5% mild side effects and 60.5% severe side effects. Chi-square test showed that no significant difference between the side effects of TB treatment in the early stages of tuberculosis treatment compliance in patients p = 0.669 at significant level of 95% (α = 0.05). There was no effect between the side effects of Tuberculosis treatment in the early stages of treatment compliance for Tuberculosis patients. It was recommended that health workers continue to monitor the side effects of tuberculosis treatment and provide motivation to carry out treatment completely.

Keywords: side effects; early stage; treatment; pulmonary tuberculosis; compliance
Within-Population Trait Variation in a Globally Invasive Plant Species Mayweed Chamomile (Anthemis cotula): Implications for Future Invasion and Management
Authors: Adhikari Subodh , Burke Ian C. , Revolinski Samuel R. , Piaskowski Julia , Eigenbrode Sanford D.
Published: February 2021

Quantification of variation for phenotypic traits within and among weed populations facilitate understanding of invasion mechanisms and management tactics. In the Pacific Northwest (PNW), USA, in response to climate change and to improve sustainability, producers are increasingly adopting broadleaf crops and cover crops, but Mayweed chamomile (Anthemis cotula L.) is a significant barrier to diversifying cropping systems because of its abundance and lack of herbicide options for its control. To quantify within-population phenotypic trait variation and heritability, plants (n = 300) from six half-sib families (i.e., seed source plants or mother plants) from each of 10 A. cotula populations (infested farms or sites) in the PNW were grown from seed through the flowering stage in the greenhouse common garden experiment. We measured percent seedling emergence, the initial date of flowering, flowering duration, plant biomass, number of flower heads, floral scent profiles, and other traits on individual plants. Trait variation was high among half-sib families within each population. For example, in two of the populations, percent seedling emergence within 30 days of planting ranged from 5 to 41% and 3 to 53%, respectively. As another example, initial date of flowering in two other populations ranged from 61 to 93 days and 58 to 92 days, respectively. Differences among half-sib families were greatest for flowering period, which differed by a month in most populations, and floral scent profiles. Heritability estimates were higher than 1.0 for most phenotypic traits, indicating that the study plants were more closely related than half-sibs (i.e., included full-sibs or products of selfing). These patterns of phenotypic trait variation are potentially caused by local edaphoclimatic factors and within-field farm management practices, suggesting that management of A. cotula might be challenging and differ within and across farms.
Dental Implants Loaded With Bioactive Agents Promote Osseointegration in Osteoporosis: A Review
Authors: Zhang Cheng , Zhang Tianjia , Geng Tengyu , Wang Xudong , Lin Kaili , Wang Penglai
Published: February 2021

Implant-supported dentures are widely used in patients with defect or loss of dentition because these have higher chewing efficiency and do not damage the adjacent teeth compared with fixed or removable denture. An implant-supported denture carries the risk of failure in some systemic diseases, including osteoporosis, because of a non-ideal local microenvironment. Clinically common physical and chemical modifications are used to change the roughness of the implant surface to promote osseointegration, but they have limitations in promoting osteoinduction and inhibiting bone resorption. Recently, many researchers have focused on the study of bioactive modification of implants and have achieved promising results. Herein we have summarized the progress in bioactive modification strategy to promote osseointegration by regulating the local osteoporotic microenvironment.
Effects of Whole-Body Vibration-Assisted Training on Lower Limb Blood Flow in Children With Myelomeningocele
Authors: Szopa Andrzej , Domagalska-Szopa Małgorzata , Siwiec Andrzej , Kwiecień-Czerwieniec Ilona
Published: February 2021

This study investigated the effectiveness of whole-body vibration (WBV) training incorporated into a conventional physiotherapy (PT) program (WBV-assisted training) in improving blood flow in the lower limbs and range of motion in the lower limb joints of children with myelomeningocele (MMC). A total of 31 children with MMC (7–15 years old) underwent a 6 weeks treatment program consisting of 2 weeks of conventional PT followed by 4 weeks of WBV-assisted training. The assessment comprised two parts: evaluation of lower limb joint range of motion and Doppler ultrasonography of the superficial femoral, popliteal, and anterior tibial arteries and was performed three times for each of the participants (at baseline, after 10 sessions of PT but before WBV-assisted training, and after 20 sessions of WBV-assisted training). Our results showed that WBV-assisted training significantly improved lower limb circulation in patients with MMC, increasing velocity and reducing resistivity in all tested arteries. Moreover, WBV-assisted training alleviated lower-extremity contractures, especially of the knee. Thus, WBV-assisted training is effective as an adjunctive rehabilitation program for improving functional mobility in children with MMC.
A Novel Species of Penicillium With Inhibitory Effects Against Pyricularia oryzae and Fungal Pathogens Inducing Citrus Diseases
Authors: Liang Li-Juan , Jeewon Rajesh , Dhandevi Pem , Durairajan Siva Sundara Kumar , Li Hongye , Lin Fu-Cheng , Wang Hong-Kai
Published: February 2021

A novel species of Penicillium, proposed as P. linzhiense sp.nov was isolated from soil collected in Linzhi Town, Linzhi County, Tibet Autonomous Region, China. DNA sequence analyses from eight different gene regions indicate that the isolate represents a novel species and most closely related to P. janczewskii. The phylogenetic analysis based on a concatenated dataset of three genes, ITS, CaM, and BenA, also confirmed the placement of the novel species within the Canescentia section of the genus Penicillium. Differences in morphology among similar species are detailed and single gene phylogenies based on ITS, CaM and BenA genes as well as a multi-loci gene phylogeny are presented. Cultural studies were performed to study inhibitory activities on plant pathogens. The results reveal a notable antifungal activity against Pyricularia oryzae causing rice blast with an inhibition rate up to 77%, while for other three citrus pathogens, Diaporthe citri, Phyllosticta citrichinaensis, and Colletotrichum gloeosporioides, inhibition rate was 40, 50, and 55% respectively. No noticeable effects were observed for Fusarium graminearum, Botryosphaeria kuwatsukai, and Rhizoctonia solani. Interestingly, unlike other reported members of Canescentia, P. linzhiense showed no antagonistic effect on root rotting fungi. The new taxon isolated here has the potential to be used as a biocontrol agent especially for economically important phytopathogens or emerging pathogens on diseases occurring on citrus or rice.
Piperlongumine Attenuates High Calcium/Phosphate-Induced Arterial Calcification by Preserving P53/PTEN Signaling
Authors: Shi Wenxiang , Lu Jieyu , Li Junhan , Qiu Ming , Lu Yan , Gu Jia , Kong Xiangqing , Sun Wei
Published: February 2021

Vascular calcification frequently occurs in the process of chronic kidney disease, atherosclerosis and aging, resulting in an increased prevalence of cardiovascular events. Piperlongumine (PLG) is a natural product isolated from Piper longum L. Here, we aimed to explore the effect of PLG in high calcium- and phosphate-induced vascular calcification and the associated mechanism. Flow cytometry assays showed that PLG at concentrations <10 μM did not promote vascular smooth muscle cells (VSMCs) apoptosis, and PLG at concentrations >2.5 μM inhibited VSMCs proliferation. Thus, 2.5 μM PLG was selected for subsequent experiments. Alizarin red staining and ALP activity assays showed that PLG inhibited calcium deposition of VSMCs treated with high calcium/phosphate medium. PLG also decreased the expression of osteogenic genes and proteins, including Runx2, Bmp2, and OPN, as determined by qRT-PCR and western blotting. In a vitamin D-induced aortic calcification mouse model, a 5 mg/kg dose of PLG decreased calcium deposition in the aortic wall as well as Runx2 expression. With regard to the mechanism, we found that the levels of P53 mRNA and protein in both VSMCs and mouse aortic tissues were decreased in the calcification models, and we observed that PLG preserved the levels of P53 and its downstream gene PTEN. Concurrent treatment of VSMCs with P53 ShRNA and PLG blunted the anti-calcific effect of PLG. In conclusion, PLG attenuates high calcium/phosphate-induced vascular calcification by upregulating P53/PTEN signaling in VSMCs. PLG may act as a promising herbal extract for the clinical management of vascular calcification.
Early Warning Signs of a Mental Health Tsunami: A Coordinated Response to Gather Initial Data Insights From Multiple Digital Services Providers
Authors: Inkster Becky ,   Digital Mental Health Data Insights Group (DMHDIG)
Published: February 2021

Introduction: The immediate impact of coronavirus 2019 (COVID-19) on morbidity and mortality has raised the need for accurate and real-time data monitoring and communication. The aim of this study is to document the initial observations from multiple digital services providers during the COVID-19 crisis, especially those related to mental health and well-being.

Methods: We used email and social media to announce an urgent call for support. Digital mental health services providers (N = 46), financial services providers (N = 4), and other relevant digital data source providers (N = 3) responded with quantitative and/or qualitative data insights. People with lived experience of distress, as service users/consumers, and carers are included as co-authors.

Results: This study provides proof-of-concept of the viability for researchers and private companies to work collaboratively toward a common good. Digital services providers reported a diverse range of mental health concerns. A recurring observation is that demand for digital mental health support has risen, and that the nature of this demand has also changed since COVID-19, with an apparent increased presentation of anxiety and loneliness.

Conclusion: Following this study, we will continue to work with providers in more in-depth ways to capture follow-up insights at regular time points. We will also onboard new providers to address data representativeness. Looking ahead, we anticipate the need for a rigorous process to interpret insights from an even wider variety of sources in order to monitor and respond to mental health needs.
Recent Advances in Screening Lithium Solid-State Electrolytes Through Machine Learning
Authors: Liu Hongcan , Ma Shun , Wu Junjun , Wang Yingkai , Wang Xinghui
Published: February 2021

Compared to liquid electrolytes, lithium solid-state electrolytes have received increased attention in the field of all-solid-state lithium ion batteries due to safety requirements and higher energy density. However, solid-state electrolytes face many challenges, including lower ionic conductivity, complex interfaces, and unstable physical or electrochemical properties. One of the most effective strategies is to find a new type of lithium solid-state electrolyte with improved properties. Traditional trial and error methods require resources and time to verify the new solid-state electrolytes. Recently, new lithium solid-state electrolytes were predicted through machine learning (ML), which has proved to be an efficient and reliable method for screening new functional materials. This paper reviews the lithium solid-state electrolytes that have been discovered based on ML algorithms. The selection and preprocessing of datasets in ML technology are initially discussed before describing the latest developments in screening lithium solid-state electrolytes through different ML algorithms in detail. Lastly, the stability of candidate solid-state electrolytes and the challenges of discovering new lithium solid-state electrolytes through ML are highlighted.
Dexamethasone and Methylprednisolone Promote Cell Proliferation, Capsule Enlargement, and in vivo Dissemination of C. neoformans
Authors: Araújo Glauber R. de S. , Alves Vinicius , Martins-de-Souza Pedro H. , Guimarães Allan J. , Honorato Leandro , Nimrichter Leonardo , Takiya Christina Maeda , Pontes Bruno , Frases Susana
Published: February 2021

Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, who often have some inflammatory condition and, therefore, end up using glucocorticoids, such as dexamethasone and methylprednisolone. Although the effects of this class of molecules during cryptococcosis have been investigated, their consequences for the biology of C. neoformans is less explored. Here, we studied the effects of dexamethasone and methylprednisolone on the metabolism and on the induction of virulence factors in C. neoformans. Our results showed that both glucocorticoids increased fungal cell proliferation and surface electronegativity but reduced capsule and secreted polysaccharide sizes, as well as capsule compaction, by decreasing the density of polysaccharide fibers. We also tested whether glucocorticoids could affect the fungal virulence in Galleria mellonella and mice. Although the survival rate of Galleria larvae increased, those from mice showed a tendency to decrease, with infected animals dying earlier after glucocorticoid treatments. The pathogenesis of spread of cryptococcosis and the interleukin secretion pattern were also assessed for lungs and brains of infected mice. While increases in the spread of the fungus to lungs were observed after treatment with glucocorticoids, a significant difference in brain was observed only for methylprednisolone, although a trend toward increasing was also observed for dexamethasone. Moreover, increases in both pulmonary and cerebral IL-10 production, reduction of IL-6 production but no changes in IL-4, IL-17, and INF-γ were also observed after glucocorticoid treatments. Finally, histopathological analysis confirmed the increase in number of fungal cells in lung and brain tissues of mice previously subjected to dexamethasone or methylprednisolone treatments. Together, our results provide compelling evidence for the effects of dexamethasone and methylprednisolone on the biology of C. neoformans and may have important implications for future clinical treatments, calling attention to the risks of using these glucocorticoids against cryptococcosis or in immunocompromised individuals.
SLC22A4 Gene in Hereditary Non-syndromic Hearing Loss: Recurrence and Incomplete Penetrance of the p.C113Y Mutation in Northwest Africa
Authors: Chiereghin Chiara , Robusto Michela , Mauri Lucia , Primignani Paola , Castorina Pierangela , Ambrosetti Umberto , Duga Stefano , Asselta Rosanna , Soldà Giulia
Published: February 2021

Inherited hearing loss is extremely heterogeneous both clinically and genetically. In addition, the spectrum of deafness-causing genetic variants differs greatly among geographical areas and ethnicities. The identification of the causal mutation in affected families allows early diagnosis, clinical follow-up, and genetic counseling. A large consanguineous family of Moroccan origin affected by autosomal recessive sensorineural hearing loss (ARSNHL) was subjected to genome-wide linkage analysis and exome sequencing. Exome-wide variant analysis and prioritization identified the SLC22A4 p.C113Y missense variant (rs768484124) as the most likely cause of ARSNHL in the family, falling within the unique significant (LOD score>3) linkage region on chromosome 5. Indeed, the same variant was previously reported in two Tunisian ARSNHL pedigrees. The variant is present in the homozygous state in all six affected individuals, but also in one normal-hearing sibling, suggesting incomplete penetrance. The mutation is absent in about 1,000 individuals from the Greater Middle East Variome study cohort, including individuals from the North African population, as well as in an additional seven deaf patients from the same geographical area, recruited and screened for mutations in the SLC22A4 gene. This study represents the first independent replication of the involvement of SLC22A4 in ARSNHL, highlighting the importance of the gene, and of the p.C113Y mutation, at least in the Northwest African population.
Transcriptome Characterization of Short Distance Transport Stress in Beef Cattle Blood
Authors: Zhao Haidong , Tang Xiaoqin , Wu Mingli , Li Qi , Yi Xiaohua , Liu Shirong , Jiang Junyi , Wang Shuhui , Sun Xiuzhu
Published: February 2021

The transportation is a crucial phase in beef cattle industry, and the annual losses caused by beef cattle transport stress are substantial. Several studies have described the effect of long distance transportation stress on animal health, such as disorder in nervous, endocrine, immune, and metabolic system. However, molecular mechanisms underlying short distance transportation stress is still poorly understood. Present study aims to investigate the effect of short distance transportation by measuring the hematological indices and transcriptomic analysis. In this study, a total 10 Qinchuan cattle were used to compare the molecular characteristics of blood before and after transportation. We have found that a stress-related marker “white blood cell count (WBC)” increased significantly after transportation. The decrease in triglyceride (TG), cholestenone (CHO), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) showed that energy expenditure was increased after transportation, but not enough to activate fatty decomposition. Intriguingly, the decrease of malondialdehyde (MDA) showed that cattle were more resilience to oxidative stress. The RNA-seq showed that 1,092 differentially expressed genes (DEGs) were found (329 up-regulated and 763 down-regulated) between group before and group after. The GO and KEGG enrichment showed that the metabolic pathway and B cell function related pathways were enriched. Furthermore, median absolute deviation (MAD) top 5,000 genes were used to construct a co-expression network by weighted correlation network analysis (WGCNA), and 11 independent modules were identified. Combing with protein-protein interaction (PPI) analysis, the verification of quantitative real-time PCR (qPCR) and the correlation of B cell function, structural maintenance of chromosomes 3 (SMC3), jun proto-oncogene (JUN), and C-X-C motif chemokine ligand 10 (CXCL10) were suggested as potential molecular markers in identification of short distance transportation. Collectively, the blood RNA-seq analysis and WGCNA indicated that the disorder of B cell differentiation, proliferation, survival, and apoptosis were the potential molecular mechanism in short distance transportation stress. In conclusion, our results provide the novel insight about potential biomarkers for short distance transportation stress, which may serve as for diagnosing and preventing this condition in beef industry.
Deep Learning in Head and Neck Tumor Multiomics Diagnosis and Analysis: Review of the Literature
Authors: Wang Xi , Li Bin-bin
Published: February 2021

Head and neck tumors are the sixth most common neoplasms. Multiomics integrates multiple dimensions of clinical, pathologic, radiological, and biological data and has the potential for tumor diagnosis and analysis. Deep learning (DL), a type of artificial intelligence (AI), is applied in medical image analysis. Among the DL techniques, the convolution neural network (CNN) is used for image segmentation, detection, and classification and in computer-aided diagnosis. Here, we reviewed multiomics image analysis of head and neck tumors using CNN and other DL neural networks. We also evaluated its application in early tumor detection, classification, prognosis/metastasis prediction, and the signing out of the reports. Finally, we highlighted the challenges and potential of these techniques.
Mesenchymal Stromal Cell Therapy in Solid Organ Transplantation
Authors: Podestà Manuel Alfredo , Remuzzi Giuseppe , Casiraghi Federica
Published: February 2021

Transplantation is the gold-standard treatment for the failure of several solid organs, including the kidneys, liver, heart, lung and small bowel. The use of tailored immunosuppressive agents has improved graft and patient survival remarkably in early post-transplant stages, but long-term outcomes are frequently unsatisfactory due to the development of chronic graft rejection, which ultimately leads to transplant failure. Moreover, prolonged immunosuppression entails severe side effects that severely impact patient survival and quality of life. The achievement of tolerance, i.e., stable graft function without the need for immunosuppression, is considered the Holy Grail of the field of solid organ transplantation. However, spontaneous tolerance in solid allograft recipients is a rare and unpredictable event. Several strategies that include peri-transplant administration of non-hematopoietic immunomodulatory cells can safely and effectively induce tolerance in pre-clinical models of solid organ transplantation. Mesenchymal stromal cells (MSC), non-hematopoietic cells that can be obtained from several adult and fetal tissues, are among the most promising candidates. In this review, we will focus on current pre-clinical evidence of the immunomodulatory effect of MSC in solid organ transplantation, and discuss the available evidence of their safety and efficacy in clinical trials.
Befriending the Hostile Tumor Microenvironment in CAR T-Cell Therapy
Authors: Lindo Lorenzo , Wilkinson Lauren Hanna , Hay Kevin Anthony
Published: February 2021

T-cells genetically engineered to express a chimeric antigen receptor (CAR) have shown remarkable results in patients with B-cell malignancies, including B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and mantle cell lymphoma, with some promising efficacy in patients with multiple myeloma. However, the efficacy of CAR T-cell therapy is still hampered by local immunosuppression and significant toxicities, notably cytokine release syndrome (CRS) and neurotoxicity. The tumor microenvironment (TME) has been identified to play a major role in preventing durable responses to immunotherapy in both solid and hematologic malignancies, with this role exaggerated in solid tumors. The TME comprises a diverse set of components, including a heterogeneous population of various cells and acellular elements that collectively contribute towards the interplay of pro-immune and immunosuppressive signaling. In particular, macrophages, myeloid-derived suppressor cells, regulatory T-cells, and cell-free factors such as cytokines are major contributors to local immunosuppression in the TME of patients treated with CAR T-cells. In order to create a more favorable niche for CAR T-cell function, armored CAR T-cells and other combinatorial approaches are being explored for potential improved outcomes compared to conventional CAR T-cell products. While these strategies may potentiate CAR T-cell function and efficacy, they may paradoxically increase the risk of adverse events due to increased pro-inflammatory signaling. Herein, we discuss the mechanisms by which the TME antagonizes CAR T-cells and how innovative immunotherapy strategies are being developed to address this roadblock. Furthermore, we offer perspective on how these novel approaches may affect the risk of adverse events, in order to identify ways to overcome these barriers and expand the clinical benefits of this treatment modality in patients with diverse cancers. Precise immunomodulation to allow for improved tumor control while simultaneously mitigating the toxicities seen with current generation CAR T-cells is integral for the future application of more effective CAR T-cells against other malignancies.
A New E-Series Resolvin: RvE4 Stereochemistry and Function in Efferocytosis of Inflammation-Resolution
Authors: Libreros Stephania , Shay Ashley E. , Nshimiyimana Robert , Fichtner David , Martin Michael J. , Wourms Nicholas , Serhan Charles N.
Published: February 2021

The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-resolving mediators (SPMs) is pivotal in the resolution of inflammation via their roles in innate immune cells. Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia. This new resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid and its bioactions in human phagocyte response.
Modulating Th2 Cell Immunity for the Treatment of Asthma
Authors: León Beatriz , Ballesteros-Tato Andre
Published: February 2021

It is estimated that more than 339 million people worldwide suffer from asthma. The leading cause of asthma development is the breakdown of immune tolerance to inhaled allergens, prompting the immune system's aberrant activation. During the early phase, also known as the sensitization phase, allergen-specific T cells are activated and become central players in orchestrating the subsequent development of allergic asthma following secondary exposure to the same allergens. It is well-established that allergen-specific T helper 2 (Th2) cells play central roles in developing allergic asthma. As such, 80% of children and 60% of adult asthma cases are linked to an unwarranted Th2 cell response against respiratory allergens. Thus, targeting essential components of Th2-type inflammation using neutralizing antibodies against key Th2 modulators has recently become an attractive option for asthmatic patients with moderate to severe symptoms. In addition to directly targeting Th2 mediators, allergen immunotherapy, also known as desensitization, is focused on redirecting the allergen-specific T cells response from a Th2-type profile to a tolerogenic one. This review highlights the current understanding of the heterogeneity of the Th2 cell compartment, their contribution to allergen-induced airway inflammation, and the therapies targeting the Th2 cell pathway in asthma. Further, we discuss available new leads for successful targeting pulmonary Th2 cell responses for future therapeutics.
Global Phylogeny and Taxonomy of the Wood-Decaying Fungal Genus Phlebiopsis (Polyporales, Basidiomycota)
Authors: Zhao Ya-Nan , He Shuang-Hui , Nakasone Karen K. , Wasantha Kumara K. L. , Chen Che-Chih , Liu Shi-Liang , Ma Hai-Xia , Huang Man-Rong
Published: February 2021

An in-depth study of the phylogeny and taxonomy of the corticioid genusPhlebiopsis(Phanerochaetaceae) was conducted. Phylogenetic analyses of the ITS1-5.8S-ITS2 and nrLSU sequences demonstrated thatPhlebiopsisis a strongly supported clade which is distinct from its sister clades ofPhaeophlebiopsis,Hapalopilus, andRhizochaete. Two genera,AustralohydnumandHjortstamia, are reduced to synonyms underPhlebiopsisas generic type speciesA. griseofuscescensandH. friesii, respectively, are embedded in thePhlebiopsisclade. Twenty-four lineages are resolved in the ITS phylogenetic tree ofPhlebiopsis, including six new taxa, viz.P. albescens,P. brunnea,P. cylindrospora,P. magnicystidiata,P. membranaceaandP. sinensis, from Sri Lanka and China. Five new combinations, viz.Phaeophlebiopsis mussooriensis,Phlebiopsis bambusicola,P. dregeana,P. griseofuscescensandP. novae-granatae, are proposed.Phlebiopsis crassais a morphological species complex with three distinct lineages.Phlebiopsis lamprocystidiatais determined to be a later synonym ofP. darjeelingensis. The new taxa are described, illustrated, and compared and contrasted to morphologically similar species. An emended description ofPhlebiopsisis provided along with an identification key to 27 accepted species.
Sensitivity of Molds From Spoiled Dairy Products Towards Bioprotective Lactic Acid Bacteria Cultures
Authors: Shi Ce , Knøchel Susanne
Published: February 2021

Fungal spoilage of dairy products is a major concern due to food waste and economical losses, some fungal metabolites may furthermore have adverse effects on human health. The use of lactic acid bacteria (LAB) is emerging as a potential clean label alternative to chemical preservatives. Here, our aim was to characterize the growth potential at three storage temperatures (5, 16, and 25°C) of a panel of molds (four Mucor and nine Penicillium strains) isolated from dairy products, then investigate the susceptibility of the molds toward 12 LAB cultures. Fungal cell growth and morphology in malt extract broth was monitored using oCelloScope at 25°C for 24 h. Mucor plumbeus 01180036 was the fastest growing and Penicillium roqueforti ISI4 (P. roqueforti ISI4) the slowest of the tested molds. On yogurt-agar plates, all molds grew at 5, 16, and 25°C in a temperature-dependent manner with Mucor strains growing faster than Penicillium strains regardless of temperature. The sensitivity toward 12 LAB cultures was tested using high-throughput overlay method and here all the molds except P. roqueforti ISI4 were strongly inhibited. The antifungal action of these LAB was confirmed when spotting mold spores on agar plates containing live cells of the LAB strains. However, if cells were removed from the fermentates, the inhibitory effects decreased markedly. The antifungal effects of volatiles tested in a plate-on-plate system without direct contact between mold and LAB culture media were modest. Some LAB binary combinations improved the antifungal activity against the growth of several molds beyond that of single cultures in yogurt serum. The role of competitive exclusion due to manganese depletion was examined as a possible antifungal mechanism for six Penicillium and two Mucor strains. It was shown that this mechanism was a major inhibition factor for the molds tested apart from the non-inhibited P. roqueforti ISI4 since addition of manganese with increasing concentrations of up to 0.1 mM resulted in partly or fully restored mold growth in yogurt. These findings help to understand the parameters influencing the mold spoilage of dairy products and the interactions between the contaminating strains, substrate, and bioprotective LAB cultures.
Staphylococcus aureus ST59: Concurrent but Separate Evolution of North American and East Asian Lineages
Authors: McClure Jo-Ann , Lakhundi Sahreena , Niazy Amani , Dong George , Obasuyi Osahon , Gordon Paul , Chen Sidong , Conly John M. , Zhang Kunyan
Published: February 2021

Despite initially being described in North America, Staphylococcus aureus (SA) sequence type ST59 is the most commonly isolated sequence type in Eastern Asia. The origins and evolution of this strain type remains unclear and therefore we gathered a collection of ST59 isolates from Canada and mainland China for a detailed genetic analysis of the lineage. Bayesian inference phylogenomic analysis of our isolates, along with previously published ST59 sequences indicated that the lineage could be divided into 6 distinct subgroups (WGS-1 thorough 6), each having distinct molecular characteristics. Analysis also demonstrated the concurrent but separate evolution of North American and East Asian lineages, as well as the extensive diversification of the East Asian lineage. The presence of a mobile element structure (MES) was found to be the major difference between these two continental lineages, absent in all North American isolates, and present in all East Asian ones. Other mobile genetic elements, such as the Immune Evasion Complex (IEC), Panton Valentine Leukocidin (PVL), and Staphylococcal Cassette Chromosome mec (SCCmec), showed significant variability within each sub-group and likely represents local selective pressures rather than major characteristics defining the groups. Our analysis also demonstrated the existence of a more ancient ST59 sub-lineage from North America, which was MES negative and contained some of the earliest reported ST59 isolates. Combined with the existence of a MES negative isolate from Taiwan, predicted to have appeared prior to diversification of the East Asian lineages, these results hint at the possibility of a North American origin for the lineage, which gained hold in Eastern Asia following acquisition of MES, and subsequently diversified.
3D Cell Culture for the Study of Microenvironment-Mediated Mechanostimuli to the Cell Nucleus: An Important Step for Cancer Research
Authors: Chhetri Apekshya , Rispoli Joseph V. , Lelièvre Sophie A.
Published: February 2021

The discovery that the stiffness of the tumor microenvironment (TME) changes during cancer progression motivated the development of cell culture involving extracellular mechanostimuli, with the intent of identifying mechanotransduction mechanisms that influence cell phenotypes. Collagen I is a main extracellular matrix (ECM) component used to study mechanotransduction in three-dimensional (3D) cell culture. There are also models with interstitial fluid stress that have been mostly focusing on the migration of invasive cells. We argue that a major step for the culture of tumors is to integrate increased ECM stiffness and fluid movement characteristic of the TME. Mechanotransduction is based on the principles of tensegrity and dynamic reciprocity, which requires measuring not only biochemical changes, but also physical changes in cytoplasmic and nuclear compartments. Most techniques available for cellular rheology were developed for a 2D, flat cell culture world, hence hampering studies requiring proper cellular architecture that, itself, depends on 3D tissue organization. New and adapted measuring techniques for 3D cell culture will be worthwhile to study the apparent increase in physical plasticity of cancer cells with disease progression. Finally, evidence of the physical heterogeneity of the TME, in terms of ECM composition and stiffness and of fluid flow, calls for the investigation of its impact on the cellular heterogeneity proposed to control tumor phenotypes. Reproducing, measuring and controlling TME heterogeneity should stimulate collaborative efforts between biologists and engineers. Studying cancers in well-tuned 3D cell culture platforms is paramount to bring mechanomedicine into the realm of oncology.
Altered Insular Subregional Connectivity Associated With Cognitions for Distinguishing the Spectrum of Pre-clinical Alzheimer's Disease
Authors: Wang Siyu , Sun Haiting , Hu Guanjie , Xue Chen , Qi Wenzhang , Rao Jiang , Zhang Fuquan , Zhang Xiangrong , Chen Jiu
Published: February 2021

Background: Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are regarded as part of the pre-clinical Alzheimer's disease (AD) spectrum. The insular subregional networks are thought to have diverse intrinsic connectivity patterns that are involved in cognitive and emotional processing. We set out to investigate convergent and divergent altered connectivity patterns of the insular subregions across the spectrum of pre-clinical AD and evaluated how well these patterns can differentiate the pre-clinical AD spectrum.

Method: Functional connectivity (FC) analyses in insular subnetworks were carried out among 38 patients with SCD, 56 patients with aMCI, and 55 normal controls (CNs). Logistic regression analyses were used to construct models for aMCI and CN, as well as SCD and CN classification. Finally, we conducted correlation analyses to measure the relationship between FCs of altered insular subnetworks and cognition.

Results: Patients with SCD presented with reduced FC in the bilateral cerebellum posterior lobe and increased FC in the medial frontal gyrus and the middle temporal gyrus. On the other hand, patients with aMCI largely presented with decreased FC in the bilateral inferior parietal lobule, the cerebellum posterior lobe, and the anterior cingulate cortex, as well as increased FC in the medial and inferior frontal gyrus, and the middle and superior temporal gyrus. Logistic regression analyses indicated that a model composed of FCs among altered insular subnetworks in patients with SCD was able to appropriately classify 83.9% of patients with SCD and CN, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.876, 81.6% sensitivity, and 81.8% specificity. A model consisting of altered insular subnetwork FCs in patients with aMCI was able to appropriately classify 86.5% of the patients with aMCI and CNs, with an AUC of 0.887, 80.4% sensitivity, and 83.6% specificity. Furthermore, some of the FCs among altered insular subnetworks were significantly correlated with episodic memory and executive function.

Conclusions: Patients with SCD and aMCI are likely to share similar convergent and divergent altered intrinsic FC patterns of insular subnetworks as the pre-clinical AD spectrum, and presented with abnormalities among subnetworks. Based on these abnormalities, individuals can be correctly differentiated in the pre-clinical AD spectrum. These results suggest that alterations in insular subnetworks can be utilized as a potential biomarker to aid in conducting a clinical diagnosis of the spectrum of pre-clinical AD.
Age Impacts the Burden That Reference Memory Imparts on an Increasing Working Memory Load and Modifies Relationships With Cholinergic Activity
Authors: Bernaud Victoria E. , Hiroi Ryoko , Poisson Mallori L. , Castaneda Arthur J. , Kirshner Ziv Z. , Gibbs Robert B. , Bimonte-Nelson Heather A.
Published: February 2021

Rodent aging research often utilizes spatial mazes, such as the water radial-arm-maze (WRAM), to evaluate cognition. The WRAM can simultaneously measure spatial working and reference memory, wherein these two memory types are often represented as orthogonal. There is evidence, however, that these two memory forms yield interference at a high working memory load. The current study systematically evaluated whether the presence of a reference memory component impacts handling of an increasing working memory load. Young and aged female rats were tested to assess whether aging impacts this relationship. Cholinergic projections from the basal forebrain to the hippocampus and cortex can affect cognitive outcomes, and are negatively impacted by aging. To evaluate whether age-related changes in working and reference memory profiles are associated with cholinergic functioning, we assessed choline acetyltransferase activity in these behaviorally-tested rats. Results showed that young rats outperformed aged rats on a task testing solely working memory. The addition of a reference memory component deteriorated the ability to handle an increasing working memory load, such that young rats performed similar to their aged counterparts. Aged rats also had challenges when reference memory was present, but in a different context. Specifically, aged rats had difficulty remembering which reference memory arms they had entered within a session, compared to young rats. Further, aged rats that excelled in reference memory also excelled in working memory when working memory demand was high, a relationship not seen in young rats. Relationships between cholinergic activity and maze performance differed by age in direction and brain region, reflecting the complex role that the cholinergic system plays in memory and attentional processes across the female lifespan. Overall, the addition of a reference memory requirement detrimentally impacted the ability to handle working memory information across young and aged timepoints, especially when the working memory challenge was high; these age-related deficits manifested differently with the addition of a reference memory component. This interplay between working and reference memory provides insight into the multiple domains necessary to solve complex cognitive tasks, potentially improving the understanding of complexities of age- and disease- related memory failures and optimizing their respective treatments.
Kinase Signaling in Dendritic Development and Disease
Authors: Nourbakhsh Kimya , Yadav Smita
Published: February 2021

Dendrites undergo extensive growth and remodeling during their lifetime. Specification of neurites into dendrites is followed by their arborization, maturation, and functional integration into synaptic networks. Each of these distinct developmental processes is spatially and temporally controlled in an exquisite fashion. Protein kinases through their highly specific substrate phosphorylation regulate dendritic growth and plasticity. Perturbation of kinase function results in aberrant dendritic growth and synaptic function. Not surprisingly, kinase dysfunction is strongly associated with neurodevelopmental and psychiatric disorders. Herein, we review, (a) key kinase pathways that regulate dendrite structure, function and plasticity, (b) how aberrant kinase signaling contributes to dendritic dysfunction in neurological disorders and (c) emergent technologies that can be applied to dissect the role of protein kinases in dendritic structure and function.
Neurotrophin-3 Promotes the Neuronal Differentiation of BMSCs and Improves Cognitive Function in a Rat Model of Alzheimer's Disease
Authors: Yan Zhongrui , Shi Xianjing , Wang Hui , Si Cuiping , Liu Qian , Du Yifeng
Published: February 2021

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has the potential to be developed into an effective treatment for neurodegenerative diseases such as Alzheimer's disease (AD). However, the therapeutic effects of BMSCs are limited by their low neural differentiation rate. We transfected BMSCs with neurotrophin-3 (NT-3), a neurotrophic factor that promotes neuronal differentiation, and investigated the effects of NT-3 gene overexpression on the differentiation of BMSCs into neurons in vitro and in vivo. We further studied the possible molecular mechanisms. We found that overexpression of NT-3 promoted the differentiation of BMSCs into neurons in vitro and in vivo and improved cognitive function in rats with experimental AD. By contrast, silencing NT-3 inhibited the differentiation of BMSCs and decreased cognitive function in rats with AD. The Wnt/β-catenin signaling pathway was involved in the mechanism by which NT-3 gene modification influenced the neuronal differentiation of BMSCs in vitro and in vivo. Our findings support the prospect of using NT-3-transduced BMSCs for the development of novel therapies for AD.