bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Analyses of circRNA Expression Profiles and Function Prediction in Chicken Cecums After Eimeria tenella Infection
Authors: Yu Hailiang , Mi Changhao , Wang Qi , Zou Wenbin , Dai Guojun , Zhang Tao , Zhang Genxi , Xie Kaizhou , Wang Jinyu , Shi Huiqiang
Published: March 2021

Coccidiosis is an important intestinal parasitic disease that causes great economic losses to the global poultry production industry. Circular RNAs (circRNAs) are long non-coding RNAs that play important roles in various infectious diseases and inflammatory responses. However, the expression profiles and functions of circRNAs during Eimeria tenella (E. tenella) infection remain unclear. In this study, high-throughput sequencing was carried out to detect circRNAs in chicken cecal tissues from the control (JC), resistant (JR), and susceptible (JS) groups on day 4.5 postinfection (pi), respectively. A total of 104 circRNAs were differentially expressed, including 47 circRNAs between the JS and JC groups, 38 between the JR and JS groups, and 19 between the JR and JC groups. Functional analyses indicated that these differentially expressed circRNAs were involved in pathways related to E. tenella infection; the adaptive immune response was enriched in the JS vs JC group, the NF-kappa B signaling and natural killer cell-mediated cytotoxicity pathways were enriched in the JS vs JC and JR vs JC groups, while the B cell receptor signaling pathway was enriched in only the JR vs JC group. Moreover, the coexpression network of differentially expressed circRNAs and mRNAs suggested that circRNA2202 and circRNA0759 associated with DTX1 in the JS vs JC group, circRNA4338 associated with VPREB3 and CXCL13L3 in the JR vs JC group, and circRNA2612 associated with IL8L1 and F2RL2 in the JR vs JS group were involved in the immune response upon E. tenella infection. In conclusion, our results provide valuable information on the circRNAs involved in the progression of chicken E. tenella infection and advance our understanding of the circRNA regulatory mechanisms of host resistance and susceptibility to E. tenella infection in chickens.
Characterization of a Deep Sea Bacillus toyonensis Isolate: Genomic and Pathogenic Features
Authors: Luo Jing-chang , Long Hao , Zhang Jian , Zhao Yan , Sun Li
Published: March 2021

Bacillus toyonensis is a group of Gram-positive bacteria belonging to the Bacillus cereus group and used in some cases as probiotics or biocontrol agents. To our knowledge, B. toyonensis from the deep sea (depth >1,000 m) has not been documented. Here, we report the isolation and characterization of a B. toyonensis strain, P18, from a deep sea hydrothermal field. P18 is aerobic, motile, and able to grow at low temperatures (4°C) and high concentrations of NaCl (8%). P18 possesses a circular chromosome of 5,250,895 bp and a plasmid of 536,892 bp, which encode 5,380 and 523 genes, respectively. Of these genes, 2,229 encode hypothetical proteins that could not be annotated based on the COG database. Comparative genomic analysis showed that P18 is most closely related to the type strain of B. toyonensis, BCT-7112T. Compared to BCT-7112T, P18 contains 1,401 unique genes, 441 of which were classified into 20 COG functional categories, and the remaining 960 genes could not be annotated. A total of 319 putative virulence genes were identified in P18, including toxin-related genes, and 24 of these genes are absent in BCT-7112T. P18 exerted strong cytopathic effects on fish and mammalian cells that led to rapid cell death. When inoculated via injection into fish and mice, P18 rapidly disseminated in host tissues and induced acute infection and mortality. Histopathology revealed varying degrees of tissue lesions in the infected animals. Furthermore, P18 could survive in fish and mouse sera and possessed hemolytic activity. Taken together, these results provide the first evidence that virulent B. toyonensis exists in deep sea environments.
A Pilot Epidemiological Exploration of Regenerative Dentistry From the Perspective of Active Clinicians Working in the UK
Authors: Neves Vitor C. M. , Jamal Hasan
Published: March 2021

Innovation has always been part of dentistry and with that comes thinking outside the box to produce guidelines for implementation of new approaches. Regenerative dentistry (RD) is a young specialty within the profession, which gathers knowledge from stem cells, molecular biology, and tissue and material engineering to produce and apply novel biologically based therapies. Since RD is an emerging branch of dentistry, it is not yet understood whether active clinicians are aware of this field and know exactly what it does. The aim of this study is to explore the awareness, understanding, and beliefs about RD of active dentists. A random selection of active dentists in the UK was approached via e-mail and face-to-face and asked to fill in a questionnaire. A total of 45 responses were received and analyzed. The results showed that active dentists in the UK are aware of the field but are not prepared to apply personalized biologically based therapies and feel a desire to educate themselves about RD further. Also, the results shine a light on the opportunities for regulatory and educational bodies to work together to prepare the clinicians for this novel field. Our research suggests that active dentists are ill-prepared for an era of personalized biologically based dental treatments. Further thinking of how to implement basic and more advanced biological knowledge and their application in dentistry is needed, and suggestions are made here.
Impacts of Indian Ocean Dipole–Like SST on Rice Yield Anomalies in Jiangsu Province
Authors: Xu Jingwei , Koldunov Nikolay V. , Xu Min , Zhu Xiuhua , Fraedrich Klaus , Jiang Xi , Zhu Shoupeng , Zhi Xiefei
Published: March 2021

One of the main water vapor sources of eastern China is the Bay of Bengal, over which the circulation is influenced by the Tropical Indian Ocean Dipole (TIOD). The TIOD has a long-lasting effect on weather patterns, which in turn influence the rice yield and quality in eastern China, such as in Jiangsu Province. To identify the main mechanism involved, we perform a detailed investigation of the connections between the TIOD-like sea surface temperature (SST) and the climatic suitability for growing rice, and the subsequent rice yield anomalies, in Jiangsu Province. In particular, we compare the relationships, and identify the underlying mechanisms, of TIOD SST with suitable sunshine duration, temperature and precipitation during the period of rice culture in the province. Singular Value Decomposition (SVD) results show that the TIOD-like SST has a close correlation with the rice yield anomalies, with a temporal correlation coefficient of 0.43 for 53 years, passing the 99% significance level. Furthermore, in the negative TIOD-like SST years, the background circulation weakens the transport effect of the atmospheric river through which water vapor is transported from the Bay of Bengal to eastern China. This decreased amount of transported water vapor decreases the precipitation and total cloud cover in the province. In turn, this significantly increases the sunshine duration, which plays a key role in rice yield anomalies. The increased sunshine duration and higher temperatures lead to positive rice yield anomalies, and vice versa. Our findings highlight that climatic factors, such as TIOD-like SST, have a far-reaching influence on agricultural production (in this case, rice yield), and thus special attention should be paid to interdisciplinary research in the fields of climate and agriculture.
Human Subsistence Strategies and Adaptations in the Lower Yangtze River Region During the Prehistoric Era
Authors: Hu Yaowu
Published: March 2021

Understanding the human subsistence strategies and adaptations in the Lower Yangtze River Region during the prehistoric period is vital to reveal the human-environment interactions, the origin and development of rice agriculture, cultural development, and social complexity. No systematic analysis of isotopic data of human bones in the region has been undertaken within the environmental (sea level), spatiotemporal (site distribution), and economic (animal and plant resources) contexts yet, in order to provide the direct evidence of human diets and trajectory of human subsistence strategies and adaptations. In this paper, I collected the isotopic data in the region as many as possible and incorporated within the environmental, spatiotemporal, and economic information. The results show that humans rarely made use of marine resources when facing the situation of rising sea levels and having good accesses to marine environment during the eastward movement. Alternatively, humans consumed large amount of terrestrial resources and supplementary freshwater or wetland resources. Rice agriculture was still of low-level production and contributed less to human diets. The unique human subsistence strategies enhanced human adaptations to the fluctuation of sea level in the Holocene in eastern China and facilitated the increases of archaeological cultures and human population, challenging the traditional opinion that the developed agriculture is the necessary pathway to develop cultures and grow human population.
Insulin Therapy in Type 2 Diabetes Is Associated With Barriers to Activity and Worse Health Status: A Cross-Sectional Study in Primary Care
Authors: Boels Anne Meike , Rutten Guy , Cleveringa Frits , van Avendonk Mariëlle , Vos Rimke
Published: March 2021

Introduction

Many individuals with type 2 diabetes mellitus (T2DM) experience “psychological insulin resistance”. Consequently, it could be expected that insulin therapy may have negative effects on psychological outcomes and well-being. Therefore, this study compared health status and psychosocial functioning of individuals with T2DM using only oral antihyperglycemic agents (OHA) and on insulin therapy (with or without OHA).

Materials and Methods

In this cross-sectional study, we used baseline data of a cluster randomized controlled trial conducted in 55 Dutch general practices in 2005. Health status was measured with the Short Form (SF)-36 (scale 0–100) and psychosocial functioning with the Diabetes Health Profile (DHP, scale 0-100). To handle missing data, we performed multiple imputation. We used linear mixed models with random intercepts per general practice to correct for clustering at practice level and to control for confounding.

Results

In total, 2,794 participants were included in the analysis, their mean age was 65.8 years and 50.8% were women. Insulin-users (n = 212) had a longer duration of T2DM (11.0 versus 5.6 years) and more complications. After correcting for confounders and multiple comparisons, insulin-users reported significantly worse outcomes on vitality (SF-36, adjusted difference -5.7, p=0.033), general health (SF-36, adjusted difference -4.8, p=0.043), barriers to activity (DHP, adjusted difference -7.2, p<0.001), and psychological distress (DHP, adjusted difference -3.7, p=0.004), all on a 0-100 scale.

Discussion

While previous studies showed similar or better health status in people with type 2 diabetes receiving insulin therapy, we found that vitality, general health and barriers to activity were worse in those on insulin therapy. Although the causality of this association cannot be established, our findings add to the discussion on the effects of insulin treatment on patient-reported outcomes in daily practice.
Maternal Diabetes Impairs Insulin and IGF-1 Receptor Expression and Signaling in Human Placenta
Authors: Tumminia Andrea , Scalisi Nunzio M. , Milluzzo Agostino , Ettore Giuseppe , Vigneri Riccardo , Sciacca Laura
Published: March 2021

Background

Maternal high blood glucose during pregnancy increases the risk for both maternal and fetal adverse outcomes. The mechanisms underlying the regulator effects of hyperglycemia on placental development and growth have not been fully illustrated yet. The placenta expresses high amounts of both insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R). It has been reported that the placenta of diabetic women has structural and functional alterations and the insulin/IGF system is likely to play a role in these changes. The aim of the present study was to measure the content of IR and IGF-1R and their phosphorylation in the placenta of women with type 1 diabetes mellitus (T1D) or with gestational diabetes mellitus (GDM) compared to women with normal glucose tolerance (NGT) during pregnancy.

Methods

Placental tissues were obtained from 80 Caucasian women with a singleton pregnancy. In particular, we collected placenta samples from 20 T1D patients, 20 GDM patients and 40 NGT women during pregnancy. Clinical characteristics and anthropometric measures of all women as well as delivery and newborn characteristics were recorded. Patients were also subdivided on the basis of peripartum glycemia either ≥90 mg/dl or <90 mg/dl, regardless of the diagnosis.

Results

In T1D patients, a higher rate of adverse outcomes was observed. Compared to the GDM women, the T1D group showed significantly higher average capillary blood glucose levels at the third trimester of pregnancy and at peripartum, and higher third-trimester HbA1c values. In both T1D and GDM women, HbA1c values during pregnancy correlated with glucose values in the peripartum period (R-squared 0.14, p=0.02). A positive correlation was observed between phosphorylation of placental IR and the glucose levels during the third trimester of GDM and T1D pregnancy (R-squared 0.21, p=0.003). In the placenta of T1D patients, IGF-1R phosphorylation and IR isoform A (IR-A) expression were significantly increased (p=0.006 and p=0.040, respectively), compared to the NGT women. Moreover, IGF-1R phosphorylation was significantly increased (p<0.0001) in the placenta of patients with peripartum glucose >90 mg/dl, while IR-A expression was increased in those with peripartum blood glucose higher than 120 mg/dl (p=0.046).

Conclusions

To the best of our knowledge, our study represents the first one in which an increased maternal blood glucose level during pregnancy is associated with an increased IGF-1R phosphorylation and IR-A expression in the placenta. Both these mechanisms can promote an excessive fetal growth.
The Stability of TSH, and Thyroid Hormones, in Patients Treated With Tablet, or Liquid Levo-Thyroxine
Authors: Antonelli Alessandro , Elia Giusy , Ragusa Francesca , Paparo Sabrina Rosaria , Cavallini Gabriella , Benvenga Salvatore , Ferrari Silvia Martina , Fallahi Poupak
Published: March 2021

Approximately, 5% of the population is affected by hypothyroidism, mainly women and persons aged more than 60 years. After the diagnosis of hypothyroidism the usual therapy is tablet levothyroxine (L-T4), with a monitoring of the thyroid-stimulating hormone (TSH) level in primary hypothyroidism every 6–8 weeks and L-T4 is adjusted as necessary to reach an euthyroid state. Once TSH is stabilized in the normal range, it is recommended to conduct annual testing in the treated subjects to warrant suitable replacement. More recently advances regarding L-T4 treatment are the introduction of new oral formulations: the liquid solution, and soft gel capsule. The soft gel capsule permits a quick dissolution in the acid gastric pH. The liquid preparation does not require an acid gastric environment. Many pharmacokinetic studies demonstrated a more rapid absorption for the liquid L-T4, or capsule, than with tablet. Many studies have shown that the liquid, or capsule, formulations can overcome the interaction with foods, drugs or malabsorptive conditions, that are able to impair the tablet L-T4 absorption. Lately studies have suggested that liquid L-T4 can permit to maintain more efficiently normal TSH levels in hypothyroid patients in the long-term follow-up, than tablet L-T4, both in patients with malabsorptive states, and in those without malabsorption. Further large, prospective, longitudinal studies are needed to evaluate the stability of TSH, in hypothyroid patients treated with different L-T4 formulations.
Local Perception in Forest Landscape Restoration Planning: A Case Study From the Brazilian Atlantic Forest
Authors: Maioli Veronica , Monteiro Lara M. , Tubenchlak Fernanda , Pepe Isabelle S. , de Carvalho Yuri B. , Gomes Fernanda D. , Strassburg Bernardo B. , Latawiec Agnieszka E.
Published: March 2021

Understanding local stakeholders' perception and their relation with the landscape and its natural resources is an important step for successfully implementing Forest Landscape Restoration (FLR). Here, we present a case study on FLR in the context of a global biodiversity hotspot—the Brazilian Atlantic Forest, using a participatory approach to include local stakeholders' knowledge and perception of the landscape into project planning. We analyzed the land use and cover, and organized a workshop with focus group methodology associated with maps and other visual representations to assess local perceptions of economic activities, production chains and their impacts on the landscape and ecosystem services. The study area encompasses seven municipalities mainly covered by native vegetation and pastures. Despite pastureland being the prominent land use in the region, they are not engaged in associations, most do not live in the region, and few participated in the workshop. Most participants were small and medium-scale landowners involved in agricultural activities who demonstrated a detailed knowledge of the territory, a disposition toward combining conservation with production practices, and a positive perception regarding ecotourism, agroecological approaches, water, and soil conservation. The participatory approach proved effective to complement the initial assessment while revealing novel aspects of the landscape and the landowners, helping test our hypotheses and adjust the engaging narratives for future FLR activities planning in the region, including environmental law compliance. More studies associating social and natural science, including participatory methods and local communities' perception, are needed to fully comprehend the drivers of stakeholders' engagement. This case study provides useful insights for other researchers and practitioners to design more effective plans for future land management.
Transcriptome Analysis of Ovarian Follicles Reveals Potential Pivotal Genes Associated With Increased and Decreased Rates of Chicken Egg Production
Authors: Chen Xiaoxia , Sun Xue , Chimbaka Ignatius Musenge , Qin Ning , Xu Xiaoxing , Liswaniso Simushi , Xu Rifu , Gonzalez John Michael
Published: March 2021

Egg production is an important economic trait in the commercial poultry industry. Ovarian follicle development plays a pivotal role in regulation of laying hen performance and reproductive physiology. However, the key genes and signaling pathways involved in the various-stages of laying hen follicular development remain poorly understood. In this study, transcriptomes of ovarian follicles at three developmental stages, the large white follicle (LWF), small yellow follicle (SYF), and large yellow follicle (LYF), were comparatively analyzed in hens with high (HR) and low (LR) egg-laying rates by RNA-sequencing. Eighteen cDNA libraries were constructed and a total of 236, 544, and 386 unigenes were significantly differentially expressed in the LWF, SYF, and LYF follicles of HR and LR hens, respectively. Among them, 47 co-transcribed differentially expressed genes (DEGs) in LWF and SYF, 68 co-expressed DEGs in SYF and LYF, and 54 co-expressed DEGs in LWF and LYF were mined. Thirteen co-expressed DEGs were found in LWF, SYF, and LYF follicles. Eighteen candidate genes, including P2RX1, CAB39L, BLK, CSMD3, GPR65, ADRB2, CSMD1, PLPP4, ATF3, PRLL, STMN3, RORB, PIK3R1, PERP1, ACSBG1, MRTO4, CDKN1A, and EDA2R were identified to be potentially related to egg production. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis indicated neuroactive ligand-receptor interaction, cell adhesion molecules, peroxisome proliferator-activated receptor pathway, and cAMP signaling pathway might elicit an important role in formation of egg-laying traits by influencing ovarian follicle development. This study represents the first transcriptome analysis of various-sized follicles between HR and LR hens. These results provide useful molecular evidence for elucidating the genetic mechanism underlying ovarian follicle development associated with egg production in chicken.
A Dual Systems Genetics Approach Identifies Common Genes, Networks, and Pathways for Type 1 and 2 Diabetes in Human Islets
Authors: Kaur Simranjeet , Mirza Aashiq H. , Overgaard Anne J. , Pociot Flemming , Størling Joachim
Published: March 2021

Type 1 and 2 diabetes (T1/2D) are complex metabolic diseases caused by absolute or relative loss of functional β-cell mass, respectively. Both diseases are influenced by multiple genetic loci that alter disease risk. For many of the disease-associated loci, the causal candidate genes remain to be identified. Remarkably, despite the partially shared phenotype of the two diabetes forms, the associated loci for T1D and T2D are almost completely separated. We hypothesized that some of the genes located in risk loci for T1D and T2D interact in common pancreatic islet networks to mutually regulate important islet functions which are disturbed by disease-associated variants leading to β-cell dysfunction. To address this, we took a dual systems genetics approach. All genes located in 57 T1D and 243 T2D established genome-wide association studies (GWAS) loci were extracted and filtered for genes expressed in human islets using RNA sequencing data, and then integrated with; (1) human islet expression quantitative trait locus (eQTL) signals in linkage disequilibrium (LD) with T1D- and T2D-associated variants; or (2) with genes transcriptionally regulated in human islets by pro-inflammatory cytokines or palmitate as in vitro models of T1D and T2D, respectively. Our in silico systems genetics approaches created two interaction networks consisting of densely-connected T1D and T2D loci genes. The “T1D-T2D islet eQTL interaction network” identified 9 genes (GSDMB, CARD9, DNLZ, ERAP1, PPIP5K2, TMEM69, SDCCAG3, PLEKHA1, and HEMK1) in common T1D and T2D loci that harbor islet eQTLs in LD with disease-associated variants. The “cytokine and palmitate islet interaction network” identified 4 genes (ASCC2, HIBADH, RASGRP1, and SRGAP2) in common T1D and T2D loci whose expression is mutually regulated by cytokines and palmitate. Functional annotation analyses of the islet networks revealed a number of significantly enriched pathways and molecular functions including cell cycle regulation, inositol phosphate metabolism, lipid metabolism, and cell death and survival. In summary, our study has identified a number of new plausible common candidate genes and pathways for T1D and T2D.
Comparative Analysis of Complete Chloroplast Genome Sequences in Edgeworthia (Thymelaeaceae) and New Insights Into Phylogenetic Relationships
Authors: Qian Shaojuan , Zhang Yonghong , Lee Shiou Yih
Published: March 2021

The complete chloroplast genomes of three species ofEdgeworthianamely,Edgeworthia albiflora,Edgeworthia chrysantha, andEdgeworthia gardneri(Thymelaeaceae), are reported and characterized. The chloroplast genomes displayed a typical quadripartite structure with conserved genome arrangement and specific divergence. The genomes ranged in length from 172,708 to 173,621 bp and displayed similar GC content of 36.5–36.7%. A total of 138–139 genes were predicted, including 92–93 protein-coding, 38 tRNAs and eight rRNAs genes. Variation in the number of short simple repeats and inverted region boundaries of the three cp genomes were observed. A mutational hotspot was detected along the nucleotide sequence from thendhF to thetrnL-UAG genes. The chloroplast genome-based and internal transcribed spacer (ITS)-based phylogenetic analyses using maximum-likelihood (ML) and Bayesian inference (BI) revealed thatE. albifloradiverged beforeE. chrysanthaandE. gardneriand placed theEdgeworthiaclade at the base of the Eurasian Daphne group with strong bootstrap support. With an effective taxonomic treatment of the species ofEdgeworthia, further molecular analyses of their intra- and interspecific genetic variation are inclined to support the treatment ofE. albifloraandE. gardnerias two natural groups. The genetic information obtained from this study will provide valuable genomic resources for the identification of additional species and for deducing the phylogenetic evolution ofEdgeworthia.
Donor/Recipient HLA Molecular Mismatch Scores Predict Primary Humoral and Cellular Alloimmunity in Kidney Transplantation
Authors: Meneghini Maria , Crespo Elena , Niemann Matthias , Torija Alba , Lloberas Nuria , Pernin Vincent , Fontova Pere , Melilli Edoardo , Favà Alexandre , Montero Nuria , Manonelles Anna , Cruzado Josep Maria , Palou Eduard , Martorell Jaume , Grinyó Josep Maria , Bestard Oriol
Published: March 2021

Donor/recipient molecular human leukocyte antigen (HLA) mismatch predicts primary B-cell alloimmune activation, yet the impact onde novodonor-specific T-cell alloimmunity (dnDST) remains undetermined. The hypothesis of our study is that donor/recipient HLA mismatches assessed at the molecular level may also influence a higher susceptibility to the development of posttransplant primary T-cell alloimmunity. In this prospective observational study, 169 consecutive kidney transplant recipients without preformed donor-specific antibodies (DSA) and with high resolution donor/recipient HLA typing were evaluated for HLA molecular mismatch scores using different informatic algorithms [amino acid mismatch, eplet MM, and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II)]. Primary donor-specific alloimmune activation over the first 2 years posttransplantation was assessed by means of both dnDSA and dnDST using single antigen bead (SAB) and IFN-γ ELISPOT assays, respectively. Also, the predominant alloantigen presenting pathway priming DST alloimmunity and the contribution of main alloreactive T-cell subsets were further characterizedin vitro. Pretransplantation, 78/169 (46%) were DST+ whereas 91/169 (54%) DST−. At 2 years, 54/169 (32%) patients showed detectable DST responses: 23/54 (42%) dnDST and 31/54 (57%) persistently positive (persistDST+). 24/169 (14%) patients developed dnDSA. A strong correlation was observed between the three distinct molecular mismatch scores and they all accurately predicted dnDSA formation, in particular at the DQ locus. Likewise, HLA molecular incompatibility predicted the advent of dnDST, especially when assessed by PIRCHE-II score (OR 1.014 95% CI 1.001–1.03, p=0.04). While pretransplant DST predicted the development of posttransplant BPAR (OR 5.18, 95% CI=1.64–16.34, p=0.005) and particularly T cell mediated rejection (OR 5.33, 95% CI=1.45–19.66, p=0.012), patients developing dnDST were at significantly higher risk of subsequent dnDSA formation (HR 2.64, 95% CI=1.08–6.45, p=0.03).In vitroexperiments showed that unlike preformed DST that is predominantly primed by CD8+ direct pathway T cells, posttransplant DST may also be activated by the indirect pathway of alloantigen presentation, and predominantly driven by CD4+ alloreactive T cells in an important proportion of patients.De novodonor-specific cellular alloreactivity seems to precede subsequent humoral alloimmune activation and is influenced by a poor donor/recipient HLA molecular matching.
Role of Lipids in Morphogenesis of T-Cell Microvilli
Authors: Cebecauer Marek
Published: March 2021

T cells communicate with the environment via surface receptors. Cooperation of surface receptors regulates T-cell responses to diverse stimuli. Recently, finger-like membrane protrusions, microvilli, have been demonstrated to play a role in the organization of receptors and, hence, T-cell activation. However, little is known about the morphogenesis of dynamic microvilli, especially in the cells of immune system. In this review, I focus on the potential role of lipids and lipid domains in morphogenesis of microvilli. Discussed is the option that clustering of sphingolipids with phosphoinositides at the plasma membrane results in dimpling (curved) domains. Such domains can attract phosphoinositide-binding proteins and stimulate actin cytoskeleton reorganization. This process triggers cortical actin opening and bundling of actin fibres to support the growing of microvilli. Critical regulators of microvilli morphogenesis in T cells are unknown. At the end, I suggest several candidates with a potential to organize proteins and lipids in these structures.
Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers
Authors: Cinetto Francesco , Scarpa Riccardo , Carrabba Maria , Firinu Davide , Lougaris Vassilios , Buso Helena , Garzi Giulia , Gianese Sabrina , Soccodato Valentina , Punziano Alessandra , Lagnese Gianluca , Tessarin Giulio , Costanzo Giulia , Landini Nicholas , Vio Stefania , Bondioni Maria Pia , Consonni Dario , Marasco Carolina , Del Giacco Stefano , Rattazzi Marcello , Vacca Angelo , Plebani Alessandro , Fabio Giovanna , Spadaro Giuseppe , Agostini Carlo , Quinti Isabella , Milito Cinzia
Published: March 2021

Background: Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival. The aim of this study was to describe clinical, immunological, laboratory and functional features of GLILD, whose combination in a predictive model might allow a timely diagnosis.

Methods: In a multicenter retrospective cross-sectional study we enrolled 73 CVID patients with radiologic features of interstitial lung disease (ILD) associated to CVID (CVID-ILD) and 125 CVID patients without ILD (controls). Of the 73 CVID-ILD patients, 47 received a definite GLILD diagnosis while 26 received a clinical-radiologic diagnosis of CVID related ILD defined as uILD.

Results: In GLILD group we found a higher prevalence of splenomegaly (84.8 vs. 39.2%), autoimmune cytopenia (59.6 vs. 6.4%) and bronchiectasis (72.3 vs. 28%), and lower IgA and IgG serum levels at CVID diagnosis. GLILD patients presented lower percentage of switched-memory B cells and marginal zone B cells, and a marked increase in the percentage of circulating CD21lo B cells (14.2 vs. 2.9%). GLILD patients also showed lower total lung capacity (TLC 87.5 vs. 5.0%) and gas transfer (DLCO 61.5 vs. 5.0%) percent of predicted. By univariate logistic regression analysis, we found IgG and IgA levels at CVID diagnosis, presence of splenomegaly and autoimmune cytopenia, CD21lo B cells percentage, TLC and DCLO percent of predicted to be associated to GLILD. The joint analysis of four variables (CD21lo B cells percentage, autoimmune cytopenia, splenomegaly and DLCO percent of predicted), together in a multiple logistic regression model, yielded an area under the ROC curve (AUC) of 0.98 (95% CI: 0.95-1.0). The AUC was only slightly modified when pooling together GLILD and uILD patients (0.92, 95% CI: 0.87-0.97).

Conclusions: we propose the combination of two clinical parameters (splenomegaly and autoimmune cytopenia), one lung function index (DLCO%) and one immunologic variable (CD21lo%) as a promising tool for early identification of CVID patients with interstitial lung disease, limiting the use of aggressive diagnostic procedures.
Optimizing Management to Reduce the Mortality of COVID-19: Experience From a Designated Hospital for Severely and Critically Ill Patients in China
Authors: Zhu Wei , Zhang Huaqiu , Li Yong , Ding Zeyang , Liu Zhuo , Ruan Yajun , Feng Huan , Li Ganxun , Liu Bo , He Fan , Zhou Ning , Jiang Jiangang , Wen Zhixiang , Xu Gang , Zhao Jianping , Zhang Bixiang , Wang Daowen , Tang Zhouping , Wang Hui , Liu Jihong
Published: March 2021

Background: The coronavirus disease 2019 (COVID-19) has swept through the world at a tremendous speed, and there is still limited data available on the treatment for COVID-19. The mortality of severely and critically ill COVID-19 patients in the Optical Valley Branch of Tongji Hospital was low. We aimed to analyze the available treatment strategies to reduce mortality.

Methods: In this retrospective, single-center study, we included 1,106 COVID-19 patients admitted to the Optical Valley Branch of Tongji Hospital from February 9 to March 9, 2020. Cases were analyzed for demographic and clinical features, laboratory data, and treatment methods. Outcomes were followed up until March 29, 2020.

Results: Inflammation-related indices (hs-CRP, ESR, serum ferritin, and procalcitonin) were significantly higher in severe and critically ill patients than those in moderate patients. The levels of cytokines, including IL-6, IL2R, IL-8, and TNF-α, were also higher in the critical patients. Incidence of acute respiratory distress syndrome (ARDS) in the severely and critically ill group was 23.0% (99/431). Sixty-one patients underwent invasive mechanical ventilation. The correlation between SpO2/FiO2 and PaO2/FiO2 was confirmed, and the cut-off value of SpO2/FiO2 related to survival was 134.43. The mortality of patients with low SpO2/FiO2 (<134.43) at intubation was higher than that of patients with high SpO2/FiO2 (>134.43) (72.7 vs. 33.3%). Among critical patients, the application rates of glucocorticoid therapy, continuous renal replacement therapy (CRRT), and anticoagulation treatment reached 55.2% (238/431), 7.2% (31/431), and 37.1% (160/431), respectively. Among the intubated patients, the application rates of glucocorticoid therapy, CRRT, and anticoagulation treatment were respectively 77.0% (47/61), 54.1% (33/61), and 98.4% (60/61).

Conclusion: No vaccines or specific antiviral drugs for COVID-19 have been shown to be sufficiently safe and effective to date. Comprehensive treatment including ventilatory support, multiple organ function preservation, glucocorticoid use, renal replacement therapy, anticoagulation, and restrictive fluid management was the main treatment strategy. Early recognition and intervention, multidisciplinary collaboration, multi-organ function support, and personalized treatment might be the key for reducing mortality.
Rapid Antimicrobial Susceptibility Testing Methods for Blood Cultures and Their Clinical Impact
Authors: Banerjee Ritu , Humphries Romney
Published: March 2021

Antimicrobial susceptibility testing (AST) of bacteria isolated in blood cultures is critical for optimal management of patients with sepsis. This review describes new and emerging phenotypic and genotypic AST methods and summarizes the evidence that implementation of these methods can impact clinical outcomes of patients with bloodstream infections.
The Role of Ribosomal Protein S6 Kinases in Plant Homeostasis
Authors: Obomighie Irabonosi , Lapenas Kestutis , Murphy Billy E. , Bowles Alexander M. C. , Bechtold Ulrike , Prischi Filippo
Published: March 2021

The p70 ribosomal S6 kinase (S6K) family is a group of highly conserved kinases in eukaryotes that regulates cell growth, cell proliferation, and stress response via modulating protein synthesis and ribosomal biogenesis. S6Ks are downstream effectors of the Target of Rapamycin (TOR) pathway, which connects nutrient and energy signaling to growth and homeostasis, under normal and stress conditions. The plant S6K family includes two isoforms, S6K1 and S6K2, which, despite their high level of sequence similarity, have distinct functions and regulation mechanisms. Significant advances on the characterization of human S6Ks have occurred in the past few years, while studies on plant S6Ks are scarce. In this article, we review expression and activation of the two S6K isoforms in plants and we discuss their roles in mediating responses to stresses and developmental cues.
Enhancing Extracellular Adenosine Levels Restores Barrier Function in Acute Lung Injury Through Expression of Focal Adhesion Proteins
Authors: Wang Wei , Chen Ning-yuan , Ren Dewei , Davies Jonathan , Philip Kemly , Eltzschig Holger K. , Blackburn Michael R. , Akkanti Bindu , Karmouty-Quintana Harry , Weng Tingting
Published: March 2021

Background: Acute respiratory distress syndrome (ARDS) is a clinical presentation of acute lung injury (ALI) with often fatal lung complication. Adenosine, a nucleoside generated following cellular stress provides protective effects in acute injury. The levels of extracellular adenosine can be depleted by equilibrative nucleoside transporters (ENTs). ENT inhibition by pharmaceutical agent dipyridamole promotes extracellular adenosine accumulation and is protective in ARDS. However, the therapeutic potential of dipyridamole in acute lung injury has not yet been evaluated.

Methods: Adenosine acts on three adenosine receptors, the adenosine A1 (Adora1), A2a (Adora2a), the A2b (Adora2b) or the adenosine A3 (Adora 3) receptor. Accumulation of adenosine is usually required to stimulate the low-affinity Adora2b receptor. In order to investigate the effect of adenosine accumulation and the contribution of epithelial-specific ENT2 or adora2b expression in experimental ALI, dipyridamole, and epithelial specific ENT2 or Adora2b deficient mice were utilized. MLE12 cells were used to probe downstream Adora2b signaling. Adenosine receptors, transporters, and targets were determined in ARDS lungs.

Results: ENT2 is mainly expressed in alveolar epithelial cells and is negatively regulated by hypoxia following tissue injury. Enhancing adenosine levels with ENT1/ENT2 inhibitor dipyridamole at a time when bleomycin-induced ALI was present, reduced further injury. Mice pretreated with the ADORA2B agonist BAY 60-6583 were protected from bleomycin-induced ALI by reducing vascular leakage (558.6 ± 50.4 vs. 379.9 ± 70.4, p < 0.05), total bronchoalveolar lavage fluid cell numbers (17.9 ± 1.8 to 13.4 ± 1.4 e4, p < 0.05), and neutrophil infiltration (6.42 ± 0.25 vs. 3.94 ± 0.29, p < 0.05). While mice lacking Adora2b in AECs were no longer protected by dipyridamole. We also identified occludin and focal adhesion kinase as downstream targets of ADORA2B, thus providing a novel mechanism for adenosine-mediated barrier protection. Similarly, we also observed similar enhanced ADORA2B (3.33 ± 0.67 to 16.12 ± 5.89, p < 0.05) and decreased occludin (81.2 ± 0.3 to 13.3 ± 0.4, p < 0.05) levels in human Acute respiratory distress syndrome lungs.

Conclusion: We have highlighted a role of dipyridamole and adenosine signaling in preventing or treating ALI and identified Ent2 and Adora2b as key mediators in important for the resolution of ALI.
Intranasal Transplantation of Human Neural Stem Cells Ameliorates Alzheimer's Disease-Like Pathology in a Mouse Model
Authors: Lu Mei-Hong , Ji Wen-Li , Chen Hong , Sun Yan-Yun , Zhao Xiu-Yun , Wang Fen , Shi Yi , Hu Yan-Ning , Liu Bo-Xiang , Wu Jing-wen , Xu De-En , Zheng Jia-Wei , Liu Chun-Feng , Ma Quan-Hong
Published: March 2021

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairments, which has no effective therapy. Stem cell transplantation shows great potential in the therapy of various disease. However, the application of stem cell therapy in neurological disorders, especially the ones with a long-term disease course such as AD, is limited by the delivery approach due to the presence of the brain blood barrier. So far, the most commonly used delivery approach in the therapy of neurological disorders with stem cells in preclinical and clinical studies are intracranial injection and intrathecal injection, both of which are invasive. In the present study, we use repetitive intranasal delivery of human neural stem cells (hNSCs) to the brains of APP/PS1 transgenic mice to investigate the effect of hNSCs on the pathology of AD. The results indicate that the intranasally transplanted hNSCs survive and exhibit extensive migration and higher neuronal differentiation, with a relatively limited glial differentiation. A proportion of intranasally transplanted hNSCs differentiate to cholinergic neurons, which rescue cholinergic dysfunction in APP/PS1 mice. In addition, intranasal transplantation of hNSCs attenuates β-amyloid accumulation by upregulating the expression of β-amyloid degrading enzymes, insulin-degrading enzymes, and neprilysin. Moreover, intranasal transplantation of hNSCs ameliorates other AD-like pathology including neuroinflammation, cholinergic dysfunction, and pericytic and synaptic loss, while enhancing adult hippocampal neurogenesis, eventually rescuing the cognitive deficits of APP/PS1 transgenic mice. Thus, our findings highlight that intranasal transplantation of hNSCs benefits cognition through multiple mechanisms, and exhibit the great potential of intranasal administration of stem cells as a non-invasive therapeutic strategy for AD.
Language Mapping Using Stereo Electroencephalography: A Review and Expert Opinion
Authors: Aron Olivier , Jonas Jacques , Colnat-Coulbois Sophie , Maillard Louis
Published: March 2021

Stereo-electroencephalography (sEEG) is a method that uses stereotactically implanted depth electrodes for extra-operative mapping of epileptogenic and functional networks. sEEG derived functional mapping is achieved using electrical cortical stimulations (ECS) that are currently the gold standard for delineating eloquent cortex. As this stands true especially for primary cortices (e.g., visual, sensitive, motor, etc.), ECS applied to higher order brain areas determine more subtle behavioral responses. While anterior and posterior language areas in the dorsal language stream seem to share characteristics with primary cortices, basal temporal language area (BTLA) in the ventral temporal cortex (VTC) behaves as a highly associative cortex. After a short introduction and considerations about methodological aspects of ECS using sEEG, we review the sEEG language mapping literature in this perspective. We first establish the validity of this technique to mapindispensablelanguage cortices in the dorsal language stream. Second, we highlight the contrast between the growing empirical ECS experience and the lack of understanding regarding the fundamental mechanisms underlying ECS behavioral effects, especially concerning the dispensable language cortex in the VTC. Evidences for considering network architecture as determinant for ECS behavioral response complexities are discussed. Further, we address the importance of designing new research in network organization of language as this could enhance ECS ability to map interindividual variability, pathology driven reorganization, and ultimately identify network resilience markers in order to better predict post-operative language deficit. Finally, based on a whole body of available studies, we believe there is strong evidence to consider sEEG as a valid, safe and reliable method for defining eloquent language cortices although there have been no proper comparisons between surgical resections with or without extra-operative or intra-operative language mapping.
Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID)
Authors: Yang Kai , Zhao Xinyue , Wang Changcai , Zeng Cheng , Luo Yan , Sun Taolei
Published: March 2021

L-DOPA is the criterion standard of treatment for Parkinson disease. Although it alleviates some of the Parkinsonian symptoms, long-term treatment induces L-DOPA–induced dyskinesia (LID). Several theoretical models including the firing rate model, the firing pattern model, and the ensemble model are proposed to explain the mechanisms of LID. The “firing rate model” proposes that decreasing the mean firing rates of the output nuclei of basal ganglia (BG) including the globus pallidus internal segment and substantia nigra reticulata, along the BG pathways, induces dyskinesia. The “firing pattern model” claimed that abnormal firing pattern of a single unit activity and local field potentials may disturb the information processing in the BG, resulting in dyskinesia. The “ensemble model” described that dyskinesia symptoms might represent a distributed impairment involving many brain regions, but the number of activated neurons in the striatum correlated most strongly with dyskinesia severity. Extensive evidence for circuit mechanisms in driving LID symptoms has also been presented. LID is a multisystem disease that affects wide areas of the brain. Brain regions including the striatum, the pallidal–subthalamic network, the motor cortex, the thalamus, and the cerebellum are all involved in the pathophysiology of LID. In addition, although both amantadine and deep brain stimulation help reduce LID, these approaches have complications that limit their wide use, and a novel antidyskinetic drug is strongly needed; these require us to understand the circuit mechanism of LID more deeply.
Heat-Treatments Affect Protease Activities and Peptide Profiles of Ruminants' Milk
Authors: Leite Juliana A. S. , Montoya Carlos A. , Loveday Simon M. , Maes Evelyne , Mullaney Jane A. , McNabb Warren C. , Roy Nicole C.
Published: March 2021

Proteases present in milk are heat-sensitive, and their activities increase or decrease depending on the intensity of the thermal treatment applied. The thermal effects on the protease activity are well-known for bovine milk but poorly understood for ovine and caprine milk. This study aimed to determine the non-specific and specific protease activities in casein and whey fractions isolated from raw bovine, ovine, and caprine milk collected in early lactation, and to determine the effects of low-temperature, long-time (63°C for 30 min) and high-temperature, short-time (85°C for 5 min) treatments on protease activities within each milk fraction. The non-specific protease activities in raw and heat-treated milk samples were determined using the substrate azocasein. Plasmin (the main protease in milk) and plasminogen-derived activities were determined using the chromogenic substrate S-2251 (D-Val-Leu-Lys-pNA dihydrochloride). Peptides were characterized using high-resolution liquid chromatography coupled with tandem mass spectrometry. The activity of all native proteases, shown as non-specific proteases, was similar between raw bovine and caprine milk samples, but lower (P < 0.05) than raw ovine milk in the whey fraction. There was no difference (P > 0.05) between the non-specific protease activity of the casein fraction of raw bovine and caprine milk samples; both had higher activity than ovine milk. After 63°C/30 min, the non-specific protease activity decreased (44%; P > 0.05) for the bovine casein fraction only. In contrast, the protease activity of the milk heated at 85°C/5 min changed depending on the species and fraction. For instance, the activity decreased by 49% for ovine whey fraction, but it increased by 68% for ovine casein fraction. Plasmin and plasminogen were in general inactivated (P > 0.05) when all milk fractions were heated at 85°C/5 min. Most of the peptides present in heat-treated milk were derived from β-casein and αS1-casein, and they matched the hydrolysis profile of cathepsin D and plasmin. Identified peptides in ruminant milk samples had purported immunomodulatory and inhibitory functions. These findings indicate that the non-specific protease activity in whey and casein fractions differed between ruminant milk species, and specific thermal treatments could be used to retain better protease activity for all ruminant milk species.
Case Report: Molecular Features and Treatment Options for Small Bowel Adenocarcinoma
Authors: Cordova-Delgado Miguel , Pizarro Gonzalo , Pinto Mauricio P. , Herrera Maria Elisa , Garrido Marcelo
Published: March 2021

Small bowel adenocarcinoma (SBA) is a rare malignancy characterized by poor prognosis. Recent efforts have sought to elucidate the genetic landscape and the molecular drivers behind this disease. Herein, we report the main molecular alterations in two metastatic (stage IV) SBA patients. Interestingly, one of them had gene alterations that affected signaling pathways previously described for SBA. However, a second patient displayed previously unreported alterations in this particular tumor type. Based on these findings we discuss potential treatment options for patients affected by this rare, aggressive disease.