bluuebunny/crossref_metadata_2025 huggingface dataset:
One-year Outcomes of a Treat-and-extend of Ranibizumab for Naive Exudative Age-related Macular Degeneration: Retrospective Analysis
Authors: Choi Young-Je , Yoo Woong-Sun , Cho Yong-Wun , Choi Yu-Jin , Chung In Young
Published: July 2021

Purpose: This study investigated the 1-year outcomes of a treat-and-extend regimen of ranibizumab for exudative age-related macular degeneration and examined the clinical results when drug treatment was changed within the same period. Methods: This retrospective analysis included 32 eyes first diagnosed with wet age-related macular degeneration and treated for more than 1 year with a treat-and-extend regimen of ranibizumab, as well as 24 eyes treated by changing from ranibizumab to aflibercept within the same period. The injection number, maximum injection interval, change in central retinal thickness, and best-corrected visual acuity were assessed in all eyes. Results: In 32 eyes that received a treat-and-extend regimen of ranibizumab, the mean best-corrected visual acuity improved from 59.46 ± 15.13 to 68.00 ± 12.48 at 12 months (p < 0.0001). The mean central retinal thickness decreased from 409 ± 141 μm to 273 ± 89 μm at 12 months (p < 0.0001). The average number of injections per year was 7.2 ± 0.85. One complication related to the 12 months of injections was a tear in the retinal pigment epithelium; no systemic complications were observed. Of 24 eyes that underwent a change in medication, the rate of maintenance or improvement in initial visual acuity was 83% (10 eyes). The central retinal thickness was initially 371.58 ± 109.96 μm, but improved to 290.33 ± 58.66 μm in 12 eyes that received three injections of aflibercept. Conclusions: At 1 year, good outcomes were obtained using treat-and-extend ranibizumab for exudative age-related macular degeneration. When the treatment was changed to aflibercept within the same period, vision was often maintained and short-term anatomical improvement was evident.
La función de ídolo de Jon Rahm en la repercusión mediática del Open de España de Golf 2018
Authors: Barbero-González Miguel Ángel , Peinado-Miguel Fernando
Published: July 2021

La celebración del Open de España 2018 supuso la recuperación de un torneo que nació en 1912 y ha vivido 91 ediciones, pero que en 2017 no se celebró por falta de patrocinadores. Este artículo es resultado de una investigación de las tres universidades públicas de Madrid en las que se estudia Periodismo, y consecuencia del interés de estos centros de enseñanza superior por el deporte del golf. Se analiza la importancia de la presencia de un deportista como Jon Rahm, que provocó la asistencia de casi 50.000 personas durante la semana de competición. Un estudio fundamentado en los impactos informativos en medios impresos de consumo y con distribución nacional de este Open de España en los dos últimos años de competición (2016 y 2018), que valora si la participación de un nuevo ídolo deportivo permite que este torneo vuelva al escenario internacional y el golf adopte una nueva mirada social no solo como deporte competitivo sino como herramienta educativa y de ocio.
Promoción de la calidad de vida a través del periodismo responsable digital
Authors: Rivera Salas Paola Eunice , Curro Lau Maria Guadalupe
Published: July 2021

Durante este siglo, la Calidad de Vida (CV) se ha convertido en una prioridad para muchos países. Existe un claro interés porque las distintas organizaciones de la sociedad, como los medios de comunicación, colaboren para que sus ciudadanos cuenten con mejores estándares de vida. El objetivo de la investigación es caracterizar la promoción de la calidad de vida en notas periodísticas de empresas latinoamericanas en el marco de un periodismo digital responsable (PDR), para lo cual se desarrolla desde el concepto de calidad de vida y los ámbitos en los que se estudia, con la intención de identificar los rasgos de la calidad de vida. Se implementó un enfoque cuantitativo, descriptivo y transversal que permitió analizar las notas publicadas en tres periódicos latinoamericanos en 2019. Los resultados demuestran que hay una baja difusión acerca de la calidad de vida en los mensajes en donde no se detectaron las características que el lector pudiera identificar con los indicadores de calidad de vida social. Sin embargo, las notas periodísticas se apegan a los principios del PDR como la veracidad, el lenguaje objetivo y la reflexionética de la profesión.
Comparative Proteomics and Phosphoproteomics Analysis Reveal the Possible Breed Difference in Yorkshire and Duroc Boar Spermatozoa
Authors: Xu Yongjie , Han Qiu , Ma Chaofeng , Wang Yaling , Zhang Pengpeng , Li Cencen , Cheng Xiaofang , Xu Haixia
Published: July 2021

Sperm cells are of unique elongated structure and function, the development of which is tightly regulated by the existing proteins and the posttranslational modifications (PTM) of these proteins. Based on the phylogenetic relationships of various swine breeds, Yorkshire boar is believed to be distinctly different from Duroc boar. The comprehensive differential proteomics and phosphoproteomics profilings were performed on spermatozoa from both Yorkshire and Duroc boars. By both peptide and PTM peptide quantification followed by statistical analyses, 167 differentially expressed proteins were identified from 1,745 proteins, and 283 differentially expressed phosphopeptides corresponding to 102 unique differentially phosphorylated proteins were measured from 1,140 identified phosphopeptides derived from 363 phosphorylated proteins. The representative results were validated by Western blots. Pathway enrichment analyses revealed that majority of differential expression proteins and differential phosphorylation proteins were primarily concerned with spermatogenesis, male gamete generation, sperm motility, energy metabolism, cilium morphogenesis, axonemal dynein complex assembly, sperm–egg recognition, and capacitation. Remarkably, axonemal dynein complex assembly related proteins, such as SMCP, SUN5, ODF1, AKAP3, and AKAP4 that play a key regulatory role in the sperm physiological functions, were significantly higher in Duroc spermatozoa than that of Yorkshire. Furthermore, phosphorylation of sperm-specific proteins, such as CABYR, ROPN1, CALM1, PRKAR2A, and PRKAR1A, participates in regulation of the boar sperm motility mainly through the cAMP/PKA signal pathway in different breeds, demonstrating that protein phosphorylation may be an important mechanism underlying the sperm diversity. Protein–protein interaction analysis revealed that the 14 overlapped proteins between differential expression proteins and differential phosphorylation proteins potentially played a key role in sperm development and motility of the flagellum, including the proteins ODF1, SMCP, AKAP4, FSIP2, and SUN5. Taken together, these physiologically and functionally differentially expressed proteins (DEPs) and differentially expressed phosphorylated proteins (DPPs) may constitute the proteomic backgrounds between the two different boar breeds. The validation will be performed to delineate the roles of these PTM proteins as modulators of Yorkshire and Duroc boar spermatozoa.
Protein Identification of Spermatozoa and Seminal Plasma in Bottlenose Dolphin (Tursiops truncatus)
Authors: Fuentes-Albero Mari-Carmen , González-Brusi Leopoldo , Cots Paula , Luongo Chiara , Abril-Sánchez Silvia , Ros-Santaella José Luis , Pintus Eliana , Ruiz-Díaz Sara , Barros-García Carlos , Sánchez-Calabuig María-Jesús , García-Párraga Daniel , Avilés Manuel , Izquierdo Rico Mᵃ José , García-Vázquez Francisco Alberto
Published: July 2021

Proteins play an important role in many reproductive functions such as sperm maturation, sperm transit in the female genital tract or sperm-oocyte interaction. However, in general, little information concerning reproductive features is available in the case of aquatic animals. The present study aims to characterize the proteome of both spermatozoa and seminal plasma of bottlenose dolphins (Tursiops truncatus) as a model organism for cetaceans. Ejaculate samples were obtained from two trained dolphins housed in an aquarium. Spermatozoa and seminal plasma were analyzed by means of proteomic analyses using an LC-MS/MS, and a list with the gene symbols corresponding to each protein was submitted to the DAVID database. Of the 419 proteins identified in spermatozoa and 303 in seminal plasma, 111 proteins were shared by both. Furthermore, 70 proteins were identified as involved in reproductive processes, 39 in spermatozoa, and 31 in seminal plasma. The five most abundant proteins were also identified in these samples: AKAP3, ODF2, TUBB, GSTM3, ROPN1 for spermatozoa and CST11, LTF, ALB, HSP90B1, PIGR for seminal plasma. In conclusion, this study provides the first characterization of the proteome in cetacean sperm and seminal plasma, opening the way to future research into new biomarkers, the analysis of conservation capacity or possible additional applications in the field of assisted reproductive technologies.
High Migration and Invasion Ability of PGCCs and Their Daughter Cells Associated With the Nuclear Localization of S100A10 Modified by SUMOylation
Authors: Zhao Qi , Zhang Kexin , Li Zugui , Zhang Hao , Fu Fangmei , Fu Junjie , Zheng Minying , Zhang Shiwu
Published: July 2021

Our previous studies have confirmed that cobalt chloride (CoCl2) or chemoradiotherapy could induce the formation of polyploid tumor giant cells (PGCCs). Polyploid giant cancer cells are a special subpopulation of cancer cells that contribute to solid tumor heterogeneity. The size of PGCC was at least three times larger than regular diploid cancer cells. PGCCs have the properties of cancer stem cells (CSCs) and can express CSC markers CD44 and CD133. Daughter cells derived from PGCCs have strong proliferation, infiltration and migration abilities. However, the detailed molecular mechanism of daughter cells expressing mesenchymal phenotype and displaying strong abilities of proliferation and migration is unclear. As a plasminogen receptor, S100A10 which is closely associated with the invasion and metastasis of malignant tumors, was highly expressed in PGCCs with their daughter cells. In this study, CoCl2 was used to induce the formation of PGCCs in LoVo and HCT116 CRC cells. Cell functional experiments, co-immunoprecipitation, MG132 and ginkgolic acid treatment, western blot, and ChIP-Seq were used to identify the mechanism of S100A10 nuclear location. The proliferation and migration abilities of PGCCs and their daughter cells decreased significantly after S100A10 knockdown. In the control cells, S100A10 was mainly ubiquitinated, while in PGCCs and daughter cells, S100A10 was mainly SUMOylated, which was associated with S100A10 nuclear location. After SUMO1 was inhibited, the nuclear S100A10 in PGCCs and daughter cells decreased, and their proliferation and migration abilities significantly decreased. ChIP-Seq combined with real-time fluorescent quantitative PCR showed that S100A10 regulated the expression of neutrophil defensin 3 (DEFA3), receptor-type tyrosine-protein phosphatase N2 (PTPRN2), and rho guanine nucleotide exchange factor 18 (ARHGEF18), which were associated with actin dynamics and cytoskeleton remodeling. The expression of S100A10 in the nuclei and cytoplasm of rectal cancer after neoadjuvant chemoradiation (nCRT) and liver metastases increased compared with that in rectal cancer without nCRT. Taken together, the expression and nuclear localization of S100A10 modified by SUMOylation were associated with the high proliferation and migration of PGCCs and their daughter cells, and the differentiation, metastases, and relapse of CRCs by regulating the expression of ARHGEF18, PTPRN2, and DEFA3.
Physiological Functions of Mcl-1: Insights From Genetic Mouse Models
Authors: Chin Hui San , Fu Nai Yang
Published: July 2021

The ability to regulate the survival and death of a cell is paramount throughout the lifespan of a multicellular organism. Apoptosis, a main physiological form of programmed cell death, is regulated by the Bcl-2 family proteins that are either pro-apoptotic or pro-survival. Thein vivofunctions of distinct Bcl-2 family members are largely unmasked by genetically engineered murine models.Mcl-1is one of the two Bcl-2 like pro-survival genes whose germline deletion causes embryonic lethality in mice. Its requisite for the survival of a broad range of cell types has been further unraveled by using conditional and inducible deletion murine model systems in different tissues or cell lineages and at distinct developmental stages. Moreover, genetic mouse cancer models have also demonstrated thatMcl-1is essential for the survival of multiple tumor types. TheMCL-1locus is commonly amplified across various cancer types in humans. Small molecule inhibitors with high affinity and specificity to human MCL-1 have been developed and explored for the treatment of certain cancers. To facilitate the pre-clinical studies of MCL-1 in cancer and other diseases, transgenic mouse models over-expressing humanMCL-1as well as humanizedMCL-1mouse models have been recently engineered. This review discusses the current advances in understanding the physiological roles of Mcl-1 based on studies using genetic murine models and its critical implications in pathology and treatment of human diseases.
Spine and Individual Vertebrae Segmentation in Computed Tomography Images Using Geometric Flows and Shape Priors
Authors: Khandelwal Pulkit , Collins D. Louis , Siddiqi Kaleem
Published: July 2021

The surgical treatment of injuries to the spine often requires the placement of pedicle screws. To prevent damage to nearby blood vessels and nerves, the individual vertebrae and their surrounding tissue must be precisely localized. To aid surgical planning in this context we present a clinically applicable geometric flow based method to segment the human spinal column from computed tomography (CT) scans. We first apply anisotropic diffusion and flux computation to mitigate the effects of region inhomogeneities and partial volume effects at vertebral boundaries in such data. The first pipeline of our segmentation approach uses a region-based geometric flow, requires only a single manually identified seed point to initiate, and runs efficiently on a multi-core central processing unit (CPU). A shape-prior formulation is employed in a separate second pipeline to segment individual vertebrae, using both region and boundary based terms to augment the initial segmentation. We validate our method on four different clinical databases, each of which has a distinct intensity distribution. Our approach obviates the need for manual segmentation, significantly reduces inter- and intra-observer differences, runs in times compatible with use in a clinical workflow, achieves Dice scores that are comparable to the state of the art, and yields precise vertebral surfaces that are well within the acceptable 2 mm mark for surgical interventions.
Influence of Solar Wind on Secondary Cosmic Rays and Atmospheric Electricity
Authors: Chum Jaroslav , Kollárik Marek , Kolmašová Ivana , Langer Ronald , Rusz Jan , Saxonbergová Dana , Strhárský Igor
Published: July 2021

A relationship between the heliospheric magnetic field, atmospheric electric field, lightning activity, and secondary cosmic rays measured on the high mount of Lomnický Štít (2,634 m a.s.l.), Slovakia, during the declining phase of the solar cycle 24 is investigated with a focus on variations related to solar rotation (about 27 days). The secondary cosmic rays are detected using a neutron monitor and the detector system SEVAN, which distinguishes between different particles and energies. Using spectral analysis, we found distinct ∼27-day periodicities in variations of Bx and By components of the heliospheric magnetic field and in pressure-corrected measurements of secondary cosmic rays. The 27-day variations of secondary cosmic rays, on average, advanced and lagged the variations of Bx and By components by about 40° and −140°, respectively. Distinct 27-day periodicities were found both in the neutron monitor and the SEVAN upper and middle detector measurements. A nondominant periodicity of ∼27 days was also found for lightning activity. A cross-spectral analysis between fluctuation of the lightning activity and fluctuation of the heliospheric magnetic field (HMF) showed that fluctuation of the lightning activity was in phase and in antiphase with Bx and By components of the HMF, respectively, which is in agreement with previous studies investigating the influence of solar activity on lightning. On the other hand, the ∼27-day periodicity was not significant in the atmospheric electric field measured in Slovakia and Czechia. Therefore, no substantial influence of Bx and By on the atmospheric electric field was observed at these middle-latitude stations.
Adapting Protocols or Models for Use in Insulin-Requiring Diabetes and Islet Transplant Recipients
Authors: Ward Glenn M. , Walters Jacqueline M. , Gooley Judith L. , Boston Raymond C.
Published: July 2021

The authors’ perspective is described regarding modifications made in their clinic to glucose challenge protocols and mathematical models in order to estimate insulin secretion, insulin sensitivity and glucose effectiveness in patients living with Insulin-Requiring Diabetes and patients who received Pancreatic Islet Transplants to treat Type I diabetes (T1D) with Impaired Awareness of Hypoglycemia. The evolutions are described of protocols and models for use in T1D, and Insulin-Requiring Type 2 Diabetes (T2D) that were the basis for studies in the Islet Recipients. In each group, the need for modifications, and how the protocols and models were adapted is discussed. How the ongoing application of the adaptations is clarifying the Islet pathophysiology in the Islet Transplant Recipients is outlined.
Relapse of Human Chorionic Gonadotropin-Induced Hyperthyroidism and Severe Hyperemesis Gravidarum Secondary to Twin-Twin Transfusion Syndrome, With Rapid Recovery Following Fetoscopic Laser Coagulation: Case Report
Authors: Lamine Faiza , Camponovo Chiara , Baud David , Werner Dominique , Marino Laura , Sykiotis Gerasimos P.
Published: July 2021

Background

Limited data have shown that, compared to uncomplicated twin pregnancies, pregnancies complicated by twin-twin transfusion syndrome (TTTS), a life-threatening condition, are associated with higher maternal serum levels of both human chorionic gonadotropin (hCG) and thyroid hormones. With the continuing expansion of assisted reproductive technologies, the rate of twin pregnancies, including those complicated by TTTS and associated hyperemesis gravidarum, is expected to increase further. Therefore, detailed descriptions of the maternal and fetal clinical outcomes of maternal thyrotoxicosis linked to TTTS can be useful for timely diagnosis and management. However, such descriptions are currently lacking in the literature.

Case Presentation

We report the case of a 30-year-old woman carrying a monochorionic twin pregnancy complicated by TTTS that induced a relapse of severe hyperemesis gravidarum with overt non-autoimmune hyperthyroidism at 17 weeks of gestation. Following fetoscopic laser coagulation (FLC), both hyperemesis and hyperthyroidism improved within 1 week.

Conclusions

The present experience contributes to the knowledge base on maternal thyrotoxicosis linked to TTTS and can be useful in the diagnosis and treatment of future cases; it also emphasizes the need for a high degree of clinical suspicion and for close collaboration between endocrinologists and obstetricians. Another key point is that TTTS-associated hyperemesis gravidarum and maternal hyperthyroidism should be considered in the differential diagnosis of refractory or relapsing hyperemesis gravidarum in women with monochorionic twin pregnancy, because this condition may require more stringent supportive treatment before and during the FLC procedure when the mother is overtly hyperthyroid.
Power Configuration Scheme for Battery Energy Storage Systems Considering the Renewable Energy Penetration Level
Authors: Chen Qing , Xie Rui , Chen Yuyan , Liu Heyu , Zhang Shengqi , Wang Fei , Shi Zhaohui , Lin Bin
Published: July 2021

With the increase of the renewable energy penetration (REP) level in the interconnected power grid, the proportion of the grid-connected conventional synchronous generators reduces continuously, resulting in the decrease of the system inertia. The insufficient system inertia brings challenges to the system frequency stability. Battery energy storage systems (BESSs), regarded as the high-quality frequency regulation resource, play an important role in maintaining the frequency stability of the system with the high REP level. To configure the proper power of BESSs in system frequency regulation, a BESS power configuration scheme (PCS) considering the REP constraint is proposed in this paper. In particular, the process to obtain the REP boundary of the interconnected grid on the premise of system frequency stability is included in the PCS, and the optimal power configuration of the BESS is further determined on the analysis of the BESS impact on the REP boundary. Furthermore, a simulation model of the Australian five-area interconnected power grid is built in MATLAB/Simulink, and the proposed REP-constrained PCS is verified and analyzed. At last, the promising results show that the PCS can take full advantages of the BESS in frequency regulation and meet the system requirement of the frequency stability at a particular REP level.
Post-Harvest N2O Emissions Can Be Mitigated With Organic Amendments
Authors: Rothardt S. , Fuß R. , Pahlmann I. , Kage H.
Published: July 2021

After the harvest of winter oilseed rape and faba bean crops, considerable high soil nitrate values may be built up before winter in central to north European regions. High precipitation and a low N uptake by the subsequent crop in fall cause a high risk of N2O emissions and nitrate leaching. Microbial decomposition of crop residues or high carbon amendments may immobilize mineral N temporarily and may prevent losses by direct N2O emissions. Five treatments, including crop residue removal and application of different organic amendments after harvest, were tested in a field trial in Northern Germany to elucidate the potential of this mechanism as a mitigation option. N2O emissions and the soil mineral nitrogen status were monitored from August to March for three consecutive years. Observed emissions ranged from 0.1 to 3.4 kg N ha−1 in 180 days. An empirical model approach was applied to separate the impact of spatially and temporally heterogeneous environmental conditions between the plots of the field experiment from treatment effects in the subsequent statistical analysis of N2O emissions. Results show that the exchange of the initial crop residues with organic amendments with high C:N ratios (i.e., winter wheat straw and sawdust) after the harvest of faba bean or oilseed rape can reduce N2O emission during fall and winter by up to 45%.
Ovine CD14- an Immune Response Gene Has a Role Against Gastrointestinal Nematode Haemonchus contortus—A Novel Report
Authors: Rawat Kavita , Pal Aruna , Banerjee Samiddha , Pal Abantika , Mandal Subhas Chandra , Batabyal Subhasis
Published: July 2021

CD14 (also known as the monocyte differentiation antigen) is an important immune response gene known to be primarily responsible for innate immunity against bacterial pathogens, and as a pattern recognition receptor (PRR), binds with LPS (endotoxin), lipoproteins, and lipotechoic acid of bacteria. So far very limited work has been conducted in parasitic immunology. In the current study, we reported the role of CD14 in parasitic immunology in livestock species (sheep) for the first time. Ovine CD14 is characterized as a horse-shoe shaped bent solenoid with a hydrophobic amino-terminal pocket for CD14 along with domains. High mutation frequency was observed, out of total 41 mutations identified, 23 mutations were observed to be thermodynamically unstable and 11 mutations were deleterious in nature, causing major functional alteration of important domains of CD14, an indication of variations in individual susceptibility for sheep againstHaemonchus contortusinfestations.In silicostudies with molecular docking reveal a role of immune response againstHaemonchus contortusin sheep, which is later confirmed with experimental evidence through differential mRNA expression analysis for sheep, which revealed better expression of CD14 inHaemonchus contortusinfected sheep compared to that of non-infected sheep. We confirmed the above findings with supportive evidence through haematological and biochemical analyses. Phylogenetic analysis was conducted to assess the evolutionary relationship with respect to humans and it was observed that sheep may well be used as model organisms due to better genetic closeness compared to that of mice.
Creation of a Single Cell RNASeq Meta-Atlas to Define Human Liver Immune Homeostasis
Authors: Rocque Brittany , Barbetta Arianna , Singh Pranay , Goldbeck Cameron , Helou Doumet Georges , Loh Yong-Hwee Eddie , Ung Nolan , Lee Jerry , Akbari Omid , Emamaullee Juliet
Published: July 2021

The liver is unique in both its ability to maintain immune homeostasis and in its potential for immune tolerance following solid organ transplantation. Single-cell RNA sequencing (scRNA seq) is a powerful approach to generate highly dimensional transcriptome data to understand cellular phenotypes. However, when scRNA data is produced by different groups, with different data models, different standards, and samples processed in different ways, it can be challenging to draw meaningful conclusions from the aggregated data. The goal of this study was to establish a method to combine ‘human liver’ scRNA seq datasets by 1) characterizing the heterogeneity between studies and 2) using the meta-atlas to define the dominant phenotypes across immune cell subpopulations in healthy human liver. Publicly available scRNA seq data generated from liver samples obtained from a combined total of 17 patients and ~32,000 cells were analyzed. Liver-specific immune cells (CD45+) were extracted from each dataset, and immune cell subpopulations (myeloid cells, NK and T cells, plasma cells, and B cells) were examined using dimensionality reduction (UMAP), differential gene expression, and ingenuity pathway analysis. All datasets co-clustered, but cell proportions differed between studies. Gene expression correlation demonstrated similarity across all studies, and canonical pathways that differed between datasets were related to cell stress and oxidative phosphorylation rather than immune-related function. Next, a meta-atlas was generated via data integration and compared against PBMC data to define gene signatures for each hepatic immune subpopulation. This analysis defined key features of hepatic immune homeostasis, with decreased expression across immunologic pathways and enhancement of pathways involved with cell death. This method for meta-analysis of scRNA seq data provides a novel approach to broadly define the features of human liver immune homeostasis. Specific pathways and cellular phenotypes described in this human liver immune meta-atlas provide a critical reference point for further study of immune mediated disease processes within the liver.
Human B Lymphomas Reveal Their Secrets Through Genetic Mouse Models
Authors: Mossadegh-Keller Noushin , Brisou Gabriel , Beyou Alicia , Nadel Bertrand , Roulland Sandrine
Published: July 2021

Lymphomas are cancers deriving from lymphocytes, arising preferentially in secondary lymphoid organs, and represent the 6th cancer worldwide and the most frequent blood cancer. The majority of B cell Non-Hodgkin lymphomas (B-NHL) develop from germinal center (GC) experienced mature B cells. GCs are transient structures that form in lymphoid organs in response to antigen exposure of naive B cells, and where B cell receptor (BCR) affinity maturation occurs to promote B cell differentiation into memory B and plasma cells producing high-affinity antibodies. Genomic instability associated with the somatic hypermutation (SHM) and class-switch recombination (CSR) processes during GC transit enhance susceptibility to malignant transformation. Most B cell differentiation steps in the GC are at the origin of frequent B cell malignant entities, namely Follicular Lymphoma (FL) and GCB diffuse large B cell lymphomas (GCB-DLBCL). Over the past decade, large sequencing efforts have provided a great boost in the identification of candidate oncogenes and tumor suppressors involved in FL and DLBCL oncogenesis. Mouse models have been instrumental to accurately mimic in vivo lymphoma-specific mutations and interrogate their normal function in the GC context and their oncogenic function leading to lymphoma onset. The limited access of biopsies during the initiating steps of the disease, the cellular and (epi)genetic heterogeneity of individual tumors across and within patients linked to perturbed dynamics of GC ecosystems make the development of genetically engineered mouse models crucial to decipher lymphomagenesis and disease progression and eventually to test the effects of novel targeted therapies. In this review, we provide an overview of some of the important genetically engineered mouse models that have been developed to recapitulate lymphoma-associated (epi)genetic alterations of two frequent GC-derived lymphoma entities: FL and GCB-DLCBL and describe how those mouse models have improved our knowledge of the molecular processes supporting GC B cell transformation.
Nlrc3 Knockout Mice Showed Renal Pathological Changes After HTNV Infection
Authors: Ma Ruixue , Zhang Xiaoxiao , Shu Jiayi , Liu Ziyu , Sun Wenjie , Hou Shiyuan , Lv Yunhua , Ying Qikang , Wang Fang , Jin Xia , Liu Rongrong , Wu Xingan
Published: July 2021

Hantaan virus (HTNV) infects humans and causes hemorrhagic fever with renal syndrome (HFRS). The development of well-characterized animal models of HFRS could accelerate the testing of vaccine candidates and therapeutic agents and provide a useful tool for studying the pathogenesis of HFRS. Because NLRC3 has multiple immunoregulatory roles, we investigated the susceptibility of Nlrc3−/− mice to HTNV infection in order to establish a new model of HFRS. Nlrc3−/− mice developed weight loss, renal hemorrhage, and tubule dilation after HTNV infection, recapitulating many clinical symptoms of human HFRS. Moreover, infected Nlrc3−/− mice showed higher viral loads in serum, spleen, and kidney than wild type C57BL/6 (WT) mice, and some of them manifested more hematological disorders and significant pathological changes within multiple organs than WT mice. Our results identify that HTNV infected Nlrc3−/− mice can develop clinical symptoms and pathological changes resembling patients with HFRS, suggesting a new model for studying the pathogenesis and testing of candidate vaccines and therapeutics.
High-Density Blood Transcriptomics Reveals Precision Immune Signatures of SARS-CoV-2 Infection in Hospitalized Individuals
Authors: Prokop Jeremy W. , Hartog Nicholas L. , Chesla Dave , Faber William , Love Chanise P. , Karam Rachid , Abualkheir Nelly , Feldmann Benjamin , Teng Li , McBride Tamara , Leimanis Mara L. , English B. Keith , Holsworth Amanda , Frisch Austin , Bauss Jacob , Kalpage Nathisha , Derbedrossian Aram , Pinti Ryan M. , Hale Nicole , Mills Joshua , Eby Alexandra , VanSickle Elizabeth A. , Pageau Spencer C. , Shankar Rama , Chen Bin , Carcillo Joseph A. , Sanfilippo Dominic , Olivero Rosemary , Bupp Caleb P. , Rajasekaran Surender
Published: July 2021

The immune response to COVID-19 infection is variable. How COVID-19 influences clinical outcomes in hospitalized patients needs to be understood through readily obtainable biological materials, such as blood. We hypothesized that a high-density analysis of host (and pathogen) blood RNA in hospitalized patients with SARS-CoV-2 would provide mechanistic insights into the heterogeneity of response amongst COVID-19 patients when combined with advanced multidimensional bioinformatics for RNA. We enrolled 36 hospitalized COVID-19 patients (11 died) and 15 controls, collecting 74 blood PAXgene RNA tubes at multiple timepoints, one early and in 23 patients after treatment with various therapies. Total RNAseq was performed at high-density, with >160 million paired-end, 150 base pair reads per sample, representing the most sequenced bases per sample for any publicly deposited blood PAXgene tube study. There are 770 genes significantly altered in the blood of COVID-19 patients associated with antiviral defense, mitotic cell cycle, type I interferon signaling, and severe viral infections. Immune genes activated include those associated with neutrophil mechanisms, secretory granules, and neutrophil extracellular traps (NETs), along with decreased gene expression in lymphocytes and clonal expansion of the acquired immune response. Therapies such as convalescent serum and dexamethasone reduced many of the blood expression signatures of COVID-19. Severely ill or deceased patients are marked by various secondary infections, unique gene patterns, dysregulated innate response, and peripheral organ damage not otherwise found in the cohort. High-density transcriptomic data offers shared gene expression signatures, providing unique insights into the immune system and individualized signatures of patients that could be used to understand the patient’s clinical condition. Whole blood transcriptomics provides patient-level insights for immune activation, immune repertoire, and secondary infections that can further guide precision treatment.
Dependence on Autophagy for Autoreactive Memory B Cells in the Development of Pristane-Induced Lupus
Authors: Jang Albert , Sharp Robert , Wang Jeffrey M. , Feng Yin , Wang Jin , Chen Min
Published: July 2021

The production of autoantibodies by autoreactive B cells plays a major role in the pathogenesis of lupus. Increases in memory B cells have been observed in human lupus patients and autoimmunelprmice. Autophagy is required for the maintenance of memory B cells against viral infections; however, whether autophagy regulates the persistence of autoantigen-specific memory B cells and the development of lupus remains to be determined. Here we show that memory B cells specific for autoantigens can be detected in autoimmunelprmice and a pristane-induced lupus mouse model. Interestingly, B cell-specific deletion of Atg7 led to significant loss of autoreactive memory B cells and reduced autoantibody production in pristane-treated mice. Autophagy deficiency also attenuated the development of autoimmune glomerulonephritis and pulmonary inflammation after pristane treatment. Adoptive transfer of wild type autoreactive memory B cells restored autoantibody production in Atg7-deficient recipients. These data suggest that autophagy is important for the persistence of autoreactive memory B cells in mediating autoantibody responses. Our results suggest that autophagy could be targeted to suppress autoreactive memory B cells and ameliorate humoral autoimmunity.
Long-Term Course of Polymorphic Light Eruption: A Registry Analysis
Authors: Gruber-Wackernagel Alexandra , Schug Tanja , Graier Thomas , Legat Franz J. , Rinner Hanna , Hofer Angelika , Quehenberger Franz , Wolf Peter
Published: July 2021

Background: Little is known about the long-term course of polymorphic light eruption (PLE).

Objective: To predict disease course, a questionnaire was sent to patients whose PLE had been diagnosed between March 1990 and December 2018 and documented in the Austrian Cooperative Registry for Photodermatoses.

Methods: In January 2019, 205 PLE patients were contacted by mail and asked to complete a questionnaire on their disease course, including whether the skin's sun sensitivity had normalized (i.e., PLE symptoms had disappeared), improved, stayed the same, or worsened over time. Patients who reported normalization of sun sensitivity were asked to report when it had occurred.

Results: Ninety-seven patients (79 females, 18 males) returned a completed questionnaire. The mean (range) duration of follow-up from PLE onset was 29.6 (17–54) years for females and 29.4 (16–47) years for males. The disease disappeared in 32 (41%) females after 17.4 (2–41) years and in 4 (24%) males after 11.8 (5–26) years. Twenty-nine (37%) females and 6 (35%) males reported improvement of symptoms over time; 15 females (19%) and 7 males (41%) reported no change; and 3 females (4%) and no males reported worsening of symptoms. Kaplan-Meier analysis revealed that after 20 years 74% (95%CI, 64–82%) of patients still suffered from PLE. PLE lesion persistence (>1 week) tended to predict a prolonged course of PLE.

Conclusions: PLE usually takes a long-term course over many years though in most patients its symptoms improve or disappear over time. How improvement relates to the pathophysiology of the disease remains to be determined.
Phase I Study to Assess Safety of Laser-Assisted Topical Administration of an Anti-TNF Biologic in Patients With Chronic Plaque-Type Psoriasis
Authors: Bauer Martin , Lackner Edith , Matzneller Peter , Al Jalali Valentin , Pajenda Sahra , Ling Vincent , Böhler Christof , Braun Werner , Braun Reinhard , Boesch Maximilian , Brunner Patrick M. , Zeitlinger Markus
Published: July 2021

Ablative fractional laser treatment facilitates epidermal drug delivery, which might be an interesting option to increase the topical efficacy of biological drugs in a variety of dermatological diseases. This work aims at investigating safety and tolerability of this new treatment approach in patients with plaque-type psoriasis. Eight patients with plaque-type psoriasis were enrolled in this study. All patients received (i) ablative fractional laser microporation (AFL) of a psoriatic lesion with an Er:YAG laser + etanercept (ETA; Enbrel® solution for injection) (AFL-ETA), (ii) ETA alone on another lesion, and, if feasible, (iii) AFL alone on an additional lesion. Overall, all treatment arms showed a favorable safety profile. AFL-ETA improved the lesion-specific TPSS score by 1.75 vs. baseline, whereas ETA or AFL alone showed a TPSS score improvement of 0.75 points, a difference that was not statistically significant and might be attributable to differences in baseline scores. Topical administration of ETA to psoriatic plaques via AFL-generated micropores was generally well-tolerated. No special precautions seem necessary in future studies. Clinical benefit will need assessment in sufficiently powered follow-up studies.
Brevibacillin 2V Exerts Its Bactericidal Activity via Binding to Lipid II and Permeabilizing Cellular Membranes
Authors: Zhao Xinghong , Wang Xiaoqi , Shukla Rhythm , Kumar Raj , Weingarth Markus , Breukink Eefjan , Kuipers Oscar P.
Published: July 2021

Lipo-tridecapeptides, a class of bacterial non-ribosomally produced peptides, show strong antimicrobial activity against Gram-positive pathogens, including antibiotic-resistant Staphylococcus aureus and Enterococcus spp. However, many of these lipo-tridecapeptides have shown high hemolytic activity and cytotoxicity, which has limited their potential to be developed into antibiotics. Recently, we reported a novel antimicrobial lipo-tridecapeptide, brevibacillin 2V, which showed no hemolytic activity against human red blood cells at a high concentration of 128 mg/L, opposite to other brevibacillins and lipo-tridecapeptides. In addition, brevibacillin 2V showed much lower cytotoxicity than the other members of the brevibacillin family. In this study, we set out to elucidate the antimicrobial mode of action of brevibacillin 2V. The results show that brevibacillin 2V acts as bactericidal antimicrobial agent against S. aureus (MRSA). Further studies show that brevibacillin 2V exerts its bactericidal activity by binding to the bacterial cell wall synthesis precursor Lipid II and permeabilizing the bacterial membrane. Combined solid-state NMR, circular dichroism, and isothermal titration calorimetry assays indicate that brevibacillin 2V binds to the GlcNAc-MurNAc moiety and/or the pentapeptide of Lipid II. This study provides an insight into the antimicrobial mode of action of brevibacillin 2V. As brevibacillin 2V is a novel and promising antibiotic candidate with low hemolytic activity and cytotoxicity, the here-elucidated mode of action will help further studies to develop it as an alternative antimicrobial agent.
Arnebia euchroma, a Plant Species of Cold Desert in the Himalayas, Harbors Beneficial Cultivable Endophytes in Roots and Leaves
Authors: Jain Rahul , Bhardwaj Priyanka , Pandey Shiv Shanker , Kumar Sanjay
Published: July 2021

The endophytic mutualism of plants with microorganisms often leads to several benefits to its host including plant health and survival under extreme environments. Arnebia euchroma is an endangered medicinal plant that grows naturally in extreme cold and arid environments in the Himalayas. The present study was conducted to decipher the cultivable endophytic diversity associated with the leaf and root tissues of A. euchroma. A total of 60 bacteria and 33 fungi including nine yeasts were isolated and characterized at the molecular level. Among these, Proteobacteria was the most abundant bacterial phylum with the abundance of Gammaproteobacteria (76.67%) and genus Pseudomonas. Ascomycota was the most abundant phylum (72.73%) dominated by class Eurotiales (42.42%) and genus Penicillium among isolated fungal endophytes. Leaf tissues showed a higher richness (Schao1) of both bacterial and fungal communities as compared to root tissues. The abilities of endophytes to display plant growth promotion (PGP) through phosphorus (P) and potassium (K) solubilization and production of ACC deaminase (ACCD), indole acetic acid (IAA), and siderophores were also investigated under in vitro conditions. Of all the endophytes, 21.51% produced ACCD, 89.25% solubilized P, 43.01% solubilized K, 68.82% produced IAA, and 76.34% produced siderophores. Six bacteria and one fungal endophyte displayed all the five PGP traits. The study demonstrated that A. euchroma is a promising source of beneficial endophytes with multiple growth-promoting traits. These endophytes can be used for improving stress tolerance in plants under nutrient-deficient and cold/arid conditions.
Adaptation of Melodic Intonation Therapy to Greek: A Clinical Study in Broca’s Aphasia With Brain Perfusion SPECT Validation
Authors: Martzoukou Maria , Nousia Anastasia , Nasios Grigorios , Tsiouris Spyridon
Published: July 2021

Melodic intonation therapy (MIT) is one of the most well-known treatment methods which is based on pitch and rhythm and was developed to increase verbal output in adults with non-fluent aphasia. Although MIT has been adapted to several languages, in Greece it is almost unknown. The aim of the proposed study is twofold: (1) to translate and adapt the MIT to the Greek language, and (2) to conduct an experimental study in order to examine the effect of MIT on Greek patients with Broca’s aphasia. To this aim, a 64-year-old, right-handed male who had a 6-year primary school education level, no musical abilities and poor performance on the recognition of prosody attended the MIT intervention program almost two and a half years after the event of suffering an ischemic stroke. The MIT intervention was administered three times per week for a 12-week period, in which each session lasted from 30 to 40 min. The patient underwent three assessments all using both the Boston Diagnostic Aphasia Examination–Short Form (BDAE-SF) and brain perfusion single-photon emission computed tomography (SPECT); (1) before the MIT, (2) immediately after, and (3) 3 months after the completion of MIT. The results from the BDAE-SF revealed an impressive improvement on both trained and prepositional speech production, immediately after the completion of the MIT, and a stable improved performance 3 months after MIT. The SPECT scan revealed reactivation of the perilesional areas of the left hemisphere, and considerably improved perfusion of the frontal lobe, the anterior temporal lobe, and the upper part of the parietal lobe of the right hemisphere. The improvement persisted and even expanded 3 months after MIT. Therefore, MIT is a promising intervention program and its positive effects last for at least 3 months after the completion of the intervention.
Effects of 1p/19q Codeletion on Immune Phenotype in Low Grade Glioma
Authors: Lv Lei , Zhang Yuliu , Zhao Yujia , Wei Qinqin , Zhao Ye , Yi Qiyi
Published: July 2021

Background:Chromosome 1p/19q codeletion is one of the most important genetic alterations for low grade gliomas (LGGs), and patients with 1p/19q codeletion have significantly prolonged survival compared to those without the codeletion. And the tumor immune microenvironment also plays a vital role in the tumor progression and prognosis. However, the effect of 1p/19q codeletion on the tumor immune microenvironment in LGGs is unclear.

Methods:Immune cell infiltration of 281 LGGs from The Cancer Genome Atlas (TCGA) and 543 LGGs from the Chinese Glioma Genome Atlas (CGGA) were analyzed for immune cell infiltration through three bioinformatics tools: ESTIMATE algorithm, TIMER, and xCell. The infiltrating level of immune cells and expression of immune checkpoint genes were compared between different groups classified by 1p/19q codeletion and IDH (isocitrate dehydrogenase) mutation status. The differential biological processes and signaling pathways were evaluated through Gene Set Enrichment Analysis (GSEA). Correlations were analyzed using Spearman correlation.

Results:1p/19q codeletion was associated with immune-related biological processes in LGGs. The infiltrating level of multiple kinds of immune cells and expression of immune checkpoint genes were significantly lower in 1p/19q codeletion LGGs compared to 1p/19q non-codeletion cohorts. There are 127 immune-related genes on chromosome 1p or 19q, such as TGFB1, JAK1, and CSF1. The mRNA expression of these genes was positively correlated with their DNA copy number. These genes are distributed in multiple immune categories, such as chemokines/cytokines, TGF-β family members, and TNF family members, regulating immune cell infiltration and expression of the immune checkpoint genes in tumors.

Conclusion:Our results indicated that 1p/19q codeletion status is closely associated with the immunosuppressive microenvironment in LGGs. LGGs with 1p/19q codeletion display less immune cell infiltration and lower expression of immune checkpoint genes than 1p/19q non-codeletion cases. Mechanistically, this may be, at least in part, due to the deletion of copy number of immune-related genes in LGGs with 1p/19q codeletion. Our findings may be relevant to investigate immune evasion in LGGs and contribute to the design of immunotherapeutic strategies for patients with LGGs.