bluuebunny/crossref_metadata_2025 huggingface dataset:
Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK
Authors: Kueffer Lauren E. , Joseph Raji E. , Andreotti Amy H.
Published: June 2021

Since Dr. Ogden Bruton’s 1952 paper describing the first human primary immunodeficiency disease, the peripheral membrane binding signaling protein, aptly named Bruton’s tyrosine kinase (BTK), has been the target of intense study. Dr. Bruton’s description of agammaglobulinemia set the stage for ultimately understanding key signaling steps emanating from the B cell receptor. BTK is a multidomain tyrosine kinase and in the decades since Dr. Bruton’s discovery it has become clear that genetic defects in the regulatory domains or the catalytic domain can lead to immunodeficiency. This finding underscores the intricate regulatory mechanisms within the BTK protein that maintain appropriate levels of signaling both in the resting B cell and during an immune challenge. In recent decades, BTK has become a target for clinical intervention in treating B cell malignancies. The survival reliance of B cell malignancies on B cell receptor signaling has allowed small molecules that target BTK to become essential tools in treating patients with hematological malignancies. The first-in-class Ibrutinib and more selective second-generation inhibitors all target the active site of the multidomain BTK protein. Therapeutic interventions targeting BTK have been successful but are plagued by resistance mutations that render drug treatment ineffective for some patients. This review will examine the molecular mechanisms that drive drug resistance, the long-range conformational effects of active site inhibitors on the BTK regulatory apparatus, and emerging opportunities to allosterically target the BTK kinase to improve therapeutic interventions using combination therapies.
The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells
Authors: Zhang Ziyu , Chen Baoyu , Zhu Yuwen , Zhang Tianyi , Zhang Xiaoling , Yuan Yibiao , Xu Yong
Published: June 2021

The small GTPase RHOJ is a key regulator of breast cancer metastasis by promoting cell migration and invasion. The prometastatic stimulus TGF-β activates RHOJ transcription via megakaryocytic leukemia 1 (MKL1). The underlying epigenetic mechanism is not clear. Here, we report that MKL1 deficiency led to disrupted assembly of the RNA polymerase II preinitiation complex on the RHOJ promoter in breast cancer cells. This could be partially explained by histone H3K9/H3K27 methylation status. Further analysis confirmed that the H3K9/H3K27 dual demethylase JHDM1D/KDM7A was essential for TGF-β-induced RHOJ transcription in breast cancer cells. MKL1 interacted with and recruited KDM7A to the RHOJ promoter to cooperatively activate RHOJ transcription. KDM7A knockdown attenuated migration and invasion of breast cancer cells in vitro and mitigated the growth and metastasis of breast cancer cells in nude mice. KDM7A expression level, either singularly or in combination with that of RHOJ, could be used to predict prognosis in breast cancer patients. Of interest, KDM7A appeared to be a direct transcriptional target of TGF-β signaling. A SMAD2/SMAD4 complex bound to the KDM7A promoter and mediated TGF-β-induced KDM7A transcription. In conclusion, our data unveil a novel epigenetic mechanism whereby TGF-β regulates the transcription of the prometastatic small GTPase RHOJ. Screening for small-molecule inhibitors of KDM7A may yield effective therapeutic solutions to treat malignant breast cancers.
Robo2 Receptor Gates the Anatomical Divergence of Neurons Derived From a Common Precursor Origin
Authors: Wurmser Maud , Muppavarapu Mridula , Tait Christine Mary , Laumonnerie Christophe , González-Castrillón Luz María , Wilson Sara Ivy
Published: June 2021

Sensory information relayed to the brain is dependent on complex, yet precise spatial organization of neurons. This anatomical complexity is generated during development from a surprisingly small number of neural stem cell domains. This raises the question of how neurons derived from a common precursor domain respond uniquely to their environment to elaborate correct spatial organization and connectivity. We addressed this question by exploiting genetically labeled mouse embryonic dorsal interneuron 1 (dI1) neurons that are derived from a common precursor domain and give rise to spinal projection neurons with distinct organization of cell bodies with axons projecting either commissurally (dI1c) or ipsilaterally (dI1i). In this study, we examined how the guidance receptor, Robo2, which is a canonical Robo receptor, influenced dI1 guidance during embryonic development. Robo2 was enriched in embryonic dI1i neurons, and loss of Robo2 resulted in misguidance of dI1i axons, whereas dI1c axons remained unperturbed within the mantle zone and ventral commissure. Further, Robo2 profoundly influenced dI1 cell body migration, a feature that was partly dependent on Slit2 signaling. These data suggest that dI1 neurons are dependent on Robo2 for their organization. This work integrated with the field support of a model whereby canonical Robo2 vs. non-canonical Robo3 receptor expression facilitates projection neurons derived from a common precursor domain to read out the tissue environment uniquely giving rise to correct anatomical organization.
Unraveling the Spatiotemporal Human Pluripotency in Embryonic Development
Authors: Ávila-González Daniela , Portillo Wendy , García-López Guadalupe , Molina-Hernández Anayansi , Díaz-Martínez Néstor E. , Díaz Néstor F.
Published: June 2021

There have been significant advances in understanding human embryogenesis using human pluripotent stem cells (hPSCs) in conventional monolayer and 3D self-organized cultures. Thus, in vitro models have contributed to elucidate the molecular mechanisms for specification and differentiation during development. However, the molecular and functional spectrum of human pluripotency (i.e., intermediate states, pluripotency subtypes and regionalization) is still not fully understood. This review describes the mechanisms that establish and maintain pluripotency in human embryos and their differences with mouse embryos. Further, it describes a new pluripotent state representing a transition between naïve and primed pluripotency. This review also presents the data that divide pluripotency into substates expressing epiblast regionalization and amnion specification as well as primordial germ cells in primates. Finally, this work analyzes the amnion’s relevance as an “signaling center” for regionalization before the onset of gastrulation.
Zebrafish Primordial Germ Cell Migration
Authors: Aalto Anne , Olguin-Olguin Adan , Raz Erez
Published: June 2021

Similar to many other organisms, zebrafish primordial germ cells (PGCs) are specified at a location distinct from that of gonadal somatic cells. Guided by chemotactic cues, PGCs migrate through embryonic tissues toward the region where the gonad develops. In this process, PGCs employ a bleb-driven amoeboid migration mode, characterized by low adhesion and high actomyosin contractility, a strategy used by other migrating cells, such as leukocytes and certain types of cancer cells. The mechanisms underlying the motility and the directed migration of PGCs should be robust to ensure arrival at the target, thereby contributing to the fertility of the organism. These features make PGCs an excellent model for studying guided single-cell migration in vivo. In this review, we present recent findings regarding the establishment and maintenance of cell polarity that are essential for motility and discuss the mechanisms by which cell polarization and directed migration are controlled by chemical and physical cues.
Changes in Microbial Community Composition Related to Sex and Colon Cancer by Nrf2 Knockout
Authors: Song Chin-Hee , Kim Nayoung , Nam Ryoung Hee , Choi Soo In , Yu Jeong Eun , Nho Heewon , Surh Young-Joon
Published: June 2021

The frequency of azoxymethane/dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in male mice is higher than that in female mice. Previous studies have reported that 17β-estradiol inhibits tumorigenesis in males by modulating nuclear factor-erythroid 2-related factor 2 (Nrf2). This study aimed to investigate the changes in mouse gut microbiome composition based on sex, AOM/DSS-induced colorectal cancer (CRC), and Nrf2 genotype. The gut microbiome composition was determined by 16S rRNA gene sequencing fecal samples obtained at week 16 post-AOM administration. In terms of sex differences, our results showed that the wild-type (WT) male control mice had higher alpha diversity (i.e. Chao1, Shannon, and Simpson) than the WT female control mice. The linear discriminant analysis effect size (LEfSe) results revealed that the abundances of Akkermansia muciniphila and Lactobacillus murinus were higher in WT male control mice than in WT female controls. In terms of colon tumorigenesis, the alpha diversity of the male CRC group was lower than that of the male controls in both WT and Nrf2 KO, but did not show such changes in females. Furthermore, the abundance of A. muciniphila was higher in male CRC groups than in male controls in both WT and Nrf2 KO. The abundance of Bacteroides vulgatus was higher in WT CRC groups than in WT controls in both males and females. However, the abundance of L. murinus was lower in WT female CRC and Nrf2 KO male CRC groups than in its controls. The abundance of A. muciniphila was not altered by Nrf2 KO. In contrast, the abundances of L. murinus and B. vulgatus were changed differently by Nrf2 KO depending on sex and CRC. Interestingly, L. murinus showed negative correlation with tumor numbers in the whole colon. In addition, B. vulgatus showed positive correlation with inflammatory markers (i.e. myeloperoxidase and IL-1β levels), tumor numbers, and high-grade adenoma, especially, developed mucosal and submucosal invasive adenocarcinoma at the distal part of the colon. In conclusion, Nrf2 differentially alters the gut microbiota composition depending on sex and CRC induction.
Improvement of Rheumatic Valvular Heart Disease in Patients Undergoing Prolonged Antibiotic Prophylaxis
Authors: Torres Renato Pedro de Almeida , Torres Rômulo Francisco de Almeida , Crombrugghe Gabrielle de , Moraes da Silva Scarllet Palacin , Cordeiro Sarah Leticia Veroneze , Bosi Karine Alessandra , Smeesters Pierre R. , Torres Rosângela Stadnick Lauth de Almeida
Published: June 2021

Secondary prophylaxis of rheumatic heart diseases is efficient in reducing disease recurrence, heart damage, and cardiac impairment. We aimed to monitor the clinical evolution of a large Brazilian cohort of rheumatic patients under prolonged secondary prophylaxis. From 1986 to 2018, a cohort of 593 patients with rheumatic fever was followed every 6 months by the Reference Center for the Control and Prevention of Rheumatic Fever and Rheumatic Cardiopathy (CPCFR), Paraná, Brazil. In this cohort, 243 (41%) patients did not present cardiac damage (group I), while 350 (59%) were diagnosed with rheumatic heart disease (RHD) (group II) using the latest case definition. Among group II, 233 and 15 patients had impairment of the mitral and aortic valves, respectively, while 102 patients had impairment of both valves. Lesions on the mitral and aortic valves presented a regression in 69.9 and 48.7% of the patients, respectively. Active patient recruitment in the reference center and early detection of oropharyngeal GAS were important factors for optimal adherence to the prophylactic treatment. Patients with disease progression were associated with noncompliance to secondary prophylaxis. No patients undergoing regular prophylaxis presented progression of the rheumatic cardiac disease. Eighteen valvular surgeries were performed, and four (0.7%) patients died. This study confirmed that tailored and active efforts invested in rheumatic heart disease secondary prevention allowed for significant clinical improvement.
Multiple Lines of Evidence for a Potentially Seismogenic Fault Along the Central-Apennine (Italy) Active Extensional Belt–An Unexpected Outcome of the MW6.5 Norcia 2016 Earthquake
Authors: Ferrarini Federica , de Nardis Rita , Brozzetti Francesco , Cirillo Daniele , Arrowsmith J Ramón , Lavecchia Giusy
Published: June 2021

The Apenninic chain, in central Italy, has been recently struck by the Norcia 2016 seismic sequence. Three mainshocks, in 2016, occurred on August 24 (MW6.0), October 26 (MW5.9) and October 30 (MW6.5) along well-known late Quaternary active WSW-dipping normal faults. Coseismic fractures and hypocentral seismicity distribution are mostly associated with failure along the Mt Vettore-Mt Bove (VBF) fault. Nevertheless, following the October 26 shock, the aftershock spatial distribution suggests the activation of a source not previously mapped beyond the northern tip of the VBF system. In this area, a remarkable seismicity rate was observed also during 2017 and 2018, the most energetic event being the April 10, 2018 (MW4.6) normal fault earthquake. In this paper, we advance the hypothesis that the Norcia seismic sequence activated a previously unknown seismogenic source. We constrain its geometry and seismogenic behavior by exploiting: 1) morphometric analysis of high-resolution topographic data; 2) field geologic- and morphotectonic evidence within the context of long-term deformation constraints; 3) 3D seismological validation of fault activity, and 4) Coulomb stress transfer modeling. Our results support the existence of distributed and subtle deformation along normal fault segments related to an immature structure, the Pievebovigliana fault (PBF). The fault strikes in NNW-SSE direction, dips to SW and is in right-lateral en echelon setting with the VBF system. Its activation has been highlighted by most of the seismicity observed in the sector. The geometry and location are compatible with volumes of enhanced stress identified by Coulomb stress-transfer computations. Its reconstructed length (at least 13 km) is compatible with the occurrence of MW≥6.0 earthquakes in a sector heretofore characterized by low seismic activity. The evidence for PBF is a new observation associated with the Norcia 2016 seismic sequence and is consistent with the overall tectonic setting of the area. Its existence implies a northward extent of the intra-Apennine extensional domain and should be considered to address seismic hazard assessments in central Italy.
Application of a Diatom Transfer Function to Quantitative Paleoclimatic Reconstruction — A Case Study of Yunlong Lake, Southwest China
Authors: Zou Yafei , Wang Luo , He Haibo , Liu Guangxin , Zhang Jiaoyang , Yan Yao , Gu Zhaoyan , Zheng Hongbo
Published: June 2021

Although diatom records from lake sediments have been used for quantitative paleoclimatic reconstruction, their validity and sensitivity have rarely been tested rigorously. At Yunlong Lake, an alpine lake in Southwest China, we studied the seasonal succession of diatom assemblages to produce a mean surface water temperature (MSWT) transfer function. In addition, based on the spatial distribution of surface diatom assemblages with water depth, we produced a diatom-water depth (WD) transfer function. Combined with the analysis of diatom assemblages in a sediment core (YL2013-A), changes in surface water temperature and water level over the last ∼100 years were quantitatively reconstructed using the diatom-based transfer functions. Comparison with records of regional meteorology and reservoir water capacity revealed that the diatom-based lake water level reconstruction is a sensitive indicator of short-term fluctuations in precipitation, and it also reflects a long-term stepwise rise in water level caused by the impounding and large-scale extension of the reservoir. In addition, the diatom-inferred MSWT is consistent with the changes in air temperature prior to large-scale human disturbance of the site. However, after the extension of the reservoir, although the regional air temperature continued to increase, the water temperature decreased substantially. This suggests that the large increase in lake water volume in the short term led to a decrease in the average water temperature, which in turn led to the occurrence of a diatom bloom in the cold season. The results demonstrate that diatom transfer functions based on modern observations of the same lake has a high environmental sensitivity and can be used for the quantitative reconstruction of regional climate change. Overall, our findings provide a foundation for the use of lake diatom records for quantitative paleoclimatic reconstruction on various timescales.
Soluble Neuropilin-1 Response to Hypoglycemia in Type 2 Diabetes: Increased Risk or Protection in SARS-CoV-2 Infection?
Authors: Moin Abu Saleh Md , Al-Qaissi Ahmed , Sathyapalan Thozhukat , Atkin Stephen L. , Butler Alexandra E.
Published: June 2021

Introduction

Neuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection.

Methods

A case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(<40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins: renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9).

Results

Baseline RAS overactivity was present with REN elevated and AGT decreased in T2D (p<0.05); ACE2 was unchanged. Baseline sNRP1, VEGF and ADAM9 did not differ between T2D and controls and remained unchanged in response to hypoglycaemia. However, 4-hours post-hypoglycemia, sNRP1, VEGF and ADAM9 were elevated in T2D(p<0.05). SEMA3A was not different at baseline; at hypoglycemia, SEMA3A decreased in controls only. Post-hypoglycemia, SEMA3A levels were higher in T2D versus controls. sNRP1 did not correlate with ACE2, REN or AGT. T2D subjects stratified according to ACE inhibitor (ACEi) therapies showed no difference in sNRP1 levels at either glucose normalization or hypoglycaemia.

Conclusion

Hypoglycemia potentiated both plasma sNRP1 level elevation and its ligands VEGF and SEMA3A, likely through an ADAM9-mediated mechanism that was not associated with RAS overactivity or ACEi therapy; however, whether this is protective or promotes increased risk for SARS-CoV-2 infection in T2D is unclear.

Clinical Trial Registration

https://clinicaltrials.gov, identifier NCT03102801.
Sex Steroids and Osteoarthritis: A Mendelian Randomization Study
Authors: Yan Yi-Shang , Qu Zihao , Yu Dan-Qing , Wang Wei , Yan Shigui , Huang He-Feng
Published: June 2021

Objective

Sex steroids are thought to contribute to the pathogenesis of osteoarthritis (OA). This study investigated the causal role of sex steroids in site- and sex-specific OA and risk of joint replacement surgery using the Mendelian randomization (MR) method.

Methods

Instrumental variables for estradiol, dehydroepiandrosterone sulfate, testosterone (T), and dihydrotestosterone (DHT) were selected. We used the inverse variance weighting (IVW) approach as the main MR method to estimate causal effects based on the summary-level data for OA and joint replacement surgery from genome-wide association studies (GWAS).

Results

A positive causal association was observed between serum T level and risks of hip OA (odds ratio [OR]=1.558, 95% confidence interval [CI]: 1.193–2.034; P=0.001) and hip replacement (OR=1.013, 95% CI: 1.008–1.018; P=2.15×10−8). Serum DHT level was also positively associated with the risk of hip replacement (OR=1.011, 95% CI: 1.006–1.015; P=4.03×10−7) and had potential causality with hip OA (OR=1.398, 95% CI: 1.054–1.855; P=0.020).

Conclusions

Serum T and DHT levels may play causal roles in the development of hip OA and contribute to the risk of hip replacement, although the underlying mechanisms require further investigation.
Identification of Novel Environmental Substances Relevant to Pediatric Graves’ Disease
Authors: Xia Qin , Liu Jingjing , Xu Xu , Gu Wei , Gu Kefeng , Chen Xiuli , Xie Rongrong , Zhang Dandan , Wu Haiying , Sun Hui , Wang Fengyun , Chen Linqi , Chen Ting
Published: June 2021

Graves’ disease (GD) is the most common cause of hyperthyroidism, yet a relatively rare disease in the pediatric population. GD is a complex disorder influenced by both genetic and environmental factors. In this study, we aimed to find new environmental factors influencing the pathogenesis of GD. We investigated serum substances in 30 newly diagnosed GD children and 30 age- and gender-matched healthy controls. We measured total iodine by inductively coupled plasma-mass spectrometry (ICP-MS), analyzed perfluorinated compounds via ultra-high-performance liquid chromatography coupled with multiple reaction monitoring mass spectrometry (UHPLC-MRM-MS), and explored other environmental substances using ultra-high-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UHPLC–QTOF/MS) analysis. Twenty-nine single-nucleotide polymorphisms (SNPs) in eight genes related to GD were analyzed by SNaPshot. The serum total iodine was significantly higher in GD group, but its association with GD onset was weak, only with Exp(B) value near 1. The perfluorinated compound levels were not different between the two groups. More importantly, we found 16 environmental substances significantly different between GD and control groups, among which ponasterone A is a risk factor (p = 0.007 and Exp(B) = 14.14), while confertifoline is a protective factor against GD onset (p = 0.002 and Exp(B) = 0.001). We also identified 10 substances correlated significantly with thyroid indices in GD patients, among which seven associated with levels of the thyroid autoantibody TPOAb. No known SNPs were found predisposing GD. In this study, we explored a broad variety of environmental substances and identified novel factors that are potentially involved in the pediatric GD pathogenesis.
Adenomatoid Tumor of the Adrenal Gland: Report of Two Cases and Review of the Literature
Authors: Guan Jiexia , Zhao Chang , Li Hengming , Zhang Wenjing , Lin Weizhen , Tang Luying , Chen Jianning
Published: June 2021

Adenomatoid tumor (AT) is an uncommon benign neoplasm of mesothelial origin, usually occurring in the female and male genital tracts. Extragenital localization such as the adrenal gland is extremely rare. Until now, only 39 cases of adrenal AT have been reported in the English literature. Here we report two novel cases of adrenal AT that occurred in male patients aged 30 and 31 years. The tumors were discovered incidentally by computed tomography (CT). Macroscopically, the tumors were unilateral and solid, and the greatest dimension of the tumors was 3.5 and 8.0 cm, respectively. Histologically, the tumors consisted of angiomatoid, cystic, and solid patterns and infiltrated the adrenal cortical or medullary tissue. The tumor cells had low nuclear/cytoplasmic ratio, with no pathological mitosis or nuclear pleomorphism. Thread-like bridging strands and signet-ring-like cells could be seen. Immunohistochemically, the tumor cells were positive for epithelial markers (AE1/AE3, CK7) and mesothelial markers (D2-40, calretinin, and WT-1). The Ki-67 index was approximately 1 and 2%, respectively. The differential diagnosis of adrenal AT includes a variety of benign and malignant tumors. The patients had neither local recurrence nor distant metastasis at 21 and 8 months after removal of the tumor. In the literature review, we comprehensively summarized the clinical, morphological, immunohistochemical, and prognostic features of adrenal AT. Adrenal ATs are morphologically and immunophenotypically identical to those that occur in the genital tracts. Combining the histology with immunohistochemical profiles is very supportive in reaching the diagnosis of this benign tumor, helping to avoid misdiagnosis and overtreatment.
Multiphysics Modeling of Thorium-Based Fuel Performance With Cr-Coated SiC/SiC Composite Under Normal and Accident Conditions
Authors: Liu Shengyu , Liu Rong , Qiu Chengjie , Zhou Wenzhong
Published: June 2021

Using the finite element multiphysics modeling method, the performance of the thorium-based fuel with Cr-coated SiC/SiC composite cladding under both normal operating and accident conditions was investigated in this work. First, the material properties of SiC/SiC composite and chromium were reviewed. Then, the implemented model was simulated, and the results were compared with those of the FRAPTRAN code to verify the correctness of the model used in this work. Finally, the fuel performance of the Th0.923U0.077O2 fuel, Th0.923Pu0.077O2 fuel, and UO2 fuel combined with the Cr-coated SiC/SiC composite cladding and Zircaloy cladding, respectively, was investigated and compared under both normal operating and accident conditions. Compared with the UO2 fuel, the Th0.923U0.077O2 and Th0.923Pu0.077O2 fuels were found to increase the fuel centerline temperature under both normal operating and reactivity-initiated accident (RIA) conditions, but decrease the fuel centerline temperature under loss-of-coolant accident (LOCA) condition. Moreover, compared to the UO2 fuel with the Zircaloy cladding, thorium-based fuels with Cr-coated SiC/SiC composite cladding were found to show better mechanical performance such as delaying the failure time by about 3 s of the Cr-coated SiC/SiC composite cladding under LOCA condition, and reducing the plenum pressure by about 0.4 MPa at the peak value in the fuel rod and the hoop strain of the cladding by about 16% under RIA condition.
Microplastics Increase Soil pH and Decrease Microbial Activities as a Function of Microplastic Shape, Polymer Type, and Exposure Time
Authors: Zhao Tingting , Lozano Yudi M. , Rillig Matthias C.
Published: June 2021

Microplastic pollution is a topic of increasing concern, especially since this issue was first addressed in soils. Results have so far been variable in terms of effects, suggesting that there is substantial context-dependency in microplastic effects in soil. To better define conditions that may affect microplastic-related impacts, we here examined effects as a function of microplastic shape and polymer type, and we tested if effects on soil properties and soil microbial activities change with incubation time. In our laboratory study, we evaluated twelve different secondary microplastics representing four microplastic shapes: fibers, films, foams and fragments; and eight polymer types: polyamide (PA), polycarbonate (PC), polyethylene (PE), polyester (PES), polyethylene terephthalate (PET), polypropylene (PP), polystyrene (PS), and polyurethane (PU). We mixed the microplastics with a sandy soil (0.4% w/w) and incubated at 25°C for 31 days. Then, we collected soil samples on the 3rd, 11th, and 31st day, and measured soil pH, respiration and four enzyme activities (soil enzymatic activities). Our results showed that microplastics could affect soil pH, respiration and enzymatic activities depending on microplastic shape and polymer type, effects that were altered with incubation time. Soil pH increased with foams and fragments and overall decreased in the first days of incubation and then increased. Soil respiration increased with PE foams and was affected by the incubation time, declining over time. Overall, acid phosphatase activity was not affected by shape or polymer type. β-D-glucosidase activity decreased with foams, cellobiosidase activity decreased with fibers, films and foams while N-acetyl-β-glucosaminidase activities decreased with fibers and fragments. Enzymatic activities fluctuated during the incubation time, except N-acetyl-β-glucosaminidase, which showed a declining trend with incubation time. Enzymatic activities were negatively correlated with soil pH and this relationship was less strong when microplastics were added to the soil. Our study adds to the evidence that research should embrace the complexity and diversity of microplastics, highlighting the role of microplastic shape and polymer type in influencing effects; additionally, we show that incubation time is also a parameter to consider, as effects are dynamic even in the short term.
Application of Topological Data Analysis to Multi-Resolution Matching of Aerosol Optical Depth Maps
Authors: Ofori-Boateng Dorcas , Lee Huikyo , Gorski Krzysztof M. , Garay Michael J. , Gel Yulia R.
Published: June 2021

Topological data analysis (TDA) combines concepts from algebraic topology, machine learning, statistics, and data science which allow us to study data in terms of their latent shape properties. Despite the use of TDA in a broad range of applications, from neuroscience to power systems to finance, the utility of TDA in Earth science applications is yet untapped. The current study aims to offer a new approach for analyzing multi-resolution Earth science datasets using the concept of data shape and associated intrinsic topological data characteristics. In particular, we develop a new topological approach to quantitatively compare two maps of geophysical variables at different spatial resolutions. We illustrate the proposed methodology by applying TDA to aerosol optical depth (AOD) datasets from the Goddard Earth Observing System, Version 5 (GEOS-5) model over the Middle East. Our results show that, contrary to the existing approaches, TDA allows for systematic and reliable comparison of spatial patterns from different observational and model datasets without regridding the datasets into common grids.
Integrated Analysis of Microarray and RNA-Seq Data for the Identification of Hub Genes and Networks Involved in the Pancreatic Cancer
Authors: Nisar Maryum , Paracha Rehan Zafar , Arshad Iqra , Adil Sidra , Zeb Sabaoon , Hanif Rumeza , Rafiq Mehak , Hussain Zamir
Published: June 2021

Pancreatic cancer (PaCa) is the seventh most fatal malignancy, with more than 90% mortality rate within the first year of diagnosis. Its treatment can be improved the identification of specific therapeutic targets and their relevant pathways. Therefore, the objective of this study is to identify cancer specific biomarkers, therapeutic targets, and their associated pathways involved in the PaCa progression. RNA-seq and microarray datasets were obtained from public repositories such as the European Bioinformatics Institute (EBI) and Gene Expression Omnibus (GEO) databases. Differential gene expression (DE) analysis of data was performed to identify significant differentially expressed genes (DEGs) in PaCa cells in comparison to the normal cells. Gene co-expression network analysis was performed to identify the modules co-expressed genes, which are strongly associated with PaCa and as well as the identification of hub genes in the modules. The key underlaying pathways were obtained from the enrichment analysis of hub genes and studied in the context of PaCa progression. The significant pathways, hub genes, and their expression profile were validated against The Cancer Genome Atlas (TCGA) data, and key biomarkers and therapeutic targets with hub genes were determined. Important hub genes identified included ITGA1, ITGA2, ITGB1, ITGB3, MET, LAMB1, VEGFA, PTK2, and TGFβ1. Enrichment analysis characterizes the involvement of hub genes in multiple pathways. Important ones that are determined are ECM–receptor interaction and focal adhesion pathways. The interaction of overexpressed surface proteins of these pathways with extracellular molecules initiates multiple signaling cascades including stress fiber and lamellipodia formation, PI3K-Akt, MAPK, JAK/STAT, and Wnt signaling pathways. Identified biomarkers may have a strong influence on the PaCa early stage development and progression. Further, analysis of these pathways and hub genes can help in the identification of putative therapeutic targets and development of effective therapies for PaCa.
A Chromosome-Level Genome Assembly of the Mandarin Fish (Siniperca chuatsi)
Authors: Ding Weidong , Zhang Xinhui , Zhao Xiaomeng , Jing Wu , Cao Zheming , Li Jia , Huang Yu , You Xinxin , Wang Min , Shi Qiong , Bing Xuwen
Published: June 2021

The mandarin fish,Siniperca chuatsi, is an economically important perciform species with widespread aquaculture practices in China. Its special feeding habit, acceptance of only live prey fishes, contributes to its delicious meat. However, little is currently known about related genetic mechanisms. Here, we performed whole-genome sequencing and assembled a 758.78 Mb genome assembly of the mandarin fish, with the scaffold and contig N50 values reaching 2.64 Mb and 46.11 Kb, respectively. Approximately 92.8% of the scaffolds were ordered onto 24 chromosomes (Chrs) with the assistance of a previously established genetic linkage map. The chromosome-level genome contained 19,904 protein-coding genes, of which 19,059 (95.75%) genes were functionally annotated. The special feeding behavior of mandarin fish could be attributable to the interaction of a variety of sense organs (such as vision, smell, and endocrine organs). Through comparative genomics analysis, some interesting results were found. For example, olfactory receptor (OR) genes (especially the beta and delta types) underwent a significant expansion, and endocrinology/vision relatednpy,spexin, andopsingenes presented various functional mutations. These may contribute to the special feeding habit of the mandarin fish by strengthening the olfactory and visual systems. Meanwhile, previously identified sex-related genes and quantitative trait locis (QTLs) were localized on the Chr14 and Chr17, respectively. 155 toxin proteins were predicted from mandarin fish genome. In summary, the high-quality genome assembly of the mandarin fish provides novel insights into the feeding habit of live prey and offers a valuable genetic resource for the quality improvement of this freshwater fish.
A Peptide Vaccine Candidate Tailored to Individuals' Genetics Mimics the Multi-Targeted T Cell Immunity of COVID-19 Convalescent Subjects
Authors: Somogyi Eszter , Csiszovszki Zsolt , Molnár Levente , Lőrincz Orsolya , Tóth József , Pattijn Sofie , Schockaert Jana , Mazy Aurélie , Miklós István , Pántya Katalin , Páles Péter , Tőke Enikő R.
Published: June 2021

Long-term immunity to coronaviruses likely stems from T cell activity. We present here a novel approach for the selection of immunoprevalent SARS-CoV-2-derived T cell epitopes using an in silico cohort of HLA-genotyped individuals with different ethnicities. Nine 30-mer peptides derived from the four major structural proteins of SARS-CoV-2 were selected and included in a peptide vaccine candidate to recapitulate the broad virus-specific T cell responses observed in natural infection. PolyPEPI-SCoV-2-specific, polyfunctional CD8+ and CD4+ T cells were detected in each of the 17 asymptomatic/mild COVID-19 convalescents' blood against on average seven different vaccine peptides. Furthermore, convalescents' complete HLA-genotype predicted their T cell responses to SARS-CoV-2-derived peptides with 84% accuracy. Computational extrapolation of this relationship to a cohort of 16,000 HLA-genotyped individuals with 16 different ethnicities suggest that PolyPEPI-SCoV-2 vaccination will likely elicit multi-antigenic T cell responses in 98% of individuals, independent of ethnicity. PolyPEPI-SCoV-2 administered with Montanide ISA 51 VG generated robust, Th1-biased CD8+, and CD4+ T cell responses against all represented proteins, as well as binding antibodies upon subcutaneous injection into BALB/c and hCD34+ transgenic mice modeling human immune system. These results have implications for the development of global, highly immunogenic, T cell-focused vaccines against various pathogens and diseases.
EASIX for Prediction of Outcome in Hospitalized SARS-CoV-2 Infected Patients
Authors: Luft Thomas , Wendtner Clemens-Martin , Kosely Florentina , Radujkovic Aleksandar , Benner Axel , Korell Felix , Kihm Lars , Bauer Matthias F. , Dreger Peter , Merle Uta
Published: June 2021

Background

The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has evoked a pandemic that challenges public health-care systems worldwide. Endothelial cell dysfunction plays a key role in pathophysiology, and simple prognosticators may help to optimize allocation of limited resources. Endothelial activation and stress index (EASIX) is a validated predictor of endothelial complications and outcome after allogeneic stem cell transplantation. Aim of this study was to test if EASIX could predict life-threatening complications in patients with COVID-19.

Methods

SARS-CoV-2-positive, hospitalized patients were enrolled onto a prospective non-interventional register study (n=100). Biomarkers were assessed at hospital admission. Primary endpoint was severe course of disease (mechanical ventilation and/or death, V/D). Results were validated in 126 patients treated in two independent institutions.

Results

EASIX at admission was a strong predictor of severe course of the disease (odds ratio for a two-fold change 3.4, 95%CI 1.8-6.3, p<0.001), time to V/D (hazard ratio (HR) for a two-fold change 2.0, 95%CI 1.5-2.6, p<0.001) as well as survival (HR for a two-fold change 1.7, 95%CI 1.2-2.5, p=0.006). The effect was retained in multivariable analysis adjusting for age, gender, and comorbidities and could be validated in the independent cohort. At hospital admission EASIX correlated with increased suppressor of tumorigenicity-2, soluble thrombomodulin, angiopoietin-2, CXCL8, CXCL9 and interleukin-18, but not interferon-alpha.

Conclusion

EASIX is a validated predictor of COVID19 outcome and an easy-to-access tool to segregate patients in need for intensive surveillance.
Cytokine Imprint in Preeclampsia
Authors: Stefańska Katarzyna , Zieliński Maciej , Jankowiak Martyna , Zamkowska Dorota , Sakowska Justyna , Adamski Przemysław , Jassem-Bobowicz Joanna , Piekarska Karolina , Leszczyńska Katarzyna , Świątkowska-Stodulska Renata , Kwiatkowski Sebastian , Preis Krzysztof , Trzonkowski Piotr , Marek-Trzonkowska Natalia
Published: June 2021

The hallmark of preeclampsia (PE) is a shift toward persistent inflammatory response, accompanied by endothelial dysfunction. The driving forces in PE are proinflammatory cytokine and growth factors, in parallel with reduced functionality of anti-inflammatory effectors, like regulatory T cells are observed. Unfortunately, no conclusive mechanism underlying preeclampsia has been identified. For this reason, research on preeclampsia is needed to provide a state of the art understanding of the pathophysiology, identification of new diagnostics tools and the development of targeted therapies. The 68 patients were divided into three groups: gestational hypertension (GH) group (n = 19) and PE group (n = 28) and a control group (n = 21). We have tested a set of 53 cytokines, chemokines and growth factors in preeclampsia and gestational hypertension, and then compared them with normal pregnancies. Using a diagnostic test assessment characteristic parameters (IL-22, MDC/CCL22, IL-2/IL-4 ratio) have been identified and cut-off values have been proposed to diagnose preeclampsia. All parameters had high negative or positive predictive values, above 80%. In conclusion, we have proposed a potential set of immune parameters to diagnose preeclampsia.
The Prospect of Nanoparticle Systems for Modulating Immune Cell Polarization During Central Nervous System Infection
Authors: Korshoj Lee E. , Shi Wen , Duan Bin , Kielian Tammy
Published: June 2021

The blood-brain barrier (BBB) selectively restricts the entry of molecules from peripheral circulation into the central nervous system (CNS) parenchyma. Despite this protective barrier, bacteria and other pathogens can still invade the CNS, often as a consequence of immune deficiencies or complications following neurosurgical procedures. These infections are difficult to treat since many bacteria, such as Staphylococcus aureus, encode a repertoire of virulence factors, can acquire antibiotic resistance, and form biofilm. Additionally, pathogens can leverage virulence factor production to polarize host immune cells towards an anti-inflammatory phenotype, leading to chronic infection. The difficulty of pathogen clearance is magnified by the fact that antibiotics and other treatments cannot easily penetrate the BBB, which requires extended regimens to achieve therapeutic concentrations. Nanoparticle systems are rapidly emerging as a promising platform to treat a range of CNS disorders. Nanoparticles have several advantages, as they can be engineered to cross the BBB with specific functionality to increase cellular and molecular targeting, have controlled release of therapeutic agents, and superior bioavailability and circulation compared to traditional therapies. Within the CNS environment, therapeutic actions are not limited to directly targeting the pathogen, but can also be tailored to modulate immune cell activation to promote infection resolution. This perspective highlights the factors leading to infection persistence in the CNS and discusses how novel nanoparticle therapies can be engineered to provide enhanced treatment, specifically through modulation of immune cell polarization.
High Fat Diet-Induced CD8+ T Cells in Adipose Tissue Mediate Macrophages to Sustain Low-Grade Chronic Inflammation
Authors: Kiran Sonia , Kumar Vijay , Murphy E. Angela , Enos Reilly T. , Singh Udai P.
Published: June 2021

Obesity in the United States and worldwide reached epidemic proportions within the last 20 years. Obesity is a very powerful health determinant or indicator that facilitates the development and progression of several metabolic diseases, insulin resistance, and low-grade chronic inflammation. Low-grade chronic inflammation in adipose tissue (AT) is marked by the accumulation of T cells, macrophages, and other immune cells and increased production of proinflammatory cytokines. During the onset of obesity but before the influx of macrophages, the AT is infiltrated by T cells that are strongly implicated in the initiation of obesity-associated inflammation. In comparing mice fed a high-fat diet (HFD) with those fed a normal diet (ND), we observed in HFD epididymal AT induction and infiltration of activated T cells, an accumulation and polarization of macrophages, and an increase in populations of activated CD4+ T cells and CD8+ T cells that express CXCR3 or killer cell lectin-like receptor subfamily G member 1 (KLRG1). Levels of inflammatory cytokines and leptin and the results of in vitro co-culture experiments revealed interactions among HFD- and ND-induced CD8+ T cells, macrophages, and adipocytes. Our findings suggest that obese tissues activate and induce both CD4+ and CD8+ CD69+ T cells and augment the expression of CXCR3 receptors, which promotes the recruitment and numbers of pro-inflammatory M1 macrophages to maintain low-grade chronic inflammation. The results support the hypothesis that CXCR3-expressing CD8+T cells play an essential role in the initiation and maintenance of adipose tissue inflammation.
Potential Implications of Quercetin in Autoimmune Diseases
Authors: Shen Pan , Lin Weiji , Deng Xuan , Ba Xin , Han Liang , Chen Zhe , Qin Kai , Huang Ying , Tu Shenghao
Published: June 2021

Autoimmune diseases are a worldwide health problem with growing rates of morbidity, and are characterized by breakdown and dysregulation of the immune system. Although their etiology and pathogenesis remain unclear, the application of dietary supplements is gradually increasing in patients with autoimmune diseases, mainly due to their positive effects, relatively safety, and low cost. Quercetin is a natural flavonoid that is widely present in fruits, herbs, and vegetables. It has been shown to have a wide range of beneficial effects and biological activities, including anti-inflammation, anti-oxidation, and neuroprotection. In several recent studies quercetin has reportedly attenuated rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus in humans or animal models. This review summarizes the evidence for the pharmacological application of quercetin for autoimmune diseases, which supports the view that quercetin may be useful for their prevention and treatment.
Nrf2 Participates in M2 Polarization by Trichinella spiralis to Alleviate TNBS-Induced Colitis in Mice
Authors: Jin Xuemin , Bai Xue , Zhao Ying , Dong Zijian , Pang Jianda , Liu Mingyuan , Liu Xiaolei
Published: June 2021

Trichinella spiralis induced alternative activated macrophages (M2), leading to protect against Crohn’s disease, known as Th1 –related inflammation, which enhances oxidative stress in the host. However, the relationship of oxidative stress and T. spiralis –mediated immune response is still unknown. In our study, we showed that nuclear factor erythroid 2-related factor-2 (Nrf2), a key transcription factor in antioxidant, participated in M2 polarization induced by T. spiralis muscle larval excretory/secretory (ES) products in vitro. ES –treated M2 were injected intravenously after TNBS challenge and we demonstrated that ES-M could alleviate the severity of the colitis in mice. Adoptive transfer of ES –treated M2 decreased the level of IFN-γ and increased the levels of IL-4 and IL-10 in vivo. However, the capacity of ES –treated Nrf2 KO macrophages to treat colitis was dramatically impaired. ES –treated Nrf2 KO macrophages was insufficient to result in the elevated levels of IL-4 and IL-10. These findings indicate that Nrf2 was required for M2 polarization induced by T. spiralis ES to alleviate colitis in mice.
Metabolic Control of Smoldering Neuroinflammation
Authors: Peruzzotti-Jametti Luca , Willis Cory M. , Hamel Regan , Krzak Grzegorz , Pluchino Stefano
Published: June 2021

Compelling evidence exists that patients with chronic neurological conditions, which includes progressive multiple sclerosis, display pathological changes in neural metabolism and mitochondrial function. However, it is unknown if a similar degree of metabolic dysfunction occurs also in non-neural cells in the central nervous system. Specifically, it remains to be clarified (i) the full extent of metabolic changes in tissue-resident microglia and infiltrating macrophages after prolonged neuroinflammation (e.g., at the level of chronic active lesions), and (ii) whether these alterations underlie a unique pathogenic phenotype that is amenable for therapeutic targeting. Herein, we discuss how cell metabolism and mitochondrial function govern the function of chronic active microglia and macrophages brain infiltrates and identify new metabolic targets for therapeutic approaches aimed at reducing smoldering neuroinflammation.