bluuebunny/crossref_metadata_2025 huggingface dataset:
Calcium, an Emerging Intracellular Messenger for the Hippo Pathway Regulation
Authors: Wei Yiju , Li Wei
Published: June 2021

The Hippo pathway is a conserved signaling network regulating organ development and tissue homeostasis. Dysfunction of this pathway may lead to various diseases, such as regeneration defect and cancer. Studies over the past decade have found various extracellular and intracellular signals that can regulate this pathway. Among them, calcium (Ca2+) is emerging as a potential messenger that can transduce certain signals, such as the mechanical cue, to the main signaling machinery. In this process, rearrangement of the actin cytoskeleton, such as calcium-activated actin reset (CaAR), may construct actin filaments at the cell cortex or other subcellular domains that provide a scaffold to launch Hippo pathway activators. This article will review studies demonstrating Ca2+-mediated Hippo pathway modulation and discuss its implication in understanding the role of actin cytoskeleton in regulating the Hippo pathway.
Boron-Doped MXenes as Electrocatalysts for Nitrogen Reduction Reaction: A Theoretical Study
Authors: Wang Yuan , Qian Xu , Zheng Guokui , Tian Ziqi , Zhang Qiuju
Published: June 2021

Electrocatalytic nitrogen reduction reaction (NRR) is a promising and sustainable approach for ammonia production. Since boron as an active center possesses electronic structure similar to that of transition metals withd-orbitals (J. Am. Chem. Soc., 2019, 141 (7), 2884), it is supposed to be able to effectively activate the triple bond in N2. MXenes can be applied as substrates due to the large specific surface area, high conductivity, and tunable surface composition. In this work, the catalytic performance of a series of MXenes-supported single boron atom systems (labeled as B@MXenes) has been systematically studied by using density functional theory (DFT). B@Nb4C3O2, B@Ti4N3O2, and B@Ti3N2O2were screened out owing to outstanding catalytic activity with limiting potentials of −0.26, −0.15, and −0.10 V, respectively. Further analysis shows that the unique property of boron that can intensely accept lone pair and back-donate the anti-bond of nitrogen contributes to the activation of inert triple bond. This work provides a new idea for the rational design of NRR catalyst and is of great significance for the future development of nitrogen reduction catalysts.
Combination of Blood Routine Examination and T-SPOT.TB Assay for Distinguishing Between Active Tuberculosis and Latent Tuberculosis Infection
Authors: Luo Ying , Tang Guoxing , Yuan Xu , Lin Qun , Mao Liyan , Song Huijuan , Xue Ying , Wu Shiji , Ouyang Renren , Hou Hongyan , Wang Feng , Sun Ziyong
Published: June 2021

Background

Distinguishing between active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains challenging.

Methods

Between 2013 and 2019, 2,059 (1,097 ATB and 962 LTBI) and another 883 (372 ATB and 511 LTBI) participants were recruited based on positive T-SPOT.TB (T-SPOT) results from Qiaokou (training) and Caidian (validation) cohorts, respectively. Blood routine examination (BRE) was performed simultaneously. Diagnostic model was established according to multivariate logistic regression.

Results

Significant differences were observed in all indicators of BRE and T-SPOT assay between ATB and LTBI. Diagnostic model built on BRE showed area under the curve (AUC) of 0.846 and 0.850 for discriminating ATB from LTBI in the training and validation cohorts, respectively. Meanwhile, TB-specific antigens spot-forming cells (SFC) (the larger of early secreted antigenic target 6 and culture filtrate protein 10 SFC in T-SPOT assay) produced lower AUC of 0.775 and 0.800 in the training and validation cohorts, respectively. The diagnostic model based on combination of BRE and T-SPOT showed an AUC of 0.909 for differentiating ATB from LTBI, with 78.03% sensitivity and 90.23% specificity when a cutoff value of 0.587 was used in the training cohort. Application of the model to the validation cohort showed similar performance. The AUC, sensitivity, and specificity were 0.910, 78.23%, and 90.02%, respectively. Furthermore, we also assessed the performance of our model in differentiating ATB from LTBI with lung lesions. Receiver operating characteristic analysis showed that the AUC of established model was 0.885, while a threshold of 0.587 yield a sensitivity of 78.03% and a specificity of 85.69%, respectively.

Conclusions

The diagnostic model based on combination of BRE and T-SPOT could provide a reliable differentiation between ATB and LTBI.
Role of Recent Therapeutic Applications and the Infection Strategies of Shiga Toxin-Producing Escherichia coli
Authors: Hwang Su-bin , Chelliah Ramachandran , Kang Ji Eun , Rubab Momna , Banan-MwineDaliri Eric , Elahi Fazle , Oh Deog-Hwan
Published: June 2021

Shiga toxin-producingEscherichia coli(STEC) is a global foodborne bacterial pathogen that is often accountable for colon disorder or distress. STEC commonly induces severe diarrhea in hosts but can cause critical illnesses due to the Shiga toxin virulence factors. To date, there have been a significant number of STEC serotypes have been evolved. STECs vary from nausea and hemorrhoid (HC) to possible lethal hemolytic-based uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP). Inflammation-based STEC is usually a foodborne illness with Shiga toxins (Stx 1and2) thought to be pathogenesis. The STEC’s pathogenicity depends significantly on developing one or more Shiga toxins, which can constrain host cell protein synthesis leading to cytotoxicity. In managing STEC infections, antimicrobial agents are generally avoided, as bacterial damage and discharge of accumulated toxins are thought the body. It has also been documented that certain antibiotics improve toxin production and the development of these species. Many different groups have attempted various therapies, including toxin-focused antibodies, toxin-based polymers, synbiotic agents, and secondary metabolites remedies. Besides, in recent years, antibiotics’ efficacy in treating STEC infections has been reassessed with some encouraging methods. Nevertheless, the primary role of synbiotic effectiveness (probiotic and prebiotic) against pathogenic STEC and other enteropathogens is less recognized. Additional studies are required to understand the mechanisms of action of probiotic bacteria and yeast against STEC infection. Because of the consensus contraindication of antimicrobials for these bacterial pathogens, the examination was focused on alternative remedy strategies for STEC infections. The rise of novel STEC serotypes and approaches employed in its treatment are highlighted.
A Multiplex and Colorimetric Reverse Transcription Loop-Mediated Isothermal Amplification Assay for Sensitive and Rapid Detection of Novel SARS-CoV-2
Authors: Juscamayta-López Eduardo , Valdivia Faviola , Horna Helen , Tarazona David , Linares Liza , Rojas Nancy , Huaringa Maribel
Published: June 2021

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a major threat to public health. Rapid molecular testing for convenient and timely diagnosis of SARS-CoV-2 infections represents a challenge that could help to control the current pandemic and prevent future outbreaks. We aimed to develop and validate a multiplex and colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay using lyophilized LAMP reagents for sensitive and rapid detection of SARS-CoV-2. LAMP primers were designed for a set of gene targets identified by a genome-wide comparison of viruses. Primer sets that showed optimal features were combined into a multiplex RT-LAMP assay. Analytical validation included assessment of the limit of detection (LoD), intra- and inter-assay precision, and cross-reaction with other respiratory pathogens. Clinical performance compared to that of real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) was assessed using 278 clinical RNA samples isolated from swabs collected from individuals tested for COVID-19. The RT-LAMP assay targeting the RNA-dependent RNA polymerase (RdRp), membrane (M), and ORF1ab genes achieved a comparable LoD (0.65 PFU/mL, CT=34.12) to RT-qPCR and was 10-fold more sensitive than RT-qPCR at detecting viral RNA in clinical samples. Cross-reactivity to other respiratory pathogens was not observed. The multiplex RT-LAMP assay demonstrated a strong robustness and acceptable intra- and inter-assay precision (mean coefficient of variation, 4.75% and 8.30%). Diagnostic sensitivity and specificity values were 100.0% (95% CI: 97.4–100.0%) and 98.6% (95% CI: 94.9–99.8%), respectively, showing high consistency (Cohen’s kappa, 0.986; 95% CI: 0.966–1.000; p<0.0001) compared to RT-qPCR. The novel one-step multiplex RT-LAMP assay is storable at room temperature and showed similar diagnostic accuracy to conventional RT-qPCR, while being faster (<45 min), simpler, and cheaper. The new assay could allow reliable and early diagnosis of SARS-CoV-2 infections in primary health care. It may aid large-scale testing in resource-limited settings, especially if it is integrated into a point-of-care diagnostic device.
Knockdown Resistance (kdr) Mutations I1532T and F1534S Were Identified in Aedes albopictus Field Populations in Zhejiang Province, Central China
Authors: Wu Yuyan , Liu Qinmei , Qi Yunpeng , Wu Yinping , Ni Qinxiang , Chen Weihua , Wang Jinna , Li Tianqi , Luo Mingyu , Hou Juan , Gong Zhenyu , Sun Jimin
Published: June 2021

Aedes albopictusis the only vector that can transmit the dengue virus in Zhejiang Province, central China, and it can develop insecticide resistance due to long-term exposure to pyrethroids. The presence of knockdown resistance (kdr) mutations is one of the mechanisms responsible for pyrethroid resistance, and has been reported in someAe. albopictuspopulations in southern China. However, little is known about the DNA diversity of the voltage-gated sodium channel (VGSC) gene inAe. albopictuspopulations in central China. FourAe. albopictusfield populations were collected, in Yiwu (YW), Quzhou (QZ), Wenzhou (WZ), and Jiaxing (JX) from Zhejiang Province, central China. The susceptibility ofAe. albopictusadults to three pyrethroids (beta-cypermethrin, deltamethrin, and permethrin) was tested using the WHO tube assay, andKdrmutations were identifiedviaPCR and sequencing. The relationship betweenkdrmutations and pyrethroid phenotypes was also analyzed. Of the four populations, none was sensitive to any pyrethroid tested, and the YW population showed the strongest pyrethroid resistance. Non-synonymouskdrmutations were detected in codons 1532 and 1534, domain III. At codon 1534, one mutant allele, TCC(S), was detected in the four populations with a frequency of 42.08%, while at codon 1532, one mutant allele, ACC(T), was detected in the JX and QZ populations, with frequencies of 4.22 and 3.03%, respectively. The F1534S mutant allele was positively correlated with both beta-cypermethrin and deltamethrin resistance phenotypes (OR > 1, P < 0.05), whereas the I1532T mutant allele was possibly negatively correlated with beta-cypermethrin, deltamethrin, and permethrin resistance phenotypes (OR < 1, P > 0.05). In conclusion, resistance and resistance mutations regarding to three pyrethroids are already present in theAe. Albopictuspopulations from Zhejiang, central China, which prompts the need to use non-insecticide-based methods of insect control.
Elevated Hyoid Bone Position in Response to Mandibular Advancing Appliance Predicts Effectiveness of the Appliance for Obstructive Sleep Apnea
Authors: Pae Eung-Kwon , Harper Ronald M.
Published: June 2021

The objective was to determine whether hyoid bone elevation induced by an anterior mandibular positioning appliance (AMP) predicts the effectiveness of the AMP in patients with obstructive sleep apnea (OSA). Fifteen patients (12 males and 3 females) underwent polysomnographic recordings and lateral cephalograms before and after AMP use of at least 6 months. Measurements of sleep variables and upper airway morphology were compared between pre-AMP and with-AMP states. The AMP appliance reduced apnea-hypopnea indices (AHI) ~53% (33.77 ± 3.29 vs. 15.85 ± 3.78, P = 0.0013). Cephalograms of the oropharyngeal airway showed that the hyoid bone moved superiorly toward the inferior mandibular border (Δ H-MP) ~5 mm (23.4 ± 1.44 vs. 18.27 ± 1.86, P = 0.0377), with the AMP inserted in the oral cavity; no airway measurement other than hyoid bone position changed. No significant correlations emerged between AHI improvement (Δ AHI) and amounts of hyoid elevation (Δ H-MP) when all patients were pooled. However, when the samples were subcategorized, the correlation coefficients increased significantly (P < 0.01) in both subgroups. This outcome suggests the presence of two distinct types among the “Good-Responders” to AMP appliance use. Overall use of the AMP appliance is effective; however, the effectiveness of the appliance appears to depend on the mode of hyoid elevations, likely resulting from muscle responsiveness in patients with AMP use. The results suggest that Δ H-MP measurements may be a useful marker to segregate patients with tongue and hyoid muscles responsive to AMP from those not-so-responsive.
Implementing a Hybrid Summer Transition Program
Authors: Gibson Stephen M. , Brinkley Kendra , Griggs Lauren A. , James Briana N. , Smith Mychal , Schwitzerlett Mark , Waller LaChelle M. , Hargraves Rosalyn Hobson
Published: June 2021

The mission of the Virginia Commonwealth University Louis Stokes Alliance for Minority Participation (VCU LSAMP) program is to increase the retention and graduation rates of students from underrepresented racial and ethnic groups in science, technology, engineering, and mathematics (STEM) majors and those who matriculate into graduate programs. VCU LSAMP offers a hybrid summer transition program (HSTP) focused on facilitating the high school to college and two-year to four-year college transition process for students majoring in STEM disciplines. The goals of the program are to 1) build community among a cohort of students, 2) orient students to VCU, 3) prepare students for the academic rigors of their first year in a STEM discipline at VCU, 4) expose students to opportunities and careers in STEM, 5) engage them in the VCU LSAMP program, and 6) provide financial support. Five distinct components of the VCU HSTP are 1) a six-week online summer component, 2) a 1 week on-campus orientation, 3) a Design Project Challenge, 4) a transfer student track, and 5) an academic year component. Evaluation data reveals that the HSTP assisted participants with adjustment to the college schedule and setting, facilitated the formation of study groups, and increased overall motivation to graduate. The online courses helped familiarize students with both the academic topics in their chemistry and mathematics classes and the behaviors and norms of STEM majors. On average, participants in the HSTP had higher retention (85%) and graduation (73%) rates when compared with their peers (81% and 64%, respectively). Furthermore, those students who complete the online classes’ requirements had a higher probability of receiving a grade of B or better in their first mathematics or chemistry class.
Wellbore Temperature and Pressure Field in Deep-water Drilling and the Applications in Prediction of Hydrate Formation Region
Authors: Sun Wantong , Wei Na , Zhao Jinzhou , Zhou Shouwei , Zhang Liehui , Li Qingping , Jiang Lin , Zhang Yao , Li Haitao , Xu Hanming , Li Cong , Shen Xuncheng , Xiong Chenyang
Published: June 2021

In the process of deep-water drilling, gas hydrate is easily formed in wellbores due to the low temperature and high pressure environment. In this study, a new, systematic, and accurate prediction method of temperature, pressure, and hydrate formation region in wellbores is developed. The mathematical models of wellbore pressure and transient heat transfer are established, the numerical solution method based on fully implicit finite difference method is developed, and the accuracy is verified by comparing with the field measured data. Combined with the hydrate phase equilibrium model, the hydrate formation region in wellbore is predicted, and the sensitivity effects of nine factors on wellbore temperature, pressure, and hydrate formation region are analyzed. Finally, the influence regularities and degree of each parameter are obtained. The increases of circulation time, geothermal gradient, displacement of drilling fluid, and injection temperature will inhibit the formation of hydrate in wellbores, and the influence degree increases in turn; the increases of wellhead backpressure and seawater depth will promote the formation of hydrate in wellbores, and the influence degree increases in turn. The changes of drilling fluid density, well depth, and hole deviation angle have little effect on the formation of hydrate in wellbores.
Spheres of Influence: Host Tree Proximity and Soil Chemistry Shape rRNA, but Not DNA, Communities of Symbiotic and Free-Living Soil Fungi in a Mixed Hardwood-Conifer Forest
Authors: Runte Gabriel C. , Smith Alex H. , Moeller Holly V. , Bogar Laura M.
Published: June 2021

Host and symbiont diversity are inextricably linked across partnerships and ecosystems, with degree of partner reliance governing the strength of this correlation. In many forest soils, symbiotic ectomycorrhizal fungi coexist and compete with free-living saprotrophic fungi, with the outcomes of these interactions shaping resource availability and competitive outcomes for the trees aboveground. Traditional approaches to characterizing these communities rely on DNA sequencing of a ribosomal precursor RNA gene (the internal transcribed spacer region), but directly sequencing the precursor rRNA may provide a more functionally relevant perspective on the potentially active fungal communities. Here, we map ectomycorrhizal and saprotrophic soil fungal communities through a mixed hardwood-conifer forest to assess how above- and belowground diversity linkages compare across these differently adapted guilds. Using highly spatially resolved transects (sampled every 2 m) and well-mapped stands of varying host tree diversity, we sought to understand the relative influence of symbiosis versus environment in predicting fungal diversity measures. Canopy species in this forest included two oaks (Quercus agrifoliaandQuercus douglasii) and one pine (Pinus sabiniana). At the scale of our study, spatial turnover in rRNA-based communities was much more predictable from measurable environmental attributes than DNA-based communities. And while turnover of ectomycorrhizal fungi and saprotrophs were predictable by the presence and abundance of different canopy species, they both responded strongly to soil nutrient characteristics, namely pH and nitrogen availability, highlighting the niche overlap of these coexisting guilds and the strong influence of aboveground plants on belowground fungal communities.
Contrasting Gymnosperm Diversity Across an Elevation Gradient in the Ecoregion of China: The Role of Temperature and Productivity
Authors: Pandey Bikram , Pan Kaiwen , Dakhil Mohammed A. , Liao Ziyan , Timilsina Arbindra , Khanal Manita , Zhang Lin
Published: June 2021

The species richness–climate relationship is a significant concept in determining the richness patterns and predicting the cause of its distribution. The distribution range of species and climatic variables along elevation have been used in evaluating the elevational diversity gradients (EDG). However, the species richness of gymnosperms along elevation and its driving factors in large geographic areas are still unknown. Here, we aimed at evaluating the EDG of gymnosperms in the ecoregions of China. We divided the geographical region of China into 34 ecoregions and determine the richness pattern of gymnosperm taxa along elevation gradients. We demonstrated the richness patterns of the 237-gymnosperm (219 threatened, 112 endemic, 189 trees, and 48 shrubs) taxa, roughly distributed between 0 and 5,300 m (above sea level) in China. As possible determinants of richness patterns, annual mean temperature (TEMP), annual precipitation (PPT), potential evapotranspiration (PET), net primary productivity (SNPP), aridity index (AI), temperature seasonality (TS), and precipitation seasonality (PS) are the major predictor variables driving the EDG in plants. We used the species interpolation method to determine the species richness at each elevation band. To evaluate the richness pattern of gymnosperms in an ecoregion, generalized additive modeling and structural equation modeling were performed. The ecoregions in the southern part of China are rich in gymnosperm species, where three distinct richness patterns—(i) hump-shaped, (ii) monotonic increase, and (iii) monotonic decline—were noticed in China. All climatic variables have a significant effect on the richness pattern of gymnosperms; however, TEMP, SNPP, TS, and PS explained the highest deviance in diversity-rich ecoregions of China. Our results suggests that the highest number of gymnosperms species was found in the southwestern and Taiwan regions of China distributed at the 1,600- and 2,800-m elevation bands. These regions could be under severe stress in the near future due to expected changes in precipitation pattern and increase of temperature due to climate change. Thus, our study provided evidence of the species–climate relationship that can support the understanding of future conservation planning of gymnosperms.
Lodgepole Pine Bole Wood Density and Decay Rate 1, 11, and 22 Years After Felling in Central Montana, United States
Authors: Lutes Duncan C. , Hardy Colin C.
Published: June 2021

Estimates of dead and down woody material (DWM) biomass are important for nutrient cycling, wildlife habitat assessment, fire effects and climate change science. Most methods used to sample woody material initially assess volume then estimates of wood density are used to convert volume to biomass. To assess initial wood density and decomposition rate, this study examined in situ wood density of lodgepole pine logs at the Tenderfoot Creek Experimental Forest (TCEF), central Montana, United States, 1, 11, and 22 years after felling. Mean wood density decreased from 0.39 to 0.27 g cm–3 over 22 years and the single exponential decay rate was k = 0.012 yr–1 1 and 11-years post-felling and 0.022 yr–1 11 and 22 years post-felling. A common 5-category decay classification system was evaluated for estimating wood density by decay class, which identified significant difference in three of four observed classes.
Expression and Prognosis Analysis of SUMOylation Regulators in Oral Squamous Cell Carcinoma Based on High-Throughput Sequencing
Authors: Meng Yutong , Li Xiaozhi
Published: June 2021

Introduction

Oral squamous cell carcinoma (OSCC) originates from oral mucosal epithelial cells, accounting for more than 90% of oral cancers. The relationship between the expression and prognostic role of SUMOylation regulators in OSCC is rarely studied.

Materials and methods

The expression and survival data of OSCC were derived from TCGA and GEO databases. Wilcoxon test was used to determine the differential expression of the SUMOylation regulators. A prognostic model based on SUMOylation regulator-related genes was constructed by Cox regression. Gene set enrichment analysis was applied to predict the potential biological functions that the genes might be involved in.

Results

RANBP2 and SENP6 had the highest SNV frequency. Eleven genes including PIAS3, RANBP2, USPL1, SENP6, SENP2, SENP5, SAE1, UBA2, PIAS4, UBE2I, and SENP3 were highly expressed in OSCC. The prognostic model based on nine SUMOylation-regulated genes (TRIM37, UFM1, FUBP1, CCNT1, FXR1, HMG20A, RANBP3, SPATA5, and DDX23) had a strong ability to predict the prognosis of OSCC.

Conclusion

This study might provide targets for prognostic evaluation and targeted therapy of patients with OSCC.
A Robust Prognostic Gene Signature Based on eRNAs-Driven Genes in Prostate Cancer
Authors: Fan Shuaishuai , Wang Zheng , Zhao Li , Zhao ChenHui , Yuan DaJiang , Wang Jingqi
Published: June 2021

Prostate cancer (PCa) is the second most common malignancy in men, but its exact pathogenetic mechanisms remain unclear. This study explores the effect of enhancer RNAs (eRNAs) in PCa. Firstly, we screened eRNAs and eRNA -driven genes from The Cancer Genome Atlas (TCGA) database, which are related to the disease-free survival (DFS) of PCa patients;. screening methods included bootstrapping, Kaplan–Meier (KM) survival analysis, and Pearson correlation analysis. Then, a risk score model was established using multivariate Cox analysis, and the results were validated in three independent cohorts. Finally, we explored the function of eRNA-driven genes through enrichment analysis and analyzed drug sensitivity on datasets from the Genomics of Drug Sensitivity in Cancer database. We constructed and validated a robust prognostic gene signature involving three eRNA-driven genes namely MAPK15, ZNF467, and MC1R. Moreover, we evaluated the function of eRNA-driven genes associated with tumor microenvironment (TME) and tumor mutational burden (TMB), and identified remarkable differences in drug sensitivity between high- and low-risk groups. This study identified a prognostic gene signature, which provides new insights into the role of eRNAs and eRNA-driven genes while assisting clinicians to determine the prognosis and appropriate treatment options for patients with PCa.
Bovine Immunology: Implications for Dairy Cattle
Authors: Vlasova Anastasia N. , Saif Linda J.
Published: June 2021

The growing world population (7.8 billion) exerts an increased pressure on the cattle industry amongst others. Intensification and expansion of milk and beef production inevitably leads to increased risk of infectious disease spread and exacerbation. This indicates that improved understanding of cattle immune function is needed to provide optimal tools to combat the existing and future pathogens and improve food security. While dairy and beef cattle production is easily the world’s most important agricultural industry, there are few current comprehensive reviews of bovine immunobiology. High-yielding dairy cattle and their calves are more vulnerable to various diseases leading to shorter life expectancy and reduced environmental fitness. In this manuscript, we seek to fill this paucity of knowledge and provide an up-to-date overview of immune function in cattle emphasizing the unresolved challenges and most urgent needs in rearing dairy calves. We will also discuss how the combination of available preventative and treatment strategies and herd management practices can maintain optimal health in dairy cows during the transition (periparturient) period and in neonatal calves.
Modulation of Gut Microbiota to Enhance Effect of Checkpoint Inhibitor Immunotherapy
Authors: Wu Jianmin , Wang Shan , Zheng Bo , Qiu Xinyao , Wang Hongyang , Chen Lei
Published: June 2021

Accumulating evidence demonstrated the crucial role of gut microbiota in many human diseases, including cancer. Checkpoint inhibitor therapy has emerged as a novel treatment and has been clinically accepted as a major therapeutic strategy for cancer. Gut microbiota is related to cancer and the effect of immune checkpoint inhibitors (ICIs), and supplement with specific bacterial species can restore or enhance the responses to the ICIs. Namely, specified bacteria can serve as the biomarkers for distinguishing the patient who will respond to ICIs and determine the effectiveness of ICIs, as well as predicting the efficacy of checkpoint inhibitor immunotherapy. Regardless of the significant findings, the relationship between gut microbiota and the effect of ICIs treatment needs a more thorough understanding to provide more effective therapeutic plans and reduce treatment complication. In this review, we summarized the role of gut microbiota played in immune system and cancer. We mainly focus on the relationship between gut microbiota and the checkpoint inhibitor immunotherapy.
The Ability of AhR Ligands to Attenuate Delayed Type Hypersensitivity Reaction Is Associated With Alterations in the Gut Microbiota
Authors: Abdulla Osama A. , Neamah Wurood , Sultan Muthanna , Alghetaa Hasan K. , Singh Narendra , Busbee Philip Brandon , Nagarkatti Mitzi , Nagarkatti Prakash
Published: June 2021

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates T cell function. The aim of this study was to investigate the effects of AhR ligands, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), and 6-Formylindolo[3,2-b]carbazole (FICZ), on gut-associated microbiota and T cell responses during delayed-type hypersensitivity (DTH) reaction induced by methylated bovine serum albumin (mBSA) in a mouse model. Mice with DTH showed significant changes in gut microbiota including an increased abundance of Bacteroidetes and decreased Firmicutes at the phylum level. Also, there was a decrease in Clostridium cluster XIV and IV, which promote anti-inflammatory responses, and an increase in Prevotella copri that facilitates pro-inflammatory responses. Interestingly, treatment of mice with TCDD attenuated the DTH response, induced Tregs, suppressed Th17 cells in the mesenteric lymph nodes (MLNs), and reversed the gut microbiota composition toward normalcy. In contrast, FICZ exacerbated the DTH response, induced heightened Th17 cells, and failed to cause a major shift in gut microbiota. Furthermore, TCDD but not FICZ caused an increase in the levels of short-chain fatty acids (SCFA), n-butyric acid, and acetic acid. Administration of sodium butyrate into mice with DTH suppressed the response, increased Tregs, and reduced Th17 cells IL17. Butyrate also caused an increase in the abundance of Clostridium and a decrease in Prevotella. Lastly, TCDD, as well as butyrate but not FICZ, were able to inhibit proinflammatory Histone deacetylases (HDACs) class I and II. Together, our data suggest that AhR ligands, such as TCDD that suppress DTH response, may mediate this effect by reversing the gut dysbiosis induced during this inflammatory response, while FICZ may fail to suppress the DTH response because of its inability to overturn the dysbiosis.
A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy Optimization
Authors: Grunewald Laura , Lam Tobias , Andersch Lena , Klaus Anika , Schwiebert Silke , Winkler Annika , Gauert Anton , Heeren-Hagemann Anja I. , Astrahantseff Kathy , Klironomos Filippos , Thomas Alexander , Deubzer Hedwig E. , Henssen Anton G. , Eggert Angelika , Schulte Johannes H. , Anders Kathleen , Kloke Lutz , Künkele Annette
Published: June 2021

Chimeric antigen receptor (CAR) T cell performance against solid tumors in mouse models and clinical trials is often less effective than predicted by CAR construct selection in two-dimensional (2D) cocultures. Three-dimensional (3D) solid tumor architecture is likely to be crucial for CAR T cell efficacy. We used a three-dimensional (3D) bioprinting approach for large-scale generation of highly reproducible 3D human tumor models for the test case, neuroblastoma, and compared these to 2D cocultures for evaluation of CAR T cells targeting the L1 cell adhesion molecule, L1CAM. CAR T cells infiltrated the model, and both CAR T and tumor cells were viable for long-term experiments and could be isolated as single-cell suspensions for whole-cell assays quantifying CAR T cell activation, effector function and tumor cell cytotoxicity. L1CAM-specific CAR T cell activation by neuroblastoma cells was stronger in the 3D model than in 2D cocultures, but neuroblastoma cell lysis was lower. The bioprinted 3D neuroblastoma model is highly reproducible and allows detection and quantification of CAR T cell tumor infiltration, representing a superiorin vitroanalysis tool for preclinical CAR T cell characterization likely to better select CAR T cells forin vivoperformance than 2D cocultures.
Survival and Functional Immune Reconstitution After Haploidentical Stem Cell Transplantation in Atm-Deficient Mice
Authors: Duecker Ruth Pia , Gronau Lucia , Baer Patrick C. , Zielen Stefan , Schubert Ralf
Published: June 2021

Hematopoietic stem cell transplantation (HSCT) has been proposed as a promising therapeutic opportunity to improve immunity and prevent hematologic malignancies in Ataxia-telangiectasia (A-T). However, experience in the transplantation strategy for A-T patients is still scarce. The aim of this study was to investigate whether different approaches of HSCT are feasible in regard to graft versus host response and sufficient concerning functional immune reconstitution. Atm-deficient mice were treated with a clinically relevant non-myeloablative host-conditioning regimen and transplanted with CD90.2-depleted, green fluorescent protein (GFP)-expressing, and ataxia telangiectasia mutated (ATM)-competent bone marrow donor cells in a syngeneic, haploidentical or allogeneic setting. Like syngeneic HSCT, haploidentical HSCT, but not allogeneic HSCT extended the lifespan of Atm-deficient mice through the reduction of thymic tumors and normalized T-cell numbers. Donor-derived splenocytes isolated from transplanted Atm-deficient mice filled the gap of cell loss in the naïve T-cell population and raised CD4 cell functionality up to wild-type level. Interestingly, HSCT using heterozygous donor cells let to a significantly improved survival of Atm-deficient mice and increased CD4 cell numbers as well as CD4 cell functionality equivalent to HSCT using with wild-type donor cells. Our data provided evidence that haploidentical HSCT could be a feasible strategy for A-T, possibly even if the donor is heterozygous for ATM. However, this basic research cannot substitute any research in humans.
The 12-CK Score: Global Measurement of Tertiary Lymphoid Structures
Authors: Li Roger , Berglund Anders , Zemp Logan , Dhillon Jasreman , Putney Ryan , Kim Youngchul , Jain Rohit K. , Grass G. Daniel , Conejo-Garcia José , Mulé James J.
Published: June 2021

There is emerging evidence that the adaptive anti-tumor activity may be orchestrated by secondary lymphoid organ-like aggregates residing in the tumor microenvironment. Known as tertiary lymphoid structures, these lymphoid aggregates serve as key outposts for lymphocyte recruitment, priming and activation. They have been linked to favorable outcomes in many tumor types, and more recently, have been shown to be effective predictors of response to immune checkpoint blockade. We have previously described a 12-chemokine (12-CK) transcriptional score which recapitulates an overwhelming enrichment for immune-related and inflammation-related genes in colorectal carcinoma. Subsequently, the 12-CK score was found to prognosticate favorable survival in multiple tumors types including melanoma, breast cancer, and bladder cancer. In the current study, we summarize the discovery and validation of the 12-CK score in various tumor types, its relationship to TLSs found within the tumor microenvironment, and explore its potential role as both a prognostic and predictive marker in the treatment of various cancers.
Connecting Metabolism to Mastitis: Hyperketonemia Impaired Mammary Gland Defenses During a Streptococcus uberis Challenge in Dairy Cattle
Authors: Swartz Turner H. , Bradford Barry J. , Mamedova Laman K.
Published: June 2021

β-hydroxybutyrate (BHB) has been associated with disease incidence in early lactation dairy cattle, but such associations do not demonstrate causation. Therefore, the objective of this study was to examine the effects of BHB during an intramammaryStreptococcus uberischallenge. A secondary objective was to elucidate the mechanisms behind BHB effects on cytokine transcript abundance using the RAW 264.7 cell line. Late lactation multiparous dairy cows (n = 12) were continuously infused intravenously with either BHB to induce hyperketonemia (target concentration: 1.8 mM) or with saline (CON) for 72 h during aS. uberisintramammary challenge. Body temperature, dry matter intake (DMI), milk production, and milkS. uberiscfu were measured daily until one week post-challenge. Blood samples were collected during infusion to assess changes in metabolism (glucose, insulin, glucagon, NEFA, and cortisol) and systemic inflammation (IL-1β and SAA). Mammary biopsies were conducted at 72 h post-challenge to assess transcript abundance of inflammation-associated genes. BHB-infused cows exhibited a delayed febrile response, noted by a lesser vaginal temperature during the final day of infusion, followed by a greater vaginal temperature 6 d post-challenge. Consequently, BHB-infused cows had greaterS. uberiscfu on d 4, 6, and 7 as compared to CON. Accordingly, BHB-infused cows consumed less DM, produced less milk, had reduced blood glucose, and had increased cortisol concentrations, however, no effects were seen on other systemic parameters or transcript abundance of inflammation-related genes in mammary tissue. To elucidate mechanisms behind the impaired immune defenses, RAW 264.7 cells were transfected with a GPR109A siRNA for 24 h and then treated with or without 1.8 mM BHB and challenged or left unchallenged withS. uberisfor an additional 3 h. Transfection with siRNA reducedGpr109aby 75%. Although BHB treatment did not significantly increaseIl10, GPR109A knockdown as compared to the scrambled control reducedIl10by 90% inS. uberischallenged macrophages treated with BHB, suggesting that macrophage immune responses toS. uberiscan be alteredviaa GPR109A-dependent mechanism. Taken together, these data suggest that BHB altered the immune response promoting tolerance towardS. uberisrather than resistance.
Glucose Metabolism: The Metabolic Signature of Tumor Associated Macrophage
Authors: Zhang Qi , Wang Junli , Yadav Dipesh Kumar , Bai Xueli , Liang Tingbo
Published: June 2021

Macrophages exist in most tissues of the body, where they perform various functions at the same time equilibrating with other cells to maintain immune responses in numerous diseases including cancer. Recently, emerging investigations revealed that metabolism profiles control macrophage phenotypes and functions, and in turn, polarization can trigger metabolic shifts in macrophages. Those findings implicate a special role of metabolism in tumor-associated macrophages (TAMs) because of the sophisticated microenvironment in cancer. Glucose is the major energy source of cells, especially for TAMs. However, the complicated association between TAMs and their glucose metabolism is still unclearly illustrated. Here, we review the recent advances in macrophage and glucose metabolism within the tumor microenvironment, and the significant transformations that occur in TAMs during the tumor progression. Additionally, we have also outlined the potential implications for macrophage-based therapies in cancer targeting TAMs.
Effect of a Seasonal Fishery Closure on Sardine and Mackerel Catch in the Visayan Sea, Philippines
Authors: Bagsit Farisal U. , Frimpong Eugene , Asch Rebecca G. , Monteclaro Harold M.
Published: June 2021

The implementation of seasonal fishery closures (SFC) can be controversial due to the frequent lack of clear objectives, monitoring and empirical evidence of management success. In the Philippines, an SFC implemented for the conservation of important fishery commodities in the Visayan Sea has been ruled a success after stricter implementation of this fishery policy in 2012. However, a comprehensive, detailed, and robust analysis of this fishery policy is lacking. Using a difference-in-differences (DID) framework, we estimated the effect of SFC on the interannual and seasonal catch for sardine and mackerel. We expanded our analysis to other species not regulated under the SFC policy. We also conducted semi-structured interviews (N= 235), focus group discussions (N= 9) and key informant interviews (N= 37) involving municipal fisheries stakeholders in the surrounding municipalities around the Visayan Sea, and representatives from the government and non-government agencies, to complement our analyses. Seasonal analyses of catch data show a significant increase in sardine catch at the end of the seasonal closure among SFC-participating provinces. However, overall, the SFC had no significant effect on sardine interannual catch among the provinces participating in the SFC. We also found no significant effect of the SFC on interannual and seasonal catch for mackerel. Furthermore, our findings show no significant changes in fishing pressure to other aquatic species. Interview results corroborate our DID findings for mackerel, but not for sardine. The varying perceptions on the outcomes of the SFC policy can be attributed to several challenges such as lack of implementing guidelines, lack of alternative livelihoods for the affected stakeholders, persistence of illegal fishing, and uneven implementation of the SFC. Since the management objective of this SFC was to conserve the regulated species, alternative management measures may be needed to achieve this goal. This could entail more consistent enforcement, improved cooperation and communication between fisheries managers and stakeholders, fish size or gear restrictions, and identification and conservation of key habitats needed to restore overexploited species.
The Influence of Depth-Dependent Seasonal Temperature Variability on Growth Signal in Arctica islandica
Authors: Caldarescu Diana E. , Brey Thomas , Abele Doris , Beierlein Lars , Lohmann Gerrit , Ionita Monica
Published: June 2021

Bivalve sclerochronological records with annually resolved growth bands are applicable proxies in reconstructing features of the hydro-climate system. Here we evaluate the relationship between growth indices of A. islandica, previously collected at approximately 82 m depth in the North Atlantic, and seasonal subsurface temperature at various depths for the 1900–2005 period. Correlations with sea surface temperature at the collection site are not significant during winter and weak for the remaining seasons. The strongest in-phase correlations persist for summer and autumn below 56 m water depth, whereas weaker correlations are lagged by one or two years. We also observe similarities with distant water bodies in the North Atlantic sector, and a corresponding large-scale oceanographic pattern that increases significantly with water depth along the trajectory of the North Atlantic Current. We suggest that by investigating the relationship with the temperature signal at various depths locally and at large-scale increases the reliability and application of bivalve shells as marine archives.
Microplastics in Invasive Freshwater Mussels (Dreissena sp.): Spatiotemporal Variation and Occurrence With Chemical Contaminants
Authors: Hoellein Timothy , Rovegno Catherine , Uhrin Amy V. , Johnson Ed , Herring Carlie
Published: June 2021

Invasive zebra and quagga mussels (Dreissena spp.) in the Great Lakes of North America are biomonitors for chemical contaminants, but are also exposed to microplastics (<5 mm). Little research has examined in situ microplastic ingestion by dreissenid mussels, or the relationship between microplastics and chemical contaminants. We measured microplastics and chemical contaminants in mussel tissue from Milwaukee Harbor (Lake Michigan, United States) harvested from reference locations and sites influenced by wastewater effluent and urban river discharge. Mussels were deployed in cages in the summer of 2018, retrieved after 30 and 60 days, sorted by size class, and analyzed for microplastics and body burdens of three classes of contaminants: alkylphenols, polyaromatic hydrocarbons, and petroleum biomarkers. Microplastics in mussels were higher in the largest mussels at the wastewater-adjacent site after 30 days deployment. However, there was no distinction among sites for microplastics in smaller mussels, and no differences among sites after 60 days of deployment. Microplastics and chemical contaminants in mussels were not correlated. Microplastics have a diversity of intrinsic and extrinsic factors which influence their ingestion, retention, and egestion by mussels, and which vary relative to chemicals. While dreissenid mussels may not serve as plastic pollution biomonitors like they can for chemical contaminants, microplastics in dreissenid mussels are widespread, variable, and have unknown effects on physiology, mussel-mediated ecosystem processes, and lake food webs. These data will inform our understanding of the spatial distribution of microplastics in urban freshwaters, the role of dreissenid mussels in plastic budgets, and models for the fate of plastic pollution.
PPAR-α Agonist Fenofibrate Prevented Diabetic Nephropathy by Inhibiting M1 Macrophages via Improving Endothelial Cell Function in db/db Mice
Authors: Feng Xiaomeng , Gao Xia , Wang Shuo , Huang Mengxiu , Sun Zhencheng , Dong Hengbei , Yu Haitian , Wang Guang
Published: June 2021

Background: Diabetic nephropathy (DN) is one of the major diabetic microvascular complications, and macrophage polarization plays a key role in the development of DN. Endothelial cells regulate macrophage polarization. Peroxisome proliferator-activated receptor (PPAR)-α agonists were demonstrated to prevent DN and improve endothelial function. In this study, we aimed to investigate whether PPAR-α agonists prevented DN through regulating macrophage phenotype via improving endothelial cell function.

Methods: Eight-week-old male C57BLKS/J db/m and db/db mice were given fenofibrate or 1% sodium carboxyl methylcellulose by gavage for 12 weeks.

Results: Db/db mice presented higher urinary albumin-to-creatinine ratio (UACR) than db/m mice, and fenofibrate decreased UACR in db/db mice. Fibrosis and collagen I were elevated in db/db mouse kidneys compared with db/m mouse kidneys; however, they were decreased after fenofibrate treatment in db/db mouse kidneys. Apoptosis and cleaved caspase-3 were enhanced in db/db mouse kidneys compared to db/m mouse kidneys, while fenofibrate decreased them in db/db mouse kidneys. Db/db mice had a suppression of p-endothelial nitric oxide synthase (eNOS)/t-eNOS and nitric oxide (NO), and an increase of angiopoietin-2 and reactive oxygen species (ROS) in kidneys compared with db/m mice, and fenofibrate increased p-eNOS/t-eNOS and NO, and decreased angiopoietin-2 and ROS in db/db mouse kidneys. Hypoxia-inducible factor (HIF)-1α and Notch1 were promoted in db/db mouse kidneys compared with db/m mouse kidneys, and were reduced after fenofibrate treatment in db/db mouse kidneys. Furthermore, the immunofluorescence staining indicated that M1 macrophage recruitment was enhanced in db/db mouse kidneys compared to db/m mouse kidneys, and this was accompanied by a significant increase of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in kidneys and in serum of db/db mice compared with db/m mice. However, fenofibrate inhibited the renal M1 macrophage recruitment and cytokines associated with M1 macrophages in db/db mice.

Conclusions: Our study indicated that M1 macrophage recruitment due to the upregulated HIF-1α/Notch1 pathway induced by endothelial cell dysfunction involved in type 2 diabetic mouse renal injury, and PPAR-α agonist fenofibrate prevented DN by reducing M1 macrophage recruitment via inhibiting HIF-1α/Notch1 pathway regulated by endothelial cell function in type 2 diabetic mouse kidneys.