bluuebunny/crossref_metadata_2025 huggingface dataset:
Two Improved Acquisition Systems for Deep Subsurface Exploration
Authors: Liu Nengchao , Yao Gang , Zou Zhihui , Wang Shangxu , Wu Di , Li Xiang , Zhou Jianye
Published: April 2022

Present land seismic surveys mainly focus on acquiring reflection data. The maximum offset is usually 1–1.5 times the depth of targets. Limited offset results in that the acquired diving waves only penetrate the shallow parts of the Earth model, far from targets. Thus, the reflection data are used to build the deep part of the velocity model with migration velocity analysis. However, two issues challenge the success of velocity model building. First, incomplete information. Limited offsets lead to a narrow aperture of observation, which results in an under-determined inversion system. One manifestation is the trade-off between the depth of interfaces/reflectors and the average velocity above them. Second, low signal-to-noise (S/N) ratios. Complex near-surface conditions and geologic structures lead to low S/N ratios for reflection data, which fails to build velocity with reflection data. The fundamental solution to these two issues is to acquire better data with an improved acquisition system. In this work, we propose two types of modified geometries to enhance the penetration depth of the diving waves, especially the first arrivals, which can be used to build a deeper velocity model effectively. Type-I geometry adds extra sparse sources on the extension line of the normal acquisition geometry, whereas Type-II geometry deploys extra sparse receivers on the extension line. Consequently, the new acquisition system includes ultra-large offsets, which acquire diving waves from the deep subsurface. These diving waves, including waveform and first-break time, are particularly useful for recovering deeper velocity, which has paramount significance for the exploration of deep and ultra-deep hydrocarbon reservoirs. Synthetic and field data examples preliminarily demonstrate the feasibility of this improved acquisition system.
Novel Approach to Estimating Glacial Moraine Reserves in the Parlung Tsangpo Basin
Authors: Wang Jiao , Cui Peng , Wang Hao , Zhang Guotao , Zou Qiang , Chen Xiaoqing
Published: April 2022

The Sichuan–Tibet Railway crosses through the largest maritime glacier region in China. A large number of moraines formed after the rapid glacial retreat caused by climate warming. Moraines could induce frequent geological hazards that seriously threatened the safe construction and operation of the railway. Accordingly, moraines in this maritime glacier region have become a new challenging research topic with respect to the formation of geological hazards. Using remote-sensing image interpretations, field investigations, and dating tests, moraines and their topographic information were systematically obtained. After analyzing the geometrical distribution characteristics of the moraine accumulations, the geometrical characteristics of three typical moraine accumulation forms were generalized into corresponding mathematical models. Consequently, a method to quickly and quantitatively estimate the moraine reserves is proposed. The moraine distribution is primarily affected by the elevation, slope, river–valley morphology, and climate conditions. Old moraines that formed in the Pleistocene epoch (the Guxiang and Baiyu glacial periods) are primarily distributed below 3,500 m above sea level, while most of the new moraines that formed in the Holocene epoch (Neoglaciation and Little Ice Age) are primarily distributed above 4,000 m above sea level. Both the new and old moraines are primarily distributed within a slope range of 10–30°. Furthermore, the main river–valley morphology has a significant impact on the distribution of the old moraines, which are primarily distributed in the Zhongba–Guxiang section of the river valley where the longitudinal slope is relatively gentle. The difference in glaciation is the main reason why the new moraines distributed on the south banks in the study area are different from those on the north banks and why those distributed upstream are different from those distributed downstream. In addition, moraines are the main source of glacial debris flows. According to the presented method, the loose moraine reserves can be accurately calculated by analyzing the position, consolidation, and supply capability of the new and old moraines in each debris flow gully. It is anticipated that the presented results can be used to better understand the formation mechanisms of glacier-related hazards and improve risk assessments.
Assimilation of GNSS and Synoptic Data in a Convection Permitting Limited Area Model: Improvement of Simulated Tropospheric Water Vapor Content
Authors: Wagner Andreas , Fersch Benjamin , Yuan Peng , Rummler Thomas , Kunstmann Harald
Published: April 2022

The assimilation of observations in limited area models (LAMs) allows to find the best possible estimate of a region’s meteorological state. Water vapor is a crucial constituent in terms of cloud and precipitation formation. Its highly variable nature in space and time is often insufficiently represented in models. This study investigates the improvement of simulated water vapor content within the Weather Research and Forecasting model (WRF) in every season by assimilating temperature, relative humidity, and surface pressure obtained from climate stations, as well as geodetically derived Zenith Total Delay (ZTD) and precipitable water vapor (PWV) data from global navigation satellite system (GNSS) ground stations. In four case studies we analyze the results of high-resolution convection-resolving WRF simulations (2.1 km) between 2016 and 2018 each in every season for a 650 × 670 km domain in the tri-border-area Germany, France and Switzerland. The impact of 3D VAR assimilation of different variables and combinations thereof, background error option, as well as the temporal and spatial resolution of assimilation is evaluated. Both column values and profiles derived from radiosondes are addressed. Best outcome was achieved when assimilating ZTD and synoptic data at an hourly resolution and a spatial thinning distance of 10 km. It is concluded that the careful selection of assimilation options can additionally improve simulation results in every season. Clear effects of assimilation on the water budgets can also be seen.
Quantitative Evaluation of Coseismic Deformations Induced by Seismogenic Faulting in Mining Exploration Area During the 2018 Xingwen and 2019 Changning Earthquakes, Sichuan, China
Authors: Sun Chunwei , Ling Sixiang , Zhao Siyuan , Wen Hong , Wang Sen
Published: April 2022

In the period between December 2018 and July 2019, a series of earthquakes (EQs), including the 16 December 2018 Ms 5.7 Xingwen mainshock and the 17 June 2019 Ms 6.0 Changning mainshock, struck the Changning shale gas exploration field in the southern margin of the Sichuan Basin. The Xingwen and Changning EQs both occurred on concealed faults, which led to hundreds of casualties, and affected a total of over 160 thousand people in southern Sichuan. The aftershock sequences following the Xingwen and Changning EQs were clustered in the vicinity of the Jianwu syncline and Changning anticline, respectively, and occurred mostly at depths of 3–7 km. In this study, coseismic surface deformation measurements obtained through differential interferometric synthetic aperture radar (D-InSAR) data were used to identify the faulting geometries and distributions. The coseismic deformation maps have maximum line-of-sight (LOS) displacements of ∼4.53 cm on the northwest side of the Xingwen EQ source fault and ∼7.84 cm on the southwest side of the Changning EQ source fault. The calculated static Coulomb stress changes indicated that most aftershocks occurred in increasing stress zones following the mainshock ruptures. From the InSAR deformation field, a complicated concealed seismogenic doublet fault was inferred, which predominately exhibited left-lateral strike-slip motion during the Xingwen and Changning EQs. The footwall ramp of the basement fault reactivated first, and resulted in the Xingwen EQ and concentrating stresses beneath the Changning anticline, which induced the Changning EQ half a year later. Compared with previous studies, we proposed that the fault network was lubricated by water that was injected during shale gas exploration, facilitating the occurrence of the Xingwen and Changning EQs. Such work evaluated the coseismic deformations of the Xingwen and Changning EQs, and derived the regional faulting distribution from aftershock sequences. It could provide useful information for monitoring and analyzing seismic activity around the hinge zones of folds in mining exploration areas, which contributes to effective risk assessment of disasters associated with seismic geo-environments.
Scientific Literacies for Change Making: Equipping the Young to Tackle Current Societal Challenges
Authors: Tasquier Giulia , Knain Erik , Jornet Alfredo
Published: April 2022

Dealing with the threatening challenges and profound changes that characterise our era requires the development of knowledge and skills to navigate the uncertainty and complexity of science as part of society and everyday life. How can we support school students in transforming the base of knowledge and experiences to face the ongoing crises and contribute as individuals, citizens, and active participants in a democratic society to enable the transformation that is called for? We address this broader question through a study framed within the Horizon 2020 project titled Science Education for Action and Engagement toward Sustainability (SEAS), aimed at promoting new forms of scientific literacy and skills to empower students to become agents of change. Most centrally, SEAS aims at incorporating a transformative dimension that is often lacking in current conceptions of scientific literacy. In SEAS, school and school science are conceived as involving learning and transformation across three spheres—the practical, the political, and the personal—where both individuals and their institutional contexts are subject to change as participants gain agency over their learning processes. In this study, we illustrate this approach and present the analysis of a first pilot iteration within the project’s Italian Local Network, which shows the kind of individual/collective dynamic that the project’s transformative activities afford.
Comparison Among Two Liquid Formulations of L-thyroxine in the Treatment of Congenital Hypothyroidism in the First Month of Life: A Pilot Study
Authors: Tuli Gerdi , Munarin Jessica , de Sanctis Luisa
Published: April 2022

The liquid formulation of L-thyroxine is the most used in the substitutive treatment of congenital hypothyroidism (CH). This formulation has higher TSH suppression rates with respect of L-thyroxine tablets and thus lower doses are indicated. Two types of liquid L-thyroxine (Tirosint© and Tifactor©) are currently approved in Italy for use in pediatric age and to date there are no data available in the Literature comparing the two liquid formulations. The aim of this study is to compare the efficacy of both formulations in normalizing TSH and fT4 levels in the first month of life and to compare the L-thyroxine requirement for both formulations over the same period. All newborns diagnosed with primary CH at the neonatal screening program in the Piedmont region of Italy in the period May 2020 – May 2021 were enrolled and divided into two groups according to the liquid formulation used: TS Group with Tirosint© and TF Group with Tifactor©. No difference was observed between the two groups considering the TSH at dried blood spot (DBS) at neonatal screening, the serum levels of TSH, fT4 and fT3 and initial dose of L-thyroxine. At 15 days the serum TSH in the TF Group was 0.08 ± 0.02 mcUI/ml, while in the TS Group it was 36.7 ± 14.7 mcUI/ml p=0.04). No differences were observed between the two groups considering fT4 levels and L-thyroxine requirement. Among the subjects in the TF Group, 5/9 showed suppressed TSH at 15 days after starting treatment, while none of the subjects in the TS Group showed TSH levels below the normal lower limit (p=0.011). Among the subjects in the TF Group, 5/9 patients showed suppressed TSH at 30 days after starting treatment, while 1/12 subjects in the TS Group showed TSH levels below the normal lower limit (p=0.017). In conclusion, this study confirms the efficacy in normalizing the thyroid hormonal profile in newborns with CH among the liquid solutions although the response seem to be different in timing therefore an individual approach is necessary considering the type of formulation used, the diagnostic category of CH and clinical features.
Reduction of Phosphorus Using Electric Arc Furnace Slag Filters in the Macatawa Watershed (Michigan)
Authors: Steinman Alan D. , Hassett Michael , Oudsema Maggie , Penn Chad J.
Published: April 2022

Eutrophication is a major problem in lakes and rivers throughout the world. One such system is Lake Macatawa, located in West Michigan, which hydrologically connects to Lake Michigan. Lake Macatawa and its watershed suffer from excess phosphorus and sediment loads. The total maximum daily load for the lake calls for a total phosphorus (TP) reduction of 75%, which would reduce the water column total phosphorus concentration from 125 μg/L to 50 μg/L. Understanding how P moves through this landscape, into Lake Macatawa, and ultimately to Lake Michigan and the St. Lawrence Seaway, is critical to managing and controlling P runoff. A potentially significant source of P to Lake Macatawa occurs through agricultural tile drainage. Various best management practices (BMPs) have been implemented in the Macatawa watershed to reduce P loading, especially surface runoff, but their overall effectiveness has been limited. Electric arc furnace (EAF) slag, a waste product from the steel industry, can chemically bind P and has been used previously in agricultural settings. Three iron slag filters were installed at the end of agricultural tile lines in the Macatawa watershed and evaluated to assess their effectiveness in removing P, while also monitoring for the presence of potentially toxic chemicals leaching from the slag. After 1 year of slag filter performance, both SRP (soluble reactive phosphorus) and TP decreased in the tile drain effluent: percent reductions of soluble reactive phosphorus and TP ranged from 7.4% to 57.3% and 59.5–76.5%, respectively. Absolute concentrations of TP were reduced to between 100 and 329 μg/L, which still exceeds the 50 μg/L goal for Lake Macatawa. Concentrations of toxic metals, polycyclic aromatic hydrocarbons compounds, and cyanide all were at levels below drinking water standards. Our preliminary conclusions are that the installation of these filters should be targeted to areas where tile drain effluent P levels are very high (SRP > 250 μg/L) to obtain an optimal cost/benefit ratio. While they are not a panacea, when installed in combination with other BMPs (Best Management Practices), EAF slag filters may play an important localized role in reducing P to Lake Macatawa and farther downstream.
Effects of Three Types of Pollen on the Growth and Development of Honey Bee Larvae (Hymenoptera, Apidae)
Authors: Pang Chunxiu , Dong Kun , Guo Yueqin , Ding Guiling , Lu Yuming , Guo Zhanbao , Wu Jie , Huang Jiaxing
Published: April 2022

Pollen serves as an essential protein source for honey bee larvae. The nutrients in pollen greatly influence larval growth and development. Here, the survival, prepupal weight, developmental stage, pollen digestibility and midgut cells in honey bee (Apis mellifera L.) larvae were evaluated by performing in vitro and 5-ethynyl-2′-deoxyuridine (EdU) assays on larvae reared on three single pollens (Brassica napus L., Armeniaca sibirica L., and Pyrus bretschneideri Rehd.) and a pollen mixture (mixture of the three pollens in equal proportions). The results showed that the survival rate of larvae fed 10 mg of rape pollen was lowest (P < 0.05), but there were no notable differences in the survival rate among the groups receiving the other types and doses of pollen (P > 0.05). The prepupal weight of larvae fed apricot pollen was significantly lower than those of the other groups (P < 0.05). The digestibility of rape pollen and the pollen mixture were dramatically higher than those of apricot and pear pollen (P < 0.05). Pear and mixed pollen exerted negative effects on the nuclear area of midgut cells in the early larval stage (P < 0.05). In conclusion, detection of larval midgut cells using the EdU assay might be an effective method to assess the pollen nutritive value in honey bees. Compared to apricot and pear pollen, rape pollen was more beneficial in larval honey bee growth and development.
Fast Learners: One Trial Olfactory Learning in Insects
Authors: Adam Elisabeth , Hansson Bill S. , Knaden Markus
Published: April 2022

Despite their comparatively small brains, insects are able to survive and thrive in their environment. In the past, it was thought that insects are driven mainly by their instincts. However, today it is well established that they possess unique abilities to learn and use their experience in future decisions. Like many higher animals insects are able to acquire and retain information on when and where to forage, which mate to choose, where to lay their eggs and how to navigate in complex habitats. Learning can be surprisingly fast with only one single encounter with a suitable food source or oviposition site shaping an insect's preference for up to a lifetime. In this review, we discuss the scope and limits of insect learning, focusing in specific on olfactory learning, and we raise the question whether currently used learning paradigms in artificial lab set-ups are able to answer all ecologically relevant questions.
Progress in the Study of Non-Coding RNAs in Multidifferentiation Potential of Dental-Derived Mesenchymal Stem Cells
Authors: Zeng Biyun , Huang Junhui
Published: April 2022

For decades, the desire for tissue regeneration has never been quenched. Dental-derived mesenchymal stem cells (DMSCs), with the potential of self-renewal and multi-directional differentiation, have attracted much attention in this topic. Growing evidence suggests that non-coding RNAs (ncRNAs) can activate various regulatory processes. Even with a slight decrease or increase in expression, ncRNAs can weaken or even subvert cellular fate. Therefore, a systematic interpretation of ncRNAs that guide the differentiation of DMSCs into cells of other tissue types is urgently needed. In this review, we introduce the roles of ncRNAs in the differentiation of DMSCs, such as osteogenic differentiation, odontogenic differentiation, neurogenic differentiation, angiogenic differentiation and myogenic differentiation. Additionally, we illustrate the regulatory mechanisms of ncRNAs in the differentiation of DMSCs, such as epigenetic regulation, transcriptional regulation, mRNA modulation, miRNA sponges and signalling. Finally, we summarize the types and mechanisms of ncRNAs in the differentiation of DMSCs, such as let-7 family, miR-17∼92 family, miR-21, lncRNA H19, lncRNA ANCR, lncRNA MEG3, circRNA CDR1as and CircRNA SIPA1L1. If revealing the intricate relationship between ncRNAs and pluripotency of DMSCs 1 day, the application of DMSCs in regenerative medicine and tissue engineering will be improved. Our work could be an important stepping stone towards this future.
Construction and Validation of a Necroptosis-Related Signature Associated With the Immune Microenvironment in Liver Hepatocellular Carcinoma
Authors: Wang Gongjun , Ding Baoning , Sun Libin , Guo Jing , Wang Shasha , Li Wenqian , Zhang Yuqi , Lv Jing , Qiu Wensheng
Published: April 2022

Background: Liver hepatocellular carcinoma (LIHC) is a widespread and often deadly neoplasm. There is increasing evidence that necroptosis mediates numerous tumor-associated behaviors, as well as the regulation of the tumor microenvironment, suggesting its use as a biomarker for tumor prognosis.

Methods: Data on mRNA expression and necroptosis regulators were acquired from the TCGA and KEGG databases, respectively. Clinical liver hepatocellular carcinoma (LIHC) patient data and information on the expression of necroptosis regulators were processed by unsupervised cluster analysis was performed on LIHC patients together with necroptotic regulator expression and, differentially expressed necroptosis-related genes (DENRGs) were identified by comparing the two clusters. A signature based on eight DENRGs was constructed and verified through independent data sets, and its relationship with the tumor microenvironment was investigated.

Results: Unsupervised cluster analysis demonstrated inherent immune differences among LIHC patients. In all, 1,516 DENRGs were obtained by comparison between the two clusters. In the training set, the final eight genes obtained by univariate, LASSO, and multivariate Cox regression were utilized for constructing the signature. The survival and receiver operating characteristic (ROC) curve achieved satisfactory results in both sets. The high-risk group was characterized by greater immune infiltration and poor prognosis. The results of survival analysis based on the expression of eight DENRGs further confirmed the signature.

Conclusion: We established and validated a risk signature based on eight DERNGs related to the tumor microenvironment. This provides a possible explanation for the different clinical effects of immunotherapy and provides a novel perspective for predicting tumor prognosis in LIHC.
Simulations to Assess the Performance of Multifactor Risk Scores for Predicting Myopia Prevalence in Children and Adolescents in China
Authors: Wang Hong , Li Liansheng , Wang Wencan , Wang Hao , Zhuang Youyuan , Lu Xiaoyan , Zhang Guosi , Wang Siyu , Lin Peng , Chen Chong , Bai Yu , Chen Qi , Chen Hao , Qu Jia , Xu Liangde
Published: April 2022

Background: Myopia is the most common visual impairment among Chinese children and adolescents. The purpose of this study is to explore key interventions for myopia prevalence, especially for early-onset myopia and high myopia.

Methods: Univariate and multivariate analyses were conducted to evaluate potential associations between risk factor exposure and myopia. LASSO was performed to prioritize the risk features, and the selected leading factors were used to establish the assembled simulation model. Finally, two forecasting models were constructed to predict the risk of myopia and high myopia.

Results: Children and adolescents with persistently incorrect posture had a high risk of myopia (OR 7.205, 95% CI 5.999–8.652), which was 2.8 times higher than that in students who always maintained correct posture. In the cohort with high myopia, sleep time of less than 7 h per day (OR 9.789, 95% CI 6.865–13.958), incorrect sitting posture (OR 8.975, 95% CI 5.339–15.086), and siblings with spherical equivalent <−6.00 D (OR 8.439, 95% CI 5.420–13.142) were the top three risk factors. The AUCs of integrated simulation models for myopia and high myopia were 0.8716 and 0.8191, respectively.

Conclusion: The findings illustrate that keeping incorrect posture is the leading risk factor for myopia onset, while the onset age of myopia is the primary factor affecting high myopia progression. The age between 8 and 12 years is the crucial stage for clinical intervention, especially for children with parental myopia.
Microbiomics: The Next Pillar of Precision Medicine and Its Role in African Healthcare
Authors: Nkera-Gutabara C. K. , Kerr R. , Scholefield J. , Hazelhurst S. , Naidoo J.
Published: April 2022

Limited access to technologies that support early monitoring of disease risk and a poor understanding of the geographically unique biological and environmental factors underlying disease, represent significant barriers to improved health outcomes and precision medicine efforts in low to middle income countries. These challenges are further compounded by the rich genetic diversity harboured within Southern Africa thus necessitating alternative strategies for the prediction of disease risk and clinical outcomes in regions where accessibility to personalized healthcare remains limited. The human microbiome refers to the community of microorganisms (bacteria, archaea, fungi and viruses) that co-inhabit the human body. Perturbation of the natural balance of the gut microbiome has been associated with a number of human pathologies, and the microbiome has recently emerged as a critical determinant of drug pharmacokinetics and immunomodulation. The human microbiome should therefore not be omitted from any comprehensive effort towards stratified healthcare and would provide an invaluable and orthogonal approach to existing precision medicine strategies. Recent studies have highlighted the overarching effect of geography on gut microbial diversity as it relates to human health. Health insights from international microbiome datasets are however not yet verified in context of the vast geographical diversity that exists throughout the African continent. In this commentary we discuss microbiome research in Africa and its role in future precision medicine initiatives across the African continent.
Construction of lncRNA-Mediated Competing Endogenous RNA Networks Correlated With T2 Asthma
Authors: Wang Zihan , Zhang Jintao , Feng Tao , Zhang Dong , Pan Yun , Liu Xiaofei , Xu Jiawei , Qiao Xinrui , Cui Wenjing , Dong Liang
Published: April 2022

Background: Precise classification has been reported as a central challenge in the clinical research on diagnosis and prediction of treatment efficacy in asthma. In this study, the aim was to investigate the underlying competing endogenous RNA network mechanism of asthma, especially T2 asthma, as well as to find more diagnostic biomarkers and effective therapeutic targets.

Methods: Multiple sets of T2 asthma airway biopsy transcription profiles were collected, which involved long non-coding RNA (lncRNA), mRNA, and microRNA (miRNA). DIANA-LncBase, targetscan, mirwalk, and miRDB databases were employed to predict interactions between lncRNAs, miRNAs and target mRNAs. To identify mRNAs correlated with T2 asthma, differential expression and network analyses were conducted through weighted gene co-expression network analysis (WGCNA). Subsequently, the expressions of potential biomarkers were examined through qRT-PCR analysis in the T2 asthma coreinteracting cellular factor (IL-13/IL-33) induced experimental model. Lastly, the ceRNA network was confirmed by plasmid transfection and RNAi experiments in a 16HBE cell line.

Results: 30 lncRNAs, 22 miRNAs and 202 mRNAs were differentially expressed in airway biopsies from T2 asthma patients. As indicated by the ROC analysis, the lncRNA, PCAT19, had high diagnostic accuracy (AUC >0.9) in distinguishing T2 asthma patients from non-T2 asthma patients and healthy controls. Furthermore, a competing ceRNA network was established, consisting of 13 lncRNAs, 12 miRNAs, as well as eight mRNAs. The reliability of this network was verified by testing several representative interactions in the network.

Conclusion: To the best of our knowledge, this study has been the first to establish an lncRNA-mediated ceRNA regulatory network for studying T2 asthma. The findings of this study may elucidate the pathogenesis and help find potential therapeutic targets for T2 asthma. In T2 asthma, PCAT19-dominated ceRNA regulation networks may play a critical role, and PCAT19 may serve as a potential immune-related biomarker for asthma and other respiratory diseases correlated with eosinophilic inflammation.
Identification of Selection Signals on the X-Chromosome in East Adriatic Sheep: A New Complementary Approach
Authors: Shihabi Mario , Lukic Boris , Cubric-Curik Vlatka , Brajkovic Vladimir , Oršanić Milan , Ugarković Damir , Vostry Luboš , Curik Ino
Published: April 2022

Sheep are one of the most important livestock species in Croatia, found mainly in the Mediterranean coastal and mountainous regions along the East Adriatic coast, well adapted to the environment and mostly kept extensively. Our main objective was therefore to map the positive selection of the X-chromosome (18,983 SNPs that passed quality control), since nothing is known about the adaptation genes on this chromosome for any of the breeds from the Balkan cluster. Analyses were performed on a sample of eight native Croatian breeds (101 females and 100 males) representing the East Adriatic metapopulation and on 10 mouflons (five females and males), all sampled in Croatia. Three classical within-population approaches (extreme Runs of Homozygosity islands, integrated Haplotype Score, and number of Segregating Sites by Length) were applied along with our new approach called Haplotype Richness Drop (HRiD), which uses only the information contained in male haplotypes. We have also shown that phylogenetic analyses, such as the Median-joining network, can provide additional information when performed with the selection signals identified by HRiD. Our new approach identifies positive selection signals by searching for genomic regions that exhibit a sudden decline in haplotype richness. In total, we identified 14 positive selection signals, 11 using the classical approach and three using the HRiD approach, all together containing 34 annotated genes. The most reliable selection signal was mapped by all four approaches in the same region, overlapping between 13.17 and 13.60 Mb, and assigned to the CA5B, ZRSR2, AP1S2, and GRPR genes. High repeatability (86%) of results was observed, as 12 identified selection signals were also confirmed in other studies with sheep. HRiD offers an interesting possibility to be used complementary to other approaches or when only males are genotyped, which is often the case in genomic breeding value estimations. These results highlight the importance of the X-chromosome in the adaptive architecture of domestic ruminants, while our novel HRiD approach opens new possibilities for research.
Pyroptosis-Related Signature Predicts Prognosis and Immunotherapy Efficacy in Muscle-Invasive Bladder Cancer
Authors: Zhang Qi , Tan Yezhen , Zhang Jianye , Shi Yue , Qi Jie , Zou Daojia , Ci Weimin
Published: April 2022

Pyroptosis has profound impacts on tumor cell proliferation, invasion, and metastasis and is of great clinical significance for different cancers. However, the role of pyroptosis in the progression and prognosis of muscle invasive bladder cancer (MIBC) remains poorly characterized. Here, we collected multicenter MIBC data and performed integrated analysis to dissect the role of pyroptosis in MIBC and provide an optimized treatment for this disease. Based on transcriptomic data, we developed a novel prognostic model named the pyroptosis-related gene score (PRGScore), which summarizes immunological features, genomic alterations, and clinical characteristics associated with the pyroptosis phenotype. Samples with high PRGScore showed enhancement in CD8+ T cell effector function, antigen processing machinery and immune checkpoint and better response to immunotherapy by programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, which indicates that PRGScore is a valuable signature in the identification of populations sensitive to immune checkpoint inhibitors. Collectively, our study provides insights into further research targeting pyroptosis and its tumor immune microenvironment (TME) and offers an opportunity to optimize the treatment of MIBC.
CpG-Activated Regulatory B-Cell Progenitors Alleviate Murine Graft-Versus-Host-Disease
Authors: Agbogan Viviane A. , Gastineau Pauline , Tejerina Emmanuel , Karray Saoussen , Zavala Flora
Published: April 2022

Development of Graft Versus Host Disease (GVHD) represents a major impediment in allogeneic hematopoietic stem cell transplantation (HSCT). The observation that the presence of bone marrow and circulating hematogones correlated with reduced GVHD risks prompted us to evaluate whether B-cell progenitors, which provide protection in various autoimmune disease models following activation with the TLR-9 agonist CpG (CpG-proBs), could likewise reduce this allogeneic disorder. In a murine model of GVHD that recapitulates an initial phase of acute GVHD followed by a phase of chronic sclerodermatous GVHD, we found that CpG-proBs, adoptively transferred during the initial phase of disease, reduced the diarrhea score and mostly prevented cutaneous fibrosis. Progenitors migrated to the draining lymph nodes and to the skin where they mainly differentiated into follicular B cells. CpG activation and IFN-γ expression were required for the protective effect, which resulted in reduced CD4+ T-cell-derived production of critical cytokines such as TGF-β, IL-13 and IL-21. Adoptive transfer of CpG-proBs increased the T follicular regulatory to T follicular helper (Tfr/Tfh) ratio. Moreover, CpG-proBs privileged the accumulation of IL-10-positive CD8+ T cells, B cells and dendritic cells in the skin. However, CpG-proBs did not improve survival. Altogether, our findings support the notion that adoptively transferred CpG-proBs exert immunomodulating effect that alleviates symptoms of GVHD but require additional anti-inflammatory strategy to improve survival.
Crosstalk Between Metabolism and Immune Activity Reveals Four Subtypes With Therapeutic Implications in Clear Cell Renal Cell Carcinoma
Authors: Wang Yi , Zheng Xin-De , Zhu Gui-Qi , Li Na , Zhou Chang-Wu , Yang Chun , Zeng Meng-Su
Published: April 2022

Clear cell renal cell carcinoma (ccRCC) is characterized by metabolic dysregulation and distinct immunological signatures. The interplay between metabolic and immune processes in the tumor microenvironment (TME) causes the complexity and heterogeneity of immunotherapy responses observed during ccRCC treatment. Herein, we initially identified two distinct metabolic subtypes (C1 and C2 subtypes) and immune subtypes (I1 and I2 subtypes) based on the occurrence of differentially expressed metabolism-related prognostic genes and immune-related components. Notably, we observed that immune regulators with upregulated expression actively participated in multiple metabolic pathways. Therefore, we further delineated four immunometabolism-based ccRCC subtypes (M1, M2, M3, and M4 subtypes) according to the results of the above classification. Generally, we found that high metabolic activity could suppress immune infiltration. Immunometabolism subtype classification was associated with immunotherapy response, with patients possessing the immune-inflamed, metabolic-desert subtype (M3 subtype) that benefits the most from immunotherapy. Moreover, differences in the shifts in the immunometabolism subtype after immunotherapy were observed in the responder and non-responder groups, with patients from the responder group transferring to subtypes with immune-inflamed characteristics and less active metabolic activity (M3 or M4 subtype). Immunometabolism subtypes could also serve as biomarkers for predicting immunotherapy response. To decipher the genomic and epigenomic features of the four subtypes, we analyzed multiomics data, including miRNA expression, DNA methylation status, copy number variations occurrence, and somatic mutation profiles. Patients with the M2 subtype possessed the highest VHL gene mutation rates and were more likely to be sensitive to sunitinib therapy. Moreover, we developed non-invasive radiomic models to reveal the status of immune activity and metabolism. In addition, we constructed a radiomic prognostic score (PRS) for predicting ccRCC survival based on the seven radiomic features. PRS was further demonstrated to be closely linked to immunometabolism subtype classification, immune score, and tumor mutation burden. The prognostic value of the PRS and the association of the PRS with immune activity and metabolism were validated in our cohort. Overall, our study established four immunometabolism subtypes, thereby revealing the crosstalk between immune and metabolic activities and providing new insights into personal therapy selection.
Case Report: A Highly Variable Clinical and Immunological Presentation of IKAROS Deficiency in a Single Family
Authors: Kuijpers Taco W. , Tromp Samantha A. M. , van Leeuwen Ester M. M. , de Bree Godelieve J.
Published: April 2022

Here we describe a novel mutation in the IKZF gene encoding IKAROS, as the cause of common variable immunodeficiency (CVID). The identification of the same defect in the IKZF gene with manifestations of asymptomatic selective IgA deficiency and chronic ITP in the father and her younger brother, respectively, demonstrates the large variability of this genetic defect in one single family, while living in the same environment with a relatively similar genetic background. As discussed, clinical penetrance of the molecular defects identified by mutations in IKZF and other common gene defects in CVID in familial immune-related abnormalities makes genetic testing a necessary step for diagnosis, management, and counseling, as part of the routine immunological workup.
Extracellular cAMP-Adenosine Pathway Signaling: A Potential Therapeutic Target in Chronic Inflammatory Airway Diseases
Authors: Pacini Enio Setsuo Arakaki , Satori Naiara Ayako , Jackson Edwin Kerry , Godinho Rosely Oliveira
Published: April 2022

Adenosine is a purine nucleoside that,viaactivation of distinct G protein-coupled receptors, modulates inflammation and immune responses. Under pathological conditions and in response to inflammatory stimuli, extracellular ATP is released from damaged cells and is metabolized to extracellular adenosine. However, studies over the past 30 years provide strong evidence for another source of extracellular adenosine, namely the “cAMP-adenosine pathway.” The cAMP-adenosine pathway is a biochemical mechanism mediated by ATP-binding cassette transporters that facilitate cAMP efflux and by specific ectoenzymes that convert cAMP to AMP (ecto-PDEs) and AMP to adenosine (ecto-nucleotidases such as CD73). Importantly, the cAMP-adenosine pathway is operative in many cell types, including those of the airways. In airways, β2-adrenoceptor agonists, which are used as bronchodilators for treatment of asthma and chronic respiratory diseases, stimulate cAMP efflux and thus trigger the extracellular cAMP-adenosine pathway leading to increased concentrations of extracellular adenosine in airways. In the airways, extracellular adenosine exerts pro-inflammatory effects and induces bronchoconstriction in patients with asthma and chronic obstructive pulmonary diseases. These considerations lead to the hypothesis that the cAMP-adenosine pathway attenuates the efficacy of β2-adrenoceptor agonists. Indeed, our recent findings support this view. In this mini-review, we will highlight the potential role of the extracellular cAMP-adenosine pathway in chronic respiratory inflammatory disorders, and we will explore how extracellular cAMP could interfere with the regulatory effects of intracellular cAMP on airway smooth muscle and innate immune cell function. Finally, we will discuss therapeutic possibilities targeting the extracellular cAMP-adenosine pathway for treatment of these respiratory diseases.
Inhibitors of PD-1 in Non-Small Cell Lung Cancer: A Meta-Analysis of Clinical and Molecular Features
Authors: Huo Gengwei , Liu Wenjie , Chen Peng
Published: April 2022

Objective

PD-1 inhibitors have become an indispensable treatment in Non-Small Cell Lung Cancer (NSCLC), but the potential predictive value of clinical and molecular features need to be clarified. The objective of the study was to study the potency of PD-1 inhibitors in patients with NSCLC in contexts of both clinical and molecular features, and to aid identification of patients for choice of type of PD-1 inhibitor therapy in order to acquire more accurate NSCLC treatment in immunotherapy.

Method

PubMed, Google Scholar, Embase Science Direct, the Cochrane library, and major oncology conferences were searched for randomized clinical trials (RCTs) that were published prior to December 2021. RCTs that had PD-1 inhibitor alone or in combination with chemotherapy with non-PD-1 inhibitor for the treatment of NSCLC patients were selected. Two authors independently selected studies, data extraction and bias risk assessment. Basic characteristics of included studies, and also the 95% confidence interval and hazard ratios of the overall patients and subgroups were recorded. The inverse variance weighted method was used to estimate pooled treatment data.

Result

A total of eleven RCTs including 5,887 patients were involved. PD-1 inhibitors-based therapy substantially enhanced OS compared with non-PD-1 inhibitor therapy in patients with age group <65 years, 65–74 years, active or previous smokers, without brain metastases, liver metastases, EGFR wild-type patients, individuals in East Asia and U.S./Canada, but not in patients with age group ≥75 years, never smokers, brain metastases, EGFR mutant patients or individuals in Europe. OS was improved in patients with NSCLC who received PD-1 inhibitors regardless of their gender (male or female), histomorphological subtypes (squamous or non-squamous NSCLC), performance status (0 or 1), and PD-L1 tumor proportion score (TPS) (<1%, ≥1%, 1–49%, or ≥50%). An analysis of subgroups revealed that, patients with age group <65 years old, male, non squamous cell carcinoma, PS 1, TPS ≥1%, and TPS ≥50% benefited from pembrolizumab treatment not related with treatment line and treatment regimen.

Conclusion

Age group, smoking history, metastasis status/site, EGFR mutation status, and region can be used to predict the potency of PD-1 inhibitors, and to be individualized to choose different types of PD-1 inhibitors, and treatment regimen for NSCLC patients.
Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity
Authors: Koppensteiner Lilian , Mathieson Layla , O’Connor Richard A. , Akram Ahsan R.
Published: April 2022

The presence of functionally efficient cytotoxic T lymphocytes (CTL) in the Tumour nest is crucial in mediating a successful immune response to cancer. The detection and elimination of cancer cells by CTL can be impaired by cancer-mediated immune evasion. In recent years, it has become increasingly clear that not only neoplastic cells themselves, but also cells of the tumour microenvironment (TME) exert immunosuppressive functions and thereby play an integral part in the immune escape of cancer. The most abundant stromal cells of the TME, cancer associated fibroblasts (CAFs), promote tumour progression via multiple pathways and play a role in dampening the immune response to cancer. Recent research indicates that T cells react to CAF signalling and establish bidirectional crosstalk that plays a significant role in the tumour immune response. This review discusses the various mechanisms by which the CAF/T cell crosstalk may impede anti-cancer immunity.
Quorum Quenching Bacteria Bacillus velezensis DH82 on Biological Control of Vibrio parahaemolyticus for Sustainable Aquaculture of Litopenaeus vannamei
Authors: Sun Xiaohui , Liu Jia , Deng Shijing , Li Renhe , Lv Wenhua , Zhou Shufeng , Tang Xu , Sun Yun-zhang , Ke Mingyue , Wang Kunming
Published: April 2022

Aquatic pathogens such as Vibrio parahaemolyticus cause a bacterial infection that reduces the economic benefits of aquaculture and affects the food quality and safety of human beings. Quorum quenching (QQ) is considered a novel strategy of microbial antagonism that inhibits pathogens and reduces the abuse of antibiotics. This study investigates a QQ bacterial strain, Bacillus velezensis DH82 from the deep sea Yap trench, in vitro to examine the effects of DH82 and its functional products against V. parahaemolyticus, focusing on the Quorum sensing (QS) regulation and the inhibition of pathogenicity and bacterial growth. The study also conducted in vivo investigation in the aquaculture of Litopenaeus vannamei challenged with V. parahaemolyticus by immersion and injection challenge. The results of the QS regulator transcription level demonstrated the multiple QQ enzymes in DH82 regulated the pathogenicity but could not fully control the biofilm formation; the effective antibacterial activity of extracellular peptides on microbial antagonism verified the inhibition on bacterial growth of V. parahaemolyticus. The in vivo experiment in aquaria demonstrated the effective enrichment of DH82 and inhibition of Vibrio in both the aquatic system and the shrimp intestine. The dietary DH82 relieved the negative effect of Vibrio on the activity of enzyme acid phosphatase (ACP), alkaline phosphatase (AKP), superoxide dismutase (SOD) under challenge of Vibrio pathogens, and was not harmful to host according to lysozyme (LZM) activity. DH82 also ameliorated the damage to the intestine and muscles induced by V. parahaemolyticus infection according to tissue imaging. Though DH82 did present some dose-dependent adverse effects to the host, the findings revealed the effective QQ and antibacterial activity of DH82 on emerging biocontrol against V. parahaemolyticus, therefore indicating the potential application of DH82 as a biological control reagent in the sustainable and green production of aquaculture.
Reproductive Biology of Female Pacific Halibut (Hippoglossus stenolepis) in the Gulf of Alaska
Authors: Fish Teresa , Wolf Nathan , Smeltz Timothy Scott , Harris Bradley P. , Planas Josep V.
Published: April 2022

Developing a robust understanding of Pacific halibut reproductive biology is essential to understanding the different components (e.g. maturity) that determine the reproductive output of the species and, therefore, for estimating the relative female spawning biomass. With these, effective and proactive management strategies can be designed and implemented to face the large-scale environmental changes to which high-latitude spawning fish are particularly vulnerable. To date, reproductive studies of Pacific halibut have mainly focused on population or regional scales, leaving the specific details of organism-level reproductive development unexamined. The work described here aimed to address information gaps in Pacific halibut reproductive biology by conducting a detailed histological examination of temporal changes in ovarian development over an annual reproductive cycle with special attention to the use of biological indicators (e.g. oocyte diameter, gonadosomatic index, hepatosomatic index, Fulton’s condition factor, somatic fat) in characterizing female developmental stages and reproductive phases. Our results provide a foundation for future studies directed at improving current maturity estimations by histological assessment and explore models that test the utility of biological indicators to predict maturity in this important fish species.