bluuebunny/crossref_metadata_2025 huggingface dataset:
The Pivotal Role of Chemical Modifications in mRNA Therapeutics
Authors: Liu Albert , Wang Xiao
Published: July 2022

After over a decade of development, mRNA has recently matured into a potent modality for therapeutics. The advantages of mRNA therapeutics, including their rapid development and scalability, have been highlighted due to the SARS-CoV-2 pandemic, in which the first two clinically approved mRNA vaccines have been spotlighted. These vaccines, as well as multiple other mRNA therapeutic candidates, are modified to modulate their immunogenicity, stability, and translational efficiency. Despite the importance of mRNA modifications for harnessing the full efficacy of mRNA drugs, the full breadth of potential modifications has yet to be explored clinically. In this review, we survey the field of mRNA modifications, highlighting their ability to tune the properties of mRNAs. These include cap and tail modifications, nucleoside substitutions, and chimeric mRNAs, each of which represents a component of mRNA that can be exploited for modification. Additionally, we cover clinical and preclinical trials of the modified mRNA platform not only to illustrate the promise of modified mRNAs but also to call attention to the room for diversifying future therapeutics.
Chromatin and the Cellular Response to Particle Radiation-Induced Oxidative and Clustered DNA Damage
Authors: Danforth John M. , Provencher Luc , Goodarzi Aaron A.
Published: July 2022

Exposure to environmental ionizing radiation is prevalent, with greatest lifetime doses typically from high Linear Energy Transfer (high-LET) alpha particles via the radioactive decay of radon gas in indoor air. Particle radiation is highly genotoxic, inducing DNA damage including oxidative base lesions and DNA double strand breaks. Due to the ionization density of high-LET radiation, the consequent damage is highly clustered wherein ≥2 distinct DNA lesions occur within 1–2 helical turns of one another. These multiply-damaged sites are difficult for eukaryotic cells to resolve either quickly or accurately, resulting in the persistence of DNA damage and/or the accumulation of mutations at a greater rate per absorbed dose, relative to lower LET radiation types. The proximity of the same and different types of DNA lesions to one another is challenging for DNA repair processes, with diverse pathways often confounding or interplaying with one another in complex ways. In this context, understanding the state of the higher order chromatin compaction and arrangements is essential, as it influences the density of damage produced by high-LET radiation and regulates the recruitment and activity of DNA repair factors. This review will summarize the latest research exploring the processes by which clustered DNA damage sites are induced, detected, and repaired in the context of chromatin.
Potential Opportunities and Challenges of Deploying Next Generation Sequencing and CRISPR-Cas Systems to Support Diagnostics and Surveillance Towards Malaria Control and Elimination in Africa
Authors: Lyimo Beatus M. , Popkin-Hall Zachary R. , Giesbrecht David J. , Mandara Celine I. , Madebe Rashid A. , Bakari Catherine , Pereus Dativa , Seth Misago D. , Ngamba Ramadhan M. , Mbwambo Ruth B. , MacInnis Bronwyn , Mbwambo Daniel , Garimo Issa , Chacky Frank , Aaron Sijenunu , Lusasi Abdallah , Molteni Fabrizio , Njau Ritha , Cunningham Jane A. , Lazaro Samwel , Mohamed Ally , Juliano Jonathan J. , Bailey Jeffrey A.  , Ishengoma Deus S.
Published: July 2022

Recent developments in molecular biology and genomics have revolutionized biology and medicine mainly in the developed world. The application of next generation sequencing (NGS) and CRISPR-Cas tools is now poised to support endemic countries in the detection, monitoring and control of endemic diseases and future epidemics, as well as with emerging and re-emerging pathogens. Most low and middle income countries (LMICs) with the highest burden of infectious diseases still largely lack the capacity to generate and perform bioinformatic analysis of genomic data. These countries have also not deployed tools based on CRISPR-Cas technologies. For LMICs including Tanzania, it is critical to focus not only on the process of generation and analysis of data generated using such tools, but also on the utilization of the findings for policy and decision making. Here we discuss the promise and challenges of NGS and CRISPR-Cas in the context of malaria as Africa moves towards malaria elimination. These innovative tools are urgently needed to strengthen the current diagnostic and surveillance systems. We discuss ongoing efforts to deploy these tools for malaria detection and molecular surveillance highlighting potential opportunities presented by these innovative technologies as well as challenges in adopting them. Their deployment will also offer an opportunity to broadly build in-country capacity in pathogen genomics and bioinformatics, and to effectively engage with multiple stakeholders as well as policy makers, overcoming current workforce and infrastructure challenges. Overall, these ongoing initiatives will build the malaria molecular surveillance capacity of African researchers and their institutions, and allow them to generate genomics data and perform bioinformatics analysis in-country in order to provide critical information that will be used for real-time policy and decision-making to support malaria elimination on the continent.
Small Cell (Neuroendocrine) Carcinoma of the Cervix: An Analysis for 19 Cases and Literature Review
Authors: Lu JunLing , Li Ya , Wang Jun
Published: July 2022

Cervical SCNEC is a rare and highly malignant invasive tumor. The incidence is low, at less than 5% of all cervical cancers. Moreover, most patients with small cell carcinoma are interrelated with high risk HPV (more familiar HPV 18). Compared to squamous cell carcinoma or adenocarcinoma, patients of cevical SCNEC are more prone to lymph node invasion early, so the clinical manifestation is usually local or distant metastasis. We summarized the clinical features of 19 patients with cervical small cell carcinoma in the Second Affiliated Hospital of Dalian Medical University from 2012 to 2021, and retrospectively analyzed data from 1576 patients in 20 related studies and more than 50 pieces of literature in recent years by searching PubMed, Google schalor, Cochrane Library, Clinicalkey, and other databases. The collected patient data included age, clinical manifestation, TCT, HPV detection, the size and morphology of the tumor, local invasion depth, stage, lymph node status, initial treatment method, tumor-free survival, and so on. The positive rates of CGA, SYN, and CD56 in our cases were high, and NSE was a moderately sensitive index. P16 and Ki67 were the most sensitive, and all patients were positive. We found that multimodal treatment can indeed improve tumor-free survival (DFS), but the prognosis of patients is still very poor. For the early stages, our treatment principles refer to the guidelines of SGO, international gynecological cancer Cooperation (GCIG), and NCCN. We suggest a combination of surgery, radiotherapy, and chemotherapy. However, the general state of advanced patients is poor, whether they can tolerate the operation after neoadjuvant chemotherapy, whether the operation area can remain tumor-free, and whether this treatment will prolong the survival time of patients still need to be further discussed. In order to better prolong the tumor-free survival and prognosis of patients, we need to find gene changes suitable for targeted therapy, so as to complete the clinical application of these treatment methods. Further works are needed to explore more effective therapy for cervical SCNEC.
Dishing up Distinction: Language Materiality and Multimodal Coherence in Elite Foodways
Authors: Thurlow Crispin , Haudenschild Noëlle
Published: July 2022

This paper arises as part of a discourse-focused commodity chain analysis of elite foodways in the international airline industry. At the center of this critical intervention sits the business class airline meal as an epitomic manifestation of contemporary class privilege. As both a fraught social hieroglyphic and a complex semiotic assemblage, “premium” airline dining is articulated across different sites and through a range of different communicative practices and modes. With this in mind, we examine the language materiality of plateware (crockery), flatware (cutlery), glassware, and other tableware used for staging and promoting airline meal services. The specific object of our analysis is the transmodal interplay between words and things which helps generate both the cohesion and coherence of meals. This kind of textual unity and “inter-semiotic harmony” is key for the performative production of order which is, in turn, central to the classist production of distinction and (elite) status.
Case Report: A Huge Calabash Heart: A Rare Case of Supracardiac Total Anomalous Pulmonary Venous Return
Authors: Tang Jianjun , Wu Zhihong , He Jia , Hu Qingdan , Yao Jun , Hu Lin , Zhou Shenghua , Chen Mingxian
Published: July 2022

A 46-year-old woman was admitted to the cardiovascular department because of a 3-month history of palpitations and exertional dyspnea. She had a history of a successful pregnancy at a very young age. The chest radiograph presented a “calabash” configuration. Echocardiogram discovered a large atrial septal defect with a suspected pulmonary vein abnormality. Cardiac CT revealed supracardiac total anomalous pulmonary venous return, whereby, all the pulmonary veins drain into a vertical vein and, finally, to the superior vena cava. Cardiac catheterization was consistent with anomalous pulmonary venous drainage without pulmonary hypertension. Finally, she underwent a successful surgical repair and appeared asymptomatic before her discharge.
Coexistence of Adjacent Siliciclastic, Carbonate, and Mixed Sedimentary Systems: An Example From Seafloor Morphology in the Northern Lesser Antilles Forearc
Authors: Morena Pierre , Ratzov Gueorgui , Cattaneo Antonio , Klingelhoefer Frauke , Beck Christian , Seibert Chloé , Marcaillou Boris , Feuillet Nathalie
Published: July 2022

Three main types of factors commonly control the nature of the clasts, the arrangement of the distinctive lithologies, and the general architecture of turbidite systems: sedimentation rate and carbonate production; climates and glacio-eustatism; and morphology and tectonics. The coexistence of adjacent systems of distinctive nature is, however, scarcely documented, and the relative influence of each factor needs better constrain. In the Northern Lesser Antilles Segment (NLAS), carbonate and siliciclastic sediment sources coexist within a 150 km lateral distance, with carbonate platforms lying onto a volcanic substratum, and by a succession of spurs and triangular valleys that are bounded by active normal faulting. To better understand the factors controlling sedimentary processes from the carbonate platform sources to the deep-sea sinks, we used backscatter, bathymetry, multichannel seismic, and sub-bottom profiles. Sedimentary systems are dominated by siliciclastic input (by retrogressive erosion of confined canyons affecting the volcanic slope), carbonate input (by carbonate sediment transported by oceanic- and wind-driven submarine currents beyond the leeward edges of carbonates platforms), or both. In the mixed systems, the retrogressive erosion of the canyon head determines the nature of the source (volcanic on the slope, carbonate when the canyons reach the shelf edge). Glacio-eustatism has a key role in carbonate availability on the platform, as attested by the presence of drowned platforms. The main contribution of this study is the identification of the major role that tectonic activity plays in the short-distance coexistence of the distinctive sedimentary systems since fault-bounded V-shaped valleys in map view offer alternating leeward and windward edges favoring carbonate or mixed systems. Additionally, the steep slope gradient induced by normal faults and regional subsidence seems to be the main factor controlling sediment dispersal. It causes multiple line sources and the dispersion of gravity-driven currents under the effect of hydraulic jumps, thus preventing the formation of a channelized system. Our study provides a modern analog of adjacent systems dominated by distinctive lithologies in a tectonically active area. The results appear particularly appropriate to decipher the nature of ancient source-to-sink systems dominated by complex tectonics, paleo-bathymetry, and sediment routings.
Leading in Entrepreneurial Universities: Do Demographics Display Different Commitments?
Authors: Fatimah Fatimah , Sarbaini Sarbaini , Arisanty Deasy
Published: July 2022

For the excellence of universities as instructional institutions, lecturers' dedication has been extensively acknowledged as a productive trajectory. Since public university in Indonesia remains the most influential place leading to the growth of a nation, it needs dedicated lecturers as strategic partners. This study analyzes the contemporary dedication of lecturers by looking at affective, continuance, or normative dimensions and assesses whether or not there is any major variance between the chosen demographics over organizational dedication questions. The information had been received from 500 full-time lecturers serving public universities in Indonesia. The findings indicate that most lecturers possess continuance commitment (CC), for they calculate the prices and advantages associated with no longer serving the university. Further, when better options are available, they will leave their universities. From the selected demographic variables examined, only the level of education and length of service significantly affect the commitment of university teachers. This study finds that the lecturers and the universities are engaged in a reciprocal relationship. When lecturers are treated professionally, they respond with more outstanding commitment as they discover them as a necessary section of the organization. Consequently, universities rely on dedicated lecturers to create and sustain a competitive advantage in maintaining world ranking.
Turnover Kinetics of Pancreatic Macrophages in Lean and Obese Diabetic Mice
Authors: Ma Ziyuan , Ruedl Christiane
Published: July 2022

Pancreatic resident macrophages, a heterogeneous family of cells with distinct origins and phenotypes, are the main myeloid cells in exocrine and endocrine tissues. Adult exocrine F4/80hi macrophages consist of three different subsets based on the embryonic marker Tim-4 and MHC II expression. Their frequencies shift during aging and obesity with the Tim-4-MHCII+ fraction becoming the predominant subpopulation in the inter acinar stroma. Endocrine resident F4/80hi macrophages are more homogenous and represent the prevalent leukocyte fraction residing within the islets in both lean and obese mice. We used an adult fate mapping mouse model to characterize turnover kinetics within the pancreatic resident macrophages under normal homeostasis and obese diabetic conditions. We demonstrate that islet resident macrophages show unique replenishment kinetics, with embryonic macrophages being gradually replaced by bone marrow-derived monocytes with increasing age. Their replenishment was independent of the CCL2/CCR2 axis. Furthermore, we confirmed that both exocrine Tim-4+MHCIIlow and Tim-4+MHCII+ fractions are long-lived and primarily independent from bone marrow-derived monocytes. In contrast, exocrine Tim-4-MHCII+ macrophages are gradually replaced through a CCR2-dependent influx of bone marrow-derived monocytes in aging. Moreover, we show that obesity and type 2 diabetes do not affect the turnover kinetics of any macrophage subpopulation residing in the pancreas. Our study uncovers new insights on pancreatic macrophage biology in aging and obesity.
Noninvasive Evaluation of GIP Effects on β-Cell Mass Under High-Fat Diet
Authors: Kiyobayashi Sakura , Murakami Takaaki , Harada Norio , Fujimoto Hiroyuki , Murata Yuki , Fujita Naotaka , Hamamatsu Keita , Ikeguchi-Ogura Eri , Hatoko Tomonobu , Lu Xuejing , Yamane Shunsuke , Inagaki Nobuya
Published: July 2022

Pancreatic β-cell mass (BCM) has an importance in the pathophysiology of diabetes mellitus. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged as a promising tool for BCM evaluation. While glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is known to be involved in high-fat diet (HFD)-induced obesity, the effect of GIP on BCM is still controversial. In this study, we investigated indium 111 (111In)-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) single-photon emission computed tomography/computed tomography (SPECT/CT) as a tool for evaluation of longitudinal BCM changes in HFD-induced obese mice, at the same time we also investigated the effects of GIP on BCM in response to HFD using GIP-knockout (GIP-/-) mice. 111In-exendin-4 SPECT/CT was able to distinguish control-fat diet (CFD)-fed mice from HFD-fed mice and the pancreatic uptake values replicated the BCM measured by conventional histological methods. Furthermore, BCM expansions in HFD-fed mice were demonstrated by time-course changes of the pancreatic uptake values. Additionally, 111In-exendin-4 SPECT/CT demonstrated the distinct changes in BCM between HFD-fed GIP-/- (GIP-/-+HFD) and wild-type (WT+HFD) mice; the pancreatic uptake values of GIP-/-+HFD mice became significantly lower than those of WT+HFD mice. The different changes in the pancreatic uptake values between the two groups preceded those in fat accumulation and insulin resistance. Taken together with the finding of increased β-cell apoptosis in GIP-/-+HFD mice compared with WT+HFD mice, these data indicated that GIP has preferable effects on BCM under HFD. Therefore, 111In-exendin-4 SPECT/CT can be useful for evaluating increasing BCM and the role of GIP in BCM changes under HFD conditions.
Energy Efficient Photovoltaic-Electric Spring for Real and Reactive Power Control in Demand-Side Management
Authors: Kollipara Keerthi Deepika , Vijay Kumar J. , R Prasanthi , Sura Srinivasa Rao , Kumar Patnaik M. S. Pradeep , Ravi Sankar R. S.
Published: July 2022

Photovoltaic-electric spring (PV-ES) is a promising topology to utilize widespread residential roof-top photovoltaic systems in demand-side management. Power control for an integrated configuration of photovoltaic-electric spring system to achieve dynamic supply-demand balance in power distribution networks is presented. Extraction of maximum power from PV panel using Perturb and Observe algorithm along with boost converter are designed. This power is given as input to the DC link of the Electric Spring. The modeling and design of the integrated system are detailed. Extensive simulations are carried out in MATLAB/Simulink to observe the performance of the PV-ES system. The effectiveness of the proposed topology was verified for changes in line voltage, PV irradiation, and reference power. It was confirmed that the proposed PV-ES precisely controls the active power consumption of the critical load, rigidly regulates the voltage at the point of common coupling (PCC), and follows the variations in reference power available for the smart load. Finally, the expansive performance of ES fed with a PV source was confirmed to be superior over an ES system fed with a DC source.
Numerical Analysis of Unsteady Internal Flow Characteristics of Impeller-Guide Vane in a Vertical Axial Flow Pump Device
Authors: Yang Fan , Chang Pengcheng , Jian Hongfu , Lv Yuting , Tang Fangping , Jin Yan
Published: July 2022

A vertical axial flow pump device has the characteristics of low head and large flow and has various forms, simple structure, and flexible installation. It is widely used in low-head pumping stations in plain areas. In order to explore the transient characteristics of the internal flow in the impeller and guide vane of the vertical axial flow pump at different flow rates, this article analyzes the internal flow field distribution on the surface of the impeller blade, the velocity and pressure distribution of the impeller inlet and outlet, and the pressure pulsation characteristics of the impeller. The flow field characteristics of the guide vane section, the entropy production loss, and the main frequency change of the pressure pulsation inside the guide vane are analyzed at different radii. The results show that under 0.8 Qbep condition, the streamline distortion area of the blade working face accounts for the largest part of the blade area, and the streamline distortion area of the blade surface decreases significantly at 1.2 Qbep. The circumferential pressure distribution at the impeller inlet presents four high-pressure regions and four low-pressure regions, and the number of regions is consistent with the number of impeller blades. The ratio of axial force to flow rate of 0.8Qbep, 1.0Qbep, and 1.2Qbep is approximately 11:10:9. The radial force on the impeller is the largest under the condition of 0.8 Qbep, and the radial force on the impeller is not significantly different between 1.0 Qbep and 1.2 Qbep. The pressure pulsation amplitude gradually decreases from the inlet to the outlet of the guide vane.
Comparing Spatio-Temporal Dynamics of Functional and Taxonomic Diversity of Phytoplankton Community in Tropical Cascading Reservoirs
Authors: Resende Nathália da Silva , Santos Juliana Barreto Oliveira dos , Josué Iollanda Ivanov Pereira , Barros Nathan Oliveira , Cardoso Simone Jaqueline
Published: July 2022

Small Hydroelectric Power Plants (SHPs) are considered hydroelectric plants of reduced size and power that modify the landscape in a lower degree. As they are generally built-in sequence along the course of a river, these reservoirs are subject to the Cascading Reservoir Continuum Concept (CRCC), which provides a gradient effect mainly observed on suspended particles and nutrients. These effects can reflect in the phytoplankton community, which respond in terms of changes in their structure and function to environmental changes. Here, we aimed to investigate whether spatial variation would be more explanatory than temporal variation for phytoplankton structure and composition in cascading SHPs reservoirs. Furthermore, we sought to understand the effect of the hydrodynamics of run-of-river and storage reservoirs for phytoplankton community composition. We assessed the predictive power of physical and chemical conditions of the water, and zooplankton density as explanatory variables for phytoplankton taxonomic and functional diversity. The study was carried out over 6 years in three SHPs located on the Paraibuna River, Brazil, totaling 24 campaigns. After counting and identification, the phytoplankton species were classified according to qualitative functional traits related to morphology, physiology, and behavior. The reservoirs had significant differences in nutrients and suspended solids, corroborating with the CRCC. Nonetheless, these variables alone were not able to explain the distribution of phytoplanktonic species. However, as significant coupling between phytoplankton and zooplankton was found, and zooplankton might have influenced the phytoplankton distribution along the longitudinal gradient of the river. Furthermore, changes in taxonomic and functional composition of phytoplankton were mainly related to reservoir hydrodynamics and temporal variation. The last reservoir in the cascade was the one with the greatest phytoplankton species and functional diversity. Taxonomic and functional diversity indices were positively correlated, but at a certain point, functional richness reached a plateau. Here we highlight the complexity of understanding the role of cascading reservoirs in the structure and function of phytoplanktonic communities, which are subject to large spatial and temporal variations, even within the same stretch of a river.
Lightning Disaster Risk Zoning in Jiangsu Province of China Based on the Analytic Hierarchy Process and Entropy Weight Method
Authors: Jin Chenlu , Shu Yu , Han Zhaoquan , Chen Qu , He Jing , Wang Song
Published: July 2022

Jiangsu Province is located in the middle coastal area of East China, and has a relatively developed economy and a large population density. Severe convection often occurs in Jiangsu Province, and the lightning activities may cause great economic losses and social impact in this region. Based on the theory of natural disaster risk assessment, this study investigates the risk of hazard factors, the sensitivity of hazard-pregnant environment, and the frangibility of a hazard-bearing body in Jiangsu Province. Then, we select thunderstorm days, cloud-to-ground (CG) lightning density, CG lightning current intensity, altitude, topographic relief, soil-electric conductivity, drainage density, population density, gross domestic product (GDP) per land area, and soil utilization type as the influencing factors, and then we use the analytic hierarchy process and entropy weight method to calculate the weights of the influencing factors. Furthermore, all the factors are weighted stacked in ArcGIS, and finally the lightning disaster risk zoning map (1 × 1 km of Jiangsu Province is presented. The results show that the risk of lightning disaster in Jiangsu is low in the north and high in the south. The area of different risk level increases with the decrease in risk level. High-risk areas are mainly in the middle of Nanjing, eastern Changzhou, eastern Wuxi, and the middle of Suzhou. Medium-risk areas are mainly in northern Nanjing, eastern Changzhou, eastern Suzhou, the Tongshan District of Xuzhou City, the Chongchuan District of Nantong City, Lianyun District of Lianyungang City, and the Xiangshui County, Sheyang County, and Dafeng District of Yancheng City. The sub–low-risk areas are mainly in Xuzhou, Suqian, Huai’an, and the middle of Yangzhou City. The low-risk areas are mainly in Lianyungang, Yancheng, northern Nantong, Taizhou, Zhenjiang, southern Nanjing, western Changzhou, western Wuxi, and western Suzhou. We hope this study could provide some references for the lightning disaster prevention and mitigation in Jiangsu Province and East China.
Exploring the Impact of the Digital Economy on Carbon Emission Efficiency Under Factor Misallocation Constraints: New Insights From China
Authors: Ge Wenfeng , Xu Yang , Liu Guangliang , Shen Bing , Su Xufeng , Liu Lu , Yang Xiaodong , Ran Qiying
Published: July 2022

The digital economy has introduced far-reaching innovations in the fields of government governance, enterprise production, and social operation. How to motivate the economic development mode towards a low-carbon and greenway transformation through the digital economy is a major issue concerning the Chinese government. However, there is scarce evidence to interpret the role mechanism of the digital economy on carbon emission efficiency from the factor misallocation scenario. Taking a database from 30 provincial-level administrative regions for the period from 2011 to 2019 in China as an example, the paper examines the effect of the digital economy on carbon emission efficiency, as well as explores its role mechanism deeply in terms of factor misallocation (capital misallocation and labor misallocation). The results suggest that there is a significant potential for the digital economy to contribute to carbon emission efficiency, as well as this finding, is valid when considering both the endogeneity issue and a series of robustness checks. Also, the digital economy can significantly contribute to carbon efficiency in both southern and northern regions, but more strongly in the northern region. Besides, the digital economy can inhibit the factor misallocation (labor misallocation and capital misallocation) level which ultimately improves carbon emission efficiency. Finally, as a digital economy, it can positively impact carbon efficiency in the long run by mitigating factor misallocation (labor misallocation and capital misallocation).
Wheat Rhizosphere Microbiota Respond to Changes in Plant Genotype, Chemical Inputs, and Plant Phenotypic Plasticity
Authors: Jacquiod Samuel , Raynaud Tiffany , Pimet Eric , Ducourtieux Chantal , Casieri Leonardo , Wipf Daniel , Blouin Manuel
Published: July 2022

Modern wheat varieties that were selected since the Green Revolution are generally grown with synthetic chemical inputs, and ancient varieties released before1960 without. Thus, when changes occur in rhizosphere microbiota structure, it is not possible to distinguish if they are due to (i) changes in wheat genotypes by breeding, (ii) modifications of the environment via synthetic chemical inputs, or (iii) phenotypic plasticity, the interaction between wheat genotype and the environment. Using a crossed factorial design in the field, we evaluated the effects of either modern or ancient wheat varieties grown with or without chemical inputs (a N fertilizer, a fungicide, and an herbicide) on “microbiome as a phenotype.” We analyzed the rhizosphere microbiota by bacterial and fungal amplicon sequencing, coupled with microscope observations of mycorrhizal associations. We found that plant genotype and phenotypic plasticity had the most influence on rhizosphere microbiota, whereas inputs had only marginal effects. Phenotypic plasticity was particularly important in explaining diversity variations in bacteria and fungi but had no impact on the mycorrhizal association. Our results show an interest in considering the interaction between wheat genotype and the environment in breeding programs, by focusing on genes involved in the phenotypic plasticity of plant-microbe interactions.
CRISPR/Cas9-Mediated Targeting of Susceptibility Factor eIF4E-Enhanced Resistance Against Potato Virus Y
Authors: Noureen Azka , Khan Muhammad Zuhaib , Amin Imran , Zainab Tayyaba , Mansoor Shahid
Published: July 2022

Potato (Solanum tuberosum L.) is an important staple food around the world, and potato virus Y (PVY) is a major constraint for potato production. The VPg protein of PVY interacts with the translation initiation factor eIF4E of the host that works as a susceptibility factor during infection. The interaction between eIF4E and VPg was disrupted by CRISPR/Cas9. The homozygous conserved region of eIF4E of the potato variety “Kruda” was mutated by CRISPR/Cas9. Tracking of insertion, deletion, and conversion events was performed by Sanger sequencing with ∼15% editing efficiency. Truncated and mutated eIF4E proteins were unable to interact with VPg, and the virus was not able to exploit the host machinery for replication and systemic spreading. Mutated eIF4E lines showed enhanced resistance to PVYO strain. DAS-ELISA and RT-PCR were used for validation of the observed resistance. PVY resistance in tetraploid lines via CRISPR/Cas9 provides a route to develop novel resistant potato cultivars.
Complement Is Activated During Normothermic Machine Perfusion of Porcine and Human Discarded Kidneys
Authors: Jager Neeltina M. , Venema Leonie H. , Arykbaeva Asel S. , Meter-Arkema Anita H. , Ottens Petra J. , van Kooten Cees , Mollnes Tom E. , Alwayn Ian P. J. , Leuvenink Henri G. D. , Pischke Soeren E. ,   PROPER study consortium
Published: July 2022

Background

The gap between demand and supply of kidneys for transplantation necessitates the use of kidneys from extended criteria donors. Transplantation of these donor kidneys is associated with inferior results, reflected by an increased risk of delayed graft function. Inferior results might be explained by the higher immunogenicity of extended criteria donor kidneys. Normothermic machine perfusion (NMP) could be used as a platform to assess the quality and function of donor kidneys. In addition, it could be useful to evaluate and possibly alter the immunological response of donor kidneys. In this study, we first evaluated whether complement was activated during NMP of porcine and human discarded kidneys. Second, we examined the relationship between complement activation and pro-inflammatory cytokines during NMP. Third, we assessed the effect of complement activation on renal function and injury during NMP of porcine kidneys. Lastly, we examined local complement C3d deposition in human renal biopsies after NMP.

Methods

NMP with a blood-based perfusion was performed with both porcine and discarded human kidneys for 4 and 6 h, respectively. Perfusate samples were taken every hour to assess complement activation, pro-inflammatory cytokines and renal function. Biopsies were taken to assess histological injury and complement deposition.

Results

Complement activation products C3a, C3d, and soluble C5b-9 (sC5b-9) were found in perfusate samples taken during NMP of both porcine and human kidneys. In addition, complement perfusate levels positively correlated with the cytokine perfusate levels of IL-6, IL-8, and TNF during NMP of porcine kidneys. Porcine kidneys with high sC5b-9 perfusate levels had significantly lower creatinine clearance after 4 h of NMP. In line with these findings, high complement perfusate levels were seen during NMP of human discarded kidneys. In addition, kidneys retrieved from brain-dead donors had significantly higher complement perfusate levels during NMP than kidneys retrieved from donors after circulatory death.

Conclusion

Normothermic kidney machine perfusion induces complement activation in porcine and human kidneys, which is associated with the release of pro-inflammatory cytokines and in porcine kidneys with lower creatinine clearance. Complement inhibition during NMP might be a promising strategy to reduce renal graft injury and improve graft function prior to transplantation.
ICAM-1 on Breast Cancer Cells Suppresses Lung Metastasis but Is Dispensable for Tumor Growth and Killing by Cytotoxic T Cells
Authors: Regev Ofer , Kizner Marina , Roncato Francesco , Dadiani Maya , Saini Massimo , Castro-Giner Francesc , Yajuk Olga , Kozlovski Stav , Levi Nehora , Addadi Yoseph , Golani Ofra , Ben-Dor Shifra , Granot Zvi , Aceto Nicola , Alon Ronen
Published: July 2022

Breast tumors and their derived circulating cancer cells express the leukocyte β2 integrin ligand Intercellular adhesion molecule 1 (ICAM-1). We found that elevated ICAM-1 expression in breast cancer cells results in a favorable outcome and prolonged survival of breast cancer patients. We therefore assessed the direct in vivo contribution of ICAM-1 expressed by breast cancer cells to breast tumorigenesis and lung metastasis in syngeneic immunocompetent mice hosts using spontaneous and experimental models of the lung metastasis of the C57BL/6-derived E0771 cell line, a luminal B breast cancer subtype. Notably, the presence of ICAM-1 on E0771 did not alter tumor growth or the leukocyte composition in the tumor microenvironment. Interestingly, the elimination of Tregs led to the rapid killing of primary tumor cells independently of tumor ICAM-1 expression. The in vivo elimination of a primary E0771 tumor expressing the ovalbumin (OVA) model neoantigen by the OVA-specific OVA-tcr-I mice (OT-I) transgenic cytotoxic T lymphocytes (CTLs) also took place normally in the absence of ICAM-1 expression by E0771 breast cancer target cells. The whole lung imaging of these cells by light sheet microscopy (LSM) revealed that both Wild type (WT)- and ICAM-1-deficient E0771 cells were equally disseminated from resected tumors and accumulated inside the lung vasculature at similar magnitudes. ICAM-1-deficient breast cancer cells developed, however, much larger metastatic lesions than their control counterparts. Strikingly, the vast majority of these cells gave rise to intravascular tumor colonies both in spontaneous and experimental metastasis models. In the latter model, ICAM-1 expressing E0771- but not their ICAM-1-deficient counterparts were highly susceptible to elimination by neutrophils adoptively transferred from E0771 tumor-bearing donor mice. Ex vivo, neutrophils derived from tumor-bearing mice also killed cultured E0771 cells via ICAM-1-dependent interactions. Collectively, our results are a first indication that ICAM-1 expressed by metastatic breast cancer cells that expand inside the lung vasculature is involved in innate rather than in adaptive cancer cell killing. This is also a first indication that the breast tumor expression of ICAM-1 is not required for CTL-mediated killing but can function as a suppressor of intravascular breast cancer metastasis to lungs.
Combination of Low-Dose Gemcitabine and PD-1 Inhibitors for Treatment in Patients With Advanced Malignancies
Authors: Huang Hao , Peng Ling , Zhang Bicheng , Till Brian G. , Yang Yonghao , Zhang Xiaojie , Zhao Lingdi , Fu Xiaomin , Li Tiepeng , Han Lu , Qin Peng , Chen Lin , Yan Xiang , Liu Yang , Wang Wenkang , Ye Zhenlong , Li Hongle , Gao Quanli , Wang Zibing
Published: July 2022

Purpose

This study determined the efficacy of low-dose gemcitabine combined with programmed death-1 (PD-1) inhibitors for treating multiple malignancies, providing a cost-effective and safe treatment option.

Study Design

This study included 61 patients with advanced solid tumors treated with low-dose gemcitabine combined with PD-1 inhibitors at the Henan Cancer Hospital between January 2018 and February 2022. We retrospectively reviewed medical records to evaluate several clinical factors, including progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and objective response to treatment.

Results

Sixty-one patients received treatment with low-dose gemcitabine combined with PD-1 inhibitors. The objective response rate (ORR) was 29.5% and the disease control rate (DCR) was 62.3%. The median PFS was 4.3 months (95% confidence interval, 2.3 to 6.3 months) and the median OS was 15.0 months (95% confidence interval, 8.8 to 21.2 months). Hematological toxicity, mainly leukopenia or thrombocytopenia, was the most common AE, with any-grade and grade 3/4 hematological toxicity reported in 60.7 and 13.1% of patients, respectively.

Conclusions

Low-dose gemcitabine combined with PD-1 inhibitors may offer a novel treatment option for patients with advanced malignancies.
Investigating the Role of the NLRP3 Inflammasome Pathway in Acute Intestinal Inflammation: Use of THP-1 Knockout Cell Lines in an Advanced Triple Culture Model
Authors: Busch Mathias , Ramachandran Haribaskar , Wahle Tina , Rossi Andrea , Schins Roel P. F.
Published: July 2022

The NLRP3 inflammasome plays an important role in intestinal homeostasis as well as inflammation. However, in vivo studies investigating the role of the NLRP3 inflammasome in inflammatory bowel disease (IBD) report contrasting results, leaving it unclear if the NLRP3 inflammasome augments or attenuates intestinal inflammation. To investigate the role of the NLRP3/caspase-1 pathway in a model of acute intestinal inflammation, we modified a previously established in vitro triple culture model of the healthy and inflamed intestine (Caco-2/HT29-MTX-E12/THP-1). Using THP-1 knockout cell lines, we analyzed how the NLRP3 inflammasome and its downstream enzyme caspase-1 (CASP1) affect inflammatory parameters including barrier integrity and cytotoxicity, as well as gene expression and secretion of pro-inflammatory cytokines and mucus. Furthermore, we investigated differences in inflammation-mediated cytotoxicity towards enterocyte-like (Caco-2) or goblet-like (HT29-MTX-E12) epithelial cells. As a complementary approach, inflammation-related cytotoxicity and gene expression of cytokines was analyzed in intestinal tissue explants from wildtype (WT) and Nlrp3-/- mice. Induction of intestinal inflammation impaired the barrier, caused cytotoxicity, and altered gene expression of pro-inflammatory cytokines and mucins in vitro, while the knockout of NLRP3 and CASP1 in THP 1 cells led to attenuation of these inflammatory parameters. The knockout of CASP1 tended to show a slightly stronger attenuating effect compared to the NLRP3 knockout model. We also found that the inflammation-mediated death of goblet-like cells is NLRP3/caspase-1 dependent. Furthermore, inflammation-related cytotoxicity and upregulation of pro-inflammatory cytokines was present in ileal tissue explants from WT, but not Nlrp3-/- mice. The here presented observations indicate a pro-inflammatory and adverse role of the NLRP3 inflammasome in macrophages during acute intestinal inflammation.
Placental Malaria is Associated with Higher LILRB2 Expression in Monocyte Subsets and Lower Anti-Malarial IgG Antibodies During Infancy
Authors: Dechavanne Celia , Nouatin Odilon , Adamou Rafiou , Edslev Sofie , Hansen Anita , Meurisse Florian , Sadissou Ibrahim , Gbaguidi Erasme , Milet Jacqueline , Cottrell Gilles , Gineau Laure , Sabbagh Audrey , Massougbodji Achille , Moutairou Kabirou , Donadi Eduardo A. , Carosella Edgardo D. , Moreau Philippe , Remarque Ed , Theisen Michael , Rouas-Freiss Nathalie , Garcia André , Favier Benoit , Courtin David
Published: July 2022

Background

Placental malaria (PM) is associated with a higher susceptibility of infants to Plasmodium falciparum (Pf) malaria. A hypothesis of immune tolerance has been suggested but no clear explanation has been provided so far. Our goal was to investigate the involvement of inhibitory receptors LILRB1 and LILRB2, known to drive immune evasion upon ligation with pathogen and/or host ligands, in PM-induced immune tolerance.

Method

Infants of women with or without PM were enrolled in Allada, southern Benin, and followed-up for 24 months. Antibodies with specificity for five blood stage parasite antigens were quantified by ELISA, and the frequency of immune cell subsets was quantified by flow cytometry. LILRB1 or LILRB2 expression was assessed on cells collected at 18 and 24 months of age.

Findings

Infants born to women with PM had a higher risk of developing symptomatic malaria than those born to women without PM (IRR=1.53, p=0.040), and such infants displayed a lower frequency of non-classical monocytes (OR=0.74, p=0.01) that overexpressed LILRB2 (OR=1.36, p=0.002). Moreover, infants born to women with PM had lower levels of cytophilic IgG and higher levels of IL-10 during active infection.

Interpretation

Modulation of IgG and IL-10 levels could impair monocyte functions (opsonisation/phagocytosis) in infants born to women with PM, possibly contributing to their higher susceptibility to malaria. The long-lasting effect of PM on infants’ monocytes was notable, raising questions about the capacity of ligands such as Rifins or HLA-I molecules to bind to LILRB1 and LILRB2 and to modulate immune responses, and about the reprogramming of neonatal monocytes/macrophages.
Resveratrol Alleviating the Ovarian Function Under Oxidative Stress by Alternating Microbiota Related Tryptophan-Kynurenine Pathway
Authors: Wang Jianping , Jia Ru , Celi Pietro , Zhuo Yong , Ding Xuemei , Zeng Qiufeng , Bai Shiping , Xu Shengyu , Yin Huadong , Lv Li , Zhang Keying
Published: July 2022

Oxidative stress (OS) is a key factor regulating the systemic pathophysiological effects and one of the fundamental mechanisms associated with aging and fertility deterioration. Previous studies revealed that resveratrol (RV) exhibits a preventive effect against oxidative stress in the ovary. However, it remains unknown whether gut microbiota respond to resveratrol during an OS challenge. In Exp. 1, layers received intraperitoneal injection of tert-butyl hydroperoxide (tBHP) (0 or 800 μmol/kg BW) or received resveratrol diets (0 or 600 mg/kg) for 28 days. In Exp. 2, the role of intestinal microbiota on the effects of resveratrol on tBHP-induced oxidative stress was assessed through fecal microbiota transplantation (FMT). The OS challenge reduced the egg-laying rate and exhibited lower pre-hierarchical follicles and higher atretic follicles. Oral RV supplementation ameliorated the egg-laying rate reduction and gut microbiota dysbiosis. RV also reversed the tryptphan-kynurenine pathway, upregulated nuclear factor E2-related factor 2 (Nrf2) and silent information regulator 1(SIRT1) levels, and decreased the expression of forkhead box O1 (FoxO1) and P53. These findings indicated that the intestinal microbiota-related tryptophan-kynurenine pathway is involved in the resveratrol-induced amelioration of ovary oxidative stress induced by tBHP in the layer model, while SIRT1-P53/FoxO1 and Nrf2-ARE signaling pathway were involved in this process.
Ecological, Social and Economic Aspects of Italian Marine Spearfishing Tournaments (2009-2020)
Authors: Terlizzi Antonio , Tarantino Giulio , Sbragaglia Valerio
Published: July 2022

Marine recreational spearfishing is practiced by a small proportion of recreational fishers and ecological, social and economic aspects of such activities are poorly understood with respect to recreational angling. The Italian Federation of Sport Fishing and Underwater Activities (FIPSAS) started in 2009 the collection of catch data related to Italian spearfishing tournaments. Here, we provide the first snapshot of this catch data regarding 48 tournaments organized in 29 different Italian localities from 2009 to 2020. We also developed a survey to collect social and economic information that has been administrated to participants to the tournaments. We retrieved 8843 specimens caught by spearfishers, which accounted for 33 species and a total biomass of 5665 kg (mean individual mass ± standard error; 0.64 ± 0.01 kg). The five most frequently species represented 78% of the specimens caught (white seabream, Diplodus sargus 48%; brown wrasse, Labrus merula 12%; brown meagre, Sciaena umbra 9%, green wrasse, Labrus viridis 5%; salema, Sarpa salpa 4%). The overall catch per unit effort for all the tournaments was 0.47 ± 0.01 kg/spearfisher/h, and we showed interesting effects of type of tournaments and type of displacement on it. We also assessed the accuracy of participants to catch fish in accordance to tournaments-specific minimum weight limits. The five most caught species showed that spearfishers committed errors around 50 g below the weight limit. The survey showed that spearfishers participating to tournaments are trophy-fish oriented (i.e., they would rather catch one or two big fish than ten smaller fish), but not particularly catch oriented (i.e., they are just as happy if they do not shoot the fish they see and a fishing trip can be successful even if no fish are caught). Regarding the motives for fishing, they fish for experiencing adventure, excitement and new and different things as well as to be underwater. Participants spent from 2 to 26 days in the tournament locations (median equal to 7 days), which implies a total expenditure to solely participate to the tournaments ranging from 800 to 3500 Euros (mean ± standard deviation; 1800 ± 591 euros). This study represents the first ecological, social and economic baseline knowledge for an integrative management of contemporary spearfishing tournaments.