bluuebunny/crossref_metadata_2025 huggingface dataset:
Desenvolvimento de rotina computacional com algoritmos genéticos para otimização do custo do consumo da água por análise de dispositivos economizadores de água
Authors: Andretta Neto Jayme José , Silva Fernando das Graças Braga da , Silva Alex Takeo Yasumura Lima , Reis José Antonio Tosta dos
Published: August 2021

O consumo racional de água residencial é uma das principais questões ambientais na sociedade, visto que este representa um importante fatia do consumo de recursos hídricos. Assim, desenvolveu-se um algoritmo para auxílio na otimização do uso de dispositivos hidráulicos em ambientes residenciais, testando essa proposta em um ambiente residencial genérico. Para alcançar este objetivo, foram feitas pesquisas mercadológicas e de referência técnica para colher dados dos dispositivos hidráulicos e posteriormente utilizado a técnica de algoritmo genético para o processamento da otimização. Como resultado foi encontrado um conjunto de cenários ótimos para a utilização dos dispositivos, garantindo a maior economia de água com o menor custo. Concluiu-se que o trabalho conseguiu propor uma rotina de otimização que pode ter aplicabilidade satisfatória para tomada de decisões na otimização do uso dispositivos hidráulicos residenciais.
Rhizocephalan infection in the Patagonian stone crab Danielethus patagonicus
Authors: Barón PJ , Leal GA , Carsen AE , Kroeck MA , Morsan EM
Published: August 2021

The system formed by a still-unidentified rhizocephalan infecting the Patagonian stone crab Danielethus (Platyxanthus) patagonicus (A. Milne-Edwards, 1879) was analyzed in northern Patagonia. Out of 3222 crabs sampled, mean prevalence of externae was 2.1%, while corrected mean prevalence based on observations of externae, scars or other indicators of infection was slightly higher (3.01%; N = 2100). Prevalence was higher in males (4.47%) than in females (1.44%). Parasitized males were morphologically feminized, while females showed no hyper-feminization. Although most parasitized crabs showed only 1 externa, 2 externae were observed in some individuals. The parasite externae were only present in intermediate-sized crabs (26.6-99.7 cm carapace width). While scanning electron microscopy images allowed detection of the ‘smooth-surface-balloon’ type of retinacula on the inner surface of the externae, typical of the Sacculinidae and Peltogastridae, the position of the mantle opening relative to the stalk, the receptacle location and the shape of the externae suggest that the parasite belongs to either the genus Sacculina or to the recently erected Parasacculina (Polyascidae).
Montesquieu’da Erkler Ayrımı (Mitosu) ve Modern Yargı Erki Üzerine
Authors: BAKIRCI Fahri
Published: August 2021

Montesquieu tarafından ortaya atıldığı sanılan ama asıl öncüsü Locke olan erkler ayrımı, günümüz demokratik hukuk devletlerinin olmazsa olmazıdır. Montesquieu’nün kuramı ortaya atarken güttüğü amaç, üyesi olduğu soylular sınıfının çıkarlarının korunmasıdır. Bu makalede bu amacın bütün yönetim biçimleri için savunulduğu gösterilmeye çalışılmaktadır. Dolayısıyla Montesquieu’yü günümüz erkler ayrımı kuramı açısından önemli yapan şey söylediklerinden çok, kuramı ortaya attığı zaman ve kuramın bu zamanın düşünceleri üzerinde yarattığı etkidir. Bu yüzden Montesquieu’y kendi zamanının içinden okumak yerine demokratik hukuk devletinin günümüzde geldiği noktadan okumak gerekir. Bu okuma, egemenliği kullanan erklerden biri olan yargı erkine ve özellikle anayasa yargısına özel bir önem vermeyi zorunlu kılar.
Human Rights. Protection and enforcement
Authors: Vynokurov V. V.
Published: August 2021

The article is devoted to the analysis of the essence and content of the categories «human rights», «protection of human rights», «human rights enforcement» in terms of the substantive relationship between the constitutional state and the individual in modern society. It is emphasized that addressing these terms through the prism of human rights in order to effectively implement them, it is necessary to clearly understand their content and scope of possible actions covered by them, as well as to distinguish between «protection» and «enforcement» at both scientific and legislativelevels, taking into account, inter alia, their lexical meaning. It is determined that everyone, on the one hand, should be able to freely choose the way to protect their rights, and on the other – must be sure that the state guarantees equal opportunities for everyone, regardless of race, language, skin color, political, religious and other beliefs, gender, ethnic and social origin, property status, place of residence, etc., to use these methods of protection. The role and importance of public authorities in the process of protection and enforcement of human rights and freedoms and the state responsibility to the individual as an integral part of ensuring constitutional human rights are also defined. It is concluded that an integral part of constitutional human rights enforcement is certainly the existence of an effective and efficient mechanism of legal responsibility of the state to the individual.

Keywords: human rights, protection of human rights, human rights enforcement, public authorities, state responsibility.
Problem issues of interpretation of doctrinal errors
Authors: Onishchenko N. M.
Published: August 2021

An interesting and little-studied issue of modern domestic doctrine is the issue of legal errors, in particular the relevantproblems of interpretation of law. After all, the analysis of their essence, nature and ways of prevention is one of the most important issues of improving legal practice in general and increasing the effectiveness of legislation in particular.

In this scientific research the task of studying the problem of doctrinal interpretation of law is set. It is safe to say thatin general this topic is considered studied, discussed and systematized. Moreover, at the doctrinal level, this is confirmed more and more accurately than in view of its practical application.

The research was based on the following: recent problems related to the legal practice of the CCU; related to theconduct of an external independent evaluation or the cancellation of the state final certification; passing exams in schools and colleges - a lot of regulatory issues that are dictated by the new realities of life in a pandemic.

The article highlights the types of legal errors, subjective and objective factors of their occurrence. A special vector of consideration is devoted to doctrinal legal errors and ways to prevent and eliminate them in the context of legal interpretation practice.

After a definitive list and analysis of research and publications, the author turned to the essence of the issue. Legal error is most often interpreted as a negative result due to unintentional, incorrect actions of legal entities (bona fide error).

The value of this work is to obtain practical advice on effective means of combating doctrinal errors.

Keywords: interpretation of legal norms, error, legal error, types of legal errors, doctrinal legal error, precautionary measures
Legal technique of judicial practice and its role in state legislation
Authors: Shutak I. D.
Published: August 2021

Purpose. The purpose of the study is to reveal the features of the legal technique of judicial practice and its role in

law-making of the state. Methodology. First of all, the principles and techniques of formal-logical methodology are used.Elements of the structural-functional approach have been widely used. Thus, the identification of intersectoral links in judicial practice is based on the functional nature of law in general and procedural means in particular, which allowed us to see intersectoral links in judicial lawmaking. In addition, dialectical, system-structural and functional methods, the method of interpretation were used in the work. Judicial lawmaking is a separate area where completely different approaches are possible. Questions about the reflection of the legal technique of judicial practice and its role in the law-making process are considered in terms of both natural law and positivist and other areas of jurisprudence. Originality. The scientific novelty lies in the theoretical understanding and delineation of the legal technique of contract lawmaking, which is interpreted as a set of methods, tools and techniques used in developing the content and structure of judicial acts of any instance in the relevant proceedings. The specifics of judicial lawmaking are shown, which consists in the presence of such features that characterize it as an independent legal phenomenon that differs from other types of lawmaking. According to its functional purpose, judicial lawmaking creates the conditions for resolving specific court cases; eliminates gaps and ambiguities of certain legislation during the trial; complements the law-making system as a whole, consistently eliminating its shortcomings. The essence of such means of legal technique in judicial law-making as judicial interpretation and judicial concretization of norms of law is revealed. Results. The study found that the effectiveness of the courts depends not only on the number and content of judicial acts, but also on their technical and legal excellence. The role of judicial practice in law-making activity is strengthened, which is manifested in the need to take it into account, in the possibility of identifying shortcomings of current legislation, identifying possible law-making ways to overcome shortcomings in current legislation. Judicial law-making is an independent type of law-making that takes place within the competence of judicial bodies, when existing defects of legal regulation are eliminated by law-making court decisions as a result of interpretation and concretization of excessively generalized and abstract rules of law and by filling gaps in law. Practical importance. The results of the study can be used in law-making activities in order to identify shortcomings in current legislation and identify possible law-making ways to overcome shortcomings in current legislation.

Keywords: legal technique, law-making, law-enforcement act, court practice, court precedent.
Numerical and experimental study of droplet-film-interaction for low pressure steam turbine erosion protection applications
Authors: Bohn Dieter , Uno Tatsuya , Yoshida Takeshi , Betcher Christian , Frohnheiser Jan , Weidtmann Kristof
Published: August 2021

One common approach for anti-erosion measures in low pressure steam turbines is to equip a hollow stator vane with slots on the airfoil surface in order to remove the water film by suction and consequently reduce the amount of secondary droplets. The purpose of this paper is to build an understanding of the predominant effects in fluid-film interaction and to examine the suitability of modern numerical methods for the design process of such slots. The performance of a suction slot in terms of collection rate and air leakage is investigated numerically in a flatplate setup with upstream injection of water. In order to model the relevant phenomena (film transport, edge stripping of droplets, transport of droplets in the surrounding fluid, wall impingement of droplets) an unsteady Eulerian-Lagrangian simulation setup is
applied. The accuracy of the numerical approach is assessed by comparison with experimental
measurements. The comparison of four cases with the measured data demonstrates that the chosen simulation approach is
able to predict the main features of film flow and interaction with the surrounding fluid. The collection
rate as well as fluid film properties show the same qualitative dependency from water mass flow rate and air velocity.
Inflation and Inflation Uncertainty in Growth Model of Barro: An Application of Random Forest Model
Authors: SENOUSSİ Houcine
Published: August 2021

One of the major problems of the empirical economists while building an economic

model is the selection of variables which should be included in the true regression

model. Conventional econometrics use several model selection criteria to determine

the variables. Recent years' developments in Machine Learning (ML) approaches introduced

an alternative way to select variables. In this paper, we have an application

of ML to select variables to include for a nonlinear relationship between inflation and

economic growth. Among ML methodologies, Random Forest

approach is one of the most powerful to capture nonlinear relationships. Therefore,

we applied RF and found that both high and low inflation can be the cause of low

economic growth which is a major contribution of the paper to economic literature.

Moreover, in the paper, as an outcome of RF there are other variables effecting

economic growth with an order of importance.
Biochemical Profiling of Resistant Phenotypes Against Bipolaris oryzae Causing Brown Spot Disease in Rice
Authors: Ashfaq Benish , Arshad Hafiz M. Imran , Atiq M. , Yousaf Sumaira , Saleem Kamran , Arshad Amna
Published: August 2021

Brown leaf spot disease of rice is a dominant lethal disease, caused by the fungus Bipolaris oryzae. The pathogen is an obligate parasite and causes qualitative and quantitative damage to rice crop. The objective of the present study was to investigate what extent the defense related biochemical compounds reflect the distinct categories of resistance phenotypes in rice against brown spot disease. This was done by determining the concentration of Catalase (CAT), Phenylalanine ammonia-lyase (PAL), Polyphenol oxidase (PPO), Peroxidase (POD), and β-1,3-Glucanase enzymes in resistant, moderately resistant and susceptible rice genotypes. The disease resistant phenotypes in rice line (PARC-7) reflect the higher accumulation of CAT, PAL, PPO, POD, and β-1,3-Glucanase. The pattern of enzyme accumulation was similar in all resistant genotypes. The rice genotypes with moderately resistant phenotypes showed significant difference with respect to the concentration of biochemical defense-related compounds. The difference in accumulation of defense related enzymes reflected the level of disease severity (% leaf area covered) on resistant and moderately resistant genotypes. The susceptible rice genotypes showed the minimum concentration of these enzymes, with the lowest concentrations found in the rice variety Bas-2000 (80% Disease Index). The differential defense response in resistant and susceptible genotypes suggests that these enzymes can be used as biochemical markers for early detection of disease resistant genotypes. The study of enzyme accumulation at different time points and at different levels of disease severity helps to understand the resistance mechanisms against brown spot disease in rice.
Front-End Governance of a Major Public Project in Laos: A Conceptual Framework for Ensuring the Right Concept
Authors: Mackhaphonh Nikhaphone , Jia Guangshe , Xu Qixiong
Published: August 2021

Major public projects in Laos are faced with multiple challenges, including project identification and its decision-making. Generally, an identification is an important key identifying the potential needs and requirements for achieving the development goal. However, the process was developed without a formal framework and assurance tools that have been criticized for negative social and environmental consequences as “white elephant projects” over the past few years. Considering this context, the study aimed to develop a conceptual framework to navigate an alternative solution for the right project. Based on contextual analysis and systematic literature review, the proposed framework provided the process of concept development and its assurance that it could be systematically developed in a cause-effect chain of needs. The findings indicate areas that reflect new insights of both strategic performance and a governance system, and reforms the decision-making process in providing new knowledge, new rules, and procedures for effective governance.
Generation of Multipotential NG2 Progenitors From Mouse Embryonic Stem Cell-Derived Neural Stem Cells
Authors: Otsu Masahiro , Ahmed Zubair , Fulton Daniel
Published: August 2021

Embryonic stem cells (ESC) have the potential to generate homogeneous immature cells like stem/progenitor cells, which appear to be difficult to isolate and expand from primary tissue samples. In this study, we developed a simple method to generate homogeneous immature oligodendrocyte (OL) lineage cells from mouse ESC-derived neural stem cell (NSC). NSC converted to NG2+/OLIG2+double positive progenitors (NOP) after culturing in serum-free media for a week. NOP expressed Prox1, but not Gpr17 gene, highlighting their immature phenotype. Interestingly, FACS analysis revealed that NOP expressed proteins for NG2, but not PDGFRɑ, distinguishing them from primary OL progenitor cells (OPC). Nevertheless, NOP expressed various OL lineage marker genes including Cspg4, Pdgfrα, Olig1/2, and Sox9/10, but not Plp1 genes, and, when cultured in OL differentiation conditions, initiated transcription of Gpr17 and Plp1 genes, and expression of PDGFRα proteins, implying that NOP converted into a matured OPC phenotype. Unexpectedly, NOP remained multipotential, being able to differentiate into neurons as well as astrocytes under appropriate conditions. Moreover, NOP-derived OPC myelinated axons with a lower efficiency when compared with primary OPC. Taken together, these data demonstrate that NOP are an intermediate progenitor cell distinguishable from both NSC and primary OPC. Based on this profile, NOP may be useful for modeling mechanisms influencing the earliest stages of oligogenesis, and exploring the cellular and molecular responses of the earliest OL progenitors to conditions that impair myelination in the developing nervous system.
Metagenomic Next-Generation Sequencing of Bloodstream Microbial Cell-Free Nucleic Acid in Children With Suspected Sepsis in Pediatric Intensive Care Unit
Authors: Yan Gangfeng , Liu Jing , Chen Weiming , Chen Yang , Cheng Ye , Tao Jinhao , Cai Xiaodi , Zhou Yang , Wang Yixue , Wang Mingbang , Lu Guoping
Published: August 2021

Bloodstream infection is a life-threatening complication in critically ill patients. Multi-drug resistant bacteria or fungi may increase the risk of invasive infections in hospitalized children and are difficult to treat in intensive care units. The purpose of this study was to use metagenomic next-generation sequencing (mNGS) to understand the bloodstream microbiomes of children with suspected sepsis in a pediatric intensive care unit (PICU). mNGS were performed on microbial cell-free nucleic acid from 34 children admitted to PICU, and potentially pathogenic microbes were identified. The associations of serological inflammation indicators, lymphocyte subpopulations, and other clinical phenotypes were also examined. mNGS of blood samples from children in PICU revealed potential eukaryotic microbial pathogens. The abundance of Pneumocystis jirovecii was positively correlated with a decrease in total white blood cell count and immunodeficiency. Hospital-acquired pneumonia patients showed a significant increase in blood bacterial species richness compared with community-acquired pneumonia children. The abundance of bloodstream bacteria was positively correlated with serum procalcitonin level. Microbial genome sequences from potential pathogens were detected in the bloodstream of children with suspected sepsis in PICU, suggesting the presence of bloodstream infections in these children.
Transforming Growth Factor-β1 Promotes M1 Alveolar Macrophage Polarization in Acute Lung Injury by Up-Regulating DNMT1 to Mediate the microRNA-124/PELI1/IRF5 Axis
Authors: Wang Yongqi , Wang Xiaoqing , Zhang Hong , Han Biao , Ye Yuanmei , Zhang Mengjie , Wang Yingbin , Xue Jianjun , Wang Chun’ai
Published: August 2021

Objective

Macrophages function as key orchestrators in the pathogenesis of acute lung injury (ALI). The current study sets out to investigate the molecular mechanism of transforming growth factor-β (TGFβ1) in the regulation of M1 alveolar macrophage polarization in ALI by modulating DNA methyltransferase 1 (DNMT1), along with the microRNA (miR)-124/Pellino 1 (PELI1)/interferon regulatory factor 5 (IRF5) axis.

Methods

First, ALI mouse models were established, and the proportion of M1 and M2 macrophages in mouse lung tissues was detected using flow cytometry. The targeting relationship between miR-124 and PELI1 was verified with the help of a dual luciferase gene reporter assay. Following TGFβ1 knockdown, RT-qPCR and Western blot assay were performed to analyze the expression patterns of TGFβ1, DNMT1, miR-124, and PELI1 and M1/M2 polarization markers in the lung tissues of ALI mice. Immunofluorescence was further employed to detect nuclear translocation of IRF5 in macrophages.

Results

The polarization of M1 macrophages was found to be positively correlated with the severity of lung injury. TGFβ1, DNMT1, PELI1 were highly expressed, while miR-124 was down-regulated in ALI mice, and IRF5 was primarily distributed in the nucleus. TGFβ1 promoted the polarization of M1 alveolar macrophages by up-regulating DNMT1. Furthermore, DNMT1 down-regulated the expression of miR-124, which led to enhancement of M1 alveolar macrophage polarization. Meanwhile, over-expression of miR-124 inhibited the nuclear translocation of IRF5 and suppressed M1 alveolar macrophage polarization. On the other hand, over-expression of PELI1 reversed the above trends.

Conclusion

Collectively, our findings indicated that TGFβ1 can promote the expression of DNMT1, which down-regulates miR-124 to activate PELI1 and nuclear translocation of IRF5, thereby aggravating ALI in mice.
An Agro-Pastoral Phenological Water Balance Framework for Monitoring and Predicting Growing Season Water Deficits and Drought Stress
Authors: Funk Chris , Turner Will , McNally Amy , Hoell Andrew , Harrison Laura , Galu Gideon , Slinski Kim , Way-Henthorne Juliet , Husak Gregory
Published: August 2021

Sharing simple ideas across a broad community of practitioners helps them to work together more effectively. For this reason, drought early warning systems spend a considerable effort on describing how hazards are detected and defined. Well-articulated definitions of drought provide a shared basis for collaboration, response planning, and impact mitigation. One very useful measure of agricultural drought stress has been the “Water Requirement Satisfaction Index” (WRSI). In this study, we develop a new, simpler metric of water requirement satisfaction, the Phenological Water Balance (PWB). We describe this metric, compare it to WRSI and yield statistics in a food-insecure region (east Africa), and show how it can be easily combined with analog-based rainfall forecasts to produce end-of-season estimates of growing season water deficits. In dry areas, the simpler PWB metric is very similar to the WRSI. In these regions, we show that the coupling between rainfall deficits and increased reference evapotranspiration amplifies the impacts of droughts. In wet areas, on the other hand, our new metric provides useful information about water excess—seasons that are so wet that they may not be conducive to good agricultural outcomes. Finally, we present a PWB-based forecast example, demonstrating how this framework can be easily used to translate assumptions about seasonal rainfall outcomes into predictions of growing season water deficits. Effective humanitarian relief efforts rely on early projections of these deficits to design and deploy appropriate targeted responses. At present, it is difficult to combine gridded satellite-gauge precipitation forecasts with climate forecasts. Our new metric helps overcome this obstacle. Future extensions could use the water requirement framework to contextualize other water supply indicators, like actual evapotranspiration values derived from satellite observations or hydrologic models.
Application-Aware Intrusion Detection: A Systematic Literature Review, Implications for Automotive Systems, and Applicability of AutoML
Authors: Schubert David , Eikerling Hendrik , Holtmann Jörg
Published: August 2021

Modern and flexible application-level software platforms increase the attack surface of connected vehicles and thereby require automotive engineers to adopt additional security control techniques. These techniques encompass host-based intrusion detection systems (HIDSs) that detect suspicious activities in application contexts. Such application-aware HIDSs originate in information and communications technology systems and have a great potential to deal with the flexible nature of application-level software platforms. However, the elementary characteristics of known application-aware HIDS approaches and thereby the implications for their transfer to the automotive sector are unclear. In previous work, we presented a systematic literature review (SLR) covering the state of the art of application-aware HIDS approaches. We synthesized our findings by means of a fine-grained classification for each approach specified through a feature model and corresponding variant models. These models represent the approaches’ elementary characteristics. Furthermore, we summarized key findings and inferred implications for the transfer of application-aware HIDSs to the automotive sector. In this article, we extend the previous work by several aspects. We adjust the quality evaluation process within the SLR to be able to consider high quality conference publications, which results in an extended final pool of publications. For supporting HIDS developers on the task of configuring HIDS analysis techniques based on machine learning, we report on initial results on the applicability of AutoML. Furthermore, we present lessons learned regarding the application of the feature and variant model approach for SLRs. Finally, we more thoroughly describe the SLR study design.
A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes
Authors: Matos-Nieves Adrianna , Manivannan Sathiyanarayanan , Majumdar Uddalak , McBride Kim L. , White Peter , Garg Vidu
Published: August 2021

Congenital heart disease (CHD) is the most common type of birth defect, affecting ~1% of all live births. Malformations of the cardiac outflow tract (OFT) account for ~30% of all CHD and include a range of CHDs from bicuspid aortic valve (BAV) to tetralogy of Fallot (TOF). We hypothesized that transcriptomic profiling of a mouse model of CHD would highlight disease-contributing genes implicated in congenital cardiac malformations in humans. To test this hypothesis, we utilized global transcriptional profiling differences from a mouse model of OFT malformations to prioritize damaging, de novo variants identified from exome sequencing datasets from published cohorts of CHD patients. Notch1+/−; Nos3−/− mice display a spectrum of cardiac OFT malformations ranging from BAV, semilunar valve (SLV) stenosis to TOF. Global transcriptional profiling of the E13.5 Notch1+/−; Nos3−/− mutant mouse OFTs and wildtype controls was performed by RNA sequencing (RNA-Seq). Analysis of the RNA-Seq dataset demonstrated genes belonging to the Hif1α, Tgf-β, Hippo, and Wnt signaling pathways were differentially expressed in the mutant OFT. Mouse to human comparative analysis was then performed to determine if patients with TOF and SLV stenosis display an increased burden of damaging, genetic variants in gene homologs that were dysregulated in Notch1+/−; Nos3−/− OFT. We found an enrichment of de novo variants in the TOF population among the 1,352 significantly differentially expressed genes in Notch1+/−; Nos3−/− mouse OFT but not the SLV population. This association was not significant when comparing only highly expressed genes in the murine OFT to de novo variants in the TOF population. These results suggest that transcriptomic datasets generated from the appropriate temporal, anatomic and cellular tissues from murine models of CHD may provide a novel approach for the prioritization of disease-contributing genes in patients with CHD.
Effects of Salt Thickness on the Structural Deformation of Foreland Fold-and-Thrust Belt in the Kuqa Depression, Tarim Basin: Insights From Discrete Element Models
Authors: Li Changsheng , Yin Hongwei , Wu Zhenyun , Zhou Peng , Wang Wei , Ren Rong , Guan Shuwei , Li Xiangyun , Luo Haoyu , Jia Dong
Published: August 2021

The salt layer is critical for the structural deformation in the salt-bearing fold-and-thrust system, which not only acts as the efficient décollement layer but also flows to form salt tectonics. Kuqa Depression has a well-preserved thin-skinned fold-and-thrust system with the salt layer as the décollement. To investigate the effects of salt thickness on the structural deformation in the Kuqa Depression, three discrete element models with different salt thicknesses were constructed. The experiment without salt was controlled by several basal décollement dominant faults, forming several imbricate sheets. The experiments with salt developed the decoupled deformation with the salt layer as the upper décollement (subsalt, intrasalt, and suprasalt), significantly similar to the Kuqa Depression along the northern margin of Tarim Basin. Basal décollement dominant imbricated thrusts formed at the subsalt units, while the monoclinal structure formed at the suprasalt units. The decoupled deformation was also observed in the tectonic deformation graphics, distortional strain fields, and max shear stress fields. However, the salt layer was thickened in the thick salt model, and the salt thickness of the thin salt model varied slightly because the thin salt weakened the flowability of the salt. The lower max shear stress zone was easily formed in the distribution region of salt under the action of compression stress, which is conducive to the flow convergence of salt and the crumpled deformation of interlayer in salt. The results are well consistent with the natural characteristics of structural deformation in the Kuqa Depression. Our modeling result concerns the structural characteristics and evolution of salt-related structures and the effects of salt thickness on the structural deformation in the compressional stress field, which might be helpful for the investigations of salt-related structures in other salt-bearing fold-and-thrust belts.
Geomorphology and InSAR-Tracked Surface Displacements in an Ice-Rich Yedoma Landscape
Authors: van Huissteden J. , Teshebaeva K. , Cheung Y. , Magnússon R. Í. , Noorbergen H. , Karsanaev S. V. , Maximov T. C. , Dolman A. J.
Published: August 2021

Ice-ridge Yedoma terrain is susceptible to vertical surface displacements by thaw and refreeze of ground ice, and geomorphological processes of mass wasting, erosion and sedimentation. Here we explore the relation between a 3 year data set of InSAR measurements of vertical surface displacements during the thaw season, and geomorphological features in an area in the Indigirka Lowlands, Northeast Siberia. The geomorphology is presented in a geomorphological map, based on interpretation of high resolution visible spectrum satellite imagery, field surveys and available data from paleo-environmental research. The main landforms comprise overlapping drained thaw lake basins and lakes, erosion remnants of Late Pleistocene Yedoma deposits, and a floodplain of a high-sinuosity anastomosing river with ancient river terrace remnants. The spatial distribution of drained thaw lake basins and Yedoma erosion remnants in the study area and its surroundings is influenced by neotectonic movements. The 3 years of InSAR measurement include 2 years of high snowfall and extreme river flooding (2017–2018) and 1 year of modest snowfall, early spring and warm summer (2019). The magnitude of surface displacements varies among the years, and show considerable spatial variation. Distinct spatial clusters of displacement trajectories can be discerned, which relate to geomorphological processes and ground ice conditions. Strong subsidence occurred in particular in 2019. In the wet year of 2017, marked heave occurred at Yedoma plateau surfaces, likely by ice accumulation at the top of the permafrost driven by excess precipitation. The spatial variability of surface displacements is high. This is explored by statistical analysis, and is attributed to the interaction of various processes. Next to ground ice volume change, also sedimentation (peat, colluvial deposition) and shrinkage or swelling of soils with changing water content may have contributed. Tussock tundra areas covered by the extreme 2017 and 2018 spring floods show high subsidence rates and an increase of midsummer thaw depths. We hypothesize that increased flood heights along Siberian lowland rivers potentially induce deeper thaw and subsidence on floodplain margins, and also lowers the drainage thresholds of thaw lakes. Both mechanisms tend to increase floodplain area. This may increase CH4 emission from floodplains, but also may enhance carbon storage in floodplain sedimentary environments.
The Causes of Debris-Covered Glacier Thinning: Evidence for the Importance of Ice Dynamics From Kennicott Glacier, Alaska
Authors: Anderson Leif S. , Armstrong William H. , Anderson Robert S. , Scherler Dirk , Petersen Eric
Published: August 2021

The cause of debris-covered glacier thinning remains controversial. One hypothesis asserts that melt hotspots (ice cliffs, ponds, or thin debris) increase thinning, while the other posits that declining ice flow leads to dynamic thinning under thick debris. Alaska’s Kennicott Glacier is ideal for testing these hypotheses, as ice cliffs within the debris-covered tongue are abundant and surface velocities decline rapidly downglacier. To explore the cause of patterns in melt hotspots, ice flow, and thinning, we consider their evolution over several decades. We compile a wide range of ice dynamical and mass balance datasets which we cross-correlate and analyze in a step-by-step fashion. We show that an undulating bed that deepens upglacier controls ice flow in the lower 8.5 km of Kennicott Glacier. The imposed velocity pattern strongly affects debris thickness, which in turn leads to annual melt rates that decline towards the terminus. Ice cliff abundance correlates highly with the rate of surface compression, while pond occurrence is strongly negatively correlated with driving stress. A new positive feedback is identified between ice cliffs, streams and surface topography that leads to chaotic topography. As the glacier thinned between 1991 and 2015, surface melt in the study area decreased, despite generally rising air temperatures. Four additional feedbacks relating glacier thinning to melt changes are evident: the debris feedback (negative), the ice cliff feedback (negative), the pond feedback (positive), and the relief feedback (positive). The debris and ice cliff feedbacks, which are tied to the change in surface velocity in time, likely reduced melt rates in time. We show this using a new method to invert for debris thickness change and englacial debris content (∼0.017% by volume) while also revealing that declining speeds and compressive flow led to debris thickening. The expansion of debris on the glacier surface follows changes in flow direction. Ultimately, glacier thinning upvalley from the continuously debris-covered portion of Kennicott Glacier, caused by mass balance changes, led to the reduction of flow into the study area. This caused ice emergence rates to decline rapidly leading to the occurrence of maximum, glacier-wide thinning under thick, insulating debris.
LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity
Authors: Lu Xuehan , Huang Lili , Huang Zhengxiang , Feng Dandan , Clark Richard J. , Chen Chen
Published: August 2021

Liver-expressed antimicrobial peptide 2 (LEAP-2), originally described as an antimicrobial peptide, has recently been recognized as an endogenous blocker of growth hormone secretagogue receptor 1a (GHS-R1a). GHS-R1a, also known as ghrelin receptor, is a G protein-coupled receptor (GPCR) widely distributed on the hypothalamus and pituitary gland where it exerts its major functions of regulating appetite and growth hormone (GH) secretion. The activity of GHS-R1a is controlled by two counter-regulatory endogenous ligands: Ghrelin (activation) and LEAP-2 (inhibition). Ghrelin activates GHS-R1a on the neuropeptide Y/Agouti-related protein (NPY/AgRP) neurons at the arcuate nucleus (ARC) to promote appetite, and on the pituitary somatotrophs to stimulate GH release. On the flip side, LEAP-2, acts both as an endogenous competitive antagonist of ghrelin and an inverse agonist of constitutive GHS-R1a activity. Such a biological property of LEAP-2 vigorously blocks ghrelin’s effects on food intake and hormonal secretion. In circulation, LEAP-2 displays an inverse pattern as to ghrelin; it increases with food intake and obesity (positive energy balance), whereas decreases upon fasting and weight loss (negative energy balance). Thus, the LEAP-2/ghrelin molar ratio fluctuates in response to energy status and modulation of this ratio conversely influences energy intake. Inhibiting ghrelin’s activity has shown beneficial effects on obesity in preclinical experiments, which sheds light on LEAP-2’s anti-obesity potential. In this review, we will analyze LEAP-2’s effects from a metabolic point of view with a focus on metabolic hormones (e.g., ghrelin, GH, and insulin), and discuss LEAP-2’s potential as a promising therapeutic target for obesity.
Thyroid Dysfunction and Sleep Disorders
Authors: Green Max E. , Bernet Victor , Cheung Joseph
Published: August 2021

Thyroid disorders and sleep disorders are common problems in the general population that can affect people of all ages, backgrounds, and sexes, but little is known about their clinical associations. We reviewed the literature assessing the associations between thyroid disease and sleep disorders and noted that hyperthyroidism and hypothyroidism have clinical overlap with sleep conditions such as insomnia, restless legs syndrome, and obstructive sleep apnea. These findings highlight the importance of identifying and managing thyroid dysfunction for patients with these common sleep disorders. Additional research is needed to further understand how thyroid dysfunction affects sleep physiology.
Cascade Deep Forest With Heterogeneous Similarity Measures for Drug–Target Interaction Prediction
Authors: Zheng Ying , Wu Zheng
Published: August 2021

Drug repositioning is a method of systematically identifying potential molecular targets that known drugs may act on. Compared with traditional methods, drug repositioning has been extensively studied due to the development of multi-omics technology and system biology methods. Because of its biological network properties, it is possible to apply machine learning related algorithms for prediction. Based on various heterogeneous network model, this paper proposes a method named THNCDF for predicting drug–target interactions. Various heterogeneous networks are integrated to build a tripartite network, and similarity calculation methods are used to obtain similarity matrix. Then, the cascade deep forest method is used to make prediction. Results indicate that THNCDF outperforms the previously reported methods based on the 10-fold cross-validation on the benchmark data sets proposed by Y. Yamanishi. The area under Precision Recall curve (AUPR) value on the Enzyme, GPCR, Ion Channel, and Nuclear Receptor data sets is 0.988, 0.980, 0.938, and 0.906 separately. The experimental results well illustrate the feasibility of this method.
Inferring Functional Epigenetic Modules by Integrative Analysis of Multiple Heterogeneous Networks
Authors: Dou Zengfa , Ma Xiaoke
Published: August 2021

Gene expression and methylation are critical biological processes for cells, and how to integrate these heterogeneous data has been extensively investigated, which is the foundation for revealing the underlying patterns of cancers. The vast majority of the current algorithms fuse gene methylation and expression into a network, failing to fully explore the relations and heterogeneity of them. To resolve these problems, in this study we define the epigenetic modules as a gene set whose members are co-methylated and co-expressed. To address the heterogeneity of data, we construct gene co-expression and co-methylation networks, respectively. In this case, the epigenetic module is characterized as a common module in multiple networks. Then, a non-negative matrix factorization-based algorithm that jointly clusters the co-expression and co-methylation networks is proposed for discovering the epigenetic modules (called Ep-jNMF). Ep-jNMF is more accurate than the baselines on the artificial data. Moreover, Ep-jNMF identifies more biologically meaningful modules. And the modules can predict the subtypes of cancers. These results indicate that Ep-jNMF is efficient for the integration of expression and methylation data.
Identification of the Mouse T Cell ADP-Ribosylome Uncovers ARTC2.2 Mediated Regulation of CD73 by ADP-Ribosylation
Authors: Leutert Mario , Duan Yinghui , Winzer Riekje , Menzel Stephan , Tolosa Eva , Magnus Tim , Hottiger Michael O. , Koch-Nolte Friedrich , Rissiek Björn
Published: August 2021

Mouse T cells express the ecto-ADP-ribosyltransferase ARTC2.2, which can transfer the ADP-ribose group of extracellular nicotinamide adenine dinucleotide (NAD+) to arginine residues of various cell surface proteins thereby influencing their function. Several targets of ARTC2.2, such as P2X7, CD8a and CD25 have been identified, however a comprehensive mouse T cell surface ADP-ribosylome analysis is currently missing. Using the Af1521 macrodomain-based enrichment of ADP-ribosylated peptides and mass spectrometry, we identified 93 ADP-ribsoylated peptides corresponding to 67 distinct T cell proteins, including known targets such as CD8a and CD25 but also previously unknown targets such as CD73. We evaluated the impact of ADP-ribosylation on the capability of CD73 to generate adenosine from adenosine monophosphate. Our results show that extracellular NAD+reduces the enzymatic activity of CD73 HEK cells co-transfected with CD73/ARTC2.2. Importantly, NAD+significantly reduced CD73 activity on WT CD8 T cells compared to ARTC2ko CD8 T cells or WT CD8 T cells treated with an ARTC2.2-blocking nanobody. Our study provides a comprehensive list of T cell membrane proteins that serve as targets for ADP-ribosylation by ARTC2.2 and whose function may be therefore affected by ADP-ribosylation.
SARS-CoV-2 Spike Protein-Directed Monoclonal Antibodies May Ameliorate COVID-19 Complications in APECED Patients
Authors: Ferré Elise M. N. , Schmitt Monica M. , Ochoa Sebastian , Rosen Lindsey B. , Shaw Elana R. , Burbelo Peter D. , Stoddard Jennifer L. , Rampertaap Shakuntala , DiMaggio Tom , Bergerson Jenna R. E. , Rosenzweig Sergio D. , Notarangelo Luigi D. , Holland Steven M. , Lionakis Michail S.
Published: August 2021

Patients with the monogenic immune dysregulatory syndrome autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene, uniformly carry neutralizing autoantibodies directed against type-I interferons (IFNs) and many develop autoimmune pneumonitis, both of which place them at high risk for life-threatening COVID-19 pneumonia. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target the SARS-CoV-2 spike protein and block entry of SARS-CoV-2 in host cells. The use of bamlanivimab and etesevimab early during infection was associated with reduced COVID-19–associated hospitalization and death in patients at high risk for progressing to severe disease, which led the US Food and Drug Administration to issue an emergency use authorization for their administration in non-hypoxemic, non-hospitalized high-risk patients. However, the safety and efficacy of these mAbs has not been evaluated in APECED patients. We enrolled two siblings with APECED on an IRB-approved protocol (NCT01386437) and admitted them prophylactically at the NIH Clinical Center for evaluation of mild-to-moderate COVID-19. We assessed the safety and clinical effects of early treatment with bamlanivimab and etesevimab. The administration of bamlanivimab and etesevimab was well tolerated and was associated with amelioration of COVID-19 symptoms and prevention of invasive ventilatory support, admission to the intensive care, and death in both patients without affecting the production of antibodies to the nucleocapsid protein of SARS-CoV-2. If given early in the course of COVID-19 infection, bamlanivimab and etesevimab may be beneficial in APECED and other high-risk patients with neutralizing autoantibodies directed against type-I IFNs.
Tumor Infiltrating Lymphocytes Target HLA-I Phosphopeptides Derived From Cancer Signaling in Colorectal Cancer
Authors: Penny Sarah A. , Abelin Jennifer G. , Malaker Stacy A. , Myers Paisley T. , Saeed Abu Z. , Steadman Lora G. , Bai Dina L. , Ward Stephen T. , Shabanowitz Jeffrey , Hunt Donald F. , Cobbold Mark
Published: August 2021

There is a pressing need for novel immunotherapeutic targets in colorectal cancer (CRC). Cytotoxic T cell infiltration is well established as a key prognostic indicator in CRC, and it is known that these tumor infiltrating lymphocytes (TILs) target and kill tumor cells. However, the specific antigens that drive these CD8+ T cell responses have not been well characterized. Recently, phosphopeptides have emerged as strong candidates for tumor-specific antigens, as dysregulated signaling in cancer leads to increased and aberrant protein phosphorylation. Here, we identify 120 HLA-I phosphopeptides from primary CRC tumors, CRC liver metastases and CRC cell lines using mass spectrometry and assess the tumor-resident immunity against these posttranslationally modified tumor antigens. Several CRC tumor-specific phosphopeptides were presented by multiple patients’ tumors in our cohort (21% to 40%), and many have previously been identified on other malignancies (58% of HLA-A*02 CRC phosphopeptides). These shared antigens derived from mitogenic signaling pathways, including p53, Wnt and MAPK, and are therefore markers of malignancy. The identification of public tumor antigens will allow for the development of broadly applicable targeted therapeutics. Through analysis of TIL cytokine responses to these phosphopeptides, we have established that they are already playing a key role in tumor-resident immunity. Multifunctional CD8+ TILs from primary and metastatic tumors recognized the HLA-I phosphopeptides presented by their originating tumor. Furthermore, TILs taken from other CRC patients’ tumors targeted two of these phosphopeptides. In another cohort of CRC patients, the same HLA-I phosphopeptides induced higher peripheral T cell responses than they did in healthy donors, suggesting that these immune responses are specifically activated in CRC patients. Collectively, these results establish HLA-I phosphopeptides as targets of the tumor-resident immunity in CRC, and highlight their potential as candidates for future immunotherapeutic strategies.