bluuebunny/crossref_metadata_2025 huggingface dataset:
Alzheimer's Disease Blood Biomarkers Associated With Neuroinflammation as Therapeutic Targets for Early Personalized Intervention
Authors: Oh Sher Li , Zhou Meikun , Chin Eunice W. M. , Amarnath Gautami , Cheah Chee Hoe , Ng Kok Pin , Kandiah Nagaendran , Goh Eyleen L. K. , Chiam Keng-Hwee
Published: July 2022

The definitive diagnosis of Alzheimer's Disease (AD) without the need for neuropathological confirmation remains a challenge in AD research today, despite efforts to uncover the molecular and biological underpinnings of the disease process. Furthermore, the potential for therapeutic intervention is limited upon the onset of symptoms, providing motivation for studying and treating the AD precursor mild cognitive impairment (MCI), the prodromal stage of AD instead. Applying machine learning classification to transcriptomic data of MCI, AD, and cognitively normal (CN) control patients, we identified differentially expressed genes that serve as biomarkers for the characterization and classification of subjects into MCI or AD groups. Predictive models employing these biomarker genes exhibited good classification performances for CN, MCI, and AD, significantly above random chance. The PI3K-Akt, IL-17, JAK-STAT, TNF, and Ras signaling pathways were also enriched in these biomarker genes, indicating their diagnostic potential and pathophysiological roles in MCI and AD. These findings could aid in the recognition of MCI and AD risk in clinical settings, allow for the tracking of disease progression over time in individuals as part of a therapeutic approach, and provide possible personalized drug targets for early intervention of MCI and AD.
Local Drug-Induced Modulation of gp130 Receptor Signaling Delays Disease Progression in a Pig Model of Temporo-Mandibular Joint Osteoarthritis
Authors: Liu Nancy Q. , Chen Shuo , Geng Dawei , Lei Jie , Zhang Jiankang , Li Liangliang , Lin Yucheng , Ouyang Yuxin , Shkhyan Ruzanna , Van Handel Ben , Bian Fangzhou , Mkaratigwa Tadiwanashe , Chai Yang , Evseenko Denis
Published: July 2022

Temporomandibular joint disorders (TMJs) are a multifaceted group of chronic disorders characterized by stiffness in the jaw, limited jaw mobility and pain when opening or closing the mouth. TMJs are relatively common, with incidence rates in the range of 5–12%, with nearly twice as many women as men being affected. One of the primary causes of TMJs is a degenerative disease of joints, such as osteoarthritis (OA), characterized by progressive loss of cartilage, which causes stiffness, swelling, and pain. Currently, there are no disease-modifying agents on the market for OA. We have recently discovered a small molecule, R805, acting as a modulator of glycoprotein 130 (gp130) receptor for the IL-6 family of cytokines. R805 enables regenerative outputs of endogenous joint stem and progenitor cells through immunomodulation in the joint microenvironment by reducing the levels of destructive cytokines and supporting chondrocyte survival and anabolism. Extensive testing has shown R805 to be safe at doses far above the therapeutic level. Here, we have conducted a pivotal efficacy study in our newly established pig model of TMJ post-traumatic OA. IA injection of R805 has shown a highly significant reduction of articular cartilage degeneration, reduced synovitis and reduced degenerative changes in subchondral bone in the mandibular condyle compared to the vehicle-treated group. These data will support additional preclinical development of R805 as a first-in-class injectable therapeutic for TMJ osteoarthritis.
Experimental Study on Shear Strengths of Ice-Roof Interface Aiming the Study of Roof Snow Sliding
Authors: Cao Xinli , Mo Huamei , Zhang Guolong , Zhang Qingwen , Fan Feng
Published: July 2022

Snow sliding of roofs is a threat to the structural safety of roof structures by causing a surcharge of local snow load on the lower roof and may pose a serious threat to pedestrians and vehicles on the ground. Therefore, it is of great significance to study the mechanism of snow sliding on roofs. Under the action of ambient temperature, solar radiation, internal heating of the building, etc., the bottom layer of roof snow is often presented in the form of porous ice after a complicated phase transition of the snow particles. Under this circumstance, the interface between roof snow and the roof can be seen as the contact between porous ice and the roofing material. In order to investigate the initialization of roof snow sliding from the material point of view, the shear performance of the interface between different roofing materials and ice with different porosities was carried out in this study. The effects of different ambient temperatures (−4, −6, and −8°C), different normal stress (0, 50, and 100 kPa), and different ice porosities (represented by the contact area ratio of 1.0, 0.8, and 0.6) on this shear performance were analyzed by direct shear tests. The test results showed that the shear failure between the ice and the roofing material was brittle, and the interface shear strength was affected by the ambient temperature, normal stress, contact area ratio, as well as the material type: the strength increases with the decrease of ambient temperature, the increase of normal stress, the increase of contact area ratio, and the increase of surface roughness of the material. Based on the test results, a quantitative relationship between the interface shear strength and the related factors was given in the article, which provides a useful reference for future experimental or simulation studies on roof snow sliding.
Were Hominins Specifically Adapted to North-Western European Territories Between 700 and 600 ka? New Insight Into the Acheulean Site of Moulin Quignon (France, Somme Valley)
Authors: Moncel Marie-Hélène , Antoine Pierre , Herisson David , Locht Jean-Luc , Hurel Arnaud , Bahain Jean-Jacques
Published: July 2022

Current data seem to suggest that the earliest hominins only occupied the Northwest of Europe during favourable climatic periods, and left the area when the climate was too cold and dry, in the same way as Neandertal and even Homo sapiens. However, several sites in England and the North of France indicate that the earliest hominins, possibly Homo antecessor and/or Homo heidelbergensis, could adapt to cool environments and open grasslands without the use of fire. Recent discoveries of Acheulean lithic assemblages in early glacial fluvial deposits at Moulin Quignon in the Somme Valley in the Northwest of France reveal new knowledge on the earliest occupations in north-western territories and indicate hominins’ capacity to live above the c. 45th N. under a cold climate. The site shows evidence of occupations at the beginning of MIS 16 at around 650–670 ka. These findings bring to the forefront the possible ability, flexibility and resilience of Acheulean hominins at around 700 ka to extend to northern territories during transitional climatic periods (interglacial/glacial events), even if the climate was not fully favourable. Recent fieldwork has changed our interpretation of the timing and characteristics of the earliest Acheulean techno-complexes in Western Europe over a large geographical area, from Northwest Europe to the Mediterranean coast. In Western Europe, the earliest evidence, Moulin Quignon, is now dated to a narrow timeframe, between 700–650 ka, and is the northernmost evidence of biface production. This latter is earlier than British Acheulean records. Based on new findings at Moulin Quignon, we explore whether Acheulean traditions and associated new technological abilities could have facilitated the dispersal of hominins in Western Europe over large territories, regardless of climatic conditions. Changes in behavioural flexibility, and not only phenotypic changes in Homo groups, have to be investigated. Here, we examine the behavioural and technological abilities of hominins in north-western Europe in light of the available environmental data and compare them to those in southern areas between 700 and 600 ka. This event occurred at the end of the “Middle Pleistocene Transition” (MPT), a period marked by cyclical climate changes and vegetation and faunal turnovers (less competition with big carnivores). The extension of the grassland habitat into higher latitudes could have led to the opening and/or closing of migration corridors in these regions, probably favouring hominin expansion depending on tolerance to climate variability.
Incidence, Morbidity and years Lived With Disability due to Type 2 Diabetes Mellitus in 204 Countries and Territories: Trends From 1990 to 2019
Authors: Zhu Rongrong , Zhou Shan , Xia Liang , Bao Xiaoming
Published: July 2022

Background

We aimed to examine the descriptive epidemiology and trends in the burden of type 2 diabetes mellitus (T2DM).

Methods

Data were extracted from the Global Burden of Disease 2019 dataset. Estimated annual percentage changes (EAPCs) were calculated to assess the trends in incidence rate, mortality and disability-adjusted life-years (DALYs) associated with T2DM. Measures were stratified by sex, region, country, age and social development index (SDI) value.

Results

The global age-standardized incidence rate of T2DM increased from 1990 to 2019, with an EAPC of 1.25 (95% CI, 1.19 to 1.31). In 2019, the highest age-standardized incidence rate of T2DM was observed in high-SDI regions, and the largest increase in this rate from 1990 to 2019 was also in high-SDI regions (EAPC, 1.74;95% CI, 1.57 to 1.90). At the regional level, Central Asia (EAPC, 2.53;95% CI, 2.45 to 2.61) had the largest increase in the age-standardized incidence rate of T2DM from 1990 to 2019. At the national level, Luxembourg (EAPC, 4.51;95% CI, 4.37 to 4.65) and Uzbekistan (EAPC, 3.63; 95% CI, 3.44 to 3.82) had the largest increases in the age-standardized incidence rate of T2DM from 1990 to 2019. The global age-standardized death and DALY rates increased from 1990 to 2019, with EAPCs of 0.26 (95% CI, 0.16 to 0.37) and 0.81 (95% CI, 0.77 to 0.85), respectively. The age-standardized death and DALY rates showed the largest increases in Central Asia, South Asia and Southern Sub-Saharan Africa.

Conclusions

Globally, the age-standardized incidence, death and DALY rates increased from 1990 to 2019. Central Asia, South Asia and Southern Sub-Saharan Africa were found to have the greatest burden of T2DM. Future strategies should focus on these high-risk regions and other high-risk populations.
A High Power Quality Buck-H Auxiliary Power Converter in Railway Applications
Authors: Lan Zheng , Wu Fangreng , He Dong , Yu Xueping , Zeng Jinhui , Xiao Fan
Published: July 2022

DC voltage utilization and AC voltage harmonics are important evaluation indexes for Auxiliary Power Converter in Railway Applications. To improve the above two indicators, a novel switch-mode modulation method and quasi-PR control strategy for Buck-H three-phase inverter is proposed in this paper. The Buck-H three-phase inverter integrates the AC side filter circuit into the DC Buck circuit, which reduces the volume of the filter capacitor and improves the filtering effect. This novel switch-mode modulation method uses only one high frequency switch per phase, which reduces the switching losses and thereby increases overall efficiency. In addition, this switch-mode modulation absence of shoot-through menace eliminates the dead time requirement. Meanwhile, the quasi-proportional-resonance (PR) controller and its control parameters are optimized to improve the AC voltage tracking performance. The influence of PR control parameters on system performance is analyzed in detail. The proposed switch-mode modulation method and control method can effectively reduce the harmonic distortion rate of the system. The effectiveness is verified through the StarSim hardware-in-the-loop experimental results.
Joint Optimal Scheduling of Renewable Energy Regional Power Grid With Energy Storage System and Concentrated Solar Power Plant
Authors: Dong Yannan , Han Zijiao , Li Xiangjun , Ma Shaohua , Gao Fulin , Li Wenwen
Published: July 2022

Under the path of global low-carbon development, increasing the proportion of renewable energy in the power grid will become the main goal in the future. But, it will also aggravate the problem of wind and solar curtailment. A joint optimal scheduling model of a renewable energy regional power grid with an energy storage system and concentrated solar power plant is proposed in this study. The proposed model takes the lowest comprehensive operation cost of the power grid as the optimization goal and considers various constraints of concentrated solar power plants, energy storage systems, thermal power units, wind power, and photovoltaic power generation. Finally, a modified IEEE 9-bus system is used to verify the validity. The results show that the model can effectively improve the system node voltage, promote the accommodation of wind and solar power, and alleviate the peak shaving of thermal power units under the premise of optimal economy pressure.
Optimization and Control for Solid Oxide Fuel Cell System Hybrid DC Microgrids From the Perspective of High Efficiency, Thermal Safety, and Transient Response
Authors: Zhang Lin , Tang Wenhui , Wang Feng , Xie Chao , Zhou Weibin , Xie Hongtu
Published: July 2022

Managing the power transients with both high efficiency and thermal management constraints is a difficult task in the solid oxide fuel cell (SOFC) hybrid direct-current (DC) microgrids. This article proposed a SOFC-based DC microgrid, which consists of the SOFC stand-alone system, DC microgrid network, and DC/DC boost converter, along with the associated DC/DC load. The control and optimization strategy of the SOFC-based DC microgrids has been designed, including the thermal and electrical characteristics analysis. First, the voltage and current regulator based on the proportional–integral (PI) is designed, which can maintain the voltage stability of the proposed SOFC system. In addition, the optimal regulator based on the optimal operating points (OOPs) is designed, which can realize high efficiency and steady-state thermal safety of the proposed SOFC system. Finally, the main performance, including the SOFC stack electrical characteristics verification, SOFC stand-alone system electrical and thermal response, load-tracking characteristics, and system efficiency is observed and discussed in the proposed control and optimization strategy. Experimental results verify the correctness of the theoretical analysis and the effectiveness of the proposed optimization and control strategy.
Nitrogen Leaching From Agricultural Soils Under Imposed Freeze-Thaw Cycles: A Column Study With and Without Fertilizer Amendment
Authors: Krogstad Konrad , Gharasoo Mehdi , Jensen Grant , Hug Laura A. , Rudolph David , Van Cappellen Philippe , Rezanezhad Fereidoun
Published: July 2022

Cold regions are warming faster than the rest of the planet, with the greatest warming occurring during the winter and shoulder seasons. Warmer winters are further predicted to result in more frequent soil freezing and thawing events. Freeze-thaw cycles affect biogeochemical soil processes and alter carbon and nutrient export from soils, hence impacting receiving ground and surface waters. Cold region agricultural management should therefore consider the possible effects on water quality of changing soil freeze-thaw dynamics under future climate conditions. In this study, soil column experiments were conducted to assess the leaching of fertilizer nitrogen (N) from an agricultural soil during the non-growing season. Identical time series temperature and precipitation were imposed to four parallel soil columns, two of which had received fertilizer amendments, the two others not. A 15-30-15 N-P-K fertilizer (5.8% ammonium and 9.2% urea) was used for fertilizer amendments. Leachates from the soil columns were collected and analyzed for major cations and anions. The results show that thawing following freezing caused significant export of chloride (Cl−), sulfate (SO42−) and nitrate (NO3−) from the fertilizer-amended soils. Simple plug flow reactor model calculations indicated that the high NO3−concentrations produced during the fertilized soil thawing events were due to nitrification of fertilizer N in the upper oxidized portion of the soil. The very low concentrations of NO3−and ammonium in the non-fertilized soils leachates implied that the freeze-thaw cycles had little impact on the mineralization of soil organic N. The findings, while preliminary, indicate that unwanted N enrichment of aquifers and rivers in agricultural areas caused by fall application of N fertilizers may be exacerbated by changing freeze-thaw activity.
Impact of Environmental Protection Regulations on Corporate Performance From Porter Hypothesis Perspective: A Study Based on Publicly Listed Manufacturing Firms Data
Authors: Mu Shaohong , Wang Xianglu , Mohiuddin Muhammad
Published: July 2022

“Porter Hypothesis” believes that environmental protection regulations contribute to cleaner production and green technology innovation which benefit to enhance manufacturing firm performance . We take China’s new “Environmental Protection Regulations (2015), as a quasi-natural experiment, using A-share listed companies in Shenzhen and Shanghai in 2012–2017 as a research sample. Using the propensity score matching and double difference (PSM-DID) method, we empirically test the impact of environmental regulations on the financial performance of these companies. The results show that the new Environmental Protection Law has significantly improved corporate profits of large enterprises large firms. Different from the innovation mechanism emphasized in the literature based on the Porter hypothesis, we find that “Compliance cost heterogeneity” caused by the scale difference of firms better explains the impact of environmental regulations on the profit margin of listed manufacturing firms. Overall, this study contributes novel insights about the economic consequences of environmental regulation and establishes an initial foundation for investigating environmental regulation from the perspective of compliance cost heterogeneity.
Characteristics of Canopy Conductance and Environmental Driving Mechanism in Three Monsoon Climate Regions of China
Authors: Wu Rui-Qiao , Jia Jian-Bo , Yan Wen-De , Hu Lei , Wang Yi-Fan , Chen Yu
Published: July 2022

Canopy conductance was an important index to measure the process of water exchange between canopy and atmosphere interface of forest ecosystem, as well as to judge the status of water use or the degree of drought stress. Therefore, the accurate estimation of forest canopy conductance was of great significance for the research of water-use efficiency. In the past, canopy conductance was measured on vegetation types in a single-point region, but there were few studies on systematic comparison in different climate zones. Based on the data sets of EC flux and conventional meteorological elements from the eddy covariance (EC) flux observation station during 2003–2010 in three typical climate zones (temperate continental monsoon climate zone, south subtropical monsoon climate zone, and mid-subtropical monsoon climate zone), Penman-Monteith model was used to calculate forest canopy conductance in different climate regions and analyze the dynamic changes of canopy conductance in different time scales. At the same time, combined with environmental factors including temperature, net radiation, soil water content, and vapor pressure deficit to explore their driving ability on the canopy conductivity of forest ecosystem in different climate regions, we finally explored the mechanism driving the canopy conductivity of forest ecosystem under different climates. The results showed that: 1) the driving ability of environmental factors in different climate regions to the canopy conductance was different, and the contribution rate of soil water content to the canopy conductance in subtropical monsoon climate zone was the largest. It was 36.01%, and the contribution rate of vapor pressure deficit to the canopy conductance in mid-subtropical monsoon climate region was the largest. It was 29.4% and the contribution rate of temperature to the canopy conductance in temperate monsoon climate region was the largest; it was 28.14%. 2). Temperature was an important factor limiting and driving canopy conductance, and there was a synergistic effect between water and temperature, which jointly drove the change in canopy conductance. 3) Environmental factors in different climate regions had threshold for the synergistic driving effect of canopy conductance. When the factors were within the appropriate threshold, the factors had a strong promoting effect on canopy conductance.
Empirical Analysis of the Impact of Industrial Internet Development Environment on Open Green Innovation of Manufacturing Enterprises
Authors: Hu Rui , Shahzad Fakhar , Abbas Adnan , Xu Nan
Published: July 2022

This study aims to expand the research perspective from the micro-enterprise level to the regional environment level to identify changes in the regional industrial Internet environment. The development and application of Industrial Internet technologies formed by these changes have spillover effects on Industrial Internet innovation. Sample data from 30 provinces and big cities of China from 2006 to 2018 were used to verify the network externality characteristics of industrial Internet development. The nonlinear impact of environmental factors, such as the proportion of Internet users and intellectual property protection on the open green innovation of manufacturing enterprises, was investigated through the panel threshold model. Meanwhile, the development level of the industrial Internet in eastern and western China is compared and analyzed. This study contributes to existing knowledge and guides practitioners to help manufacturing organizations develop industrial Internet environments.
Historical Spruce Abundance in Central Europe: A Combined Dendrochronological and Palynological Approach
Authors: Seim Andrea , Marquer Laurent , Bisson Ugo , Hofmann Jutta , Herzig Franz , Kontic Raymond , Lechterbeck Jutta , Muigg Bernhard , Neyses-Eiden Mechthild , Rzepecki Andreas , Rösch Manfred , Walder Felix , Weidemüller Julia , Tegel Willy
Published: July 2022

Spruce is the most cultivated tree species in modern forestry in Central Europe, since it has the ability to grow on many soil types with profitable biomass accumulation. However, even-aged and uniform spruce forests are affected by recurring droughts and associated biotic stressors leading to large-scale diebacks across Central Europe causing controversies among foresters and nature conservationists. We investigate the role of spruce in historical woodlands by using 15666 spruce timbers from historical buildings and on the basis of pollen-based land cover estimates using the REVEALS model from 157 pollen sites in southern Central Europe. Start and end dates of the spruce timber samples and their dendrological characteristics (age, growth rates and stem diameters) were used to obtain information on past forest structures. Tree rings and REVEALS estimates are combined at a spatial scale of 1° × 1° resolution, grouped in four sub-regions, and a temporal resolution of 100-year time windows starting from 1150 to 1850 CE. We found that spruce dominates the species assemblage of construction timber with almost 41% and that the harvest age varies little through time, whereas a declining trend in growth rates and stem diameters are observed toward times before modern forestry. Temporal and regional differences in spruce abundance and building activity were found highlighting periods of (i) land abandonment and forest expansion in the 14th century, (ii) increased wood consumption during the 16th century due to population increase and beginning industrial developments, (iii) a forest recovery during and after the Thirty years' war, and (iv) afforestation efforts from the 1650s onwards. Furthermore, this study shows that spruce was constantly present in the study area in most studied sub-regions for the last 800 years. We demonstrate the need of combining tree-ring and pollen data to identify spatiotemporal patterns in spruce abundance and utilization.
Characterizing the Dependence on Non-timber Forest Products Among Communities Living Around Forest Conservation Areas in Marrupa-Mecula Corridor, Niassa Special Reserve, Niassa Province of Mozambique
Authors: Lubega Gerald , Falcão Mário Paulo , Ssekandi Joseph , Ribeiro Natasha Sofia
Published: July 2022

The role of forests across the world has been recognized as key natural assets that offer several goods and services, especially to communities adjacent to them. Given this role, there have been minimal efforts to determine the factors characterizing this dependence of communities on non-timber forest products (NTFPs), especially in developing nations. This study surveyed and assessed different factors influencing household dependence on NTFPs in the Marrupa-Mecula Corridor, Niassa Special Reserve, Niassa Province of Mozambique. In total, 377 household members from eight villages attended the interview while employing proportional random sampling. Data analysis was done using descriptive statistics and binary logistic regression. The study revealed that 90.9% of the households participate in collecting, producing, and selling NTFPs. Three factors, namely, social, economic, and physical, with twenty sub-factors or characteristics were found to have a significant association with dependence on forest resources. They include the availability of NTFPs, taking a collection of NTFPs as a family job, strong cultural attachment to forests, seasonal engagement in collection, nearby forests being home for community leaders, distance to the nearby forest, the housing needs of forests, forests being a major source of medicine, forests being a resource for educational institutions, forests being a major source of household food security, forests being a ready income for households, forests being a tourist attraction in the area, and affordability of distance to markets. The binary logistic regression revealed that gender, age, education, family size, and time spent in the area are significantly associated with dependence on NTFPs. Additionally, strong cultural attachment to forests, seasonal engagement in collection, nearby forests being homes for community leaders, distance to the nearby forest, housing needs, a major source of medicine, education, household food security, ready income, tourist attraction, and affordability of distance to markets were found to have a significant influence. On the contrary, scary dangerous wild animals, restriction of cultivation in non-gazetted forests, restriction of hunting in non-gazetted forests, and forest fires negatively affected the dependence on NTFPs/resources. As a way of achieving sustainable utilization of NTFPs, management plans and strategies need to incorporate these factors characterizing the dependence on NTFPs.
Genome-wide Association Study for Yield and Yield-Related Traits in Diverse Blackgram Panel (Vigna mungo L. Hepper) Reveals Novel Putative Alleles for Future Breeding Programs
Authors: Singh Lovejit , Dhillon Guriqbal Singh , Kaur Sarabjit , Dhaliwal Sandeep Kaur , Kaur Amandeep , Malik Palvi , Kumar Ashok , Gill Ranjit Kaur , Kaur Satinder
Published: July 2022

Blackgram (Vigna mungo L. Hepper) is an important tropical and sub-tropical short-duration legume that is rich in dietary protein and micronutrients. Producing high-yielding blackgram varieties is hampered by insufficient genetic variability, absence of suitable ideotypes, low harvest index and susceptibility to biotic-abiotic stresses. Seed yield, a complex trait resulting from the expression and interaction of multiple genes, necessitates the evaluation of diverse germplasm for the identification of novel yield contributing traits. Henceforth, a panel of 100 blackgram genotypes was evaluated at two locations (Ludhiana and Gurdaspur) across two seasons (Spring 2019 and Spring 2020) for 14 different yield related traits. A wide range of variability, high broad-sense heritability and a high correlation of grain yield were observed for 12 out of 14 traits studied among all environments. Investigation of population structure in the panel using a set of 4,623 filtered SNPs led to identification of four sub-populations based on ad-hoc delta K and Cross entropy value. Using Farm CPU model and Mixed Linear Model algorithms, a total of 49 significant SNP associations representing 42 QTLs were identified. Allelic effects were found to be statistically significant at 37 out of 42 QTLs and 50 known candidate genes were identified in 24 of QTLs.
Optimal Sparsity Selection Based on an Information Criterion for Accurate Gene Regulatory Network Inference
Authors: Seçilmiş Deniz , Nelander Sven , Sonnhammer Erik L. L.
Published: July 2022

Accurate inference of gene regulatory networks (GRNs) is important to unravel unknown regulatory mechanisms and processes, which can lead to the identification of treatment targets for genetic diseases. A variety of GRN inference methods have been proposed that, under suitable data conditions, perform well in benchmarks that consider the entire spectrum of false-positives and -negatives. However, it is very challenging to predict which single network sparsity gives the most accurate GRN. Lacking criteria for sparsity selection, a simplistic solution is to pick the GRN that has a certain number of links per gene, which is guessed to be reasonable. However, this does not guarantee finding the GRN that has the correct sparsity or is the most accurate one. In this study, we provide a general approach for identifying the most accurate and sparsity-wise relevant GRN within the entire space of possible GRNs. The algorithm, called SPA, applies a “GRN information criterion” (GRNIC) that is inspired by two commonly used model selection criteria, Akaike and Bayesian Information Criterion (AIC and BIC) but adapted to GRN inference. The results show that the approach can, in most cases, find the GRN whose sparsity is close to the true sparsity and close to as accurate as possible with the given GRN inference method and data. The datasets and source code can be found at https://bitbucket.org/sonnhammergrni/spa/.
A Glycosyltransferase-Related Signature for Predicting Overall Survival in Head and Neck Squamous Cell Carcinoma
Authors: Wu Huili , Zhao Xiao , Zhu Tingting , Rong Di , Wang Ying , Leng Diya , Wu Daming
Published: July 2022

Background: Here, we establish a prognostic signature based on glycosyltransferase-related genes (GTRGs) for head and neck squamous cell carcinoma (HNSCC) patients.

Methods: The prognostic signature of GTRGs was constructed via univariate and multivariate Cox analyses after obtaining the expression patterns of GTRGs from the TCGA. A nomogram based on the signature and clinical parameters was established to predict the survival of each HNSCC patient. Potential mechanisms were explored through gene set enrichment analysis (GSEA) and immune cell infiltration, immune checkpoints, immunotherapy, and tumor mutational burden (TMB) analyses. The expression differences and prognostic efficacy of the signature were verified through the gene expression omnibus (GEO) and several online databases.

Results: The prognostic signature was constructed based on five glycosyltransferases (PYGL, ALG3, EXT2, FUT2, and KDELC1) and validated in the GSE65858 dataset. The pathways enriched in the high- and low-risk groups were significantly different. The high-risk group had higher tumor purity; lower infiltration of immune cells, such as CD8+ T cells and Tregs; higher cancer-associated fibroblast (CAF) infiltration; lower immune function; and lower checkpoint expression. The signature can also be applied to distinguish whether patients benefit from immunotherapy. In addition, the high-risk group had a higher TMB and more gene mutations, including those in TP53, CSMD1, CDKN2A, and MUC17.

Conclusion: We propose a prognostic signature based on glycosyltransferases for HNSCC patients that may provide potential targets and biomarkers for the precise treatment of HNSCC.
lncRNAs Functioned as ceRNA to Sponge miR-15a-5p Affects the Prognosis of Pancreatic Adenocarcinoma and Correlates With Tumor Immune Infiltration
Authors: Wang Yu , Wang Zhen , Li KaiQiang , Xiang WeiLing , Chen BinYu , Jin LiQin , Hao Ke
Published: July 2022

Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors with poor prognosis worldwide. Mounting evidence suggests that the expression of lncRNAs and the infiltration of immune cells have prognostic value for patients with PAAD. We used Gene Expression Omnibus (GEO) database and identified six genes (COL1A2, ITGA2, ITGB6, LAMA3, LAMB3, and LAMC2) that could affect the survival rate of pancreatic adenocarcinoma patients. Based on a series of in silico analyses for reverse prediction of target genes associated with the prognosis of PAAD, a ceRNA network of mRNA (COL1A2, ITGA2, LAMA3, LAMB3, and LAMC2)–microRNA (miR-15a-5p)–long non-coding RNA (LINC00511, LINC01578, PVT1, and TNFRSF14-AS1) was constructed. We used the algorithm “CIBERSORT” to assess the proportion of immune cells and found three overall survival (OS)–associated immune cells (monocytes, M1 macrophages, and resting mast cell). Moreover, the OS-associated gene level was significantly positively associated with immune checkpoint expression and biomarkers of immune cells. In summary, our results clarified that ncRNA-mediated upregulation of OS-associated genes and tumor-infiltration immune cells (monocytes, M1 macrophages M1, and resting mast cell resting) correlated with poor prognosis in PAAD.
Case Report: Identification of Two Variants of ALG13 in Families With or Without Seizure and Binocular Strabismus: Phenotypic Spectrum Analysis
Authors: Cai Tao , Huang Jieting , Ma Xiuwei , Hu Siqi , Zhu Lina , Zhu Jinwen , Feng Zhichun
Published: July 2022

Background: Genetic causes in most affected children with intellectual disability and/or development delay remain unknown.

Methods: To identify potential variants responsible for these disorders, we recruited 161 affected families and performed whole-exome sequencing and associated bioinformatics analysis.

Results: In the present study, we report the identification of variants in the ALG13 gene in two of the families. In family 1, a known pathogenic missense variant (c.23T > C; p.V8A) of ALG13 was identified in a boy and his mother. In family 2, a novel missense variant (c.862C > G; p.L288V) of the same gene was identified in the affected boy and his phenotypically normal mother. Genotype–phenotype correlation analysis by comparing reported 28 different variants (HGMD) showed that three major phenotypes, including various seizures/epilepsy, intellectual disability, and development delay (such as growth, speech, motor, etc.), are present in most affected individuals. However, other phenotypes, such as strabismus and absence of seizure in our second patient, are not reported if any, which may represent a unique case of X-linked recessive nonsyndromic disorder caused by a mutation in ALG13.

Conclusion: We identified two missense variants in ALG13 in a cohort of 161 families with affected individuals diagnosed as intellectual disability and/or development delay. A novel c.862C > G mutation may represent a case of X-linked recessive.
A Novel Necroptosis-Related Gene Signature in Skin Cutaneous Melanoma Prognosis and Tumor Microenvironment
Authors: Song Binyu , Wu Pingfan , Liang Zhen , Wang Jianzhang , Zheng Yu , Wang Yuanyong , Chi Hao , Li Zichao , Song Yajuan , Yin Xisheng , Yu Zhou , Song Baoqiang
Published: July 2022

Background: Necroptosis has been identified recently as a newly recognized programmed cell death that has an impact on tumor progression and prognosis, although the necroptosis-related gene (NRGs) potential prognostic value in skin cutaneous melanoma (SKCM) has not been identified. The aim of this study was to construct a prognostic model of SKCM through NRGs in order to help SKCM patients obtain precise clinical treatment strategies.

Methods: RNA sequencing data collected from The Cancer Genome Atlas (TCGA) were used to identify differentially expressed and prognostic NRGs in SKCM. Depending on 10 NRGs via the univariate Cox regression analysis usage and LASSO algorithm, the prognostic risk model had been built. It was further validated by the Gene Expression Omnibus (GEO) database. The prognostic model performance had been assessed using receiver operating characteristic (ROC) curves. We evaluated the predictive power of the prognostic model for tumor microenvironment (TME) and immunotherapy response.

Results: We constructed a prognostic model based on 10 NRGs (FASLG, TLR3, ZBP1, TNFRSF1B, USP22, PLK1, GATA3, EGFR, TARDBP, and TNFRSF21) and classified patients into two high- and low-risk groups based on risk scores. The risk score was considered a predictive factor in the two risk groups regarding the Cox regression analysis. A predictive nomogram had been built for providing a more beneficial prognostic indicator for the clinic. Functional enrichment analysis showed significant enrichment of immune-related signaling pathways, a higher degree of immune cell infiltration in the low-risk group than in the high-risk group, a negative correlation between risk scores and most immune checkpoint inhibitors (ICIs), anticancer immunity steps, and a more sensitive response to immunotherapy in the low-risk group.

Conclusions: This risk score signature could be applied to assess the prognosis and classify low- and high-risk SKCM patients and help make the immunotherapeutic strategy decision.
Integrated Full-Length Transcriptome and MicroRNA Sequencing Approaches Provide Insights Into Salt Tolerance in Mangrove (Sonneratia apetala Buch.-Ham.)
Authors: Chen Beibei , Ding Zeyi , Zhou Xiang , Wang Yue , Huang Fei , Sun Jiaxin , Chen Jinhui , Han Weidong
Published: July 2022

MicroRNAs (miRNAs) are small RNA molecules that serve as key players in plant stress responses. Although stress-regulated miRNAs have been explored in various plants, they are not well studied in mangroves. Herein, we combined PacBio isoform sequencing (Iso-Seq) with BGISEQ short-read RNA-seq to probe the role of miRNAs in the salt stress response of the mangrove plant, Sonneratia apetala Buch.-Ham. A total of 1,702,463 circular consensus sequencing reads were generated that produced 295,501 nonredundant full-length transcripts from the leaves of a 1-year-old S. apetala. After sequencing nine small RNA libraries constructed from control and 1- and 28-day 300 mM NaCl treatments, we identified 143 miRNAs (114 known and 29 novel) from a total of >261 million short reads. With the criteria of |log2FC| ≥ 1 and q-value < 0.05, 42 and 70 miRNAs were differentially accumulated after 1- and 28-day salt treatments, respectively. These differential accumulated miRNAs potentially targeted salt-responsive genes encoding transcription factors, ion homeostasis, osmotic protection, and detoxificant-related proteins, reminiscent of their responsibility for salinity adaptation in S. apetala. Particularly, 62 miRNAs were Sonneratia specific under salt stress, of which 34 were co-expressed with their 131 predicted targets, thus producing 140 miRNA–target interactions. Of these, 82 miRNA-target pairs exhibited negative correlations. Eighteen miRNA targets were categorized for the ‘environmental information processing’ during KEGG analysis and were related to plant hormone signal transduction (ko04075), MAPK signaling pathway–plant (ko04016), and ABC transporters (ko02010). These results underscored miRNAs as possible contributors to mangrove success in severe environments and offer insights into an miRNA-mediated regulatory mechanism of salt response in S. apetala.
Effect of Dysglycemia on Urinary Lipid Mediator Profiles in Persons With Pulmonary Tuberculosis
Authors: Arriaga María B. , Karim Farina , Queiroz Artur T.L. , Araújo-Pereira Mariana , Barreto-Duarte Beatriz , Sales Caio , Moosa Mahomed-Yunus S. , Mazibuko Matilda , Milne Ginger L. , Maruri Fernanda , Serezani Carlos Henrique , Koethe John R. , Figueiredo Marina C. , Kritski Afrânio L. , Cordeiro-Santos Marcelo , Rolla Valeria C. , Sterling Timothy R. , Leslie Alasdair , Andrade Bruno B. ,   the RePORT Brazil and South Africa consortia
Published: July 2022

Background

Oxidized lipid mediators such as eicosanoids play a central role in the inflammatory response associated with tuberculosis (TB) pathogenesis. Diabetes mellitus (DM) leads to marked changes in lipid mediators in persons with TB. However, the associations between diabetes-related changes in lipid mediators and clearance of M. tuberculosis (Mtb) among persons on anti-TB treatment (ATT) are unknown. Quantification of urinary eicosanoid metabolites can provide insights into the circulating lipid mediators involved in Mtb immune responses.

Methods

We conducted a multi-site prospective observational study among adults with drug-sensitive pulmonary TB and controls without active TB; both groups had sub-groups with or without dysglycemia at baseline. Participants were enrolled from RePORT-Brazil (Salvador site) and RePORT-South Africa (Durban site) and stratified according to TB status and baseline glycated hemoglobin levels: a) TB-dysglycemia (n=69); b) TB-normoglycemia (n=64); c) non-TB/dysglycemia (n=31); d) non-TB/non-dysglycemia (n=29). We evaluated the following urinary eicosanoid metabolites: 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (major urinary metabolite of prostaglandin E2, PGE-M), tetranor-PGE1 (metabolite of PGE2, TN-E), 9α-hydroxy-11,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (metabolite of PGD2, PGD-M), 11-dehydro-thromboxane B2 (11dTxB2), 2,3-dinor-6-keto-PGF1α (prostaglandin I metabolite, PGI-M), and leukotriene E4 (LTE4). Comparisons between the study groups were performed at three time points: before ATT and 2 and 6 months after initiating therapy.

Results

PGE-M and LTE4 values were consistently higher at all three time-points in the TB-dysglycemia group compared to the other groups (p<0.001). In addition, there was a significant decrease in PGI-M and LTE4 levels from baseline to month 6 in the TB-dysglycemia and TB-normoglycemia groups. Finally, TB-dysglycemia was independently associated with increased concentrations of PGD-M, PGI-M, and LTE4 at baseline in a multivariable model adjusting for age, sex, BMI, and study site. These associations were not affected by HIV status.

Conclusion

The urinary eicosanoid metabolite profile was associated with TB-dysglycemia before and during ATT. These observations can help identify the mechanisms involved in the pathogenesis of TB-dysglycemia, and potential biomarkers of TB treatment outcomes, including among persons with dysglycemia.
Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma
Authors: Zhang Zhen , Zeng Xiangyang , Wu Yinghua , Liu Yang , Zhang Xi , Song Zewen
Published: July 2022

Aims

Cuproptosis is a recently identified form of programmed cell death; however, its role in hepatocellular carcinoma (HCC) remains unclear.

Methods

A set of bioinformatic tools was integrated to analyze the expression and prognostic significance of ferredoxin 1 (FDX1), the key regulator of cuproptosis. A cuproptosis-related risk score (CRRS) was developed via correlation analyses, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression. The metabolic features, mutation signatures, and immune profile of CRRS-classified HCC patients were investigated, and the role of CRRS in therapy guidance was analyzed.

Results

FDX1 was significantly downregulated in HCC, and its high expression was associated with longer survival time. HCC patients in the high-CRRS group showed a significantly lower overall survival (OS) and enriched in cancer-related pathways. Mutation analyses revealed that the high-CRRS HCC patients had a high mutational frequency of some tumor suppressors such as tumor protein P53 (TP53) and Breast-cancer susceptibility gene 1 (BRCA1)-associated protein 1 (BAP1) and a low frequency of catenin beta 1 (CTNNB1). Besides, HCC patients with high CRRS showed an increase of protumor immune infiltrates and a high expression of immune checkpoints. Moreover, the area under the curve (AUC) values of CRRS in predicting the efficiency of sorafenib and the non-responsiveness to transcatheter arterial chemoembolization (TACE) in HCC patients reached 0.877 and 0.764, respectively.

Significance

The cuproptosis-related signature is helpful in prognostic prediction and in guiding treatment for HCC patients.
Homeostasis Maintenance in Plasmodium-Infected Placentas: Is There a Role for Placental Autophagy During Malaria in Pregnancy?
Authors: Barateiro André , Junior Alexsander Rodrigues Carvalho , Epiphanio Sabrina , Marinho Claudio Romero Farias
Published: July 2022

Malaria represents a significant public health burden to populations living in developing countries. The disease takes a relevant toll on pregnant women, who are more prone to developing severe clinical manifestations. Inflammation triggered in response toP. falciparumsequestration inside the placenta leads to physiological and structural changes in the organ, reflecting locally disrupted homeostasis. Altogether, these events have been associated with poor gestational outcomes, such as intrauterine growth restriction and premature delivery, contributing to the parturition of thousands of African children with low birth weight. Despite significant advances in the field, the molecular mechanisms that govern these outcomes are still poorly understood. Herein, we discuss the idea of how some housekeeping molecular mechanisms, such as those related to autophagy, might be intertwined with the outcomes of malaria in pregnancy. We contextualize previous findings suggesting that placental autophagy is dysregulated inP. falciparum-infected pregnant women with complementary research describing the importance of autophagy in healthy pregnancies. Since the functional role of autophagy in pregnancy outcomes is still unclear, we hypothesize that autophagy might be essential for circumventing inflammation-induced stress in the placenta, acting as a cytoprotective mechanism that attempts to ensure local homeostasis and better gestational prognosis in women with malaria in pregnancy.