bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: A Novel LAMP2 Splice-Altering Mutation Causes Cardiac-Only Danon Disease
Authors: Li Zongzhe , Ma Fei , Li Rui , Xiao Zhichao , Zeng Hesong , Wang Dao Wen
Published: December 2021

Danon disease (DD) is a rare glycogen storage lysosomal disorder caused by mutations in the LAMP2 gene. Patients with DD are usually characterized clinically by severe multisystem syndromes. We describe a specific family with a novel pathogenic splice-altering mutation in the LAMP2 gene (c.741+2T>C) with cardiac-only symptoms (frequent ventricular tachycardia, intraventricular block, and hypertrophic cardiomyopathy). Minigene assays were used to evaluate the consequence of the splice-site mutation in the LAMP2 gene. The results showed that the c.741+2T>C mutation led to extra 6-bp preservation of intron 5 at the junction between exons 5 and 6 during transcriptional processing of the mRNA, which creates a stop codon and truncated the LAMP2 protein to 248-amino-acid residues. The mutant LAMP2 protein was predicted to have a conformational change, lacks the important transmembrane domain, and subsequent protein destabilization.
Comparison of Drug-Coated Balloon Angioplasty vs. Drug-Eluting Stent Implantation for Drug-Eluting Stent Restenosis in the Routine Clinical Practice: A Meta-Analysis of Randomized Controlled Trials
Authors: Zhu Yong , Liu Kesen , Kong Xiangyun , Nan Jing , Gao Ang , Liu Yan , Han Hongya , Li Hong , Zhu Huagang , Zhang Jianwei , Zhao Yingxin
Published: December 2021

Introduction: In-stent restenosis (ISR) remains a challenging issue despite the great advance of drug-eluting stents (DES). In addition, the consensus was lacking regarding the optimal strategy for DES-ISR. Therefore, we aimed to evaluate angiographic and clinical outcomes of the two most effective treatments DES vs. drug-eluting balloon (DCB) for patients with DES-ISR.

Methods: This meta-analysis used the data from the randomized controlled trials (RCTs), which were identified by a systematic search in the databases of PubMed, Embase, and Cochrane Library. Target lesion revascularization (TLR) was regarded as the primary endpoint. In addition, the late angiographic outcomes and other clinical outcomes, namely, cardiac death, myocardial infarction (MI), target vessel revascularization, stent thrombosis, and major adverse cardiac events, were also included for analysis.

Results: Five RCTs with about 1,193 patients were included in this meta-analysis for the analysis. For the primary endpoint, the overall pooled outcomes suggested repeat DES implantation was associated with a significant reduction in the term of TLR compared with DCB angioplasty (risk ratio = 1.53, 95% CI 1.15–2.04, p = 0.003). But no significant difference in angiographic outcomes and other clinical endpoints were observed between DES and DCB. In the subgroup analysis, DCB was inferior to new-generation DES (NG-DES)/everolimus-eluting stent (EES) in the term of TLR. In addition, this non-significant trend was also noted in the subgroup of the paclitaxel-eluting stent (PES) vs. DCB. For the angiographic endpoints, EES, not PES, was associated with larger minimum lumen diameter [mean difference (MD) = −0.25, 95% CI −0.38 to −0.11, p = 0.0003], lower percent diameter stenosis (MD = 7.29%, 95% CI 2.86–11.71%, p = 0.001), and less binary restenosis (OR = 2.20, 95% CI 1.18–4.11, p = 0.01). But NG-DES/EES was comparable to DCB in cardiac death, MI, and stent thrombosis.

Conclusions: For the patients with DES-ISR, treatment with DES, especially NG-DES/EES could reduce the risk of TLR significantly compared to DCB at long-term follow-up.
Emerging Microfluidic Approaches for Platelet Mechanobiology and Interplay With Circulatory Systems
Authors: Zhang Yingqi , Ramasundara Savindi De Zoysa , Preketes-tardiani Renee Ellen , Cheng Vivian , Lu Hongxu , Ju Lining Arnold
Published: December 2021

Understanding how platelets can sense and respond to hemodynamic forces in disturbed blood flow and complexed vasculature is crucial to the development of more effective and safer antithrombotic therapeutics. By incorporating diverse structural and functional designs, microfluidic technologies have emerged to mimic microvascular anatomies and hemodynamic microenvironments, which open the floodgates for fascinating platelet mechanobiology investigations. The latest endothelialized microfluidics can even recapitulate the crosstalk between platelets and the circulatory system, including the vessel walls and plasma proteins such as von Willebrand factor. Hereby, we highlight these exciting microfluidic applications to platelet mechanobiology and platelet–circulatory system interplay as implicated in thrombosis. Last but not least, we discuss the need for microfluidic standardization and summarize the commercially available microfluidic platforms for researchers to obtain reproducible and consistent results in the field.
High Perceived Stress May Shorten Activated Partial Thromboplastin Time and Lead to Worse Clinical Outcomes in Patients With Coronary Heart Disease
Authors: Yin Han , Cheng Xingyu , Liang Yanting , Liu Anbang , Wang Haochen , Liu Fengyao , Guo Lan , Ma Huan , Geng Qingshan
Published: December 2021

Objective: To determine the association of perceived stress with coagulation function and their predictive values for clinical outcomes.

Methods: This prospective cohort study derived from a cross-sectional study for investigating the psychological status of inpatients with suspicious coronary heart disease (CHD). In this study, the 10-item Perceived Stress Scale (PSS-10) as an optional questionnaire was used to assess the severity of perceived stress. Coagulation function tests, such as activated partial thromboplastin time (APTT), prothrombin time (PT), and fibrinogen were measured within 1 h after admission. Furthermore, 241 patients with CHD out of 705 consecutive inpatients were included in the analyses and followed with a median of 26 months for the clinical outcomes.

Results: The patients in high perceived stress status (PSS-10 score > 16) were with shorter APTT (36.71 vs. 38.45 s, p = 0.009). Shortened APTT ( ≤ 35.0 s) correlated with higher PSS-10 score (14.67 vs. 11.22, p = 0.003). The association of APTT with depression or anxiety was not found. Multiple linear models adjusting for PT estimated that every single point increase in PSS-10 was relevant to approximately 0.13 s decrease in APTT (p = 0.001) regardless of the type of CHD. APTT (every 5 s increase: hazard ratio (HR) 0.68 [0.47–0.99], p = 0.041) and perceived stress (every 5 points increase: HR 1.31 [1.09–1.58], p = 0.005) could predict the cardiovascular outcomes. However, both predictive values would decrease when they were simultaneously adjusted. After adjusting for the physical clinical features, the associated of perceived stress on cardiac (HR 1.25 [1.04–1.51], p = 0.020) and composite clinical outcomes (HR 1.24 [1.05–1.47], p = 0.011) persisted.

Conclusions: For the patients with CHD, perceived stress strongly correlates with APTT. The activation of the intrinsic coagulation pathway is one of the mechanisms that high perceived stress causes cardiovascular events. This hints at an important role of the interaction of mental stress and coagulation function on cardiovascular prognosis. More attention needs to be paid to the patients with CHD with high perceived stress.
Mitochondrial Transfer in Cardiovascular Disease: From Mechanisms to Therapeutic Implications
Authors: Chen Jun , Zhong Jinjie , Wang Lin-lin , Chen Ying-ying
Published: December 2021

Mitochondrial dysfunction has been proven to play a critical role in the pathogenesis of cardiovascular diseases. The phenomenon of intercellular mitochondrial transfer has been discovered in the cardiovascular system. Studies have shown that cell-to-cell mitochondrial transfer plays an essential role in regulating cardiovascular system development and maintaining normal tissue homeostasis under physiological conditions. In pathological conditions, damaged cells transfer dysfunctional mitochondria toward recipient cells to ask for help and take up exogenous functional mitochondria to alleviate injury. In this review, we summarized the mechanism of mitochondrial transfer in the cardiovascular system and outlined the fate and functional role of donor mitochondria. We also discussed the advantage and challenges of mitochondrial transfer strategies, including cell-based mitochondrial transplantation, extracellular vesicle-based mitochondrial transplantation, and naked mitochondrial transplantation, for the treatment of cardiovascular disorders. We hope this review will provide perspectives on mitochondrial-targeted therapeutics in cardiovascular diseases.
Identification of CALU and PALLD as Potential Biomarkers Associated With Immune Infiltration in Heart Failure
Authors: Liu Xing , Xu Shiyue , Li Ying , Chen Qian , Zhang Yuanyuan , Peng Long
Published: December 2021

Background: Inflammatory activation and immune infiltration play important roles in the pathologic process of heart failure (HF). The current study is designed to investigate the immune infiltration and identify related biomarkers in heart failure patients due to ischemic cardiomyopathy.

Methods: Expression data of HF due to ischemic cardiomyopathy (CM) samples and non-heart failure (NF) samples were downloaded from gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) between CM and NF samples were identified. Single sample gene set enrichment analysis (ssGSEA) was performed to explore the landscape of immune infiltration. Weighted gene co-expression network analysis (WGCNA) was applied to screen the most relevant module associated with immune infiltration. The diagnostic values of candidate genes were evaluated by receiver operating curves (ROC) curves. The mRNA levels of potential biomarkers in the peripheral blood mononuclear cells (PBMCs) isolated from 10 CM patients and 10 NF patients were analyzed to further assess their diagnostic values.

Results: A total of 224 DEGs were identified between CM and NF samples in GSE5406, which are mainly enriched in the protein processing and extracellular matrix related biological processes and pathways. The result of ssGSEA showed that the abundance of dendritic cells (DC), mast cells, natural killer (NK) CD56dim cells, T cells, T follicular helper cells (Tfh), gammadelta T cells (Tgd) and T helper 2 (Th2) cells were significantly higher, while the infiltration of eosinophils and central memory T cells (Tcm) were lower in CM samples compared to NF ones. Correlation analysis revealed that Calumenin (CALU) and palladin (PALLD) were negatively correlated with the abundance of DC, NK CD56dim cells, T cells, Tfh, Tgd and Th2 cells, but positively correlated with the level of Tcm. More importantly, CALU and PALLD were significantly lower in PBMCs from CM patients compared to NF ones.

Conclusion: Our study revealed that CALU and PALLD are potential biomarkers associated with immune infiltration in heart failure due to ischemic cardiomyopathy.
The Role of Immune Microenvironment in Maxillofacial Bone Homeostasis
Authors: Li Na , Fu Lin , Li Zehan , Ke Yue , Wang Yanqiu , Wu Jintao , Yu Jinhua
Published: December 2021

Maxillofacial bone defects are common medical problems caused by congenital defects, necrosis, trauma, tumor, inflammation, and fractures non-union. Maxillofacial bone defects often need bone graft, which has many difficulties, such as limited autogenous bone supply and donor site morbidity. Bone tissue engineering is a promising strategy to overcome the above-mentioned problems. Osteoimmunology is the inter-discipline that focuses on the relationship between the skeletal and immune systems. The immune microenvironment plays a crucial role in bone healing, tissue repair and regeneration in maxillofacial region. Recent studies have revealed the vital role of immune microenvironment and bone homeostasis. In this study, we analyzed the complex interaction between immune microenvironment and bone regeneration process in oral and maxillofacial region, which will be important to improve the clinical outcome of the bone injury treatment.
Progress on Modeling of Dynamic Productivity of Fractured Gas Condensate Reservoir Based on a Fluid-Solid Coupling Method
Authors: Wang Shuai , Tan Xianhong , Xia Yang , Tian Bo , Liang Bin
Published: December 2021

Bozhong 19-6 gas field is the first discovered large-scale gas condensate field in eastern China, which is also one of the largest metamorphic rock gas condensate fields in the world. It is a buried hill type, low permeability reservoir, with ultra-high condensate content where the fluid is nearly at its dew point pressure. No similar experience with such reservoirs have previously been reported in the context of gas field development in China and step-by-step progresses is been made to characterize this reservoir. Overall, documentation concerning this type of reservoir is rarely seen worldwide. This paper includes key successful results from multiple perspectives including experiments correlations, numerical modeling and the significance of incorporating certain details. Based on a fluid-solid coupling method, the simulations consider several factors including the fracture distribution, low permeability, medium deformation, and condensate characteristics, as well as their effects on the gas productivity. In the laboratory experiments, the stress sensitivity of the rock was tested using representative core samples. Here, experiment-based correlations of the starting pressure gradient of the gas condensate reservoir are proposed. The starting pressure gradient of different fluid types, such as black oil and gas condensate are highlighted as accurately simulating the reservoir. As a result, the numerical model to predict the dynamic productivity of a single well was successfully established considering all those factors. This paper can serve as a reference for studying other studies of metamorphic, fractured gas condensate reservoirs.
Fostering Distance Education: Lessons From a United States-England Partnered Collaborative Online International Learning Approach
Authors: Ingram Lucy A. , Monroe Courtney , Wright Hayley , Burrell Amy , Jenks Rebecca , Cheung Simon , Friedman Daniela B.
Published: December 2021

Collaborative Online International Learning (COIL) is a teaching and learning approach whereby entire courses or modules are co-developed and team taught by instructors from different institutions for students of both institutions. Since 2006, the approach has been gaining in mass appeal; however, considering our present-day global coronavirus pandemic, COILs have a renewed relevance in academia. Faculty from the University of South Carolina (United States) and Coventry University (England) embarked on a COIL partnership yielding a valuable experience that can serve as a model for other institutions that are interested in developing innovative and cross-cultural distance learning opportunities. The purpose of this paper is to explain how the institutional partnership emerged, describe the course content, and provide lessons that our team learned through the COIL development and implementation process. Our experience as a first-time COIL partnership is a model for others to consider as the landscape for the academic enterprise expands the confines of brick-and-mortar institutions.
Higher Peripheral Cholesterol and a Positive Correlation With Risk for Large-For-Gestational-Age Neonates in Pre-Pregnancy Underweight Women
Authors: Wang Dongyu , Ding Wenjing , Ding Chengcheng , Chen Haitian , Zhao Weihua , Sun Bo , Wang Zilian
Published: December 2021

Objective

As the high proportion of underweight pregnant women, omission of their weight gain and blood lipids management during gestation might lead to adverse pregnancy outcomes. This study aimed to determine the relationship between lipid profile and risks for adverse pregnancy outcomes in pre-pregnancy underweight women.

Methods

This study was part of an ongoing cohort study including Chinese gravidas delivered from January 2015 to December 2016. Included subjects were grouped into underweight, normal-weight, and overweight by BMI before conception. Logistic regression was used to assess the association between lipid profiles during second trimester and adverse obstetric outcomes in each group. A subgroup analysis according to the gestational weight gain, in which subjects in each group were divided into above and within the Institute of Medicine (IOM) recommendations, was performed.

Results

A total of 6, 223 women were included. The proportion of underweight (19.3%) was similar to that of overweight women (19.4%) in South China. Peripheral total cholesterol (TC) level in underweight women was significantly higher than that in overweight women (P <0.001). After adjusting maternal age, TC level was positively correlated to the risk for large-for-gestational-age (LGA) [aOR =2.24, 95%CI (1.08, 4.63)], and negatively related to the risk for small-for-gestational age (SGA) [aOR =0.71, 95%CI (0.59, 0.85)] in underweight women, but not in normal-weight or overweight women. The subgroup analysis showed that maternal TC level was positively correlated with the risk of LGA only in underweight women who gained weight more than the IOM recommendations.

Conclusion

Underweight pregnant women with high TC levels had a higher risk for LGA, especially among women whose gestational weight gain were above the IOM recommendations. Therefore, clinical management of lipids and weight gain during gestation should also be recommended for underweight women.
Nutritional Regulation of Hepatic FGF21 by Dietary Restriction of Methionine
Authors: Fang Han , Stone Kirsten P. , Forney Laura A. , Wanders Desiree , Gettys Thomas W.
Published: December 2021

FGF21 is a potent metabolic regulator of energy balance, body composition, lipid metabolism, and glucose homeostasis. Initial studies reported that it was increased by fasting and the associated increase in ketones, but more recent work points to the importance of dietary protein and sensing of essential amino acids in FGF21 regulation. For example, dietary restriction of methionine produces a rapid transcriptional activation of hepatic FGF21 that results in a persistent 5- to 10-fold increase in serum FGF21. Although FGF21 is a component of a complex transcriptional program activated by methionine restriction (MR), loss-of-function studies show that FGF21 is an essential mediator of the resulting effects of the MR diet on energy balance, remodeling of adipose tissue, and enhancement of insulin sensitivity. These studies also show that FGF21 signaling in the brain is required for the MR diet-induced increase in energy expenditure (EE) and reduction of adiposity. Collectively, the evidence supports the view that the liver functions as a sentinel to detect and respond to changes in dietary amino acid composition, and that the resulting mobilization of hepatic FGF21 is a key element of the homeostatic response. These findings raise the interesting possibility that therapeutic diets could be developed that produce sustained, biologically effective increases in FGF21 by nutritionally modulating its transcription and release.
Techno-Economic Analysis of a Concentrating Solar Power Plant Using Redox-Active Metal Oxides as Heat Transfer Fluid and Storage Media
Authors: Gorman Brandon T. , Lanzarini-Lopes Mariana , Johnson Nathan G. , Miller James E. , Stechel Ellen B.
Published: December 2021

We present results for a one-dimensional quasi-steady-state thermodynamic model developed for a 111.7 MWe concentrating solar power (CSP) system using a redox-active metal oxide as the heat storage media and heat transfer agent integrated with a combined cycle air Brayton power block. In the energy charging and discharging processes, the metal oxide CaAl0.2Mn0.8O2.9-δ (CAM28) undergoes a reversible, high temperature redox cycle including an endothermic oxygen-releasing reaction and exothermic oxygen-incorporation reaction. Concentrated solar radiation heats the redox-active oxide particles under partial vacuum to drive the reduction extent deeper for increased energy density at a fixed temperature, thereby increasing storage capacity while limiting the required on sun temperature. Direct counter-current contact of the reduced particles with compressed air from the Brayton compressor releases stored chemical and sensible energy, heating the air to 1,200°C at the turbine inlet while cooling and reoxidizing the particles. The cool oxidized particles recirculate through the solar receiver subsystem for another cycle of heating and reduction (oxygen release). We applied the techno-economic model to 1) size components, 2) examine intraday operation with varying solar insolation, 3) estimate annual performance characteristics over a simulated year, 4) estimate the levelized cost of electricity (LCOE), and 5) perform sensitivity analyses to evaluate factors that affect performance and cost. Simulations use hourly solar radiation data from Barstow, California to assess the performance of a 111.7 MWe system with solar multiples (SMs) varying from 1.2 to 2.4 and storage capacities of 6–14 h. The baseline system with 6 h storage and SM of 1.8 has a capacity factor of 54.2%, an increase from 32.3% capacity factor with no storage, and an average annual energy efficiency of 20.6%. Calculations show a system with an output of 710 GWhe net electricity per year, 12 h storage, and SM of 2.4 to have an installed cost of $329 million, and an LCOE of 5.98 ¢/kWhe. This value meets the U.S. Department of Energy’s SunShot 2020 target of 6.0 ¢/kWhe (U. S Department of Energy, 2012), but falls just shy of the 5.0 ¢/kWhe 2030 CSP target for dispatchable electricity (U. S Department of Energy, 2017). The cost and performance results are minimally sensitive to most design parameters. However, a one-point change in the weighted annual cost of capital from 8 to 7% (better understood as a 12.5% change) translates directly to an 11% decrease (0.66 ¢/kWhe) in the LCOE.
Equivalent Firm Capacity Assessment of HDR-PV Hybrid Power System: A Distributionally Robust Approach
Authors: Si Yang , Ma Linrui , Chen Laijun , Ma Hengrui , Mei Shengwei
Published: December 2021

Aiming at the reliable grid connection of photovoltaic (PV) systems in frigid plateau regions, this work first designs a flexible hot dry rock (HDR) hybrid power system (HPS), making full use of the potential of HDR for energy storage and power generation. Based on the operation of HPS, a comprehensive energy system credible capacity assessment method considering the overall economy of the system and the reliability of the grid is established. In this method, the power allowable fluctuation rate of the grid as the equivalent firm capacity (EFC) constraint is considered. Then, the constraint is converted into a set of linear chance conditions through the distributionally robust method so that the capacity assessment of the HDR-PV HPS can be converted into a mixed-integer linear optimization problem for a solution. The proposed assessment method is verified by real HDR-PV HPS in the Gonghe Basin of Qinghai Province. The results show that the flexible HDR plant increases the credible capacity of the HPS by 113.38%. The profit of the flexible HDR plant was increased by 3.02% at the same time. The parameter analysis shows that the HDR-PV HPS obtains the most profit when the allowable fluctuation rate is 7%, but 10% can fully utilize the geothermal. The assessment method can effectively assess the credible capacity of the system under the premise of ensuring the overall economy of the HPS, thereby guiding power grid dispatching.
Research on Leakage Current Waveform Spectrum Characteristics of Artificial Pollution Porcelain Insulator
Authors: Fang Chunhua , Tao Yuning , Wang Jianguo , You Haixin , Cui Yan , Zhou Mi
Published: December 2021

The surface discharge development processes of polluted porcelain insulators for power transmission lines are tightly related with the development of leakage current (LC), the characteristics of LC, the insulating condition, and discharge intensity of the insulator surface have an important significance for revealing the contamination discharge state of insulators. In order to analyze the LC characteristics of porcelain insulators in the process of pollution flashover, artificial pollution flashover tests on porcelain insulators were conducted in the artificial fog cabinet, and the characteristics of LC waveforms in time-domain and frequency-domain were simultaneously measured and analyzed during the tests. The results indicated that the amplitude of LC, fundamental harmonic, the third harmonic, and fifth harmonic had a strong correlation, the maximum of LC(Im), the rate of total harmonics (THD), and the phase difference of fundamental harmonic (θ) were used for the representation of the characteristics of the LC waveform. The LC has the characteristics of high amplitude, low proportion harmonic, and small phase difference between the fundamental harmonic and voltage before the flashover occurrence. The test results provide effective reference for porcelain insulators in pollution flashover forecasting.
Single Shot MultiBox Detector for Urban Plantation Single Tree Detection and Location With High-Resolution Remote Sensing Imagery
Authors: Zheng Yueyuan , Wu Gang
Published: December 2021

Using high-resolution remote sensing images to automatically identify individual trees is of great significance to forestry ecological environment monitoring. Urban plantation has realistic demands for single tree management such as catkin pollution, maintenance of famous trees, landscape construction, and park management. At present, there are problems of missed detection and error detection in dense plantations and complex background plantations. This paper proposes a single tree detection method based on single shot multibox detector (SSD). Optimal SSD is obtained by adjusting feature layers, optimizing the aspect ratio of a preset box, reducing parameters and so on. The optimal SSD is applied to single tree detection and location in campuses, orchards, and economic plantations. The average accuracy based on SSD is 96.0, 92.9, and 97.6% in campus green trees, lychee plantations, and palm plantations, respectively. It is 11.3 and 37.5% higher than the latest template matching method and chan-vese (CV) model method, and is 43.1 and 54.2% higher than the traditional watershed method and local maximum method. Experimental results show that SSD has a strong potential and application advantage. This research has reference significance for the application of an object detection framework based on deep learning in agriculture and forestry.
Future of Freshwater Ecosystems in a 1.5°C Warmer World
Authors: Capon Samantha J. , Stewart-Koster Ben , Bunn Stuart E.
Published: December 2021

Freshwater ecosystems are highly vulnerable to global warming because 1) their chief drivers, water quality and flow regimes, are highly sensitive to atmospheric warming, and 2) they are already extremely threatened by a wide range of interacting anthropogenic pressures. Even relatively modest global warming of 1.5°C poses a considerable threat to freshwater ecosystems and the many critical services these provide to people. Shifts in the composition and function of freshwater ecosystems are widely anticipated with adverse consequences for ecosystem services, including those underpinning water and food security. While the extent and severity of effects is likely to be significantly reduced if global warming is limited to 1.5°C, concerted efforts to implement widely recognised priorities for policy and management are required to mitigate unavoidable impacts and reduce the likelihood of perverse outcomes of climate mitigation and adaptation efforts in other sectors—all of which rely on fresh water supply. Freshwater ecosystems and their services, including provision of fresh water, must therefore be considered first and foremost when developing and implementing any climate action.
Multiproxy Holocene Fire Records From the Tropical Savannas of Northern Cape York Peninsula, Queensland, Australia
Authors: Rehn Emma , Rowe Cassandra , Ulm Sean , Gadd Patricia , Zawadzki Atun , Jacobsen Geraldine , Woodward Craig , Bird Michael
Published: December 2021

Paleoecology has demonstrated potential to inform current and future land management by providing long-term baselines for fire regimes, over thousands of years covering past periods of lower/higher rainfall and temperatures. To extend this potential, more work is required for methodological innovation able to generate nuanced, relevant and clearly interpretable results. This paper presents records from Cape York Peninsula, Queensland, Australia, as a case study where fire management is an important but socially complex modern management issue, and where palaeofire records are limited. Two new multiproxy palaeofire records are presented from Sanamere Lagoon (8,150–6,600 cal BP) and Big Willum Swamp (3,900 cal BP to present). These records combine existing methods to investigate fire occurrence, vegetation types, and relative fire intensity. Results presented here demonstrate a diversity of fire histories at different sites across Cape York Peninsula, highlighting the need for finer scale palaeofire research. Future fire management planning on Cape York Peninsula must take into account the thousands of years of active Indigenous management and this understanding can be further informed by paleoecological research.
Herbaria Reveal Herbivory and Pathogen Increases and Shifts in Senescence for Northeastern United States Maples Over 150 Years
Authors: Garretson Alexis , Forkner Rebecca E.
Published: December 2021

Recent studies suggest climate-related delays in the timing of leaf coloration and abscission in maple trees but lack baseline data prior to the late 20th century. To better understand how autumn foliar phenology and late-season damage risks have changed for this genus over the past century, we evaluated 2,972 digitized herbaria specimens of red and sugar maple collected between 1826 and 2016 for the presence of leaves, autumn leaf coloration, and pathogen or herbivore damage. We found that the onset (first appearance) of colored leaves has shifted 0.26 days later each year, leading to a delay of more than a month in autumn phenology since 1880. We find that these shifts are related to precipitation regimes in both the fall and summer seasons and that more severe droughts are associated with higher probabilities of colored leaves. Moreover, we found that the probability of both herbivory and pathogen damage has increased significantly over the study period. In particular, we find a strong association between increasing summer drought conditions and increased probability of herbivory. Furthermore, the presence of foliar damage increased the probability of leaf coloration on herbaria specimens. However, the end-of-season abscission date (last appearance of leaves) was strongly associated with herbivory and climate in a contrary direction: Increasing yearly drought, higher fall temperatures, and the presence of herbivory were associated with earlier abscission. In fact, the last leaf dates for specimens with herbivory were nearly 2 weeks earlier than specimens without herbivore damage. Our study documents significant changes in maple senescence over the last 150 years and suggests that incorporating herbivory into models may improve our ability to predict forest responses to climate shifts.
Identification of a New Infectious Pancreatic Necrosis Virus (IPNV) Variant in Atlantic Salmon (Salmo salar L.) that can Cause High Mortality Even in Genetically Resistant Fish
Authors: Hillestad Borghild , Johannessen Stein , Melingen Geir Olav , Moghadam Hooman K.
Published: December 2021

Infectious pancreatic necrosis (IPN) is an important viral disease of salmonids that can affect fish during various life cycles. In Atlantic salmon, selecting for genetically resistant fish against IPN has been one of the most highly praised success stories in the history of fish breeding. During the late 2000s, the findings that resistance against this disease has a significant genetic component, which is mainly controlled by variations in a single gene, have helped to reduce the IPN outbreaks to a great extent. In this paper, we present the identification of a new variant of the IPN virus from a field outbreak in Western Norway that had caused mortality, even in genetically resistant salmon. We recovered and assembled the full-length genome of this virus, following the deep-sequencing of the head-kidney transcriptome. The comparative sequence analysis revealed that for the critical amino acid motifs, previously found to be associated with the degree of virulence, the newly identified variant is similar to the virus’s avirulent form. However, we detected a set of deduced amino acid residues, particularly in the hypervariable domain of the VP2, that collectively are unique to this variant compared to all other reference sequences assessed in this study. We suggest that these mutations have likely equipped the virus with the capacity to escape the host defence mechanism more efficiently, even in the genetically deemed IPN resistant fish.
Comparative Chloroplast Genome Analyses of the Winter-Blooming Eastern Asian Endemic Genus Chimonanthus (Calycanthaceae) With Implications For Its Phylogeny and Diversification
Authors: Jamal Abbas , Wen Jun , Ma Zhi-Yao , Ahmed Ibrar , Abdullah  , Chen Long-Qing , Nie Ze-Long , Liu Xiu-Qun
Published: December 2021

Chimonanthusof Calycanthaceae is a small endemic genus in China, with unusual winter-blooming sweet flowers widely cultivated for ornamentals and medicinal uses. The evolution ofChimonanthusplastomes and its phylogenetic relationships remain unresolved due to limited availability of genetic resources. Here, we report fully assembled and annotated chloroplast genomes of fiveChimonanthusspecies. The chloroplast genomes of the genus (size range 153,010 – 153,299 bp) reveal high similarities in gene content, gene order, GC content, codon usage, amino acid frequency, simple sequence repeats, oligonucleotide repeats, synonymous and non-synonymous substitutions, and transition and transversion substitutions. Signatures of positive selection are detected inatpFandrpoBgenes inC. campanulatus. The correlations among substitutions, InDels, and oligonucleotide repeats reveal weak to strong correlations in distantly related species at the intergeneric levels, and very weak to weak correlations among closely relatedChimonanthusspecies. Chloroplast genomes are used to reconstruct a well-resolved phylogenetic tree, which supports the monophyly ofChimonanthus. WithinChimonanthus,C. praecoxandC. campanulatusform one clade, whileC. grammatus,C. salicifolius,C. zhejiangensis, andC. nitensconstitute another clade.Chimonanthus nitensappears paraphyletic and is closely related toC. salicifoliusandC. zhejiangensis, suggesting the need to reevaluate the species delimitation ofC. nitens.ChimonanthusandCalycanthusdiverged in mid-Oligocene; the radiation of extantChimonanthusspecies was dated to the mid-Miocene, whileC. grammatusdiverged from otherChimonanthusspecies in the late Miocene.C. salicifolius,C. nitens(a), andC. zhejiangensisare inferred to have diverged in the Pleistocene of the Quaternary period, suggesting recent speciation of a relict lineage in the subtropical forest regions in eastern China. This study provides important insights into the chloroplast genome features and evolutionary history ofChimonanthusand family Calycanthaceae.
Deep Learning Algorithms Achieved Satisfactory Predictions When Trained on a Novel Collection of Anticoronavirus Molecules
Authors: Harigua-Souiai Emna , Heinhane Mohamed Mahmoud , Abdelkrim Yosser Zina , Souiai Oussama , Abdeljaoued-Tej Ines , Guizani Ikram
Published: December 2021

Drug discovery and repurposing against COVID-19 is a highly relevant topic with huge efforts dedicated to delivering novel therapeutics targeting SARS-CoV-2. In this context, computer-aided drug discovery is of interest in orienting the early high throughput screenings and in optimizing the hit identification rate. We herein propose a pipeline for Ligand-Based Drug Discovery (LBDD) against SARS-CoV-2. Through an extensive search of the literature and multiple steps of filtering, we integrated information on 2,610 molecules having a validated effect against SARS-CoV and/or SARS-CoV-2. The chemical structures of these molecules were encoded through multiple systems to be readily useful as input to conventional machine learning (ML) algorithms or deep learning (DL) architectures. We assessed the performances of seven ML algorithms and four DL algorithms in achieving molecule classification into two classes: active and inactive. The Random Forests (RF), Graph Convolutional Network (GCN), and Directed Acyclic Graph (DAG) models achieved the best performances. These models were further optimized through hyperparameter tuning and achieved ROC-AUC scores through cross-validation of 85, 83, and 79% for RF, GCN, and DAG models, respectively. An external validation step on the FDA-approved drugs collection revealed a superior potential of DL algorithms to achieve drug repurposing against SARS-CoV-2 based on the dataset herein presented. Namely, GCN and DAG achieved more than 50% of the true positive rate assessed on the confirmed hits of a PubChem bioassay.
The History and Challenges of Women in Genetics: A Focus on Non-Western Women
Authors: Elbardisy Hadeel , Abedalthagafi Malak
Published: December 2021

“Women in much of the world lack support for fundamental functions of a human life.” This truthful portrait was pointed out by Martha Nussbaum in her book “Introduction: Feminism & International Development.” Throughout history, gender inequality has been persistent in many aspects of life, including health and empowerment. Unfortunately, this inequality has not been excluded from the field of science. Perpetual assumption that women’s absence or restriction to secondary roles in various disciplines is an acceptable law of nature misrepresents women’s contribution to science and maintains hurdles for participation in the future. According to a recent UNESCO’s report, women make up only 30% of researchers worldwide. But despite all the obstacles, women made major contributions with discoveries that shaped the progress in many scientific fields. In the field of genetics, Rosalind Franklin is an example of unwittingly compromised women’s scientific achievements. Franklin was an expert in X-ray crystallography; her data, especially the “photo 51,” was critical to James Watson and Francis Crick along with their own data to publish the discovery of the double helix DNA structure in 1953. Her contribution was acknowledged posthumously in Watson’s memoir in 1968. Barbara McClintock was a 20th century American cytogeneticist who remains up to date the only woman receiving an unshared Nobel prize in Physiology or Medicine. McClintock dedicated her work to cytogenetics and discovered the phenomenon of mobile genes. Her research was initially subjected to skepticism in the 1950s. It was not until the late 1960s that the community realized the significance of McClintock’s discovery. The history of science is occupied with a myriad of similar tales of such inspiring women that, after tremendous struggles, thrived and achieved breakthroughs in their respective fields. It is prominent our limited knowledge of women’s experience and struggle in science in non-western world. Addressing the stories of this outstanding minority is critical to expand the understanding of the gender disparity factors embedded in diverse cultures. In this article, we attempt to put the spotlight on some fascinating non-western women and their significant contributions to the field of genetics.
Novel Partial Exon 51 Deletion in the Duchenne Muscular Dystrophy Gene Identified via Whole Exome Sequencing and Long-Read Whole-Genome Sequencing
Authors: Li Qianqian , Chen Zhanni , Xiong Hui , Li Ranran , Yu Chenguang , Meng Jingjing , Shi Panlai , Kong Xiangdong
Published: December 2021

Duchenne muscular dystrophy (DMD), one of the most common progressive and severely disabling neuromuscular diseases in children, can be largely attributed to the loss of function of the DMD gene on chromosome Xp21.2-p21.1. This paper describes the case of a 10-year-old boy diagnosed with DMD. Whole exome sequencing confirmed the hypothesized large partial exonic deletion of c.7310-11543_7359del (chrX:g.31792260_31803852del) spanning exon 51 and intron 50 in DMD. This large deletion was verified to be de novo by PCR, and the two breakpoints were further confirmed by Sanger sequencing and long-read whole-genome sequencing. Notably, this partial exonic deletion was the only complex variation in the deep intron regions or intron–exon junction regions in DMD. In addition, the case study demonstrates the clinical importance of using multiple molecular genetic testing methods for the diagnosis of rare diseases.
A Novel Immune-Gene Pair Signature Revealing the Tumor Microenvironment Features and Immunotherapy Prognosis of Muscle-Invasive Bladder Cancer
Authors: Zheng Xiaonan , Zhou Xianghong , Xu Hang , Jin Di , Yang Lu , Shen Bairong , Qiu Shi , Ai Jianzhong , Wei Qiang
Published: December 2021

Immunotherapy has been a milestone for muscle-invasive bladder cancer (MIBC), but only a small portion of patients can benefit from it. Therefore, it is crucial to develop a robust individualized immune-related signature of MIBC to identify patients potentially benefiting from immunotherapy. The current study identified patients from the Cancer Genome Atlas (TCGA) and immune genes from the ImmPort database, and used improved data analytical methods to build up a 45 immune-related gene pair signature, which could classify patients into high-risk and low-risk groups. The signature was then independently validated by a Gene Expression Omnibus (GEO) dataset and IMvigor210 data. The subsequent analysis confirmed the worse survival outcomes of the high-risk group in both training (p < 0.001) and validation cohorts (p = 0.018). A signature-based risk score was proven to be an independent risk factor of overall survival (p < 0.001) and could predict superior clinical net benefit compared to other clinical factors. The CIBERSORT algorithm revealed the low-risk group had increased CD8+ T cells plus memory-activated CD4+ T-cell infiltration. The low-risk group also had higher expression of PDCD1 (PD-1), CD40, and CD27, and lower expression of CD276 (B7-H3) and PDCD1LG2 (PD-L2). Importantly, IMvigor210 data indicated that the low-risk group had higher percentage of “inflamed” phenotype plus less “desert” phenotype, and the survival outcomes were significantly better for low-risk patients after immunotherapy (p = 0.014). In conclusion, we proposed a novel and promising prognostic immune-related gene pair (IRGP) signature of MIBC, which could provide us a panoramic view of the tumor immune microenvironment of MIBC and independently identify MIBC patients who might benefit from immunotherapy.
Identification and Validation of an Immune and Ferroptosis-Combined Index for Non–Small Cell Lung Cancer
Authors: Teng Yang , Wang Bo , Shang Desi , Yang Ning
Published: December 2021

Background: Non–small cell lung cancer (NSCLC) is among the major health problems around the world. Reliable biomarkers for NSCLC are still needed in clinical practice. We aimed to develop a novel ferroptosis- and immune-based index for NSCLC.

Methods: The training and testing datasets were obtained from TCGA and GEO databases, respectively. Immune- and ferroptosis-related genes were identified and used to establish a prognostic model. Then, the prognostic and therapeutic potential of the established index was evaluated.

Results: Intimate interaction of immune genes with ferroptosis genes was observed. A total of 32 prognosis-related signatures were selected to develop a predictive model for NSCLC using LASSO Cox regression. Patients were classified into the high- and low-risk group based on the risk score. Patients in the low-risk group have better OS in contrast with that in the high-risk group in independent verification datasets. Besides, patients with a high risk score have shorter OS in all subgroups (T, N, and M0 subgroups) and pathological stages (stage I, II, and III). The risk score was positively associated with Immune Score, Stromal Score, and Ferroptosis Score in TCGA and GEO cohorts. A differential immune cell infiltration between the high-risk and the low-risk groups was also observed. Finally, we explored the significance of our model in tumor-related pathways, and different enrichment levels in the therapeutic pathway were observed between the high- and low-risk groups.

Conclusion: The present study developed an immune and ferroptosis-combined index for the prognosis of NSCLC.
The Unique Genetic and Histological Characteristics of DMBA-Induced Mammary Tumors in an Organoid-Based Carcinogenesis Model
Authors: Naruse Mie , Ishigamori Rikako , Imai Toshio
Published: December 2021

Here, we report a model system using in vitro 7,12-dimethylbenz[a]anthracene (DMBA; 0.6 μM)-treated mammary tissue-derived organoids generated from heterozygous BALB/c-Trp53 knockout mice to induce tumors after injection into the nude mouse subcutis. In parallel, a single oral dose of DMBA (50 mg/kg bodyweight) to the same murine strain induced mammary adenocarcinomas, characterized by biphasic structures differentiated into luminal and myoepithelial lineages and frequent Hras mutations at codon 61. In the present study, the genetic and histological characteristics of DMBA-induced tumors in the organoid-based model were evaluated to validate its similarities to the in vivo study. The organoid-derived tumors were low-grade adenocarcinomas composed of luminal and basal/myoepithelial cells. When the organoid-derived carcinomas were passaged to other nude mice, they partly progressed to squamous cell carcinomas (SCCs). Whole exome sequencing revealed no mutations at Hras codon 61 in the organoid-derived tumors. However, various mutations were detected in other genes such as Tusc3 and Tgfbr2, which have been reported as cancer-associated or homeostatic squamous cell genes. The most common mutational pattern observed in these genes were the G:C to T:A transversions and G:C to A:T transitions, which are not typical of the mutations caused by DMBA treatment. In conclusion, DMBA exhibited carcinogenicity in the both the ex vivo and in vivo mammary carcinogenesis models, albeit with distinct histological and genetical alterations. Further studies are needed to clarify whether organoid-based carcinogenesis models generated following chemical treatment in vitro could be applied to the clarification of the novel mode of action of chemical carcinogenesis.