bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex Differences in Behavioral Symptoms and the Levels of Circulating GFAP, Tau, and NfL in Patients With Traumatic Brain Injury
Authors: Sass Dilorom , Guedes Vivian A. , Smith Ethan G. , Vorn Rany , Devoto Christina , Edwards Katie A. , Mithani Sara , Hentig James , Lai Chen , Wagner Chelsea , Dunbar Kerri , Hyde David R. , Saligan Leorey , Roy Michael J. , Gill Jessica
Published: December 2021

Traumatic brain injury (TBI) affects millions of Americans each year and has been shown to disproportionately impact those subject to greater disparities in health. Female sex is one factor that has been associated with disparities in health outcomes, including in TBI, but sex differences in biomarker levels and behavioral outcomes after TBI are underexplored. This study included participants with both blunt and blast TBI with majority rating their TBI as mild. Time since injury was 5.4 (2.0, 15.5) years for females and 6.8 (2.4, 11.3) years for males. The aim of this cross sectional study is to investigate the relationship between postconcussive, depression, and post-traumatic stress disorder (PTSD) symptoms, as well as health related quality of life (HRQOL), and the levels of glial fibrillary acidic protein (GFAP), total tau (t-tau), neurofilament light chain (NfL), and ubiquitin C-terminal hydrolase-L1 (UCH-L1). Behavioral outcomes were evaluated with the Neurobehavioral Symptom Inventory (NSI), Patient Health Questionnaire-9 (PHQ-9), PTSD Checklist- Civilian Version (PCL-C), short form (SF)-36, and plasma levels of total tau, GFAP, NfL, and UCHL-1 measured with the Simoa-HDX. We observed that females had significantly higher levels of GFAP and tau (ps < 0.05), and higher PHQ-9 scores, NSI total scores, NSI- vestibular, NSI-somatosensory, NSI-affective sub-scale scores (ps < 0.05)), than males. In addition, females had lower scores in HRQOL outcomes of role limitations due to emotional problems, vitality, emotional well-being, social functioning, and pain compared to males (ps < 0.05). Correlation analysis showed positive associations between levels of tau and the NSI-total and NSI-cognitive sub-scale scores (ps < 0.05) in females. No significant associations were found for NfL or GFAP with NSI scores. For female participants, negative correlations were observed between tau and NfL concentrations and the SF-36 physical function subscale (ps < 0.05), as well as tau and the social function subscale (p < 0.001), while GFAP levels positively correlated with role limitations due to emotional problems (p = 0.004). No significant associations were observed in males. Our findings suggest that sex differences exist in TBI-related behavioral outcomes, as well as levels of biomarkers associated with brain injury, and that the relationship between biomarker levels and behavioral outcomes is more evident in females than males. Future studies are warranted to corroborate these results, and to determine the implications for prognosis and treatment. The identification of candidate TBI biomarkers may lead to development of individualized treatment guidelines.
3D-QSAR, Molecular Docking, and MD Simulations of Anthraquinone Derivatives as PGAM1 Inhibitors
Authors: Wang Yuwei , Guo Yifan , Qiang Shaojia , Jin Ruyi , Li Zhi , Tang Yuping , Leung Elaine Lai Han , Guo Hui , Yao Xiaojun
Published: December 2021

PGAM1 is overexpressed in a wide range of cancers, thereby promoting cancer cell proliferation and tumor growth, so it is gradually becoming an attractive target. Recently, a series of inhibitors with various structures targeting PGAM1 have been reported, particularly anthraquinone derivatives. In present study, the structure–activity relationships and binding mode of a series of anthraquinone derivatives were probed using three-dimensional quantitative structure–activity relationships (3D-QSAR), molecular docking, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, r2 = 0.97, q2 = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2 = 0.96, q2 = 0.82) techniques were performed to produce 3D-QSAR models, which demonstrated satisfactory results, especially for the good predictive abilities. In addition, molecular dynamics (MD) simulations technology was employed to understand the key residues and the dominated interaction between PGAM1 and inhibitors. The decomposition of binding free energy indicated that the residues of F22, K100, V112, W115, and R116 play a vital role during the ligand binding process. The hydrogen bond analysis showed that R90, W115, and R116 form stable hydrogen bonds with PGAM1 inhibitors. Based on the above results, 7 anthraquinone compounds were designed and exhibited the expected predictive activity. The study explored the structure–activity relationships of anthraquinone compounds through 3D-QSAR and molecular dynamics simulations and provided theoretical guidance for the rational design of new anthraquinone derivatives as PGAM1 inhibitors.
Synergetic Effect of 4-Phenylbutyric Acid in Combination with Cyclosporine A on Cardiovascular Function in Sepsis Rats via Inhibition of Endoplasmic Reticulum Stress and Mitochondrial Permeability Transition Pore Opening
Authors: Kuang Lei , Zhu Yu , Wu Yue , Peng Xiaoyong , Tian Kunlun , Liu Liangming , Li Tao
Published: December 2021

Background: Sepsis/septic shock is a common complication in the intensive care unit, and the opening of the mitochondrial permeability transition pore (mPTP), as well as the endoplasmic reticulum stress (ERS), play important roles in this situation. Whether the combination of anti-ERS and anti-mPTP by 4-phenylbutyric acid (PBA) and Cyclosporine A (CsA) could benefit sepsis is unclear.

Methods: The cecal ligation and puncture-induced septic shock models were replicated in rats, and lipopolysaccharide (LPS)-challenged primary vascular smooth muscle cells and H9C2 cardiomyocytes in vitro models were also used. The therapeutic effects of CsA, PBA, and combined administration on oxygen delivery, cardiac and vascular function, vital organ injury, and the underlying mechanisms were observed.

Results: Septic shock significantly induced cardiovascular dysfunction, hypoperfusion, and organ injury and resulted in high mortality in rats. Conventional treatment including fluid resuscitation, vasoactive agents, and antibiotics slightly restored tissue perfusion and organ function in septic rats. Supplementation of CsA or PBA improved the tissue perfusion, organ function, and survival of septic shock rats. The combined application of PBA and CsA could significantly enhance the beneficial effects, compared with using PBA or CsA alone. Further study showed that PBA enhanced CsA-induced cardiovascular protection, which contributed to better therapeutic effects.

Conclusion: Anti-ERS and anti-mPTP-opening by the combination of PBA and CsA was beneficial to septic shock. PBA enforced the CsA-associated cardiovascular protection and contributed to the synergetic effect.
Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses
Authors: Walsh Kenneth B. , McKinney Amanda E. , Holmes Andrea E.
Published: December 2021

The medicinal use of Cannabis sativa L. can be traced back thousands of years to ancient China and Egypt. While marijuana has recently shown promise in managing chronic pain and nausea, scientific investigation of cannabis has been restricted due its classification as a schedule 1 controlled substance. A major breakthrough in understanding the pharmacology of cannabis came with the isolation and characterization of the phytocannabinoids trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This was followed by the cloning of the cannabinoid CB1 and CB2 receptors in the 1990s and the subsequent discovery of the endocannabinoid system. In addition to the major phytocannabinoids, Δ9-THC and CBD, cannabis produces over 120 other cannabinoids that are referred to as minor and/or rare cannabinoids. These cannabinoids are produced in smaller amounts in the plant and are derived along with Δ9-THC and CBD from the parent cannabinoid cannabigerolic acid (CBGA). While our current knowledge of minor cannabinoid pharmacology is incomplete, studies demonstrate that they act as agonists and antagonists at multiple targets including CB1 and CB2 receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), serotonin 5-HT1a receptors and others. The resulting activation of multiple cell signaling pathways, combined with their putative synergistic activity, provides a mechanistic basis for their therapeutic actions. Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders. This review focuses on the molecular pharmacology of the minor cannabinoids and highlights some important therapeutic uses of the compounds.
Altered Cortico-Subcortical Network After Adolescent Alcohol Exposure Mediates Behavioral Deficits in Flexible Decision-Making
Authors: Gómez-A Alexander , Dannenhoffer Carol A. , Elton Amanda , Lee Sung-Ho , Ban Woomi , Shih Yen-Yu Ian , Boettiger Charlotte A. , Robinson Donita L.
Published: December 2021

Behavioral flexibility, the ability to modify behavior according to changing conditions, is essential to optimize decision-making. Deficits in behavioral flexibility that persist into adulthood are one consequence of adolescent alcohol exposure, and another is decreased functional connectivity in brain structures involved in decision-making; however, a link between these two outcomes has not been established. We assessed effects of adolescent alcohol and sex on both Pavlovian and instrumental behaviors and resting-state functional connectivity MRI in adult animals to determine associations between behavioral flexibility and resting-state functional connectivity. Alcohol exposure impaired attentional set reversals and decreased functional connectivity among cortical and subcortical regions-of-interest that underlie flexible behavior. Moreover, mediation analyses indicated that adolescent alcohol-induced reductions in functional connectivity within a subnetwork of affected brain regions statistically mediated errors committed during reversal learning. These results provide a novel link between persistent reductions in brain functional connectivity and deficits in behavioral flexibility resulting from adolescent alcohol exposure.
Ginger from Farmyard to Town: Nutritional and Pharmacological Applications
Authors: Unuofin Jeremiah Oshiomame , Masuku Nelisiwe Prenate , Paimo Oluwatomiwa Kehinde , Lebelo Sogolo Lucky
Published: December 2021

Ginger (Zingiber officinale) is one of the most widely used natural products consumed as a spice and medicine for treating diabetes, flatulent intestinal colic, indigestion, infertility, inflammation, insomnia, a memory booster, nausea, rheumatism, stomach ache, and urinary tract infections. To date, over 400 bioactive components, such as diarylheptanoids, gingerol analogues, phenylalkanoids, sulfonates, monoterpenoid glycosides, steroids, and terpene compounds have been derived from ginger. Increasing evidence has revealed that ginger possesses a broad range of biological activities, especially protective effects against male infertility, nausea and vomiting, analgesic, anti-diabetic, anti-inflammatory, anti-obesity, and other effects. The pharmacological activities of ginger were mainly attributed to its active phytoconstituents such as 6-gingerol, gingerdiol, gingerol, gingerdione, paradols, shogaols, sesquiterpenes, zingerone, besides other phenolics and flavonoids. In recent years, in silico molecular docking studies revealed that gingerol (6-gingerol, 8-gingerol, and 10-gingerol) and Shogaol (6-shogaol, 8-shogaol, 10-shogaol) had the best binding affinities to the receptor protein in disease conditions such as diabetes, inflammation, obesity, and SARS-CoV-2. Furthermore, some clinical trials have indicated that ginger can be consumed for alleviation of nausea and vomiting induced by surgery, pain, diabetes, obesity, inflammation, male infertility. This review provides an updated understanding of the scientific evidence on the development of ginger and its active compounds as health beneficial agents in future clinical trials.
Roles of Major RNA Adenosine Modifications in Head and Neck Squamous Cell Carcinoma
Authors: Huo Xing-xing , Wang Shu-jie , Song Hang , Li Ming-de , Yu Hua , Wang Meng , Gong Hong-xiao , Qiu Xiao-ting , Zhu Yong-fu , Zhang Jian-ye
Published: December 2021

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer malignancy worldwide and is known to have poor prognosis. The pathogenesis behind the development of HNSCC is not fully understood. Modifications on RNA are involved in many pathophysiological processes, such as tumor development and inflammation. Adenosine-related RNA modifications have shown to be linked to cancer and may play a role in cancer occurrence and development. To date, there are at least 170 different chemical RNA modifications that modify coding and non-coding RNAs (ncRNAs). These modifications affect RNA stability and transcription efficiency. In this review, we focus on the current understanding of the four major RNA adenosine modifications (N6-Methyladenosine, N1-Methyladenosine, Alternative Polyadenylation Modification and A-to-I RNA editing) and their potential molecular mechanisms related to HNSCC development and progression. We also touch on how these RNA modifications affect treatment of HNSCCs.
An NIR-Triggered Au Nanocage Used for Photo-Thermo Therapy of Chronic Wound in Diabetic Rats Through Bacterial Membrane Destruction and Skin Cell Mitochondrial Protection
Authors: Ding Jiaxin , Gao Binbin , Chen Zhenhua , Mei Xifan
Published: December 2021

Bacterial infection and its severe oxidative stress reaction will cause damage to skin cell mitochondria, resulting in long-lasting wound healing and great pain to patients. Thus, delayed wound healing in diabetic patients with Staphylococcus aureus infection is a principal challenge worldwide. Therefore, novel biomaterials with multifunction of bacterial membrane destruction and skin cell mitochondrial protection are urgently needed to be developed to address this challenge. In this work, novel gold cage (AuNCs) modified with epigallocatechin gallate (EGCG) were prepared to treat delayed diabetic wounds. The results showed that Au-EGCG had a high and stable photothermal conversion efficiency under near-infrared irradiation, and the scavenging rate of Au-EGCG for S. aureus could reach 95%. The production of large amounts of reactive oxygen species (ROS) leads to the disruption of bacterial membranes, inducing bacterial lysis and apoptosis. Meanwhile, Au-EGCG fused into hydrogel (Au-EGCG@H) promoted the migration and proliferation of human umbilical cord endothelial cells, reduced cellular mitochondrial damage and oxidative stress in the presence of infection, and significantly increased the basic fibroblast growth factor expression and vascular endothelial growth factor. In addition, animal studies showed that wound closure was 97.2% after 12 days of treatment, and the healing of chronic diabetic wounds was significantly accelerated. Au-EGCG nanoplatforms were successfully prepared to promote cell migration and angiogenesis in diabetic rats while removing S. aureus, reducing oxidative stress in cells, and restoring impaired mitochondrial function. Au-EGCG provides an effective, biocompatible, and multifunctional therapeutic strategy for chronic diabetic wounds.
Alantolactone: A Natural Plant Extract as a Potential Therapeutic Agent for Cancer
Authors: Cai Yuan , Gao Kewa , Peng Bi , Xu Zhijie , Peng Jinwu , Li Juanni , Chen Xi , Zeng Shuangshuang , Hu Kuan , Yan Yuanliang
Published: December 2021

Alantolactone (ALT) is a natural compound extracted from Chinese traditional medicine Inula helenium L. with therapeutic potential in the treatment of various diseases. Recently, in vitro and in vivo studies have indicated cytotoxic effects of ALT on various cancers, including liver cancer, colorectal cancer, breast cancer, etc. The inhibitory effects of ALT depend on several cancer-associated signaling pathways and abnormal regulatory factors in cancer cells. Moreover, emerging studies have reported several promising strategies to enhance the oral bioavailability of ALT, such as combining ALT with other herbs and using ALT-entrapped nanostructured carriers. In this review, studies on the anti-tumor roles of ALT are mainly summarized, and the underlying molecular mechanisms of ALT exerting anticancer effects on cells investigated in animal-based studies are also discussed.
Roles of Macrophages in Atherogenesis
Authors: Farahi Lia , Sinha Satyesh K. , Lusis Aldons J.
Published: December 2021

Atherosclerosis is a chronic inflammatory disease that may ultimately lead to local proteolysis, plaque rupture, and thrombotic vascular disease, resulting in myocardial infarction, stroke, and sudden cardiac death. Circulating monocytes are recruited to the arterial wall in response to inflammatory insults and differentiate into macrophages which make a critical contribution to tissue damage, wound healing, and also regression of atherosclerotic lesions. Within plaques, macrophages take up aggregated lipoproteins which have entered the vessel wall to give rise to cholesterol-engorged foam cells. Also, the macrophage phenotype is influenced by various stimuli which affect their polarization, efferocytosis, proliferation, and apoptosis. The heterogeneity of macrophages in lesions has recently been addressed by single-cell sequencing techniques. This article reviews recent advances regarding the roles of macrophages in different stages of disease pathogenesis from initiation to advanced atherosclerosis. Macrophage-based therapies for atherosclerosis management are also described.
Storax, A Promising Botanical Medicine for Treating Cardio-Cerebrovascular Diseases: A Review
Authors: Xu Zhuo , Lu Danni , Yuan Jianmei , Ren Mihong , Ma Rong , Xie Qian , Li Yong , Li Jinxiu , Wang Jian
Published: December 2021

In recent years, the incidence and mortality of cardio-cerebrovascular diseases have been increasing year by year, which has become global burden and challenge. Based on the holistic thinking of “brain disease affects the heart” and “heart disease affects the brain,” as well as the characteristics of multi-target and multi-path effects of Chinese medicine, Chinese medicine is more advantageous in the treatment of cardio-cerebrovascular diseases. As a botanical medicine, storax is known for its resuscitation, filth avoidance and pain-relieving effects in the treatment of cardio-cerebrovascular diseases. By reviewing and collating the relevant domestic and international literature in the past 10 years, we have sorted out an overview of the medicinal parts, traditional uses and chemical composition of storax. For the first time, based on the idea of “cerebral and cardiac simultaneous treatment,” the pharmacological activities and mechanisms of heart and brain protection of storax for treating cardio-cerebrovascular diseases were summarized and analyzed, showing that storax has the pharmacological effects of anti-cerebral ischemia, regulation of blood-brain barrier, bidirectional regulation of the central nervous system, anti-myocardial ischemia, anti-arrhythmia, anti-thrombosis and anti-platelet aggregation. It mainly exerts its protective effects on the brain and heart through mechanisms such as inhibition of inflammatory immune factors, anti-oxidative stress, anti-apoptosis, pro-neovascularization and regulation of NO release. On the basis of the current findings and limitations, the future research strategies and perspectives of storax are proposed, with a view to providing a reference for further application and development of this medicine, as well as contributing new thoughts and visions for the clinical application of “treating brain-heart synchronously”.
Thermal Correction to the Kinnersley Black Hole in a Lorentz-Violating Dirac Field Theory
Authors: Liu Zhi-E. , Zhang Jie , Yang Shu-Zheng
Published: December 2021

According to Lorentz-violating theory, the dynamical equation of Dirac particles in the Kinnersley black hole with variably accelerated linear motion is modified. The Hawking quantum tunneling radiation characteristics of Kinnersley black hole are obtained by solving the modified equation. The expression of the Hawking temperature of Kinnersley black hole has been updated.
Fluctuations and Pinning for Individually Manipulated Skyrmions
Authors: Reichhardt C. J. O. , Reichhardt C.
Published: December 2021

We numerically examine the dynamics of individually dragged skyrmions interacting simultaneously with an array of other skyrmions and quenched disorder. For drives just above depinning, we observe a broadband noise signal with a 1/f characteristic, while at higher drives, narrowband or white noise appears. Even in the absence of quenched disorder, the threshold force that must be applied to translate the driven skyrmion is finite due to elastic interactions with other skyrmions. The depinning threshold increases as the strength of the quenched disorder is raised. Above the depinning force, the skyrmion moves faster in the presence of quenched disorder than in a disorder-free system since the pinning sites prevent other skyrmions from being dragged along with the driven skyrmion. For strong pinning, we find a stick-slip motion of the driven skyrmion which produces a telegraph noise signature. The depinning threshold increases monotonically with skyrmion density in the absence of quenched disorder, but when pinning is present, the depinning threshold changes nonmonotonically with skyrmion density, and there are reentrant pinned phases due to a competition between pinning induced by the quenched disorder and that produced by the elastic interactions of the skyrmion lattice.
A Study on Drivers of Water Consumption in China From a Complex Network Perspective
Authors: Du Ruijin , Zheng Xiaoxia , Tian Lixin , Liu Kaihui , Qian Lijuan , Wu Qi , Fang Guochang
Published: December 2021

Water consumption has been one of the most important topics in the field of environment and economy. Even though the driving factors of water consumption have been well studied, it is still a daunting task to reveal the influence of the status of provinces in the entire supply chain. By combining the multi-regional input-output (MRIO) model and complex network theory, an inter-provincial virtual water transfer (V WT) network was constructed to analyze the overall structural characteristics of the network model and identify the structural roles of each province. The constructed inter-provincial V WT network exhibited the characteristics of a small-world network, that is, virtual water can be easily transferred from one province to another. Moreover, network analysis revealed that provinces with different positions in the V WT network played discrepant structural roles. Panel regression analysis was further used to quantify the impact of provincial structural roles on their water consumption. The results showed that water consumption in China largely depended on some structural role characteristics in the V WT network. Out-degree and out-strength characterizing the ability of direct exporting virtual water exerted significant positive influences, while in-closeness featuring the indirect virtual water importing rate had a significant negative effect on water usage. This indicated that adjusting the uneven provincial consumption structure, the direct production demand of downstream provinces and the indirect production activities in the supply chain would help reduce water consumption. Therefore, to come true the goal of water conservation in China, it would be necessary to improve the trade structure between direct and indirect exporters and importers in the entire supply chain.
Effects of Resistance Training With Constant, Inertial, and Combined Loads on Muscle Power and Strength Output
Authors: Đurić Saša , Knezevic Olivera M. , Sember Vedrana , Cuk Ivan , Nedeljkovic Aleksandar , Pajek Maja , Mirkov Dragan M.
Published: December 2021

The aim of this study was to investigate the resistance-specific gains in muscle power and strength (1RM) following the training of maximum bench-press throws (BPT) against constant, inertial, and combined resistance. Forty-eight male participants (age 20.5 ± 2.0 years) were randomly assigned to the constant, inertial, combined resistance, or control group. Participants underwent 8 weeks of training of BPT against the loads that corresponded to the different effects of mass of 40 kg (∼50% of 1RM). The gains in average and maximum power, and 1RM were significant in all experimental groups (P < 0.01), but not in the control group (P > 0.1). Relative gains in the average (26.3 ± 9.8%) and maximum power (25.2 ± 9.8%) were larger than that in the 1RM (mean 7.2 ± 6.9%; both P < 0.001). The gains in the average (F4, 66 = 6.0; P < 0.01) and maximum power (F4, 66 = 4.7; P < 0.01) were higher when tested against the training-specific resistance than when tested against the remaining two resistance types. Differences in 1RM among experimental groups were not significant (P = 0.092). The most important and rather novel finding of the study is that the training against the weight and inertial resistance, and their combination results in resistance-specific gains in muscle power, although the overall gains muscle strength and power remain comparable across the training protocols.
Cancer—A Major Cardiac Comorbidity With Implications on Cardiovascular Metabolism
Authors: Finke Daniel , Heckmann Markus B. , Frey Norbert , Lehmann Lorenz H.
Published: December 2021

Cardiovascular diseases have multifactorial causes. Classical cardiovascular risk factors, such as arterial hypertension, smoking, hyperlipidemia, and diabetes associate with the development of vascular stenoses and coronary heart disease. Further comorbidities and its impact on cardiovascular metabolism have gotten more attention recently. Thus, also cancer biology may affect the heart, apart from cardiotoxic side effects of chemotherapies. Cancer is a systemic disease which primarily leads to metabolic alterations within the tumor. An emerging number of preclinical and clinical studies focuses on the interaction between cancer and a maladaptive crosstalk to the heart. Cachexia and sarcopenia can have dramatic consequences for many organ functions, including cardiac wasting and heart failure. These complications significantly increase mortality and morbidity of heart failure and cancer patients. There are concurrent metabolic changes in fatty acid oxidation (FAO) and glucose utilization in heart failure as well as in cancer, involving central molecular regulators, such as PGC-1α. Further, specific inflammatory cytokines (IL-1β, IL-6, TNF-α, INF-β), non-inflammatory cytokines (myostatin, SerpinA3, Ataxin-10) and circulating metabolites (D2-HG) may mediate a direct and maladaptive crosstalk of both diseases. Additionally, cancer therapies, such as anthracyclines and angiogenesis inhibitors target common metabolic mechanisms in cardiomyocytes and malignant cells. This review focuses on cardiovascular, cancerous, and cancer therapy-associated alterations on the systemic and cardiac metabolic state.
Aging Affects KV7 Channels and Perivascular Adipose Tissue-Mediated Vascular Tone
Authors: Wang Yibin , Yildiz Fatima , Struve Andrey , Kassmann Mario , Markó Lajos , Köhler May-Britt , Luft Friedrich C. , Gollasch Maik , Tsvetkov Dmitry
Published: December 2021

Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3–5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3–5 channels represent a promising target in cardiovascular aging.
Sentinels in Salmon Aquaculture: Heart Rates Across Seasons and During Crowding Events
Authors: Warren-Myers Fletcher , Hvas Malthe , Vågseth Tone , Dempster Tim , Oppedal Frode
Published: December 2021

Advances in tag technology now make it possible to monitor the behavior of small groups of individual fish as bioindicators of population wellbeing in commercial aquaculture settings. For example, tags may detect unusual patterns in fish heart rate, which could serve as an early indicator of whether fish health or welfare is becoming compromised. Here, we investigated the use of commercially available heart rate biologgers implanted into 24 Atlantic salmon weighing 3.6 ± 0.8 kg (mean ± SD) to monitor fish over 5 months in a standard 12 m × 12 m square sea cage containing ∼6,000 conspecifics. Post tagging, fish established a diurnal heart rate rhythm within 24 h, which stabilized after 4 days. Whilst the registered tagged fish mortality over the trial period was 0%, only 75% of tagged fish were recaptured at harvest, resulting in an unexplained tag loss rate of 25%. After 5 months, tagged fish were approximately 20% lighter and 8% shorter, but of the similar condition when compared to untagged fish. Distinct diurnal heart rate patterns were observed and changed with seasonal day length of natural illumination. Fish exhibited lower heart rates at night [winter 39 ± 0.2 beats per min (bpm), spring 37 ± 0.2 bpm, summer 43 ± 0.3 bpm, mean ± SE] than during the day (winter 50 ± 0.3 bpm, spring 48 ± 0.2 bpm, summer 49 ± 0.2 bpm) with the difference between night and day heart rates near half during the summer (6 bpm) compared to winter and spring (both 11 bpm). When fish experienced moderate and severe crowding events in early summer, the highest hourly heart rates reached 60 ± 2.5 bpm and 72 ± 2.4 bpm, respectively, on the day of crowding. Here, if the negative sublethal effects on fish that carry tags (e.g., growth rate) can be substantially reduced, the ability to monitor diurnal heart rate patterns across seasons and detect changes during crowding events, and using heart rate biologgers could be a useful warning mechanism for detecting sudden changes in fish behavior in sea cages.
Aging Does Not Exacerbate Muscle Loss During Denervation and Lends Unique Muscle-Specific Atrophy Resistance With Akt Activation
Authors: You Jae-Sung , Chen Jie
Published: December 2021

Sarcopenia, or age-related skeletal muscle atrophy and weakness, imposes significant clinical and economic burdens on affected patients and societies. Neurological degeneration, such as motoneuron death, has been recognized as a key contributor to sarcopenia. However, little is known about how aged/sarcopenic muscle adapts to this denervation stress. Here, we show that mice at 27months of age exhibit clear signs of sarcopenia but no accelerated denervation-induced muscle atrophy when compared to 8-month-old mice. Surprisingly, aging lends unique atrophy resistance to tibialis anteria muscle, accompanied by an increase in the cascade of mammalian target of rapamycin complex 1 (mTORC1)-independent anabolic events involving Akt signaling, rRNA biogenesis, and protein synthesis during denervation. These results expand our understanding of age-dependent stress responses and may help develop better countermeasures to sarcopenia.
Protein Kinase SGK2 Is Induced by the β3 Adrenergic Receptor-cAMP-PKA-PGC-1α/NT-PGC-1α Axis but Dispensable for Brown/Beige Adipose Tissue Thermogenesis
Authors: Park Chul-Hong , Moon Jiyoung , Park Minsung , Cheng Helia , Lee Jisu , Chang Ji Suk
Published: December 2021

Brown and beige adipocytes are specialized to dissipate energy as heat. Sgk2, encoding a serine/threonine kinase, has been identified as a brown and beige adipocyte-specific gene in rodents and humans; however, its function in brown/beige adipocytes remains unraveled. Here, we examined the regulation and role of Sgk2 in brown/beige adipose tissue thermogenesis. We found that transcriptional coactivators PGC-1α and NT-PGC-1α activated by the β3 adrenergic receptor-cAMP-PKA pathway are recruited to the Sgk2 promoter, triggering Sgk2 transcription in response to cold. SGK2 elevation was closely associated with increased serine/threonine phosphorylation of proteins carrying the consensus RxRxxS/T phosphorylation site. However, despite cold-dependent activation of SGK2, mice lacking Sgk2 exhibited normal cold tolerance at 4°C. In addition, Sgk2+/+ and Sgk2−/− mice induced comparable increases in energy expenditure during pharmacological activation of brown and beige adipose tissue with a β3AR agonist. In vitro loss- and gain-of-function studies further demonstrated that Sgk2 ablation or activation does not alter thermogenic gene expression and mitochondrial respiration in brown adipocytes. Collectively, our results reveal a new signaling component SGK2, although dispensable for cold-induced thermogenesis that adds an additional layer of complexity to the β3AR signaling network in brown/beige adipose tissue.
Deployment of Brassica carinata A. Braun Derived Brassica juncea (L.) Czern. Lines for Improving Heterosis and Water Use Efficiency Under Water Deficit Stress Conditions
Authors: Limbalkar Omkar Maharudra , Singh Rajendra , Kumar Parvesh , Nanjundan Joghee , Parihar Chiter Mal , Vasisth Prashant , Yadava Devendra Kumar , Chinnusamy Viswanathan , Singh Naveen
Published: December 2021

AmongBrassicaspecies, Ethiopian mustard (Brassica carinataA. Braun) is known to tolerate most abiotic stresses, including drought. Drought caused by low and erratic rainfall in semi-arid regions consistently challenges rapeseed mustard productivity. Development ofB. carinata-derived lines (CDLs) inBrassica juncea(L.) Czern. nuclear background, carrying genomic segments fromB. carinata, are expected to tolerate moisture deficit stress conditions. The present study was, thus, aimed to establish the phenomenon “heterosis” for drought tolerance and water use efficiency by evaluating 105 hybrids developed from intermating 15 CDLs in half diallel fashion. Data on 17 seed yield and yield contributing traits were recorded under two different environments,viz., irrigated and rainfed conditions. Traits under study were found to be governed by both additive and non-additive types of gene action. Average degree of dominance was higher (>2) for yield and yield contributing traits,viz., secondary branches/plant, point to first siliqua on main shoot, total siliquae/plant, 1,000-seed weight, seed yield/plant, biological yield, harvest index, and seed yield/hectare under rainfed conditions, clearly indicating that higher productivity under drought conditions can be realised through the development of hybrids. Out of 15, highly significant general combining ability (GCA) effects for seven CDLs were observed under rainfed condition. Furthermore, nine and six hybrids expressed highly significant specific combining ability (SCA) effects and > 50% heterobeltiosis for yield contributing traits under rainfed and irrigated conditions, respectively. Water use efficiency (WUE) of parental CDLs and hybrids varied from 2.05 to 2.57 kg m–3under rainfed, while 1.10 to 1.28 kg m–3under irrigated conditions. Hybrids expressed higher WUE than parental lines under both water regimes. Furthermore, selection indices such as drought tolerance index (DTI) and mean relative performance (MRP) were identified to be efficient in the selection of productive CDLs and hybrids under drought conditions. Nine hybrids, identified as highly productive in the present study, can further be exploited for improving the yield of Indian mustard in drought-prone areas. Usefulness of interspecific hybridisation in the development ofB. carinata-derivedB. juncealines for improving heterosis and WUE is, thus, well demonstrated through the present study.
Unraveling Cuticle Formation, Structure, and Properties by Using Tomato Genetic Diversity
Authors: Petit Johann , Bres Cécile , Reynoud Nicolas , Lahaye Marc , Marion Didier , Bakan Bénédicte , Rothan Christophe
Published: December 2021

The tomato (Solanum lycopersicum) fruit has a thick, astomatous cuticle that has become a model for the study of cuticle formation, structure, and properties in plants. Tomato is also a major horticultural crop and a long-standing model for research in genetics, fruit development, and disease resistance. As a result, a wealth of genetic resources and genomic tools have been established, including collections of natural and artificially induced genetic diversity, introgression lines of genome fragments from wild relatives, high-quality genome sequences, phenotype and gene expression databases, and efficient methods for genetic transformation and editing of target genes. This mini-review reports the considerable progresses made in recent years in our understanding of cuticle by using and generating genetic diversity for cuticle-associated traits in tomato. These include the synthesis of the main cuticle components (cutin and waxes), their role in the structure and properties of the cuticle, their interaction with other cell wall polymers as well as the regulation of cuticle formation. It also addresses the opportunities offered by the untapped germplasm diversity available in tomato and the current strategies available to exploit them.
Mutation of GmAITR Genes by CRISPR/Cas9 Genome Editing Results in Enhanced Salinity Stress Tolerance in Soybean
Authors: Wang Tianya , Xun Hongwei , Wang Wei , Ding Xiaoyang , Tian Hainan , Hussain Saddam , Dong Qianli , Li Yingying , Cheng Yuxin , Wang Chen , Lin Rao , Li Guimin , Qian Xueyan , Pang Jinsong , Feng Xianzhong , Dong Yingshan , Liu Bao , Wang Shucai
Published: December 2021

Breeding of stress-tolerant plants is able to improve crop yield under stress conditions, whereas CRISPR/Cas9 genome editing has been shown to be an efficient way for molecular breeding to improve agronomic traits including stress tolerance in crops. However, genes can be targeted for genome editing to enhance crop abiotic stress tolerance remained largely unidentified. We have previously identified abscisic acid (ABA)-induced transcription repressors (AITRs) as a novel family of transcription factors that are involved in the regulation of ABA signaling, and we found that knockout of the entire family of AITR genes in Arabidopsis enhanced drought and salinity tolerance without fitness costs. Considering that AITRs are conserved in angiosperms, AITRs in crops may be targeted for genome editing to improve abiotic stress tolerance. We report here that mutation of GmAITR genes by CRISPR/Cas9 genome editing leads to enhanced salinity tolerance in soybean. By using quantitative RT-PCR analysis, we found that the expression levels of GmAITRs were increased in response to ABA and salt treatments. Transfection assays in soybean protoplasts show that GmAITRs are nucleus proteins, and have transcriptional repression activities. By using CRISPR/Cas9 to target the six GmAITRs simultaneously, we successfully generated Cas9-free gmaitr36 double and gmaitr23456 quintuple mutants. We found that ABA sensitivity in these mutants was increased. Consistent with this, ABA responses of some ABA signaling key regulator genes in the gmaitr mutants were altered. In both seed germination and seedling growth assays, the gmaitr mutants showed enhanced salt tolerance. Most importantly, enhanced salinity tolerance in the mutant plants was also observed in the field experiments. These results suggest that mutation of GmAITR genes by CRISPR/Cas9 is an efficient way to improve salinity tolerance in soybean.
Correction by Focus: Cleft Constructions and the Cross-Linguistic Variation in Phonological Form
Authors: Greif Markus , Skopeteas Stavros
Published: December 2021

A challenging issue of cross-linguistic variation is that the same syntactic construction may appear in different arrays of contexts depending on language. For instance, cleft constructions appear with contrastive focus in English, but in a larger array of contexts in French. A part of the cross-linguistic variation may be due to prosodic differences, since prosodic possibilities determine the array of focus structures that can be mapped onto one and the same syntactic configuration. In the present study, we compare languages with flexible nuclear-accent placement (English, German), with languages that do not use this prosodic strategy (French, Mandarin Chinese). In a speech production experiment, we examine the prosodic realization of contrastive focus and identify prosodic reflexes of focus in all languages. The presence of different phonetic reflexes of focus suggests that – anything else being equal – the same syntactic constructions should be possible in the same array of contexts. In an acceptability study with written questionnaires, we examined the felicity of cleft constructions in contexts licensing a focus within the cleft clause. This focus structure is orthogonal to the preferred focus structure of cleft constructions and can appear in cases of second-occurrence foci (in contexts of correction). The obtained judgments reveal a distinction between languages with flexible nuclear-accent placement (English, German) and languages with other types of reflexes of focus (French, Chinese): languages of the former type have an advantage in using cleft constructions with a focus within the cleft clause, which shows that the array of contexts of using clefts in English and German is not a proper subset of the array of contexts applying to the same constructions in French and Chinese. The obtained differences can be explained by the role of prosodic devices and corroborate the view that prosodic reflexes of focus have different semantic-pragmatic import: it is easier to establish a focus structure that is orthogonal to the syntax in a language with flexible nuclear-accent placement (English, German); this does not hold for prosodic correlates of focus that reinforce the articulation of prosodic constituents (French) or the articulation of lexical tones (Chinese).
A Meta-Analytic Review of Moral Disengagement and Cyberbullying
Authors: Zhao Lijun , Yu Junjian
Published: December 2021

With the development of technology, cyberbullying prevalence rates are increasing worldwide, and a growing body of the literature has begun to document cyberbullying behavior. Moral disengagement is often considered a key correlate factor in cyberbullying. This article aims to conduct a meta-analysis review of the relationship between moral disengagement and cyberbullying and some psychosocial and cultural variables. Based on the PRISMA method, a random-effects meta-analysis is employed in this study to obtain reliable estimates of effect sizes and examine a range of moderators (age, gender, measure method, and cultural background). Relevant studies, published from 2005 to February 30, 2021, were identified through a systematic search of the Web of Science, ScienceDirect, SpringerLink, Pubmed, EBSCO, and Wiley Online Library. Finally, 38 studies (N=38,425) met the inclusion criteria. The meta-analysis conclusion demonstrated that moral disengagement positively correlated medium intensity with cyberbullying (r=0.341). Age, gender, and cultural background had moderated the relationship between moral disengagement and cyberbullying.
The Impact of Ecological Civilization Theory on University Students’ Pro-environmental Behavior: An Application of Knowledge-Attitude-Practice Theoretical Model
Authors: Wang Kuan , Zhang Lu
Published: December 2021

In environmental education, environmental knowledge is considered to be one of the most important factors affecting university students’ pro-environmental behavior. First, in this paper, the ecological civilization theory (ECT) was understood as a new kind of environmental knowledge. Based on this, a new theoretical model for analyzing the relationships among environmental knowledge, environmental attitude, and environmental behavior was designed in this paper according to ECT and the Knowledge-Attitude-Practice (KAP) theoretical model. Second, from the perspective of students, a questionnaire was designed for students according to ECT, so as to understand the level of ECT of students. On this basis, an empirical test of the relationship between the ECT level, pro-environmental attitude level, and pro-environmental behavior level was carried out. This research shows that ECT as environmental knowledge is as important as science-oriented environmental knowledge (SEK) in environmental education. As a result, the role of environmental knowledge in environmental education should not be ignored but environmental knowledge should be enriched by adding ECT to the environmental knowledge system and improving the environmental knowledge education curriculum, contributing to environmental education in China.
A Challenge for Contrastive L1/L2 Corpus Studies: Large Inter- and Intra-Individual Variation Across Morphological, but Not Global Syntactic Categories in Task-Based Corpus Data of a Homogeneous L1 German Group
Authors: Shadrova Anna , Linscheid Pia , Lukassek Julia , Lüdeling Anke , Schneider Sarah
Published: December 2021

In this paper, we present corpus data that questions the concept of native speaker homogeneity as it is presumed in many studies using native speakers (L1) as a control group for learner data (L2), especially in corpus contexts. Usage-based research on second and foreign language acquisition often investigates quantitative differences between learners, and usually a group of native speakers serves as a control group, but often without elaborating on differences within this group to the same extent. We examine inter-personal differences using data from two well-controlled German native speaker corpora collected as control groups in the context of second and foreign language research. Our results suggest that certain linguistic aspects vary to an extent in the native speaker data that undermines general statements about quantitative expectations in L1. However, we also find differences between phenomena: while morphological and syntactic sub-classes of verbs and nouns show great variability in their distribution in native speaker writing, other, coarser categories, like parts of speech, or types of syntactic dependencies, behave more predictably and homogeneously. Our results highlight the necessity of accounting for inter-individual variance in native speakers where L1 is used as a target ideal for L2. They also raise theoretical questions concerning a) explanations for the divergence between phenomena, b) the role of frequency distributions of morphosyntactic phenomena in usage-based linguistic frameworks, and c) the notion of the individual adult native speaker as a general representative of the target language in language acquisition studies or language in general.