bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonal Aspects of Radiative and Advective Air Temperature Populations: A Canadian Perspective
Authors: Žaknić-Ćatović Ana , Gough William A.
Published: June 2022

Canadian high-frequency temperature time series exhibit physical heterogeneity in the coexistence of radiative and advective populations in the total air temperature sample. This work examines forty-five Canadian hourly air temperature records to study seasonal characteristics and variability of radiative and advective population counts and their corresponding temperature biases and trends. The Linear Pattern Discrimination algorithm, conceptualized in a previous study, was adjusted to seasonal analysis on the equinox-to-equinox time scale. Count analysis of radiative and advective days supports the existence of two distinct thermal regimes, Spring–Summer and Fall–Winter. Further, seasonal advective counts for the majority of examined stations typically decrease in numbers. The consistently warmer winter radiative temperature extrema points to the critical role of the advective population in control of the overall temperature magnitude. Canadian northwest warming trends are found to be the highest, indicating the amplifying effect of decreasing advective counts with rapidly increasing temperatures that weaken the advective population’s moderating ability to control the magnitude of the total temperature population.
PM2.5 Pollution Levels and Chemical Components at Teahouses along the Poon Hill Trek in Nepal
Authors: Johnston James D. , Beard John D. , Novilla M. Lelinneth B. , Weber Frank X. , Chartier Ryan T.
Published: June 2022

Unhealthy levels of fine particulate matter (PM2.5) from the local burning of solid fuels, and from regional transport of pollutants, remain a major public health problem in the Himalayan foothill villages in Nepal. Teahouses (i.e., mountain lodges) along popular hiking trails in the lower Himalayas commonly use wood as the primary energy source for heating; however, little is known about teahouse air quality. The purpose of this study was to characterize the levels and chemical constituents of indoor and ambient PM2.5 at three villages along the Poon Hill circuit trek in the Annapurna Conservation Area in Nepal. A convenience sample of five PM2.5 measurements was collected with portable MicroPEM V.3.2A exposure monitors. Filters were analyzed for black and brown carbon using integrating sphere optical transmittance and 33 elemental constituents using energy-dispersive X-ray fluorescence. Median indoor PM2.5 over the sampling period was 41.3 µg/m3, whereas median ambient PM2.5 over the sampling period was 34.7 µg/m3. Chemical species associated with wood smoke, such as potassium (GM = 0.88 µg/m3), predominated. High indoor and ambient PM2.5 levels may pose a significant occupational health risk to teahouse workers, who may experience chronic exposures during trekking seasons. Our findings warrant additional research to characterize teahouse air pollution exposures more fully and to evaluate intervention measures.
Study on Improving the Air Quality with Emission Enhanced Control Measures in Beijing during a National Parade Event
Authors: Huang Bingbo , Deng Minjun , Gao Qingxian , Ma Zhanyun , Chen Mindong
Published: June 2022

Research on the enhanced control and emission-reduction measures to improve air quality during major events could provide data theory and scientific support for air-quality improvement during non-activities. Based on the air-quality data published by the China Environmental Monitoring Station and the meteorological elements and weather conditions released by the China Meteorological Administration, this paper explored the characteristics of air-quality evolution in Beijing from 5 August to 18 September 2015 and the weather situation during the Military Parade. The results showed that: (1) Emission-reduction measures implemented for air quality by Beijing and its surrounding area were induced, and we explored the contribution of these measures to pollutants or AQI in the locality. (2) During the 2015 Military Parade, Beijing was in the front or lower part of the high-pressure system. Due to the strong effect of North or Northeast winds, the weather situation was conducive to the diffusion of pollutants. When before or after the implementation, once the atmospheric diffusion was poor, the pollutants would accumulate gradually. Thus, it can be seen that the weather situation had a great impact on air quality. (3) During the implementation, PM2.5, PM10, NO2 and other pollutants decreased significantly, of which the concentration of PM10 decreased the most, from 109 μg·m−3 down to 34 μg·m−3, and the concentration of PM2.5 decreased by 72.73%. According to the changes between before and during the implementation or during and after the implementation, the concentration of PM10 and PM2.5 increased when the implementation of the emission-reduction measures had been finished, indicating that the enhanced control measures made a great contribution to the emission reduction in particles. (4) In addition, the annual average of AQI in the three years is 87.49, and the average value of a normal year was the average value of 2013 and 2014. The average value of the normal year during the military parade is 64.63, which was 70.40% lower than the average value of AQI during the military parade. The goal of reaching the secondary standard of GB-3095-2012 was achieved, and there was still a long way to go from the primary standard. In a few words, in order to achieve the goal of better air quality throughout the year, all parties still needed to coordinate control and make joint efforts.
Chemical Compositions of Rainfall Water in Nyingchi City, Tibet
Authors: Wang Wei , Guan Lixue , Zhao Jiamin , Sha Zhipeng , Fang Jiangping
Published: June 2022

Understanding precipitation chemistry is highlighted as important worldwide due to its close relationship with air quality and impacts on ecosystems. However, the chemical composition of precipitation is limited in Tibet, where alpine ecosystems are sensitive to global change. Here, rainwater samples were collected in Nyingchi city from January 2021 to December 2021, and a total of 44 samples were obtained. Major ions (NO3−, NH4+, Cl−, SO42−, Na+, K+, Ca2+ and Mg2+) were analyzed. Results showed that the predominant ions in the precipitation were Ca2+, Na+, SO42−, and Cl−. Precipitation was mainly concentrated in summer, accounting for 65.2% of all samples collected during the monitoring period. As a result, ion deposition fluxes were mainly concentrated in summer, accounting for 55%, 53%, 84%, 82%, 61%, 63%, 75.8%, and 37.8% of the annual Ca2+, K+, Mg2+, Na+, NH4+, Cl−, SO42−, and NO3−, respectively. Backward trajectory analysis revealed that airmasses were mainly from the southern direction, but the sources varied widely. In addition, Na+ and Cl− ions were dominated by the sea source fraction; the ions of Ca2+ and K+ were dominated by crustal fraction sources. The NH4+ and NO3− ions were mainly influenced by local pollution. However, SO42− was mainly from long distance transports. Our results suggest that ions abundance was varied largely in different direction airmasses in southeast Tibet. Considering that ion deposition fluxes were mainly concentrated in the summer and the airmasses were mainly from the southern direction in this season, the pollutants from the southern direction the environmental effects of those ions should be given more attention in the future.
Shelter Efficiency of Various Shelterbelt Configurations: A Wind Tunnel Study
Authors: Li Huiliang , Wang Yongdong , Li Shengyu , Askar Aikedai , Wang Haifeng
Published: June 2022

The construction of protective forests in Nursultan is key to reducing near-surface wind speeds and snowstorm effects in urban areas. This study analyzed the effects of the number of plant rows and spacing of the shelterbelts on the flow field around protective forests to evaluate the wind protection benefits of the existing configuration of the shelterbelt in Nursultan and guide the construction of protective forests. We measured the airflow fields of four shelterbelts with different numbers of rows, seven double pure shelterbelts, and double mixed shelterbelts of arbors and shrubs with different spacings. The results showed that the airflow field around the shelterbelts can be divided into five characteristic regions based on shelter efficiency: a deceleration region before the shelterbelt, acceleration region above the canopy, strong deceleration region in the canopy layer, deceleration region behind the shelterbelt, and recovery region behind the shelterbelt. In terms of windproof ability, the wind protection benefits of a shelterbelt with six rows are the best in a single shelterbelt. Behind the shelterbelt, the wind protection benefits of double pure shelterbelts are greater than that of double mixed shelterbelts of arbor and shrub. On the contrary, the windbreak benefits of the latter are stronger than those of the former between the two shelterbelts.
A New Interior Search Algorithm for Energy-Saving Flexible Job Shop Scheduling with Overlapping Operations and Transportation Times
Authors: Liu Lu , Jiang Tianhua , Zhu Huiqi , Shang Chunlin
Published: June 2022

Energy-saving scheduling has been pointed out as an interesting research issue in the manufacturing field, by which energy consumption can be effectively reduced through production scheduling from the operational management perspective. In recent years, energy-saving scheduling problems in flexible job shops (ESFJSPs) have attracted considerable attention from scholars. However, the majority of existing work on ESFJSPs assumed that the processing of any two consecutive operations in a job cannot be overlapped. In order to be close to real production, the processing overlapping of consecutive operations is allowed in this paper, while the job transportation tasks are also involved between different machines. To formulate the problem, a mathematical model is set up to minimize total energy consumption. Due to the NP-hard nature, a new interior search algorithm (NISA) is elaborately proposed following the feature of the problem. A number of experiments are conducted to verify the effectiveness of the NISA algorithm. The experimental results demonstrate that the NISA provides promising results for the considered problem. In addition, the computational results indicate that the increasing transportation time and sub-lot number will increase the transportation energy consumption, which is largely responsible for the increase in total energy consumption.
Stability of Fractional-Order Quasi-Linear Impulsive Integro-Differential Systems with Multiple Delays
Authors: Kalidass Mathiyalagan , Zeng Shengda , Yavuz Mehmet
Published: June 2022

In this paper, some novel conditions for the stability results for a class of fractional-order quasi-linear impulsive integro-differential systems with multiple delays is discussed. First, the existence and uniqueness of mild solutions for the considered system is discussed using contraction mapping theorem. Then, novel conditions for Mittag–Leffler stability (MLS) of the considered system are established by using well known mathematical techniques, and further, the two corollaries are deduced, which still gives some new results. Finally, an example is given to illustrate the applications of the results.
A Theoretical Dynamical Noninteracting Model for General Manipulation Systems Using Axiomatic Geometric Structures
Authors: Mercorelli Paolo
Published: June 2022

This paper presents a new theoretical approach to the study of robotics manipulators dynamics. It is based on the well-known geometric approach to system dynamics, according to which some axiomatic definitions of geometric structures concerning invariant subspaces are used. In such a framework, certain typical problems in robotics are mathematically formalised and analysed in axiomatic form. The outcomes are sufficiently general that it is possible to discuss the structural properties of robotic manipulation. A generalized theoretical linear model is used, and a thorough analysis is made. The noninteracting nature of this model is also proven through a specific theorem.
Effects on Tissue Integration of Collagen Scaffolds Used for Local Delivery of Gentamicin in a Rat Mandible Defect Model
Authors: Billings Caroline , Bow Austin J. , Newby Steven D. , Donnell Robert L. , Dhar Madhu , Anderson David E.
Published: June 2022

Surgical site infections (SSIs) are a common complication following orthopedic surgery. SSIs may occur secondary to traumatic or contaminated wounds or may result from invasive procedures. The development of biofilms is often associated with implanted materials used to stabilize injuries and to facilitate healing. Regardless of the source, SSIs can be challenging to treat. This has led to the development of devices that act simultaneously as local antibiotic delivery vehicles and as scaffolds for tissue regeneration. The goal for the aforementioned devices is to increase local drug concentration in order to enhance bactericidal activity while reducing the risk of systemic side effects and toxicity from the administered drug. The aims of this study were to assess the effect of antibiotic loading of a collagen matrix on the tissue integration of the matrix using a rat mandibular defect model. We hypothesized that the collagen matrix could load and elute gentamicin, that the collagen matrix would be cytocompatible in vitro, and that the local delivery of a high dose of gentamicin via loaded collagen matrix would negatively impact the tissue–scaffold interface. The results indicate that the collagen matrix could load and elute the antimicrobial gentamicin and that it was cytocompatible in vitro with or without the presence of gentamicin and found no significant impact on the tissue–scaffold interface when the device was loaded with a high dose of gentamicin.
Manganese Porphyrin Promotes Post Cardiac Arrest Recovery in Mice and Rats
Authors: Wang Peng , Li Ying , Yan Baihui , Yang Zhong , Li Litao , Cao Zhipeng , Li Xuan , Batinic-Haberle Ines , Spasojevic Ivan , Warner David , Sheng Huaxin
Published: June 2022

Introduction Cardiac arrest (CA) and resuscitation induces global cerebral ischemia and reperfusion, causing neurologic deficits or death. Manganese porphyrins, superoxide dismutase mimics, are reportedly able to effectively reduce ischemic injury in brain, kidney, and other tissues. This study evaluates the efficacy of a third generation lipophilic Mn porphyrin, MnTnBuOE-2-PyP5+, Mn(III) ortho meso-tetrakis (N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE, BMX-001), in both mouse and rat models of CA. Methods Forty-eight animals were subjected to 8 min of CA and resuscitated subsequently by chest compression and epinephrine infusion. Vehicle or MnBuOE was given immediately after resuscitation followed by daily subcutaneous injections. Body weight, spontaneous activity, neurologic deficits, rotarod performance, and neuronal death were assessed. Kidney tubular injury was assessed in CA mice. Data were collected by the investigators who were blinded to the treatment groups. Results Vehicle mice had a mortality of 20%, which was reduced by 50% by MnBuOE. All CA mice had body weight loss, spontaneous activity decline, neurologic deficits, and decreased rotarod performance that were significantly improved at three days post MnBuOE daily treatment. MnBuOE treatment reduced cortical neuronal death and kidney tubular injury in mice (p < 0.05) but not hippocampus neuronal death (23% MnBuOE vs. 34% vehicle group, p = 0.49). In rats, they had a better body-weight recovery and increased rotarod latency after MnBuOE treatment when compared to vehicle group (p < 0.01 vs. vehicle). MnBuOE-treated rats had a low percentage of hippocampus neuronal death (39% MnBuOE vs. 49% vehicle group, p = 0.21) and less tubular injury (p < 0.05) relative to vehicle group. Conclusions We demonstrated the ability of MnBuOE to improve post-CA survival, as well as functional outcomes in both mice and rats, which jointly account for the improvement not only of brain function but also of the overall wellbeing of the animals. While MnBuOE bears therapeutic potential for treating CA patients, the females and the animals with comorbidities must be further evaluated before advancing toward clinical trials.
Mercury-Induced Oxidative Stress Response in Benthic Foraminifera: An In Vivo Experiment on Amphistegina lessonii
Authors: Ciacci Caterina , Betti Michele , Abramovich Sigal , Cavaliere Marco , Frontalini Fabrizio
Published: June 2022

The evaluation of the effects of pollution (e.g., Hg pollution) is a difficult task and relies mostly on biomonitoring based on bioindicators. The application of biomarkers may represent a complementary or alternative approach in environmental biomonitoring. Mercury is known to pose a significant health hazard due to its ability to cross cellular membranes, bioaccumulate, and biomagnify. In the present research, the effects of short-term (i.e., 24 h) Hg exposure in the symbiont-bearing benthic foraminiferal species Amphistegina lessonii are evaluated using several biomarkers (i.e., proteins and enzymes). Mercury leads to significant changes in the biochemistry of cells. Its effects are mainly associated with oxidative stress (i.e., production of reactive oxygen species: ROS), depletion of glutathione (GSH), and alteration of protein synthesis. Specifically, our findings reveal that exposure to Hg leads to the consumption of GSH by GPx and GST for the scavenging of ROS and the activation of antioxidant-related enzymes, including SOD and GSH-enzymes (GST, GSR, GPx, and Se-GPx), that are directly related to a defense mechanism against ROS. The Hg exposure also activates the MAPK (e.g., p-p38) and HSP (e.g., HSP 70) pathways. The observed biochemical alterations associated with Hg exposure may represent effective and reliable proxies (i.e., biomarkers) for the evaluation of stress in A. lessonii and lead to a possible application for the detection of early warning signs of environmental stress in biomonitoring.
Alterations in Gut Microbiota and Upregulations of VPAC2 and Intestinal Tight Junctions Correlate with Anti-Inflammatory Effects of Electroacupuncture in Colitis Mice with Sleep Fragmentation
Authors: Liu Geng-Hao , Zhuo Xin-Cheng , Huang Yueh-Hsiang , Liu Hsuan-Miao , Wu Ren-Chin , Kuo Chia-Jung , Chen Ning-Hung , Chuang Li-Pang , Lin Shih-Wei , Chen Yen-Lung , Yang Huang-Yu , Lee Tzung-Yan
Published: June 2022

The relationship between inflammatory bowel disease and sleep disturbances is complicated and of increasing interest. We investigated the inflammatory and immunological consequences of EA in sleep-deprived colitis and found that dextran sulfate sodium (DSS)-induced colitis in sleep-fragmented (SF) mice was more severe than that in mice with normal sleep. This increase in the severity of colitis was accompanied by reduced body weight, shortened colon length, and deteriorated disease activity index. DSS with SF mice presented obvious diminished intestinal tight junction proteins (claudin-1 and occludin), elevated proinflammatory cytokines (CRP, IFN-γ, IL-6), lowered melatonin and adiponectin levels, downregulated vasoactive intestinal peptide (VIP) type 1 and 2 receptor (VPAC1, VPAC2) expression, and decreased diversity of gut bacteria. EA ameliorated colitis severity and preserved the performance of the epithelial tight junction proteins and VIP receptors, especially VPAC2. Meanwhile, the innate lymphoid cells-derived cytokines in both group 2 (IL-4, IL5, IL-9, IL-13) and group 3 (IL-22, GM-CSF) were elevated in mice colon tissue. Furthermore, dysbiosis was confirmed in the DSS group with and without SF, and EA could maintain the species diversity. Firmicutes could be restored, such as Lachnospiraceae, and Proteobacteria become rebalanced, mainly Enterobacteriaceae, after EA intervention. On the other hand, SF plays different roles in physiological and pathological conditions. In normal mice, interrupted sleep did not affect the expression of claudin-1 and occludin. But VPAC1, VPAC2, and gut microbiota diversity, including Burkholderiaceae and Rhodococcus, were opposite to mice in an inflamed state.
Complex Network Model Reveals the Impact of Inspiratory Muscle Pre-Activation on Interactions among Physiological Responses and Muscle Oxygenation during Running and Passive Recovery
Authors: Manchado-Gobatto Fúlvia Barros , Torres Ricardo Silva , Marostegan Anita Brum , Rasteiro Felipe Marroni , Hartz Charlini Simoni , Moreno Marlene Aparecida , Pinto Allan Silva , Gobatto Claudio Alexandre
Published: June 2022

Although several studies have focused on the adaptations provided by inspiratory muscle (IM) training on physical demands, the warm-up or pre-activation (PA) of these muscles alone appears to generate positive effects on physiological responses and performance. This study aimed to understand the effects of inspiratory muscle pre-activation (IMPA) on high-intensity running and passive recovery, as applied to active subjects. In an original and innovative investigation of the impacts of IMPA on high-intensity running, we proposed the identification of the interactions among physical characteristics, physiological responses and muscle oxygenation in more and less active muscle to a running exercise using a complex network model. For this, fifteen male subjects were submitted to all-out 30 s tethered running efforts preceded or not preceded by IMPA, composed of 2 × 15 repetitions (1 min interval between them) at 40% of the maximum individual inspiratory pressure using a respiratory exercise device. During running and recovery, we monitored the physiological responses (heart rate, blood lactate, oxygen saturation) and muscle oxygenation (in vastus lateralis and biceps brachii) by wearable near-infrared spectroscopy (NIRS). Thus, we investigated four scenarios: two in the tethered running exercise (with or without IMPA) and two built into the recovery process (after the all-out 30 s), under the same conditions. Undirected weighted graphs were constructed, and four centrality metrics were analyzed (Degree, Betweenness, Eigenvector, and Pagerank). The IMPA (40% of the maximum inspiratory pressure) was effective in increasing the peak and mean relative running power, and the analysis of the complex networks advanced the interpretation of the effects of physiological adjustments related to the IMPA on exercise and recovery. Centrality metrics highlighted the nodes related to muscle oxygenation responses (in more and less active muscles) as significant to all scenarios, and systemic physiological responses mediated this impact, especially after IMPA application. Our results suggest that this respiratory strategy enhances exercise, recovery and the multidimensional approach to understanding the effects of physiological adjustments on these conditions.
Isolation of Chitinolytic Bacteria from European Sea Bass Gut Microbiota Fed Diets with Distinct Insect Meals
Authors: Rangel Fábio , Santos Rafaela A. , Monteiro Marta , Lavrador Ana Sofia , Gasco Laura , Gai Francesco , Oliva-Teles Aires , Enes Paula , Serra Cláudia R.
Published: June 2022

Insect meal (IM), recently authorized for use in aquafeeds, positions itself as a promising commodity for aquafeed inclusion. However, insects are also rich in chitin, a structural polysaccharide present in the exoskeleton, which is not digested by fish, resulting in lower fish performance. Through the application of a dietary pressure, this study aimed to modulate European sea bass gut microbiota towards the enrichment of chitinolytic bacteria to allow the isolation of novel probiotics capable of improving the use of IM-containing diets, overcoming chitin drawbacks. Five isoproteic (44%) and isolipidic (18%) diets were used: a fish meal (FM)-based diet (diet CTR), a chitin-supplemented diet (diet CHIT5), and three diets with either 25% of Hermetia illucens and Tenebrio molitor larvae meals (HM25 and TM25, respectively) or H. illucens exuviae meal (diet HEM25) as partial FM substitutes. After an 8-week feeding trial, the results showed a clear modulatory effect towards spore-forming bacteria by HM25 and HEM25 diets, with the latter being responsible for the majority of the chitinolytic fish isolates (FIs) obtained. Sequential evaluation of the FI hemolytic activity, antibiotic resistance, total chitinolytic activity, sporulation, and survival in gastrointestinal-like conditions identified FI645 and FI658 as the most promising chitinolytic probiotics for in vivo application.
The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors
Authors: Joshi Abhinav , Ito Takeshi , Picard Didier , Neckers Len
Published: June 2022

The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in mitochondrial biology. TRAP1 is more homologous to the bacterial HSP90, HtpG, than to eukaryotic HSP90. Lacking co-chaperones, the unique structural features of TRAP1 likely regulate its temperature-sensitive ATPase activity and shed light on the alternative mechanisms driving the chaperone’s nucleotide-dependent cycle in a defined environment whose physiological temperature approaches 50 °C. TRAP1 appears to be an important bioregulator of mitochondrial respiration, mediating the balance between oxidative phosphorylation and glycolysis, while at the same time promoting mitochondrial homeostasis and displaying cytoprotective activity. Inactivation/loss of TRAP1 has been observed in several neurodegenerative diseases while TRAP1 expression is reported to be elevated in multiple cancers and, as with HSP90, evidence of addiction to TRAP1 has been observed. In this review, we summarize what is currently known about this unique HSP90 paralog and why a better understanding of TRAP1 structure, function, and regulation is likely to enhance our understanding of the mechanistic basis of mitochondrial homeostasis.
A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions
Authors: Kouhnavardi Shima , Ecevitoglu Alev , Dragačević Vladimir , Sanna Fabrizio , Arias-Sandoval Edgar , Kalaba Predrag , Kirchhofer Michael , Lubec Jana , Niello Marco , Holy Marion , Zehl Martin , Pillwein Matthias , Wackerlig Judith , Murau Rita , Mohrmann Andrea , Beard Kathryn R. , Sitte Harald H. , Urban Ernst , Sagheddu Claudia , Pistis Marco , Plasenzotti Roberto , Salamone John D. , Langer Thierry , Lubec Gert , Monje Francisco J.
Published: June 2022

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson’s and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders.
l-Ornithine-N5-monooxygenase (PvdA) Substrate Analogue Inhibitors for Pseudomonas aeruginosa Infections Treatment: Drug Repurposing Computational Studies
Authors: Rosy Joseph , Babkiewicz Ewa , Maszczyk Piotr , Mrówka Piotr , Kumar Banoth , Murugesan Sankaranarayanan , Kunjiappan Selvaraj , Sundar Krishnan
Published: June 2022

Pseudomonas aeruginosa is an opportunistic pathogen that can cause acute and severe infections. Increasing resistance to antibiotics has given rise to the urgent need for an alternative antimicrobial agent. A promising strategy is the inhibition of iron sequestration in the bacteria. The current work aimed to screen for inhibitors of pyoverdine-mediated iron sequestration in P. aeruginosa. As a drug target, we choose l-ornithine-N5-monooxygenase (PvdA), an enzyme involved in the biosynthesis of pyoverdine that catalyzes the FAD-dependent hydroxylation of the side chain amine of ornithine. As drug repurposing is a fast and cost-efficient way of discovering new applications for known drugs, the approach may help to solve emerging clinical problems. In this study, we use data about molecules from drug banks for screening. A total of 15 drugs that are similar in structure to l-ornithine, the substrate of PvdA, and 30 drugs that are sub-structures of l-ornithine were virtually docked against PvdA. N-2-succinyl ornithine and cilazapril were found to be the top binders with a binding energy of −12.8 and −9.1 kcal mol−1, respectively. As the drug-likeness and ADME properties of the drugs were also found to be promising, molecular dynamics studies were performed to further confirm the stability of the complexes. The results of this in silico study indicate that N-2-succinyl ornithine could potentially be explored as a drug for the treatment of P. aeruginosa infections.
Characterization of Endothelium-Dependent Relaxation in the Saphenous Artery and Its Caudal Branches in Young and Old Adult Sprague Dawley Rats
Authors: Wang Andrea N. , Fraser Graham M. , McGuire John J.
Published: June 2022

Ageing is associated with reduced endothelium-derived nitric oxide (NO) production in the femoral artery of Sprague Dawley (SD) rats. In the current study, we examined endothelium-dependent relaxation (EDR) in the saphenous artery and its caudal branches. We used acetylcholine and the Proteinase-Activated receptor-2 (PAR2)-specific agonist (2fLIGRLO) with nitroarginine methylester (L-NAME) to assess EDR in two groups of male SD rats (age in weeks: young, 10–12; old, 27–29). Acetylcholine and 2fLIGRLO were potent NO-dependent relaxant agents in all arteries. For all arteries, EDR by acetylcholine decreased significantly in old compared to young SD rats. Interestingly, PAR2-induced EDR of proximal saphenous artery segments and caudal branches decreased significantly in old compared to young, but did not differ for the in-between middle and distal ends of the saphenous artery. L-NAME treatment increased subsequent contractions of proximal and middle segments of saphenous arteries by phenylephrine and U46619 in young, but not in old, SD rats. We conclude the SD saphenous artery and caudal branches exhibit regional characteristics that differ in response to specific EDR agonists, endothelial NO synthase inhibitor, and changes to endothelium function with increased age, which are, in part, attributed to decreased sensitivity of vascular smooth muscle to the gaseous transmitter NO.
Exploring TRPC3 Interaction with Cholesterol through Coarse-Grained Molecular Dynamics Simulations
Authors: Clarke Amy , Groschner Klaus , Stockner Thomas
Published: June 2022

Transient receptor potential canonical 3 (TRPC3) channel belongs to the superfamily of transient receptor potential (TRP) channels which mediate Ca2+ influx into the cell. These channels constitute essential elements of cellular signalling and have been implicated in a wide range of diseases. TRPC3 is primarily gated by lipids and its surface expression has been shown to be dependent on cholesterol, yet a comprehensive exploration of its interaction with this lipid has thus far not emerged. Here, through 80 µs of coarse-grained molecular dynamics simulations, we show that cholesterol interacts with multiple elements of the transmembrane machinery of TRPC3. Through our approach, we identify an annular binding site for cholesterol on the pre-S1 helix and a non-annular site at the interface between the voltage-sensor-like domain and pore domains. Here, cholesterol interacts with exposed polar residues and possibly acts to stabilise the domain interface.
2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells
Authors: Jung Young Yun , Mohan Chakrabhavi Dhananjaya , Eng Huiyan , Narula Acharan S. , Namjoshi Ojas A. , Blough Bruce E. , Rangappa Kanchugarakoppal S. , Sethi Gautam , Kumar Alan Prem , Ahn Kwang Seok
Published: June 2022

Epithelial-mesenchymal transition (EMT) is a crucial process in which the polarized epithelial cells acquire the properties of mesenchymal cells and gain invasive properties. We have previously demonstrated that manganese superoxide dismutase (MnSOD) can regulate the EMT phenotype by modulating the intracellular reactive oxygen species. In this report, we have demonstrated the EMT-suppressive effects of 2,3,5,6-Tetramethylpyrazine (TMP, an alkaloid isolated from Chuanxiong) in colon cancer cells. TMP suppressed the expression of MnSOD, fibronectin, vimentin, MMP-9, and N-cadherin with a parallel elevation of occludin and E-cadherin in unstimulated and TGFβ-stimulated cells. Functionally, TMP treatment reduced the proliferation, migration, and invasion of colon cancer cells. TMP treatment also modulated constitutive activated as well as TGFβ-stimulated PI3K/Akt/mTOR, Wnt/GSK3/β-catenin, and MAPK signaling pathways. TMP also inhibited the EMT program in the colon cancer cells-transfected with pcDNA3-MnSOD through modulation of MnSOD, EMT-related proteins, and oncogenic pathways. Overall, these data indicated that TMP may inhibit the EMT program through MnSOD-mediated abrogation of multiple signaling events in colon cancer cells.
Biotechnological Approaches to Optimize the Production of Amaryllidaceae Alkaloids
Authors: Koirala Manoj , Karimzadegan Vahid , Liyanage Nuwan Sameera , Mérindol Natacha , Desgagné-Penix Isabel
Published: June 2022

Amaryllidaceae alkaloids (AAs) are plant specialized metabolites with therapeutic properties exclusively produced by the Amaryllidaceae plant family. The two most studied representatives of the family are galanthamine, an acetylcholinesterase inhibitor used as a treatment of Alzheimer’s disease, and lycorine, displaying potent in vitro and in vivo cytotoxic and antiviral properties. Unfortunately, the variable level of AAs’ production in planta restricts most of the pharmaceutical applications. Several biotechnological alternatives, such as in vitro culture or synthetic biology, are being developed to enhance the production and fulfil the increasing demand for these AAs plant-derived drugs. In this review, current biotechnological approaches to produce different types of bioactive AAs are discussed.
Alternative CAR Therapies: Recent Approaches in Engineering Chimeric Antigen Receptor Immune Cells to Combat Cancer
Authors: Moreno Carlos , Haynie Christopher , Cheever Abigail , Weber K.
Published: June 2022

For nearly three decades, chimeric antigen receptors (CARs) have captivated the interest of researchers seeking to find novel immunotherapies to treat cancer. CARs were first designed to work with T cells, and the first CAR T cell therapy was approved to treat B cell lymphoma in 2017. Recent advancements in CAR technology have led to the development of modified CARs, including multi-specific CARs and logic gated CARs. Other immune cell types, including natural killer (NK) cells and macrophages, have also been engineered to express CARs to treat cancer. Additionally, CAR technology has been adapted in novel approaches to treating autoimmune disease and other conditions and diseases. In this article, we review these recent advancements in alternative CAR therapies and design, as well as their mechanisms of action, challenges in application, and potential future directions.
Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation
Authors: Laurain Audrey , Rubera Isabelle , Razzouk-Cadet Micheline , Bonnafous Stéphanie , Albuquerque Miguel , Paradis Valérie , Patouraux Stéphanie , Duranton Christophe , Lesaux Olivier , Lefthériotis Georges , Tran Albert , Anty Rodolphe , Gual Philippe , Iannelli Antonio , Favre Guillaume
Published: June 2022

Liver fibrosis is associated with arterial calcification (AC). Since the liver is a source of inorganic pyrophosphate (PPi), an anti-calcifying compound, we investigated the relationship between plasma PPi ([PPi]pl), liver fibrosis, liver function, AC, and the hepatic expression of genes regulating PPi homeostasis. To that aim, we compared [PPi]pl before liver transplantation (LT) and 3 months after LT. We also assessed the expression of four key regulators of PPi in liver tissues and established correlations between AC, and scores of liver fibrosis and liver failure in these patients. LT candidates with various liver diseases were included. AC scores were assessed in coronary arteries, abdominal aorta, and aortic valves. Liver fibrosis was evaluated on liver biopsies and from non-invasive tests (FIB-4 and APRI scores). Liver functions were assessed by measuring serum albumin, ALBI, MELD, and Pugh–Child scores. An enzymatic assay was used to dose [PPi]pl. A group of patients without liver alterations from a previous cohort provided a control group. Gene expression assays were performed with mRNA extracted from liver biopsies and compared between LT recipients and the control individuals. [PPi]pl negatively correlated with APRI (r = −0.57, p = 0.001, n = 29) and FIB-4 (r = −0.47, p = 0.006, n = 29) but not with interstitial fibrosis index from liver biopsies (r = 0.07, p = 0.40, n = 16). Serum albumin positively correlated with [PPi]pl (r = 0.71; p < 0.0001, n = 20). ALBI, MELD, and Pugh–Child scores correlated negatively with [PPi]pl (r = −0.60, p = 0.0005; r = −0.56, p = 0.002; r = −0.41, p = 0.02, respectively, with n = 20). Liver fibrosis assessed on liver biopsies by FIB-4 and by APRI positively correlated with coronary AC (r = 0.51, p = 0.02, n = 16; r = 0.58, p = 0.009, n = 20; r = 0.41, p = 0.04, n = 20, respectively) and with abdominal aorta AC (r = 0.50, p = 0.02, n = 16; r = 0.67, p = 0.002, n = 20; r = 0.61, p = 0.04, n = 20, respectively). FIB-4 also positively correlated with aortic valve calcification (r = 0.40, p = 0.046, n = 20). The key regulator genes of PPi production in liver were lower in patients undergoing liver transplantation as compared to controls. Three months after surgery, serum albumin levels were restored to physiological levels (40 [37–44] vs. 35 [30–40], p = 0.009) and [PPi]pl was normalized (1.40 [1.07–1.86] vs. 0.68 [0.53–0.80] µmol/L, p = 0.0005, n = 12). Liver failure and/or fibrosis correlated with AC in several arterial beds and were associated with low plasma PPi and dysregulation of key proteins involved in PPi homeostasis. Liver transplantation normalized these parameters.
Probiotics: Evolving as a Potential Therapeutic Option against Acetaminophen-Induced Hepatotoxicity
Authors: Dewanjee Saikat , Dua Tarun K. , Paul Paramita , Dey Abhijit , Vallamkondu Jayalakshmi , Samanta Sonalinandini , Kandimalla Ramesh , De Feo Vincenzo
Published: June 2022

Acetaminophen (APAP) is the most common prescription medicine around the world for the treatment of pain and fever and is considered to be a safe drug at its therapeutic dose. However, a single overdose or frequent use of APAP can cause severe acute liver injury. APAP hepatotoxicity is a prevalent cause of acute liver disease around the world and the lack of suitable treatment makes it a serious problem. In recent years, there has been a surge in interest in using probiotics and probiotic-derived products, known as postbiotics, as health and disease negotiators. A growing body of evidence revealed that they can be equally effective against APAP hepatotoxicity. Different probiotic bacteria were found to be pre-clinically effective against APAP hepatotoxicity. Different postbiotics have also shown exciting results in preclinical models of APAP hepatotoxicity. This review summarized the protective roles and mechanisms of the different probiotic bacteria and postbiotics against APAP hepatotoxicity, with critical discussion. A brief discussion on potential novel probiotics and postbiotics for oxidative liver injury was also included. This review was written in an attempt to pique the interest of researchers in developing a safe therapeutic option against oxidative liver damage using probiotics and/or postbiotics as dietary supplements.
Increased Oxidative Stress in Asthma—Relation to Inflammatory Blood and Lung Biomarkers and Airway Remodeling Indices
Authors: Bazan-Socha Stanisława , Wójcik Krzysztof , Olchawa Magdalena , Sarna Tadeusz , Pięta Jakub , Jakieła Bogdan , Soja Jerzy , Okoń Krzysztof , Zarychta Jacek , Zaręba Lech , Stojak Michał , Potaczek Daniel P. , Bazan Jan G. , Celińska-Lowenhoff Magdalena
Published: June 2022

Airway inflammation in asthma is related to increased reactive oxygen species generation, potentially leading to tissue injury and subsequent airway remodeling. We evaluated oxidative stress in peripheral blood from asthmatic subjects (n = 74) and matched controls (n = 65), using recently developed real-time monitoring of the protein hydroperoxide (HP) formation by the coumarin boronic acid (CBA) assay. We also investigated the relation of the systemic oxidative stress response in asthma to disease severity, lung function, airway remodeling indices (lung computed tomography and histology), and blood and bronchoalveolar lavage fluid (BAL) inflammatory biomarkers. We documented enhanced systemic oxidative stress in asthma, reflected by 35% faster and 58% higher cumulative fluorescent product generation in the CBA assay (p < 0.001 for both). The dynamics of HP generation correlated inversely with lung function but not with asthma severity or histological measures of airway remodeling. HP generation was associated positively with inflammatory indices in the blood (e.g., C-reactive protein) and BAL (e.g., interleukin [IL]-6, IL-12p70, and neutrophil count). Bronchial obstruction, thicker airway walls, increased BAL IL-6, and citrullinated histone 3 in systemic circulation independently determined increased HP formation. In conclusion, a real-time CBA assay showed increased systemic HP generation in asthma. In addition, it was associated with inflammatory biomarkers, suggesting that proper disease control can also lead to a decrease in oxidative stress.
Paneth Cells Regulate Lymphangiogenesis under Control of Microbial Signals during Experimental Portal Hypertension
Authors: Hassan Mohsin , Juanola Oriol , Keller Irene , Nanni Paolo , Wolski Witold , Martínez-López Sebastián , Caparrós Esther , Francés Rubén , Moghadamrad Sheida
Published: June 2022

Intestinal microbiota can modulate portal hypertension through the regulation of the intestinal vasculature. We have recently demonstrated that bacterial antigens activate Paneth cells (PCs) to secrete products that regulate angiogenesis and portal hypertension. In the present work we hypothesized that Paneth cells regulate the development of lymphatic vessels under the control of intestinal microbiota during experimental portal hypertension. We used a mouse model of inducible PCs depletion (Math1Lox/LoxVilCreERT2) and performed partial portal vein ligation (PPVL) to induce portal hypertension. After 14 days, we performed mRNA sequencing and evaluated the expression of specific lymphangiogenic genes in small intestinal tissue. Intestinal and mesenteric lymphatic vessels proliferation was assessed by immunohistochemistry. Intestinal organoids with or without PCs were exposed to pathogen-associated molecular patterns, and conditioned media (CM) was used to stimulate human lymphatic endothelial cells (LECs). The lymphangiogenic activity of stimulated LECs was assessed by tube formation and wound healing assays. Secretome analysis of CM was performed using label-free proteomics quantification methods. Intestinal immune cell infiltration was evaluated by immunohistochemistry. We observed that the intestinal gene expression pattern was altered by the absence of PCs only in portal hypertensive mice. We found a decreased expression of specific lymphangiogenic genes in the absence of PCs during portal hypertension, resulting in a reduced proliferation of intestinal and mesenteric lymphatic vessels as compared to controls. In vitro analyses demonstrated that lymphatic tube formation and endothelial wound healing responses were reduced significantly in LECs treated with CM from organoids without PCs. Secretome analyses of CM revealed that PCs secrete proteins that are involved in lipid metabolism, cell growth and proliferation. Additionally, intestinal macrophages infiltrated the ileal mucosa and submucosa of mice with and without Paneth cells in response to portal hypertension. Our results suggest that intestinal microbiota signals stimulate Paneth cells to secrete factors that modulate the intestinal and mesenteric lymphatic vessels network during experimental portal hypertension.
Connexins and Pannexins—Similarities and Differences According to the FOD-M Model
Authors: Roterman Irena , Stapor Katarzyna , Fabian Piotr , Konieczny Leszek
Published: June 2022

Connexins and pannexins are the transmembrane proteins of highly distinguished biological activity in the form of transport of molecules and electrical signals. Their common role is to connect the external environment with the cytoplasm of the cell, while connexin is also able to link two cells together allowing the transport from one to another. The analysis presented here aims to identify the similarities and differences between connexin and pannexin. As a comparative criterion, the hydrophobicity distribution in the structure of the discussed proteins was used. The comparative analysis is carried out with the use of a mathematical model, the FOD-M model (fuzzy oil drop model in its Modified version) expressing the specificity of the membrane’s external field, which in the case of the discussed proteins is significantly different from the external field for globular proteins in the polar environment of water. The characteristics of the external force field influence the structure of protein allowing the activity in a different environment.