bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient X-ray Security Images for Dangerous Goods Detection Based on Improved YOLOv7
Authors: Liu Yan , Zhang Enyan , Yu Xiaoyu , Wang Aili
Published: April 2024

In response to the problems of complex background, multi-scale dangerous goods and severe stacking in X-ray security images, this paper proposes a high-accuracy dangerous goods detection algorithm for X-ray security images based on the improvement of YOLOv7. Firstly, by combining the coordinate attention mechanism, the downsampling structure of the backbone network is improved to enhance the model’s target feature localization ability. Secondly, a weighted bidirectional feature pyramid network is used as the feature fusion structure to achieve multi-scale feature weighted fusion and further simplify the network. Then, combined with dynamic snake convolution, a downsampling structure was designed to facilitate the extraction of features at different scales, providing richer feature representations. Finally, drawing inspiration from the idea of group convolution and combining it with Conv2Former, a feature extraction module called a multi-convolution transformer (MCT) was designed to enhance the network’s feature extraction ability by combining multi-scale information. The improved YOLOv7 in this article was tested on the public datasets SIXRay, CLCXray, and PIDray. The average detection accuracy (mAP) of the improved model was 96.3%, 79.3%, and 84.7%, respectively, which was 4.7%, 2.7%, and 3.1% higher than YOLOv7. This proves the effectiveness and universality of the method proposed in this article. Compared to the current mainstream X-ray image dangerous goods detection models, this model effectively reduces the false detection rate of dangerous goods in X-ray security inspection images and has achieved significant improvement in the detection of small and multi-scale targets, achieving higher accuracy in dangerous goods detection.
Benchmarking Large Language Model (LLM) Performance for Game Playing via Tic-Tac-Toe
Authors: Topsakal Oguzhan , Harper Jackson B.
Published: April 2024

This study investigates the strategic decision-making abilities of large language models (LLMs) via the game of Tic-Tac-Toe, renowned for its straightforward rules and definitive outcomes. We developed a mobile application coupled with web services, facilitating gameplay among leading LLMs, including Jurassic-2 Ultra by AI21, Claude 2.1 by Anthropic, Gemini-Pro by Google, GPT-3.5-Turbo and GPT-4 by OpenAI, Llama2-70B by Meta, and Mistral Large by Mistral, to assess their rule comprehension and strategic thinking. Using a consistent prompt structure in 10 sessions for each LLM pair, we systematically collected data on wins, draws, and invalid moves across 980 games, employing two distinct prompt types to vary the presentation of the game’s status. Our findings reveal significant performance variations among the LLMs. Notably, GPT-4, GPT-3.5-Turbo, and Llama2 secured the most wins with the list prompt, while GPT-4, Gemini-Pro, and Mistral Large excelled using the illustration prompt. GPT-4 emerged as the top performer, achieving victory with the minimum number of moves and the fewest errors for both prompt types. This research introduces a novel methodology for assessing LLM capabilities using a game that can illuminate their strategic thinking abilities. Beyond enhancing our comprehension of LLM performance, this study lays the groundwork for future exploration into their utility in complex decision-making scenarios, offering directions for further inquiry and the exploration of LLM limits within game-based frameworks.
The Effect of Information and Communication Technology on Electricity Intensity in Korea
Authors: Kim Suyi
Published: April 2024

This study investigated the impact of information and communication technology (ICT) on electricity intensity, incorporating electricity prices, financial development, and population growth in Korea from 1990 to 2020, using the ARDL (autoregressive distributed lag) model. Three cases were considered, each relating to a different ICT proxy: Internet use, mobile cellular phone use, and exports of ICT-related products. The results varied depending on the proxy used to represent ICT. An increase in mobile cellular phone use leads to an increase in electricity intensity in the long run; however, the short-run effects of this change are unclear. An increase in Internet use also leads to an increase in electricity intensity in the long run but induces a decrease in electricity intensity in the short run. Increments in the exports of ICT-related products lead to an increase in electricity intensity in the short run; however, this effect is negligible in the long run. Electricity prices do not affect electricity intensity in all cases, and financial development reduces the intensity of electricity in the cases of the use of both mobile cellular phones and the Internet as proxies for ICT, whereas population growth increases electricity intensity in all cases.
Managing Costs of the Capacity Charge through Real-Time Adjustment of the Demand Pattern
Authors: Sawczuk Marcin , Stawowy Adam , Okrzesik Olga , Kurek Damian , Sawczuk Mariola
Published: April 2024

This work presents a production management platform developed to minimize the costs of the capacity charge, part of the electricity bill associated with the cost of maintaining grid capacity during periods of high, fluctuating loads. After a summary of the regulatory solutions on the capacity market in Poland, a capacity charge management system is presented, specifically designed for production facilities within the Energy-Intensive Industry sector. The proposed platform combines hardware data collection, a simulation tool analyzing the electrical energy demand profile to predict the future impact on the capacity charge, and a cloud-based user interface providing real-time recommendations to the plant operators regarding the corrective actions needed to minimize the cost of operation. It was pilot tested in collaboration with a large production facility in Poland, for which the capacity charge was among the main components of the electricity distribution costs. Pilot tests were conducted in the period from January 2022 to September 2023. The tested platform allowed us to shorten the time span of elevated capacity charges from 33% in the year 2022 to only 7% in the year 2023. It also reduced the benchmark capacity charge indicator by more than 11%, from 4.02% to −7.56%, over the duration of the experiments. This improvement was achieved without major changes to the organization and planning of the work.
Smart Transmission Expansion Planning Based on the System Requirements: A Comparative Study with Unconventional Lines
Authors: Dhamala Bhuban , Ghassemi Mona
Published: April 2024

This paper introduces a new concept in transmission expansion planning based on unconventional lines, termed “smart transmission expansion planning”. Traditionally, the domains of transmission expansion planning (TEP) and transmission line design are separate entities. TEP planners typically rely on the electrical specifications of a limited set of standard conventional line designs to evaluate planning scenarios, ultimately leading to the construction of the selected candidate line. In this context, it is noted that cost-effective scenarios often diverge from meeting the technical criteria of load flow analysis. To address this discrepancy, this paper proposes an alternative approach wherein TEP is conducted based on the specific requirements of the system earmarked for expansion. The transmission expansion planner initiates the process by determining optimal line parameter values that not only meet the operational criteria but also ensure cost-effectiveness. Subsequently, a line is designed to embody these optimal parameters. A detailed comparative analysis is conducted in this study, comparing the outcomes of TEP analyses conducted with conventional lines, unconventional lines, and lines featuring optimal parameters. Through extensive load flow analysis performed under normal and all single-contingency scenarios across three distinct loading conditions (peak load, dominant load representing 60% of peak load, and light load representing 40% of peak load), the results reveal that transmission lines engineered with optimal parameters demonstrate effective operation, with fewer transmission lines required to meet identical demands compared to other approaches.
A Comparative Experimental Analysis of Natural Gas Dual Fuel Combustion Ignited by Diesel and Poly OxyMethylene Dimethyl Ether
Authors: Partridge Kendyl Ryan , Hariharan Deivanayagam , Narayanan Abhinandhan , Pearson Austin Leo , Srinivasan Kalyan Kumar , Krishnan Sundar Rajan
Published: April 2024

Dual-fuel low-temperature combustion is a possible solution for alleviating the tradeoff between oxides of nitrogen and soot emissions in conventional diesel combustion, albeit with poor combustion stability, high carbon monoxide, and unburned hydrocarbon emissions at low engine loads. The present work compares emissions and combustion (heat release and other metrics) of both diesel and poly-oxy methylene dimethyl ether as high-reactivity fuels to ignite natural gas while leveraging spray-targeted reactivity stratification, which involved multiple injections of the high-reactivity fuels. The experiments included six parametric sweeps of: (1) start of first injection, (2) start of second injection, (3) percentage of energy substitution of natural gas, (4) commanded injection duration ratio, (5) rail pressure, and (6) intake pressure. The experiments were performed on a 1.8 L heavy-duty single-cylinder research engine operating at a medium speed of 1339 rev/min. Not-to-exceed limits for the indicated oxides of nitrogen emissions, maximum pressure rise rate, and the coefficient of variation of the indicated mean effective pressure were set to 1 g/kWh, 10 bar/CAD, and 10%, respectively. The indicated emissions decreased and combustion improved significantly for both fueling combinations when the experimental procedure was applied.
Balance of Anthropogenic and Natural Greenhouse Gas Fluxes of All Inland Ecosystems of the Russian Federation and the Contribution of Sequestration in Forests
Authors: Romanovskaya Anna , Korotkov Vladimir
Published: April 2024

In order to achieve global climate goals, it is necessary to estimate greenhouse gas (GHG) fluxes from ecosystems. To obtain a comprehensive assessment of CO2, CH4, and N2O natural fluxes for the Russian Federation, we used the “bottom-up” method and updated estimates for forest ecosystems based on State Forest Inventory data and satellite monitoring of forest disturbances. For grassland ecosystems, it was based on the correct distribution of areas between steppe and non-steppe zones. The estimated net uptake of natural ecosystems in Russia was 1.1 ± 1.8 billion tons of CO2-eq./year. The study shows that if only CO2 is taken into account, the net absorption of terrestrial ecosystems in Russia corresponds to more than −2.5 billion tons of CO2 (35% of forests’ contribution). However, given the emissions of non-CO2 GHGs, total net absorption in Russia’s natural ecosystems is reduced to about −1 billion tons of CO2-eq (with the forests’ contribution increasing to 80%). With regard to anthropogenic fluxes, the overall balance of GHGs in Russia corresponds to net emissions of 1 billion tons of CO2-eq/year into the atmosphere. To improve reporting under the Paris Agreement, countries should aim to include only anthropogenic (“manageable”) GHG fluxes on managed land.
Controllability of Mild Solution to Hilfer Fuzzy Fractional Differential Inclusion with Infinite Continuous Delay
Authors: Al-Dosari Aeshah Abdullah Muhammad
Published: April 2024

This work investigates the solvability of the generalized Hilfer fractional inclusion associated with the solution set of a controlled system of minty type–fuzzy mixed quasi-hemivariational inequality (FMQHI). We explore the assumed inclusion via the infinite delay and the semi-group arguments in the area of solid continuity that sculpts the compactness area. The conformable Hilfer fractional time derivative, the theory of fuzzy sets, and the infinite delay arguments support the solution set’s controllability. We explain the existence due to the convergence properties of Mittage–Leffler functions (Eα,β), that is, hatching the existing arguments according to FMQHI and the continuity of infinite delay, which has not been presented before. To prove the main results, we apply the Leray–Schauder nonlinear alternative thereom in the interpolation of Banach spaces. This problem seems to draw new extents on the controllability field of stochastic dynamic models.
The Injection of Gels Through an Intact Annulus Maintains Biomechanical Performance without Extrusion Risk
Authors: Wilke Hans-Joachim , Fuchs Holger , Benz Karin , Mollenhauer Juergen , Gaissmaier Christoph , Heuer Frank , Neidlinger-Wilke Cornelia
Published: April 2024

For autologous-disc-derived chondrocyte transplantation (ADCT) a transglutaminase crosslinked gelatine gel and an albumin hyaluronic acid gel, crosslinked with bis-thio-polyethylene glycol, were injected through a syringe into a degenerated intervertebral disc, where they solidified in situ. This biomechanical in vitro study with lumbar bovine motion segments evaluated disc height changes, motion characteristics in a quasi-static spine loading simulators, and the potential extrusion risk of these biomaterials in a complex dynamic multi-axial loading set-up with 100,000 loading cycles. After the injection and formation of the gel in the center of the nucleus, the disc height increase was about 0.3 mm. During cyclic testing, a gradual decrease in height could be detected due to viscoelastic effects and fluid loss. No gel extrusion could be observed for all specimens during the entire test procedure. A macroscopic inspection after dissections showed an accumulation of the solidified gel in the center of the nucleus. The results demonstrate that the injection of in situ solidifying gels through the intact annulus allows for the stable maintenance of the injected gel at the target location, with high potential for use as a suitable scaffold to anchor therapeutically applied cells for disc regeneration within the treated nucleus pulposus.
Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome
Authors: Misceo Doriana , Strømme Petter , Bitarafan Fatemeh , Chawla Maninder Singh , Sheng Ying , Bach de Courtade Sandra Monica , Eide Lars , Frengen Eirik
Published: April 2024

Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called “primary mitochondrial disorders” (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause PMDs, which have an estimated birth prevalence of 1:5000. Here, we describe a 4-year-old female presenting from early childhood with psychomotor delay and white matter signal changes affecting several brain regions, including the brainstem, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome, a genetically heterogeneous subgroup of PMDs. Whole genome sequencing of the family trio identified a homozygous 12.9 Kb deletion, entirely overlapping the NDUFA4 gene. Sanger sequencing of the breakpoints revealed that the genomic rearrangement was likely triggered by Alu elements flanking the gene. NDUFA4 encodes for a subunit of the respiratory chain Complex IV, whose activity was significantly reduced in the patient’s fibroblasts. In one family, dysfunction of NDUFA4 was previously documented as causing mitochondrial Complex IV deficiency nuclear type 21 (MC4DN21, OMIM 619065), a relatively mild form of Leigh syndrome. Our finding confirms the loss of NDUFA4 function as an ultra-rare cause of Complex IV defect, clinically presenting as Leigh syndrome.
Effects of Progressive Drought Stress on the Growth, Ornamental Values, and Physiological Properties of Begonia semperflorens
Authors: Zhao Zhimin , Liu Airong , Zhang Yuanbing , Yang Xiaodong , Yang Shuyue , Zhao Kunkun
Published: April 2024

Water is one of the most important elements affecting the growth of ornamental plants. To investigate the effects of drought stress on the growth, ornamental values, and physiological properties of Begonia semperflorens, watering treatments with 250 mL (control check, CK), 200 mL (extremely light drought, ELD), 150 mL (light drought, LD), 100 mL (moderate drought, MD), 50 mL (severe drought, SD), and 25 mL (extremely severe drought, ESD) on the B. semperflorens variety “Chao Ao” were performed in this study. As a result, compared to the control (CK), the number of flowers, leaves, and branches, leaf size, plant height, crown diameter, as well as water content, transpiration rate, net photosynthetic rate, stomatal conductance, intercellular CO2 concentration, and chlorophyll content in leaves decreased, followed by an increased amount of drought stress. The contents of the osmotic adjustment substances, such as soluble sugar, soluble protein, proline, and betaine, were increased under drought stress. Indicators related to antioxidant activities, such as SOD activity, increased and then decreased. The POD activity, CAT activity, MDA content, and plasma membrane permeability of B. semperflorens were higher under increased drought stress than in the control condition. The APX activity decreased and then increased under drought stress. In conclusion, B. semperflorens responds to drought stress by increasing osmotic adjustment substances and antioxidant activities and reducing the water loss, growth potential, and photosynthetic rate. The correlation analysis showed that, except for APX, the drought resistance coefficients of 23 other indexes were correlated in different degrees. Therefore, this study suggests that B. semperflorens has a strong drought resistance ability, retaining high ornamental values in conditions of moderate drought stress, and can still survive under extremely high drought stress.
On the Scalability of a Membrane Unit for Ultrapure Hydrogen Separation
Authors: Narcisi Vincenzo , Farina Luca , Santucci Alessia
Published: April 2024

Hydrogen permeation sparked a renewed interest in the second half of the 20th century due to the favorable features of this element as an energy factor. Furthermore, niche applications such as nuclear fusion gained attention for the highest selectivity ensured by self-supported dense metallic membranes, especially those consisting of Pd-based alloys. In this framework, the ENEA Frascati laboratories have decades of experience in the manufacturing, integration, and operation of Pd-Ag permeators. Most of the experimental investigations were performed on single-tube membranes, proving their performance under relevant operational conditions. Nowadays, once the applicability of this technology has been demonstrated, the scalability of the single-tube experience over medium- and large-scale units must be verified. To do this, ENEA Frascati laboratories have designed and constructed a multi-tube permeator, namely the Medium-Scaled Membrane Reactor (MeSMeR), focused on scalability assessment. In this work, the results obtained with the MeSMeR facility have been compared with previous experimental campaigns conducted on single-tube units, and the scalability of the permeation results has been proven. Moreover, post-test simulations have been performed based on single-tube finite element modeling, proving the scalability of the numerical outcomes and the possibility of using this tool for scale-up design procedures.
Multicomponent Behavioural Intervention during Pregnancy to Reduce Home Exposure to Second-Hand Smoke: A Pilot Randomised Controlled Trial in Bangladesh and India
Authors: Satyanarayana Veena A. , Jackson Cath , Siddiqi Kamran , Dherani Mukesh , Parrott Steve , Li Jinshuo , Huque Rumana , Chandra Prabha S. , Rahman Atif
Published: April 2024

Background: Pregnant women exposed to second-hand smoke (SHS) are at increased risk of poor birth outcomes. We piloted multicomponent behavioural intervention and trial methods in Bangalore, India, and Comilla, Bangladesh. Methods: A pilot individual randomised controlled trial with economic and process evaluation components was conducted. Non-tobacco-using pregnant women exposed to SHS were recruited from clinics and randomly allocated to intervention or control (educational leaflet) arms. The process evaluation captured feedback on the trial methods and intervention components. The economic component piloted a service use questionnaire. The primary outcome was saliva cotinine 3 months post-intervention. Results: Most pregnant women and many husbands engaged with the intervention and rated the components highly, although the cotinine report elicited some anxiety. Forty-eight (Comilla) and fifty-four (Bangalore) women were recruited. The retention at 3 months was 100% (Comilla) and 78% (Bangalore). Primary outcome data were available for 98% (Comilla) and 77% (Bangalore). Conclusions: The multicomponent behavioural intervention was feasible to deliver and was acceptable to the interventionists, pregnant women, and husbands. With the intervention, it was possible to recruit, randomise, and retain pregnant women in Bangladesh and India. The cotinine data will inform sample size calculations for a future definitive trial.
Optimizing the Selection of Mass Vaccination Sites: Access and Equity Consideration
Authors: Aljohani Basim , Hall Randolph
Published: April 2024

In the early phases of the COVID-19 pandemic, vaccine accessibility was limited, impacting large metropolitan areas such as Los Angeles County, which has over 10 million residents but only nine initial vaccination sites, which resulted in people experiencing long travel times to get vaccinated. We developed a mixed-integer linear model to optimize site selection, considering equitable access for vulnerable populations. Analyzing 277 zip codes between December 2020 and May 2021, our model incorporated factors such as car ownership, ethnic group disease vulnerability, and the Healthy Places Index, alongside travel times by car and public transit. Our optimized model significantly outperformed actual site allocations for all ethnic groups. We observed that White populations faced longer travel times, likely due to their residences being in more remote, less densely populated areas. Conversely, areas with higher Latino and Black populations, often closer to the city center, benefited from shorter travel times in our model. However, those without cars experienced greater disadvantages. While having many vaccination sites might improve access for those dependent on public transit, that advantage is diminished if people must search among many sites to find a location with available vaccines.
Evaluating the Impact of Human Activities on Vegetation Restoration in Mining Areas Based on the GTWR
Authors: Guo Li , Li Jun , Zhang Chengye , Xu Yaling , Xing Jianghe , Hu Jingyu
Published: April 2024

The clarification of the impact of human activities on vegetation in mining areas contributes to the harmonization of mining and environmental protection. This study utilized Geographically and Temporally Weighted Regression (GTWR) to establish a quantitative relationship among the Normalized Difference Vegetation Index (NDVI), temperature, precipitation, and Digital Elevation Model (DEM). Furthermore, residual analysis was performed to remove the impact of natural factors and separately assess the impact of human activities on vegetation restoration. The experiment was carried out in Shangwan Mine, China, and following results were obtained: (1) During the period of 2000 to 2020, intensified huan activities corresponded to positive vegetation changes (NDVI-HA) that exhibited an upward trend over time. (2) The spatial heterogeneity of vegetation restoration was attributed to the DEM. It is negatively correlated with NDVI in natural conditions, while under the environment of mining activities, there is a positive correlation between NDVI-HA and DEM. (3) The contribution of human activities to vegetation restoration in mining areas has been steadily increasing, surpassing the influences of temperature and precipitation since 2010. The results of this study can provide important references for the assessment of vegetation restoration to some extent in mining areas.
Nutritional Support: The Use of Antioxidants in Inflammatory Bowel Disease
Authors: Jarmakiewicz-Czaja Sara , Ferenc Katarzyna , Sokal-Dembowska Aneta , Filip Rafał
Published: April 2024

The problem of treating inflammatory bowel disease continues to be a topic of great interest for researchers. Despite the complexity surrounding their treatment and strategies to prolong periods of remission, there is a promising exploration of various compounds that have potential in combating inflammation and alleviating symptoms. Selenium, calcium, magnesium, zinc, and iron are among these compounds, offering a glimpse of hope in the treatment of IBD. These essential minerals not only hold the promise of reducing inflammation in these diseases, but also show the potential to enhance immune function and possibly influence the balance of intestinal microflora. By potentially modulating the gut microbiota, they may help support overall immune health. Furthermore, these compounds could play a crucial role in mitigating inflammation and minimising complications in patients with IBD. Furthermore, the protective effect of these compounds against mucosal damage in IBD and the protective effect of calcium itself against osteoporosis in this group of patients are notable.
TRPC3 Is Downregulated in Primary Hyperparathyroidism
Authors: Kirstein Emilie , Schaudien Dirk , Wagner Mathias , Diebolt Coline M. , Bozzato Alessandro , Tschernig Thomas , Englisch Colya N.
Published: April 2024

Transient receptor potential canonical sub-family channel 3 (TRPC3) is considered to play a critical role in calcium homeostasis. However, there are no established findings in this respect with regard to TRPC6. Although the parathyroid gland is a crucial organ in calcium household regulation, little is known about the protein distribution of TRPC channels—especially TRPC3 and TRPC6—in this organ. Our aim was therefore to investigate the protein expression profile of TRPC3 and TRPC6 in healthy and diseased human parathyroid glands. Surgery samples from patients with healthy parathyroid glands and from patients suffering from primary hyperparathyroidism (pHPT) were investigated by immunohistochemistry using knockout-validated antibodies against TRPC3 and TRPC6. A software-based analysis similar to an H-score was performed. For the first time, to our knowledge, TRPC3 and TRPC6 protein expression is described here in the parathyroid glands. It is found in both chief and oxyphilic cells. Furthermore, the TRPC3 staining score in diseased tissue (pHPT) was statistically significantly lower than that in healthy tissue. In conclusion, TRPC3 and TRPC6 proteins are expressed in the human parathyroid gland. Furthermore, there is strong evidence indicating that TRPC3 plays a role in pHPT and subsequently in parathyroid hormone secretion regulation. These findings ultimately require further research in order to not only confirm our results but also to further investigate the relevance of these channels and, in particular, that of TRPC3 in the aforementioned physiological functions and pathophysiological conditions.
Novel Concept of Alpha Satellite Cascading Higher-Order Repeats (HORs) and Precise Identification of 15mer and 20mer Cascading HORs in Complete T2T-CHM13 Assembly of Human Chromosome 15
Authors: Glunčić Matko , Vlahović Ines , Rosandić Marija , Paar Vladimir
Published: April 2024

Unraveling the intricate centromere structure of human chromosomes holds profound implications, illuminating fundamental genetic mechanisms and potentially advancing our comprehension of genetic disorders and therapeutic interventions. This study rigorously identified and structurally analyzed alpha satellite higher-order repeats (HORs) within the centromere of human chromosome 15 in the complete T2T-CHM13 assembly using the high-precision GRM2023 algorithm. The most extensive alpha satellite HOR array in chromosome 15 reveals a novel cascading HOR, housing 429 15mer HOR copies, containing 4-, 7- and 11-monomer subfragments. Within each row of cascading HORs, all alpha satellite monomers are of distinct types, as in regular Willard’s HORs. However, different HOR copies within the same cascading 15mer HOR contain more than one monomer of the same type. Each canonical 15mer HOR copy comprises 15 monomers belonging to only 9 different monomer types. Notably, 65% of the 429 15mer cascading HOR copies exhibit canonical structures, while 35% display variant configurations. Identified as the second most extensive alpha satellite HOR, another novel cascading HOR within human chromosome 15 encompasses 164 20mer HOR copies, each featuring two subfragments. Moreover, a distinct pattern emerges as interspersed 25mer/26mer structures differing from regular Willard’s HORs and giving rise to a 34-monomer subfragment. Only a minor 18mer HOR array of 12 HOR copies is of the regular Willard’s type. These revelations highlight the complexity within the chromosome 15 centromeric region, accentuating deviations from anticipated highly regular patterns and hinting at profound information encoding and functional potential within the human centromere.
Modulation of the Circadian Rhythm and Oxidative Stress as Molecular Targets to Improve Vascular Dementia: A Pharmacological Perspective
Authors: Trujillo-Rangel Walter Ángel , Acuña-Vaca Sofía , Padilla-Ponce Danna Jocelyn , García-Mercado Florencia Guillermina , Torres-Mendoza Blanca Miriam , Pacheco-Moises Fermín P. , Escoto-Delgadillo Martha , García-Benavides Leonel , Delgado-Lara Daniela L. C.
Published: April 2024

The circadian rhythms generated by the master biological clock located in the brain’s hypothalamus influence central physiological processes. At the molecular level, a core set of clock genes interact to form transcription–translation feedback loops that provide the molecular basis of the circadian rhythm. In animal models of disease, a desynchronization of clock genes in peripheral tissues with the central master clock has been detected. Interestingly, patients with vascular dementia have sleep disorders and irregular sleep patterns. These alterations in circadian rhythms impact hormonal levels, cardiovascular health (including blood pressure regulation and blood vessel function), and the pattern of expression and activity of antioxidant enzymes. Additionally, oxidative stress in vascular dementia can arise from ischemia-reperfusion injury, amyloid-beta production, the abnormal phosphorylation of tau protein, and alterations in neurotransmitters, among others. Several signaling pathways are involved in the pathogenesis of vascular dementia. While the precise mechanisms linking circadian rhythms and vascular dementia are still being studied, there is evidence to suggest that maintaining healthy sleep patterns and supporting proper circadian rhythm function may be important for reducing the risk of vascular dementia. Here, we reviewed the main mechanisms of action of molecular targets related to the circadian cycle and oxidative stress in vascular dementia.
Dietary High Salt Intake Exacerbates SGK1-Mediated T Cell Pathogenicity in L-NAME/High Salt-Induced Hypertension
Authors: Maaliki Dina , Itani Maha , Jarrah Hala , El-Mallah Carla , Ismail Diana , El Atie Yara E. , Obeid Omar , Jaffa Miran A. , Itani Hana A.
Published: April 2024

Sodium chloride (NaCl) activates Th17 and dendritic cells in hypertension by stimulating serum/glucocorticoid kinase 1 (SGK1), a sodium sensor. Memory T cells also play a role in hypertension by infiltrating target organs and releasing proinflammatory cytokines. We tested the hypothesis that the role of T cell SGK1 extends to memory T cells. We employed mice with a T cell deletion of SGK1, SGK1fl/fl × tgCD4cre mice, and used SGK1fl/fl mice as controls. We treated the mice with L-NAME (0.5 mg/mL) for 2 weeks and allowed a 2-week washout interval, followed by a 3-week high-salt (HS) diet (4% NaCl). L-NAME/HS significantly increased blood pressure and memory T cell accumulation in the kidneys and bone marrow of SGK1fl/fl mice compared to knockout mice on L-NAME/HS or groups on a normal diet (ND). SGK1fl/fl mice exhibited increased albuminuria, renal fibrosis, and interferon-γ levels after L-NAME/HS treatment. Myography demonstrated endothelial dysfunction in the mesenteric arterioles of SGK1fl/fl mice. Bone marrow memory T cells were adoptively transferred from either mouse strain after L-NAME/HS administration to recipient CD45.1 mice fed the HS diet for 3 weeks. Only the mice that received cells from SGK1fl/fl donors exhibited increased blood pressure and renal memory T cell infiltration. Our data suggest a new therapeutic target for decreasing hypertension-specific memory T cells and protecting against hypertension.
Impact of Serotonergic 5HT1A and 5HT2A Receptor Activation on the Respiratory Response to Hypercapnia in a Rat Model of Parkinson’s Disease
Authors: Andrzejewski Kryspin , Orłowska Magdalena E. , Zaremba Małgorzata , Joniec-Maciejak Ilona , Kaczyńska Katarzyna
Published: April 2024

In Parkinson’s disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT1A and 5-HT2A agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO2 in O2) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO2 and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HT1AR agonist 8-OH-DPAT and 5-HT2AR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HT2AR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD.
Regulation of Mertk Surface Expression via ADAM17 and γ-Secretase Proteolytic Processing
Authors: Lahey Kevin C. , Varsanyi Christopher , Wang Ziren , Aquib Ahmed , Gadiyar Varsha , Rodrigues Alcina A. , Pulica Rachael , Desind Samuel , Davra Viralkumar , Calianese David C. , Liu Dongfang , Cho Jong-Hyun , Kotenko Sergei V. , De Lorenzo Mariana S. , Birge Raymond B.
Published: April 2024

Mertk, a type I receptor tyrosine kinase and member of the TAM family of receptors, has important functions in promoting efferocytosis and resolving inflammation under physiological conditions. In recent years, Mertk has also been linked to pathophysiological roles in cancer, whereby, in several cancer types, including solid cancers and leukemia/lymphomas. Mertk contributes to oncogenic features of proliferation and cell survival as an oncogenic tyrosine kinase. In addition, Mertk expressed on macrophages, including tumor-associated macrophages, promotes immune evasion in cancer and is suggested to act akin to a myeloid checkpoint inhibitor that skews macrophages towards inhibitory phenotypes that suppress host T-cell anti-tumor immunity. In the present study, to better understand the post-translational regulation mechanisms controlling Mertk expression in monocytes/macrophages, we used a PMA-differentiated THP-1 cell model to interrogate the regulation of Mertk expression and developed a novel Mertk reporter cell line to study the intracellular trafficking of Mertk. We show that PMA treatment potently up-regulates Mertk as well as components of the ectodomain proteolytic processing platform ADAM17, whereas PMA differentially regulates the canonical Mertk ligands Gas6 and Pros1 (Gas6 is down-regulated and Pros1 is up-regulated). Under non-stimulated homeostatic conditions, Mertk in PMA-differentiated THP1 cells shows active constitutive proteolytic cleavage by the sequential activities of ADAM17 and the Presenilin/γ-secretase complex, indicating that Mertk is cleaved homeostatically by the combined sequential action of ADAM17 and γ-secretase, after which the cleaved intracellular fragment of Mertk is degraded in a proteasome-dependent mechanism. Using chimeric Flag-Mertk-EGFP-Myc reporter receptors, we confirm that inhibitors of γ-secretase and MG132, which inhibits the 26S proteasome, stabilize the intracellular fragment of Mertk without evidence of nuclear translocation. Finally, the treatment of cells with active γ-carboxylated Gas6, but not inactive Warfarin-treated non-γ-carboxylated Gas6, regulates a distinct proteolytic itinerary-involved receptor clearance and lysosomal proteolysis. Together, these results indicate that pleotropic and complex proteolytic activities regulate Mertk ectodomain cleavage as a homeostatic negative regulatory event to safeguard against the overactivation of Mertk.
Pathway Activation Analysis for Pan-Cancer Personalized Characterization Based on Riemannian Manifold
Authors: Li Xingyi , Hao Jun , Li Junming , Zhao Zhelin , Shang Xuequn , Li Min
Published: April 2024

The pathogenesis of carcinoma is believed to come from the combined effect of polygenic variation, and the initiation and progression of malignant tumors are closely related to the dysregulation of biological pathways. Quantifying the alteration in pathway activation and identifying coordinated patterns of pathway dysfunction are the imperative part of understanding the malignancy process and distinguishing different tumor stages or clinical outcomes of individual patients. In this study, we have conducted in silico pathway activation analysis using Riemannian manifold (RiePath) toward pan-cancer personalized characterization, which is the first attempt to apply the Riemannian manifold theory to measure the extent of pathway dysregulation in individual patient on the tangent space of the Riemannian manifold. RiePath effectively integrates pathway and gene expression information, not only generating a relatively low-dimensional and biologically relevant representation, but also identifying a robust panel of biologically meaningful pathway signatures as biomarkers. The pan-cancer analysis across 16 cancer types reveals the capability of RiePath to evaluate pathway activation accurately and identify clinical outcome-related pathways. We believe that RiePath has the potential to provide new prospects in understanding the molecular mechanisms of complex diseases and may find broader applications in predicting biomarkers for other intricate diseases.
The Catalysis Mechanism of E. coli Nitroreductase A, a Candidate for Gene-Directed Prodrug Therapy: Potentiometric and Substrate Specificity Studies
Authors: Valiauga Benjaminas , Bagdžiūnas Gintautas , Sharrock Abigail V. , Ackerley David F. , Čėnas Narimantas
Published: April 2024

E. coli nitroreductase A (NfsA) is a candidate for gene-directed prodrug cancer therapy using bioreductively activated nitroaromatic compounds (ArNO2). In this work, we determined the standard redox potential of FMN of NfsA to be −215 ± 5 mV at pH 7.0. FMN semiquinone was not formed during 5-deazaflavin-sensitized NfsA photoreduction. This determines the two-electron character of the reduction of ArNO2 and quinones (Q). In parallel, we characterized the oxidant specificity of NfsA with an emphasis on its structure. Except for negative outliers nitracrine and SN-36506, the reactivity of ArNO2 increases with their electron affinity (single-electron reduction potential, E17) and is unaffected by their lipophilicity and Van der Waals volume up to 386 Å. The reactivity of quinoidal oxidants is not clearly dependent on E17, but 2-hydroxy-1,4-naphthoquinones were identified as positive outliers and a number of compounds with diverse structures as negative outliers. 2-Hydroxy-1,4-naphthoquinones are characterized by the most positive reaction activation entropy and the negative outlier tetramethyl-1,4-benzoquinone by the most negative. Computer modelling data showed that the formation of H bonds with Arg15, Arg133, and Ser40, plays a major role in the binding of oxidants to reduced NfsA, while the role of the π–π interaction of their aromatic structures is less significant. Typically, the calculated hydride-transfer distances during ArNO2 reduction are smallwer than for Q. This explains the lower reactivity of quinones. Another factor that slows down the reduction is the presence of positively charged aliphatic substituents.
Functional Characterization of PmDXR, a Critical Rate-Limiting Enzyme, for Turpentine Biosynthesis in Masson Pine (Pinus massoniana Lamb.)
Authors: Li Rong , Zhu Lingzhi , Chen Peizhen , Chen Yu , Hao Qingqing , Zhu Peihuang , Ji Kongshu
Published: April 2024

As one of the largest and most diverse classes of specialized metabolites in plants, terpenoids (oprenoid compounds, a type of bio-based material) are widely used in the fields of medicine and light chemical products. They are the most important secondary metabolites in coniferous species and play an important role in the defense system of conifers. Terpene synthesis can be promoted by regulating the expressions of terpene synthase genes, and the terpene biosynthesis pathway has basically been clarified in Pinus massoniana, in which there are multiple rate-limiting enzymes and the rate-limiting steps are difficult to determine, so the terpene synthase gene regulation mechanism has become a hot spot in research. Herein, we amplified a PmDXR gene (GenBank accession no. MK969119.1) of the MEP pathway (methyl-erythritol 4-phosphate) from Pinus massoniana. The DXR enzyme activity and chlorophyll a, chlorophyll b and carotenoid contents of overexpressed Arabidopsis showed positive regulation. The PmDXR gene promoter was a tissue-specific promoter and can respond to ABA, MeJA and GA stresses to drive the expression of the GUS reporter gene in N. benthamiana. The DXR enzyme was identified as a key rate-limiting enzyme in the MEP pathway and an effective target for terpene synthesis regulation in coniferous species, which can further lay the theoretical foundation for the molecularly assisted selection of high-yielding lipid germplasm of P. massoniana, as well as provide help in the pathogenesis of pine wood nematode disease.
Environmental Exposure to Persistent Organic Pollutants and Its Association with Endometriosis Risk: Implications in the Epithelial–Mesenchymal Transition Process
Authors: Martín-Leyva Ana , Peinado Francisco M. , Ocón-Hernández Olga , Olivas-Martínez Alicia , Luque Antonio , León Josefa , Lendínez Inmaculada , Cardona Jesús , Lara-Ramos Ana , Olea Nicolás , Fernández Mariana F. , Artacho-Cordón Francisco
Published: April 2024

We aimed to explore the relationship of adipose tissue concentrations of some persistent organic pollutants (POPs) with the risk of endometriosis and the endometriotic tissue expression profile of genes related to the endometriosis-related epithelial–mesenchymal transition (EMT) process. This case–control study enrolled 109 women (34 cases and 75 controls) between January 2018 and March 2020. Adipose tissue samples and endometriotic tissues were intraoperatively collected to determine concentrations of nine POPs and the gene expression profiles of 36 EMT-related genes, respectively. Associations of POPs with endometriosis risk were explored with multivariate logistic regression, while the relationship between exposure and gene expression profiles was assessed through Spearman correlation or Mann–Whitney U tests. After adjustment, increased endometriosis risk was associated with p,p’-DDT, PCB-180, and ΣPCBs. POP exposure was also associated with reduced gene expression levels of the CLDN7 epithelial marker and increased levels of the ITGB2 mesenchymal marker and a variety of EMT promoters (HMGA1, HOXA10, FOXM1, DKK1, CCR1, TNFRSF1B, RRM2, ANG, ANGPT1, and ESR1). Our findings indicate that exposure to POPs may increase the risk of endometriosis and might have a role in the endometriosis-related EMT development, contributing to the disease onset and progression. Further studies are warranted to corroborate these findings.
Histochemical Evidence for Reduced Immune Response in Nasal Mucosa of Patients with COVID-19
Authors: Power Guerra Nicole , Bierkämper Martin , Pablik Jessica , Hummel Thomas , Witt Martin
Published: April 2024

The primary entry point of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the nasal mucosa, where viral-induced inflammation occurs. When the immune response fails against SARS-CoV-2, understanding the altered response becomes crucial. This study aimed to compare SARS-CoV-2 immunological responses in the olfactory and respiratory mucosa by focusing on epithelia and nerves. Between 2020 and 2022, we obtained post mortem tissues from the olfactory cleft from 10 patients with histologically intact olfactory epithelia (OE) who died with or from COVID-19, along with four age-matched controls. These tissues were subjected to immunohistochemical reactions using antibodies against T cell antigens CD3, CD8, CD68, and SARS spike protein for viral evidence. Deceased patients with COVID-19 exhibited peripheral lymphopenia accompanied by a local decrease in CD3+ cells in the OE. However, SARS-CoV-2 spike protein was sparsely detectable in the OE. With regard to the involvement of nerve fibers, the present analysis suggested that SARS-CoV-2 did not significantly alter the immune response in olfactory or trigeminal fibers. On the other hand, SARS spike protein was detectable in both nerves. In summary, the post mortem investigation demonstrated a decreased T cell response in patients with COVID-19 and signs of SARS-CoV-2 presence in olfactory and trigeminal fibers.