bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary Fibre Supplementation Improves Semen Production by Increasing Leydig Cells and Testosterone Synthesis in a Growing Boar Model
Authors: Lin Yan , Wu De , Che Lianqiang , Fang Zhengfeng , Xu Shengyu , Feng Bin , Zhuo Yong , Li Jian , Wu Caimei , Zhang Junjie , Li Lujie
Published: March 2022

Testicular development is imperative to spermatogenesis, and pre-puberty is the key period for testis development. This study, therefore, investigated the effects of fibre supplementation on testis development and its possible mechanism in a growing boar model. Thirty Yorkshire boars were randomly divided into a control group (Control) and a fibre group (Fibre) from day 0 to 90 after weaning, with three pigs per pen and five pens per treatment. Blood and testes were collected for analysis. Dietary fibre supplementation had no significant effect on growth performance, testicular volume, or libido but increased the semen production of boars. Boars fed with fibre had lower serum cholesterol (CHO) and low-density lipoprotein (LDL) levels compared to those on the Control diet; however, testicular CHO, triglyceride (TG), and LDL concentration in the Fibre group were significantly higher than the Control group (P < 0.01). Testicular histological analysis showed that seminiferous tubules and testicular germ cells of 120-day-old boars were densely arranged in the Fibre group, and the number of Leydig cells was significantly higher than that of the Control group (P < 0.001). Furthermore, the diet supplemented with fibre significantly decreased leptin, leptin receptor (Leptor), and luteinising hormone (LH) concentrations in boar serum (P < 0.05), whereas follicle-stimulating hormone (FSH) and testosterone concentrations were significantly increased (P < 0.05). Meanwhile, the expression of AMH, AMHR2, and SYCP3 genes related to proliferation and differentiation, and hormone-related genes STAR and SOCS3, were significantly up-regulated (P < 0.05). OCCLUDIN expression was up-regulated, whereas CDH2 expression was down-regulated. In conclusion, increased fibre intake during the pre-puberty period in growing boar is crucial for Leydig cell proliferation, up-regulating the expression of genes related to hormone synthesis and thereby promoting the secretion of testosterone and semen production.
Ensemble Machine Learning Model to Predict the Waterborne Syndrome
Authors: Gollapalli Mohammed
Published: March 2022

The COVID-19 epidemic has highlighted the significance of sanitization and maintaining hygienic access to clean water to reduce mortality and morbidity cases worldwide. Diarrhea is one of the prevalent waterborne diseases caused due to contaminated water in many low-income countries with similar living conditions. According to the latest statistics from the World Health Organization (WHO), diarrhea is among the top five primary causes of death worldwide in low-income nations. The condition affects people in every age group due to a lack of proper water used for daily living. In this study, a stacking ensemble machine learning model was employed against traditional models to extract clinical knowledge for better understanding patients’ characteristics; disease prevalence; hygienic conditions; quality of water used for cooking, bathing, and toiletries; chemicals used; therapist’s medications; and symptoms that are reflected in the field study data. Results revealed that the ensemble model provides higher accuracy with 98.90% as part of training and testing phases when experimented against frequently used J48, Naïve Bayes, SVM, NN, PART, Random Forest, and Logistic Regression models. Managing outcomes of this research in the early stages could assist people in low-income countries to have a better lifestyle, fewer infections, and minimize expensive hospital visits.
Nanomechanical Study of Enzyme: Coenzyme Complexes: Bipartite Sites in Plastidic Ferredoxin-NADP+ Reductase for the Interaction with NADP+
Authors: Pérez-Domínguez Sandra , Caballero-Mancebo Silvia , Marcuello Carlos , Martínez-Júlvez Marta , Medina Milagros , Lostao Anabel
Published: March 2022

Plastidic ferredoxin-NADP+ reductase (FNR) transfers two electrons from two ferredoxin or flavodoxin molecules to NADP+, generating NADPH. The forces holding the Anabaena FNR:NADP+ complex were analyzed by dynamic force spectroscopy, using WT FNR and three C-terminal Y303 variants, Y303S, Y303F, and Y303W. FNR was covalently immobilized on mica and NADP+ attached to AFM tips. Force–distance curves were collected for different loading rates and specific unbinding forces were analyzed under the Bell–Evans model to obtain the mechanostability parameters associated with the dissociation processes. The WT FNR:NADP+ complex presented a higher mechanical stability than that reported for the complexes with protein partners, corroborating the stronger affinity of FNR for NADP+. The Y303 mutation induced changes in the FNR:NADP+ interaction mechanical stability. NADP+ dissociated from WT and Y303W in a single event related to the release of the adenine moiety of the coenzyme. However, two events described the Y303S:NADP+ dissociation that was also a more durable complex due to the strong binding of the nicotinamide moiety of NADP+ to the catalytic site. Finally, Y303F shows intermediate behavior. Therefore, Y303, reported as crucial for achieving catalytically competent active site geometry, also regulates the concerted dissociation of the bipartite nucleotide moieties of the coenzyme.
Multifaceted Roles of the KEAP1–NRF2 System in Cancer and Inflammatory Disease Milieu
Authors: Panda Harit , Wen Huaichun , Suzuki Mikiko , Yamamoto Masayuki
Published: March 2022

In a multicellular environment, many different types of cells interact with each other. The KEAP1–NRF2 system defends against electrophilic and oxidative stresses in various types of cells. However, the KEAP1–NRF2 system also regulates the expression of genes involved in cell proliferation and inflammation, indicating that the system plays cell type-specific roles. In this review, we introduce the multifarious roles of the KEAP1–NRF2 system in various types of cells, especially focusing on cancer and inflammatory diseases. Cancer cells frequently hijack the KEAP1–NRF2 system, and NRF2 activation confers cancer cells with a proliferative advantage and therapeutic resistance. In contrast, the activation of NRF2 in immune cells, especially in myeloid cells, suppresses tumor development. In chronic inflammatory diseases, such as sickle cell disease, NRF2 activation in myeloid and endothelial cells represses the expression of proinflammatory cytokine and adherent molecule genes, mitigating inflammation and organ damage. Based on these cell-specific roles played by the KEAP1–NRF2 system, NRF2 inducers have been utilized for the treatment of inflammatory diseases. In addition, the use of NRF2 inducers and/or inhibitors with canonical antineoplastic drugs is an emerging approach to cancer treatment.
Loranthus regularis Ameliorates Neurodegenerative Factors in the Diabetic Rat Retina
Authors: Ola Mohammad , Alanazi Ahmed , Malik Ajamaluddin , Malik Abdul , Ahmed Mohammed , Al-Rejaie Salim , Alhomida Abdullah
Published: March 2022

Diabetic retinopathy remains a primary source of blindness with the growing pandemic of diabetes. Numerous studies have shown that early neurodegeneration caused by elevated oxidative stress may initiate microvascular damage in the diabetic retina during the last few decades. A variety of preventive and treatment strategies using phytochemicals that possess high antioxidants have shown great promise in reducing diabetes-induced neurodegeneration retinal damage. In this investigation, we employed an extract of Loranthus regularis, a traditional medicinal herb which is found to improve diabetes and associated complications in experimental studies. We orally treated STZ-induced diabetic rats with L. regularis and analyzed the neurodegenerative factors in the retina. After treatments, we used Western blotting techniques to analyze the protein content of neurotrophic factors (NGF, BDNF, TrkB), apoptotic factors (cytochrome c, Bcl-2, Bax), and phosphorylation of AKT in the diabetic retina. Additionally, we used ELISA methods to measure the contents of BDNF and the activity of Caspase-3 and biochemical procedures to determine the levels of glutathione and lipid peroxidation (TBARS). Our findings show that L. regularis treatments resulted in a considerable increase in neurotrophic factors and a decrease in apoptotic factors in the diabetic retina. Furthermore, in diabetic retina treated with L. regularis, the level of Bcl-2 protein increased, while the phosphor-AKT signaling improved. As a result, L. regularis may protect against diabetic-induced retinal neuronal damage by increasing neurotrophic support and reducing oxidative stress and apoptosis. Therefore, this study suggests that in diabetic retinopathy, L. regularis could be a potential therapy option for preventing neuronal cell death.
Isolation of Jannaschia sedimins sp. nov. from East Coast of China: Bacterial Taxonomy and Antimicrobial Resistance Analysis
Authors: Sha Sha , Li Shuqian , Zhao Lihua , Zhao Jinxin , Chen Guanjun
Published: March 2022

A Gram-stain-negative, facultatively aerobic, pink and oval bacterium, designed OS4T, was isolated from a sediment sample taken from a coastal zone in China. The growth of OS4T occurred at 20–37 °C (optimal 25 °C), pH 7.0–8.5 (optimal pH 8.0), in 0–5.0% (w/v) NaCl (optimal 2.0%). According to the phylogenetic analysis, strain OS4T showed the highest sequence similarity (96.04%) with Jannaschia aquimarina GSW-M26T and shared 94.98% similarity with the type species of genus Jannaschia-strain J. helgolandensis 14858T. Chemotaxonomic analysis showed that the sole respiratory quinone was ubiquinone 10, and the major fatty acids (>5.0%) included C18:1 ω6c/ω7c, C18:0, and C10:0 3OH. The polar lipids consist of three phospholipids, two unknown amino-lipids, and four unknown glycerolipids. The DNA G + C content was 72.7 mol%. Based on the evidence presented in this study, strain OS4T represents a novel species of the genus Jannaschia, for which the name Jannaschia sedimins sp. nov. is proposed. The type strain is OS4T (=KCTC 82508T = MCCC 1K03755T). Both the phenotypic and the genetic analysis on the antimicrobial resistance genes indicate that OS4T is resistant to a wide range of classes of antibiotics, which highlights that the ocean could potentially serve as the natural reservoir of antimicrobial resistance genes.
EnGS-DGR: Traffic Flow Forecasting with Indefinite Forecasting Interval by Ensemble GCN, Seq2Seq, and Dynamic Graph Reconfiguration
Authors: Han Shi-Yuan , Zhao Qiang , Sun Qi-Wei , Zhou Jin , Chen Yue-Hui
Published: March 2022

An accurate and reliable forecast for traffic flow is regarded as one of the foundational functions in an intelligent transportation system. In this paper, a new model for traffic flow forecasting, named EnGS-DGR, is designed based on ensemble learning of graph convolutional network (GCN), sequence-to-sequence (Seq2Seq) learning model, and dynamic graph reconfiguration (DGR) algorithm. At the first stage, instead of employing entire nodes in the traffic network, the DGR algorithm is proposed to reconstruct the traffic graph topology consisting of traffic nodes with tight correlation under a specific forecasting interval, where the degree of correlation among the traffic nodes is quantized from the perspective of multi-view clustering. At the second stage, GCN-Seq2Seq integration strategy is introduced to extract the data of the spatio-temporal dependence and forecast traffic flow. We applied the proposed EnGS-DGR to two different datasets from the highways of Los Angeles County and of California’s Bay Area; the simulation results show that the proposed EnGS-DGR is superior to other eight popular models for traffic flow forecasting in terms of three common performance metrics.
A Tribute to Sergey Odinokov
Authors: Odinokova Olga I. , Kolyuchkin Vasiliy Ya. , Solomashenko Artem B. , Shishova Maria V. , Zlokazov Evgenii Yu. , Starikov Rostislav S. , Evtikhiev Nikolay N. , Nikonorov Nikolay V. , Shoydin Sergey A. , Tanin Leonid V. , Gavrilov Gennadiy A. , Ganzherli Nina M. , Lukin Anatoliy V. , Melnikov Andrei N. , Makaeva Rosalia Kh. , Pavlycheva Nadezhda K. , Bogachevskaya Elena N. , Lembessis Alkis , Thomas Rajan , Grosmann Michel , Shevtsov Michael K. , Gentet Yves , Kalenkov Sergey G. , Tikhomirova Olga F. , Istomina Natalia L. , Andreeva Olga V. , Venediktov Vladimir Yu. , Petrov Nikolay V.
Published: March 2022

“My main goal was to point out new phenomena and spread the ideas, which will become the starting points for new research” [...]
Phase Reversal Method for Damage Imaging in Composite Laminates Based on Data Fusion
Authors: Han Wei , Feng Kan , Yang Huagen
Published: March 2022

This paper proposes a phase-reversal method (PRM) for damage imaging in plate structures. The PRM is a novel Lamb-wave-based method that mainly focuses on phase spectrum information of scattering waves reflected from a defect. The PRM reverses the phase angle along the propagation path by using the inverse Fourier transform first, and then the reversal reconstruction of the wave field in the frequency domain is performed for damage imaging. The proposed method analyzes the scattered wave field without using the baseline data and structural parameters. Moreover, dispersion characteristics and anisotropy are not involved in the process of damage positioning, thus making the PRM suitable for damage monitoring of composite laminates. To improve the PRM accuracy further, a combined addition and multiplication method of the correlation coefficient (CAMM) is proposed, which can reduce the effects of phase and noise artifacts and distortion. The results of the finite element simulations and experiments show that the combination of the PRM and CAMM methods can accurately locate damage in composite structures. Therefore, the PRM and CAMM methods have great application potential in damage imaging in composite laminates.
Double Branch Attention Block for Discriminative Representation of Siamese Trackers
Authors: Xi Jiaqi , Yang Jin , Chen Xiaodong , Wang Yi , Cai Huaiyu
Published: March 2022

Siamese trackers have achieved a good balance between accuracy and efficiency in generic object tracking. However, background distractors cause side effects to the discriminative representation of the target. To suppress the sensitivity of trackers to background distractors, we propose a Double Branch Attention (DBA) block and a Siamese tracker equipped with the DBA block named DBA-Siam. First, the DBA block concatenates channels of multiple layers from two branches of the Siamese framework to obtain rich feature representation. Second, the channel attention is applied to the two concatenated feature blocks to enhance the robust features selectively, thus enhancing the ability to distinguish the target from the complex background. Finally, the DBA block collects the contextual relevance between the Siamese branches and adaptively encodes it into the feature weight of the detection branch for information compensation. Ablation experiments show that the proposed block can enhance the discriminative representation of the target and significantly improve the tracking performance. Results on two popular benchmarks show that DBA-Siam performs favorably against its counterparts. Compared with the advanced algorithm CSTNet, DBA-Siam improves the EAO by 18.9% on VOT2016.
Analysis of Statistical and Artificial Intelligence Algorithms for Real-Time Speed Estimation Based on Vehicle Detection with YOLO
Authors: Rodríguez-Rangel Héctor , Morales-Rosales Luis Alberto , Imperial-Rojo Rafael , Roman-Garay Mario Alberto , Peralta-Peñuñuri Gloria Ekaterine , Lobato-Báez Mariana
Published: March 2022

Automobiles have increased urban mobility, but traffic accidents have also increased. Therefore, road safety is a significant concern involving academics and government. Transit studies are the main supply for studying road accidents, congestion, and flow traffic, allowing the understanding of traffic flow. They require special equipment (sensors) to measure the car’s speed. With technological advances, artificial intelligence, and videos, it is possible to estimate the speed in real-time without modifying the installed urban infrastructure. We need to employ public databases that provide reliable monocular videos to generate automated traffic studies. The problem of speed estimation with a monocular camera involves synchronizing data recording, tracking, and detecting the vehicles over the road considering the lanes and distance between cars. Usually, a set of constraints are considered, such as camera calibration, flat roads, including methods based on the homography and augmented intrusion lines, patterns or regions, or prior knowledge about the actual dimensions of some of the objects. In this paper, we present a system that generates a dataset from videos recorded from a highway—obtaining 532 samples; we separated the vehicle’s detection by lane, estimating its speed. We use this data set to compare five different statistical methods and three machine learning methods to evaluate their accuracy in estimating the cars’ speed in real-time. Our vehicle estimation requires a feature extraction process using YOLOv3 and Kalman filter to detect and track vehicles. The Linear Regression Model (LRM) yielded the best results obtaining a Mean Absolute Error (MAE) of 1.694 km/h for the center lane and 0.956 km/h for the last lane. The results were compared with several state-of-the-art works, having competitive performance. Hence, LRM is fast estimating speed in real time and does not require high computational resources allowing a future hardware implementation.
Suitability and Sensitivity of the Potential Distribution of Cyclobalanopsis glauca Forests under Climate Change Conditions in Guizhou Province, Southwestern China
Authors: Li Wangjun , Hu Jun , Feng Tu , Liu Qing
Published: March 2022

Global climate change is becoming increasingly prominent and has already begun to influence natural biological systems. Assessing the potential impact of climate change on ecosystems is an important research topic of the International Geosphere-Biosphere Programme (IGBP). Based on current distribution data, climate data, climate change scenarios (RCP8.5 scenario, 2070–2099), and application of the MaxEnt model, this study assessed suitability and sensitivity of the potential distribution of Cyclobalanopsis glauca forests under climate change conditions in Guizhou Province. The results were as follows: (1) Area under the curve values of training data and texting data indicated excellent performance of the model; (2) Compared to the current climate, areas of probability <0.4 were decreased, and the other areas presented an increasing trend under the RCP8.5 scenario; (3) Positive sensitivity areas were much larger than negative sensitivity areas under climate change. In either case, slight sensitivity areas accounted for the largest proportion; (4) The mean altitude of slight sensitivity areas measured the lowest, and highly negative sensitivity areas were the highest.
The Spectral Distribution of Random Mixed Graphs
Authors: Guan Yue , Cheng Bo , Chen Minfeng , Liang Meili , Liu Jianxi , Wang Jinxun , Yang Chao , Zeng Li
Published: March 2022

In this work, we propose a random mixed graph model Gn(p(n),q(n)) that incorporates both the classical Erdős-Rényi’s random graph model and the random oriented graph model. We show that the empirical spectral distribution of Gn(p(n),q(n)) converges to the standard semicircle law under some mild condition, and the Monte Carlo simulation highly agrees with our result.
Biosafety Analysis of Metabolites of Streptomyces tauricus Strain 19/97 M, Promising for the Production of Biological Products
Authors: Gaidasheva Irina I. , Shashkova Tatiana L. , Orlovskaya Irina A. , Gromovykh Tatyana I.
Published: March 2022

A biosafety study was carried out concerning the metabolites of Streptomyces tauricus strain 19/97 M. This strain is a promising producer of biological preparations and shows antagonistic properties against Fusarium fungi, which cause Fusarium wilt disease. The strain has a pronounced biological activity against conifers, cereals and legumes. The treatment of planting material reduces infections, increases germination and furthers plant productivity. Using metabolites, we understood the culture liquid separated by filtration after the cultivation of the strain. Animals of different taxonomic affiliations were used as test objects: (CBA × C57BI/6) F1 hybrid mice (Mus musculus) (warm-blooded organisms), Daphnia magna Straus (planktonic crustaceans) and the unicellular alga Chlorella vulgaris Beijer. In the study, we were guided by the test standards for acute oral toxicity and irritation to the skin, mucous membranes of the eyes and inhalation toxicity. The research results showed that the metabolites of the strain are not acutely toxic to organisms of different taxonomic levels. The metabolites of the strain do not have an irritating effect on the skin and mucous membranes of warm-blooded animals. Based on the studies carried out, metabolites can be used for creating a fungicidal biological preparation.
Validation of Psychophysiological Measures for Caffeine Oral Films Characterization by Machine Learning Approaches
Authors: Batista Patrícia , Rodrigues Pedro Miguel , Ferreira Miguel , Moreno Ana , Silva Gabriel , Alves Marco , Pintado Manuela , Oliveira-Silva Patrícia
Published: March 2022

(1) Background: The oral films are a new delivery system that can carry several molecules, such as neuromodulator molecules, including caffeine. These delivery systems have been developed and characterized by pharmacokinetics assays. However, new methodologies, such as psychophysiological measures, can complement their characterization. This study presents a new protocol with psychophysiological parameters to characterize the oral film delivery systems based on a caffeine model. (2) Methods: Thirteen volunteers (61.5% females and 38.5% males) consumed caffeine oral films and placebo oral films (in different moments and without knowing the product). Electrocardiogram (ECG), electrodermal (EDA), and respiratory frequency (RF) data were monitored for 45 min. For the data analysis, the MATLAB environment was used to develop the analysis program. The ECG, EDA, and RF signals were digitally filtered and processed, using a windowing process, for feature extraction and an energy mean value for 5 min segments. Then, the data were computed and presented to the entries of a set of Machine Learning algorithms. Finally, a data statistical analysis was carried out using SPSS. (3) Results: Compared with placebo, caffeine oral films led to a significant increase in power energy in the signal spectrum of heart rate, skin conductance, and respiratory activity. In addition, the ECG time-series power energy activity revealed a better capacity to detect caffeine activity over time than the other physiological modalities. There was no significant change for the female or male gender. (4) Conclusions: The protocol developed, and the psychophysiological methodology used to characterize the delivery system profile were efficient to characterize the drug delivery profile of the caffeine. This is a non-invasive, cheap, and easy method to apply, can be used to determine the neuromodulator drugs delivery profile, and can be implemented in the future.
Maternal Relationships among Ancient and Modern Southern African Sheep: Newly Discovered Mitochondrial Haplogroups
Authors: Horsburgh K. Ann , Beckett Devri B. , Gosling Anna L.
Published: March 2022

We investigated the genetic diversity and historic relationships among southern African sheep as well as the relationships between them and sheep outside the continent by sourcing both archaeological and modern sheep samples. Archaeological sheep samples derived from the site Die Kelders 1, near Cape Town, date to approximately 1500 years ago. The modern samples were taken as ear snips from Damara, Namaqua Afrikaner, and Ronderib Afrikaner sheep on a farm in Prieska in the Northern Cape. Illumina sequencing libraries were constructed for both ancient and modern specimens. Ancient specimens were enriched for the mitochondrial genome using an in-solution hybridization protocol and modern specimens were subjected to shotgun sequencing. Sequences were mapped to the Ovis aries reference genome, assigned to haplogroups and subhaplogroups, and used to calculate a phylogenetic tree using previously published, geographically dispersed mitochondrial genome sheep sequences. Genetic diversity statistics show that southern African sheep have lower diversity than sheep in other regions. Phylogenetic analysis reveals that many modern southern African sheep are likely descended from prehistoric indigenous sheep populations and not from sheep imported from Europe during the historic period.
Selected vs. Non-Selected Under-20 National Futsal Players: Differences between Physical Performance and Training Intensity Experienced in Training Camps
Authors: Silva Ana Filipa , González-Fernández Francisco Tomás , Oliveira Rafael , Clemente Filipe Manuel , Bezerra Pedro , Hung Chin-Hwai , Chiu Yi-Wen , Kuo Cheng-Deng , Chen Yung-Sheng
Published: March 2022

The aim of this study was two-fold: (i) analyze the variations in the physical fitness of selected and non-selected under-20 male national futsal players; and (ii) analyze the variations in training intensity monitored during training camps. Thirty-three Taiwan under-20 national futsal players were monitored for training intensity during 18 training camps. They were divided into two groups: selected (n = 14) and non-selected (n = 17) players. The physical assessments included the following measures: body mass, distance covered at Yo-Yo intermittent recovery test Level 1, final velocity at 30-15 Intermittent Fitness Test (30-15 IFT), standing long jump, maximum heart rate (HR), and 1-min sit-up. The training intensity was monitored using the rate of perceived exertion (RPE), HR at different intensity zones, and locomotor demands measured at different speed thresholds. The results revealed that the selected players were significantly faster in the 15-m sprint with ball (p = 0.001) and 30-m sprint (p = 0.001). Additionally, the selected players presented significantly greater HRaverage and time spent above 90% maximum HR during the three-to-six-day training camps (p < 0.05) compared to the non-selected players. Interestingly, the NS demonstrated a greater number of sprints during the training camps (p = 0.001), while the selected players presented greater distance/minute and average speed (p = 0.001). A regression analysis showed that the distance/minute and average speed was a significant predictor of maximum HR in the selected players. As conclusions, the physical fitness outcomes are different between the selected and non-selected national futsal players. The selected players spent more time in high intensity HR demands in training sessions.
Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions
Authors: De Giorgi Francesca , Abdul-Shukkoor Muhammed Bilal , Kashyrina Marianna , Largitte Leslie-Ann , De Nuccio Francesco , Kauffmann Brice , Lends Alons , Laferrière Florent , Bonhommeau Sébastien , Lofrumento Dario Domenico , Bousset Luc , Bezard Erwan , Buffeteau Thierry , Loquet Antoine , Ichas François
Published: March 2022

The distinct neuropathological features of the different α-Synucleinopathies, as well as the diversity of the α-Synuclein (α-Syn) intracellular inclusion bodies observed in post mortem brain sections, are thought to reflect the strain diversity characterizing invasive α-Syn amyloids. However, this “one strain, one disease” view is still hypothetical, and to date, a possible disease-specific contribution of non-amyloid factors has not been ruled out. In Multiple System Atrophy (MSA), the buildup of α-Syn inclusions in oligodendrocytes seems to result from the terminal storage of α-Syn amyloid aggregates first pre-assembled in neurons. This assembly occurs at the level of neuronal cytoplasmic inclusions, and even earlier, within neuronal intranuclear inclusions (NIIs). Intriguingly, α-Syn NIIs are never observed in α-Synucleinopathies other than MSA, suggesting that these inclusions originate (i) from the unique molecular properties of the α-Syn fibril strains encountered in this disease, or alternatively, (ii) from other factors specifically dysregulated in MSA and driving the intranuclear fibrillization of α-Syn. We report the isolation and structural characterization of a synthetic human α-Syn fibril strain uniquely capable of seeding α-Syn fibrillization inside the nuclear compartment. In primary mouse cortical neurons, this strain provokes the buildup of NIIs with a remarkable morphology reminiscent of cat’s eye marbles (see video abstract). These α-Syn inclusions form giant patterns made of one, two, or three lentiform beams that span the whole intranuclear volume, pushing apart the chromatin. The input fibrils are no longer detectable inside the NIIs, where they become dominated by the aggregation of endogenous α-Syn. In addition to its phosphorylation at S129, α-Syn forming the NIIs acquires an epitope antibody reactivity profile that indicates its organization into fibrils, and is associated with the classical markers of α-Syn pathology p62 and ubiquitin. NIIs are also observed in vivo after intracerebral injection of the fibril strain in mice. Our data thus show that the ability to seed NIIs is a strain property that is integrally encoded in the fibril supramolecular architecture. Upstream alterations of cellular mechanisms are not required. In contrast to the lentiform TDP-43 NIIs, which are observed in certain frontotemporal dementias and which are conditional upon GRN or VCP mutations, our data support the hypothesis that the presence of α-Syn NIIs in MSA is instead purely amyloid-strain-dependent.
Disruption of the Ubiquitin-Proteasome System and Elevated Endoplasmic Reticulum Stress in Epilepsy
Authors: Poliquin Sarah , Kang Jing-Qiong
Published: March 2022

The epilepsies are a broad group of conditions characterized by repeated seizures, and together are one of the most common neurological disorders. Additionally, epilepsy is comorbid with many neurological disorders, including lysosomal storage diseases, syndromic intellectual disability, and autism spectrum disorder. Despite the prevalence, treatments are still unsatisfactory: approximately 30% of epileptic patients do not adequately respond to existing therapeutics, which primarily target ion channels. Therefore, new therapeutic approaches are needed. Disturbed proteostasis is an emerging mechanism in epilepsy, with profound effects on neuronal health and function. Proteostasis, the dynamic balance of protein synthesis and degradation, can be directly disrupted by epilepsy-associated mutations in various components of the ubiquitin-proteasome system (UPS), or impairments can be secondary to seizure activity or misfolded proteins. Endoplasmic reticulum (ER) stress can arise from failed proteostasis and result in neuronal death. In light of this, several treatment modalities that modify components of proteostasis have shown promise in the management of neurological disorders. These include chemical chaperones to assist proper folding of proteins, inhibitors of overly active protein degradation, and enhancers of endogenous proteolytic pathways, such as the UPS. This review summarizes recent work on the pathomechanisms of abnormal protein folding and degradation in epilepsy, as well as treatment developments targeting this area.
Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution
Authors: Longo Miriam , Paolini Erika , Meroni Marica , Dongiovanni Paola
Published: March 2022

Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by the hepatic deficiency of porphobilinogen deaminase (PBGD) and the slowdown of heme biosynthesis. AIP symptomatology includes life-threatening, acute neurovisceral or neuropsychiatric attacks manifesting in response to precipitating factors. The latter promote the upregulation of 5-aminolevulinic acid synthase-1 (ALAS1), the first enzyme of heme biosynthesis, which promotes the overload of neurotoxic porphyrin precursors. Hemin or glucose infusions are the first-line therapies for the reduction of ALAS1 levels in patients with mild to severe AIP, while liver transplantation is the only curative treatment for refractory patients. Recently, the RNA-interference against ALAS1 was approved as a treatment for adult and adolescent patients with AIP. These emerging therapies aim to substitute dysfunctional PBGD with adeno-associated vectors for genome editing, human PBGD mRNA encapsulated in lipid nanoparticles, or PBGD protein linked to apolipoprotein A1. Finally, the impairment of glucose metabolism linked to insulin resistance, and mitochondrial aberrations during AIP pathophysiology provided new therapeutic targets. Therefore, the use of liver-targeted insulin and insulin-mimetics such as α-lipoic acid may be useful for overcoming metabolic dysfunction in these subjects. Herein, the present review aims to provide an overview of AIP pathophysiology and management, focusing on conventional and recent therapeutical approaches.
The Antiplatelet Action of S-Nitroso Human Serum Albumin in Whole Blood
Authors: Tsiountsioura Melina , Cvirn Gerhard , Schlagenhauf Axel , Haidl Harald , Zischmeier Kathrin , Janschitz Nicole , Koestenberger Martin , Wonisch Willibald , Paar Margret , Wagner Thomas , Weiss Eva-Christine , Hallström Seth
Published: March 2022

Nitric oxide donors (NO-donors) have been shown to have therapeutic potential (e.g., ischemia/reperfusion injury). However, due to their release rate/antiplatelet properties, they may cause bleeding in patients. We therefore studied the antiplatelet effects of the two different NO-donors, i.e., S-NO-Human Serum Albumin (S-NO-HSA) and Diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate) in whole blood (WB) samples. WB samples were spiked with S-NO-HSA or DEA-NONOate (100 µmol/L or 200 µmol/L), and the NO release rate (nitrite/nitrate levels via HPLC) and antiplatelet efficacy (impedance aggregometry, platelet function analyzer, Cone-and-platelet analyzer, thrombelastometry) were assessed. S-NO-HSA had a significantly lower NO release compared to equimolar concentrations of DEA-NONOate. Virtually no antiplatelet action of S-NO-HSA was observed in WB samples, whereas DEA-NONOate significantly attenuated platelet function in WB. Impedance aggregometry measurements revealed that Amplitudes (slope: −0.04022 ± 0.01045 ohm/µmol/L, p = 0.008) and Lag times (slope: 0.6389 ± 0.2075 s/µmol/L, p = 0.0051) were dose-dependently decreased and prolonged by DEA-NONOate. Closure times (Cone-and-platelet analyzer) were dose-dependently prolonged (slope: 0.3738 ± 0.1403 s/µmol/L, p = 0.0174 with collagen/ADP coating; slope: −0.5340 ± 0.1473 s/µmol/L, p = 0.0019 with collagen/epinephrine coating) by DEA-NONOate. These results in WB further support the pharmacological potential of S-NO-HSA as an NO-donor due to its ability to presumably prevent bleeding events even at high concentrations up to 200 µmol/L.
Endothelial Dysfunction in SARS-CoV-2 Infection
Authors: Nappi Francesco , Avtaar Singh Sanjeet Singh
Published: March 2022

One of the hallmarks of the SARS-CoV-2 infection has been the inflammatory process that played a role in its pathogenesis, resulting in mortality within susceptible individuals. This uncontrolled inflammatory process leads to severe systemic symptoms via multiple pathways; however, the role of endothelial dysfunction and thrombosis have not been truly explored. This review aims to highlight the pathogenic mechanisms of these inflammatory triggers leading to thrombogenic complications. There are direct and indirect pathogenic pathways of the infection that are examined in detail. We also describe the case of carotid artery thrombosis in a patient following SARS-CoV-2 infection while reviewing the literature on the role of ACE2, the endothelium, and the different mechanisms by which SARS-CoV-2 may manifest both acutely and chronically. We also highlight differences from the other coronaviruses that have made this infection a pandemic with similarities to the influenza virus.
Assessing the Future of Solid Tumor Immunotherapy
Authors: Guha Prajna , Heatherton Kara R. , O’Connell Kyle P. , Alexander Ian S. , Katz Steven C.
Published: March 2022

With the advent of cancer immunotherapy, there has been a major improvement in patient’s quality of life and survival. The growth of cancer immunotherapy has dramatically changed our understanding of the basics of cancer biology and has altered the standards of care (surgery, radiotherapy, and chemotherapy) for patients. Cancer immunotherapy has generated significant excitement with the success of chimeric antigen receptor (CAR) T cell therapy in particular. Clinical results using CAR-T for hematological malignancies have led to the approval of four CD19-targeted and one B-cell maturation antigen (BCMA)-targeted cell therapy products by the US Food and Drug Administration (FDA). Also, immune checkpoint inhibitors such as antibodies against Programmed Cell Death-1 (PD-1), Programmed Cell Death Ligand-1 (PD-L1), and Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) have shown promising therapeutic outcomes and long-lasting clinical effect in several tumor types and patients who are refractory to other treatments. Despite these promising results, the success of cancer immunotherapy in solid tumors has been limited due to several barriers, which include immunosuppressive tumor microenvironment (TME), inefficient trafficking, and heterogeneity of tumor antigens. This is further compounded by the high intra-tumoral pressure of solid tumors, which presents an additional challenge to successfully delivering treatments to solid tumors. In this review, we will outline and propose specific approaches that may overcome these immunological and physical barriers to improve the outcomes in solid tumor patients receiving immunotherapies.
Current Medical Care Situation of Patients in Germany Undergoing Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)
Authors: Horvath Philipp , Yurttas Can , Baur Isabella , Steidle Christoph , Reymond Marc , Girotti Paolo , Königsrainer Alfred , Königsrainer Ingmar
Published: March 2022

Objective: Tailored approaches in gastrointestinal oncology have been more frequently introduced in past years and for patients with peritoneal metastases. This article attempts to overview the current strategies in surgical gastrointestinal oncology, with a focus on gastrointestinal peritoneal metastases. Methods: In 2019, all patients undergoing PIPAC therapy in Germany were retrospectively analyzed regarding morbidity and in-hospital mortality rates. Furthermore, patients with chemotherapy-refractory peritoneal metastases from gastric cancer undergoing PIPAC-therapy at our institution were analyzed. Results: In 2019, 534 patients received PIPAC treatment in german hospitals. The in-hospital mortality rate was 0%. In total, 36 patients suffered from postoperative complications (8%). From April 2016 to September 2021, a total of 44 patients underwent 93 PIPAC applications at our institution. The non-access-rate was 0%. The median PRGS was two (range, 1–4). Eleven patients (44%) showed histologically stable disease, whereas six patients (24%) showed histological regression. Median survival, calculated from the date of the first PIPAC application, was 181 days (range, 43–636 days). Conclusions: PIPAC is a safe and feasible procedure with a low in-hospital morbidity and mortality. Furthermore, PIPAC in the palliative and chemorefractory setting and is an appealing approach for patient management in the future.
Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism
Authors: Hoang Dinh Hoa , Morales Corey , Rodriguez Ivan Rodriguez , Valerio Melissa , Guo Jiamin , Chen Min-Hsuan , Wu Xiwei , Horne David , Gandhi Varsha , Chen Lisa S. , Zhang Bin , Pullarkat Vinod , Rosen Steven T. , Marcucci Guido , Buettner Ralf , Nguyen Le Xuan Truong
Published: March 2022

It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado inhibits ribosomal RNA (rRNA) synthesis through the downregulation of transcription initiation factor TIF-IA that is associated with increasing levels of p53. Paradoxically, 8-Cl-Ado-induced p53 increased FAO and OXPHOS, thereby self-limiting the activity of 8-Cl-Ado on LSCs. Since VEN inhibits amino acid-driven OXPHOS, the addition of VEN significantly enhanced the activity of 8-Cl-Ado by counteracting the self-limiting effect of p53 on FAO and OXPHOS. Overall, our results indicate that VEN and 8-Cl-Ado can cooperate in targeting rRNA synthesis and OXPHOS and in decreasing the survival of the LSC-enriched cell population, suggesting the VEN/8-Cl-Ado regimen as a promising therapeutic approach for patients with R/R AML.
(18-Crown-6)-bis(tetrahydrofuran)-potassium Anthracenide: The Salt of a Free Radical Anion Crystallizing as a Kryptoracemate
Authors: Bernal Ivan , Lalancette Roger A.
Published: March 2022

K[(18-crown-6)-bis(tetrahydrofuran)anthracenide] was independently prepared by three groups, and its structure described by two of them. The third structure description, though listed in the Cambridge Crystallographic Data Centre (CSD) collection, contains no space group or atomic coordinates, but the cell constants leave no doubt that it is the same species as the two others, which were reported in 2006 and 2016. The compound crystallizes in space group P21, with Z′ = 2.0 at T = 123 K and R = 4.91% (I), and at 100 K and R = 4.44% (II); both impressive results in their individual quality and agreement, despite differences in experimental methods and the temperature of data collection. A more detailed examination of the published data for (I) and (II) reveals that the correct description for this very unusual, and thus far unique substance, is that it contains a radical anion crystallizing as a kryptoracemate rather than as a simple example of a Sohncke space group with Z′ = 2.0. The anthracenide anions present in (I) and (II) are virtually identical; in contrast, the internal pair of cationic species differ from one another in the dissymmetry of the flexible tetrahydrofuran ligands, having significantly different internal and external torsional angles. The two THF molecules attached to the K(crown-ether) cations are not centrosymmetrically related, and this is what makes this portion of the asymmetric unit responsible for the crystal being a kryptoracemate. Our presentation will be based on the more fully documented sample (II), unless specifically stated.
Rapid On-Site Detection of Illicit Drugs in Smuggled Samples with a Portable Electrochemical Device
Authors: Parrilla Marc , Slosse Amorn , Van Echelpoel Robin , Felipe Montiel Noelia , Langley Amelia R. , Van Durme Filip , De Wael Karolien
Published: March 2022

The smuggling of illicit drugs urges the development of new tools for rapid on-site identification in cargos. Current methods rely on presumptive color tests and portable spectroscopic techniques. However, these methods sometimes exhibit inaccurate results due to commonly used cutting agents, the colorful nature of the sample or because the drugs are smuggled in common goods. Interestingly, electrochemical sensors can deal with these specific problems. Herein, an electrochemical device is presented that uses affordable screen-printed electrodes for the electrochemical profiling of several illicit drugs by square-wave voltammetry (SWV). The identification of the illicit compound is based on the oxidation potential of the analyte. Hence, a library of electrochemical profiles is built upon the analysis of illicit drugs and common cutting agents. This library allows the design of a tailor-made script that enables the identification of each drug through a user-friendly interface (laptop or mobile phone). Importantly, the electrochemical test is compared by analyzing 48 confiscated samples with other portable devices based on Raman and FTIR spectroscopy as well as a laboratory standard method (i.e., gas chromatography–mass spectrometry). Overall, the electrochemical results, obtained through the analysis of different samples from confiscated cargos at an end-user site, present a promising alternative to current methods, offering low-cost and rapid testing in the field.
Epidemiology of Phenylketonuria Disease in Jordan: Medical and Nutritional Challenges
Authors: Dababneh Safwan , Alsbou Mohammed , Taani Nashat , Sharkas Ghazi , Ismael Refqi , Maraqa Latifeh , Nemri Omar , Al-Jawaldeh Hanin , Kopti Nadeen , Atieh Enas , Almasri Arab
Published: March 2022

Background: Phenylketonuria (PKU) is the most frequent inborn error in amino acid metabolism caused by a deficiency of the phenylalanine hydroxylase enzyme (PAH). If PKU is left untreated, high concentrations of phenylalanine (Phe) accumulate in the blood, leading to severe brain dysfunction, neurodevelopmental, behavioral and psychological problems. Data concerning the epidemiology of PKU in Jordan are limited. The main objectives of our study were to determine the prevalence of PKU in Jordan, analyze the PKU phenotypes, and identify major challenges in providing dietary management to PKU patients. Methods: Data were collected utilizing the medical records of PKU patients attending the PKU clinic at the Ministry of Health in Amman, Jordan, between 2008 and 2021. Results: The total number of patients diagnosed with PKU was 294. The prevalence of PKU was estimated to be 1/5263. Most patients were Jordanians (90.8%), and 9.2% were non-Jordanians. More than half of the patients (56%) were diagnosed through the national newborn screening (NBS) program. Regarding the phenotypes of PKU, 46.6% had moderate PKU, whereas 42.9% had the classic type of PKU and only 8 (2.7%) had cofactor Tetrahydrobiopterin (BH4) deficiency (atypical PKU). According to the age of diagnosis, 66% of patients were diagnosed more than 30 days post-birth. Consanguinity was found in 87.4% of patients, and the majority of patients, 218 (74.2%), had first-degree consanguinity. The most common complication was mental retardation (31%). Most patients were committed to dietary management (83%) and developed fewer complications. Conclusion: In our study, we demonstrated the importance of the NBS program in the early identification and diagnosis of new PKU cases which allows the initiation of treatment and dietary management to prevent severe complications of PKU in Jordan.