bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring Aegilops caudata: A Comprehensive Study of the CslF6 Gene and β-Glucan
Authors: Marcotuli Ilaria , Caranfa Davide , Colasuonno Pasqualina , Giove Stefania Lucia , Gadaleta Agata
Published: January 2024

In the quest for sustainable and nutritious food sources, exploration of ancient grains and wild relatives of cultivated cereals has gained attention. Aegilops caudata, a wild wheatgrass species, stands out as a promising genetic resource due to its potential for crop enhancement and intriguing nutritional properties. This manuscript investigates the CslF6 gene sequence and protein structure of Aegilops caudata, employing comparative analysis with other grass species to identify potential differences impacting β-glucan content. The study involves comprehensive isolation and characterization of the CslF6 gene in Ae. caudata, utilizing genomic sequence analysis, protein structure prediction, and comparative genomics. Comparisons with sequences from diverse monocots reveal evolutionary relationships, highlighting high identities with wheat genomes. Specific amino acid motifs in the CslF6 enzyme sequence, particularly those proximal to key catalytic motifs, exhibit variations among monocot species. These differences likely contribute to alterations in β-glucan composition, notably impacting the DP3:DP4 ratio, which is crucial for understanding and modulating the final β-glucan content. The study positions Ae. caudata uniquely within the evolutionary landscape of CslF6 among monocots, suggesting potential genetic divergence or unique functional adaptations within this species. Overall, this investigation enriches our understanding of β-glucan biosynthesis, shedding light on the role of specific amino acid residues in modulating enzymatic activity and polysaccharide composition.
miR-425-5p Regulates Proliferation of Bovine Mammary Epithelial Cells by Targeting TOB2
Authors: Li Yuchao , Chen Guanhe , Xu Shuxiang , Xia Siqi , Sun Wenqiang , Wang Jie , Chen Shiyi , Lai Songjia , Jia Xianbo
Published: January 2024

In recent years, rising temperatures have caused heat stress (HS), which has had a significant impact on livestock production and growth, presenting considerable challenges to the agricultural industry. Research has shown that miR-425-5p regulates cellular proliferation in organisms. However, the specific role of miR-425-5p in bovine mammary epithelial cells (BMECs) remains to be determined. The aim of this study was to investigate the potential of miR-425-5p in alleviating the HS-induced proliferation stagnation in BMECs. The results showed that the expression of miR-425-5p significantly decreased when BMEC were exposed to HS. However, the overexpression of miR-425-5p effectively alleviated the inhibitory effect of HS on BMEC proliferation. Furthermore, RNA sequencing analysis revealed 753 differentially expressed genes (DEGs), comprising 361 upregulated and 392 downregulated genes. Some of these genes were associated with proliferation and thermogenesis through enrichment analyses. Further experimentation revealed that TOB2, which acts as a target gene of miR-425-5p, is involved in the regulatory mechanism of BMEC proliferation. In summary, this study suggests that miR-425-5p can promote the proliferation of BMECs by regulating TOB2. The miR-425-5p/TOB2 axis may represent a potential pathway through which miR-425-5p ameliorates the proliferation stagnation of BMECs induced by HS.
The Genetic Basis of the First Patient with Wiedemann–Rautenstrauch Syndrome in the Russian Federation
Authors: Kovalskaia Valeriia A. , Kungurtseva Anastasiia L. , Bostanova Fatima M. , Vasiliev Peter A. , Tabakov Vyacheslav Y. , Orlova Mariia D. , Povolotskaya Inna S. , Novoselova Olga G. , Bikanov Roman A. , Akhyamova Mariia A. , Tikhonovich Yulia V. , Popovich Anastasiia V. , Vitebskaya Alisa V. , Dadali Elena L. , Ryzhkova Oxana P.
Published: January 2024

Bi-allelic pathogenic variations within POLR3A have been associated with a spectrum of hereditary disorders. Among these, a less frequently observed condition is Wiedemann–Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome. This syndrome typically manifests neonatally and is characterized by growth retardation, evident generalized lipodystrophy with distinctively localized fat accumulations, sparse scalp hair, and atypical facial features. Our objective was to elucidate the underlying molecular mechanisms of Wiedemann–Rautenstrauch syndrome (WRS). In this study, we present a clinical case of a 7-year-old female patient diagnosed with WRS. Utilizing whole-exome sequencing (WES), we identified a novel missense variant c.3677T>C (p.Leu1226Pro) in the POLR3A gene (NM_007055.4) alongside two cis intronic variants c.1909+22G>A and c.3337-11T>C. Via the analysis of mRNA derived from fibroblasts, we reconfirmed the splicing-affecting nature of the c.3337-11T>C variant. Furthermore, our investigation led to the reclassification of the c.3677T>C (p.Leu1226Pro) variant as a likely pathogenic variant. Therefore, this is the first case demonstrating the molecular genetics of a patient with Wiedemann–Rautenstrauch syndrome from the Russian Federation. A limited number of clinical cases have been documented until this moment; therefore, broadening the linkage between phenotype and molecular changes in the POLR3A gene will significantly contribute to the comprehensive understanding of the molecular basis of POLR3A-related disorders.
Topside Ionospheric Structures Determined via Automatically Detected DEMETER Ion Perturbations during a Geomagnetically Quiet Period
Authors: Li Mei , Yan Hongzhu , Zhang Yongxian
Published: January 2024

In this study, 117,718 ionospheric perturbations, with a space size (t) of 20–300 s but no amplitude (A) limit, were automatically globally searched via software utilizing ion density data measured by the DEMETER satellite for over 6 years. The influence of geomagnetic storms on the ionosphere was first examined. The results demonstrated that storms can globally enhance positive ionospheric irregularities but rarely induce plasma variations of more than 100%. The probability of PERs with a space size falling in 200–300 s (1400–2100 km if a satellite velocity of 7 km/s is considered) occurring in a geomagnetically perturbed period shows more significance than that in a quiet period. Second, statistical work was performed on ion PERs to check their dependence on local time, and it was shown that 24.8% of the perturbations appeared during the daytime (10:30 LT) and 75.2% appeared during the nighttime (22:30 LT). Ionospheric fluctuations with an absolute amplitude of A < 10% tend to be background variations, and the percentages of positive perturbations with a small A < 20% occur at an amount of 64% during the daytime and 26.8% during the nighttime, but this number is reversed for mid–large-amplitude PERs. Large positive PERs with A > 100% mostly occurred at night and negative ones with A < −100% occurred entirely at night. There was a demarcation point in the space size of t = 120 s, and the occurrence probabilities of day PERs were always higher than that of nighttime ones before this point, while this trend was contrary after this point. Finally, distributions of PERs according to different ranges of amplitude and space scale were characterized by typical seasonal variations either in the daytime or nighttime. EIA only exists in the dayside equinox and winter, occupying two low-latitude crests with a lower Np in both hemispheres. Large WSAs appear within all periods, except for dayside summer, and are full of PERs with an enhanced amplitude, especially on winter nights. The WN-like structure is obvious during all seasons, showing large-scale space. On the other hand, several magnetically anomalous zones of planetary-scale non-dipole fields, such as the SAMA, Northern Africa anomaly, and so on, were also successfully detected by extreme negative ion perturbations during this time.
A Multiphysics Simulation of the Effects of Wicking Geotextile on Mitigating Frost Heave under Cold Region Pavement
Authors: Jiang Yusheng , Alajlan Zaid , Zapata Claudia , Yu Xiong
Published: January 2024

Geotextile offers numerous benefits in improving pavement performance, including drainage, barrier functionality, filtration, and reinforcement. Wicking geotextile, a novel variant in this category, possesses the intrinsic ability to drain water autonomously from soils. This paper details the development and application of a comprehensive multiphysics model that simulates the performance of wicking geotextile within a pavement system under freezing climates. The model considers the inputs of various environmental dynamics, including the impact of meteorological factors, groundwater levels, ground heat, and drainage on the pavement system. The model was firstly validated using field data from a long-term pavement performance (LTPP) road section in the cold region. It was subsequently applied to assess the impacts of wicking geotextile if it was installed on the road section. The model simulated the coupled temporal and spatial variations in soil moisture content and temperature. The simulation results demonstrated that wicking geotextile would create a suction zone around its installation location to draw water from surrounding soils, therefore reducing the overall unfrozen water content in the pavement. The results also showed that the installation of wicking geotextile would delay the initiation of frost heave and reduce its magnitude in cold region pavement.
Collagenous Colitis with Escitalopram Use: A Case Report and Literature Review
Authors: Gray Emily , Wettergreen Sara A.
Published: January 2024

We present the case of a 42-year-old female whose escitalopram use potentially contributed to a diagnosis of collagenous colitis. The patient presented with significant watery, nonbloody diarrhea, abdominal cramping and pain, and weight loss. Established risk factors of microscopic colitis in this patient include a history of smoking and female gender. The patient underwent a colonoscopy, which confirmed histological changes consistent with collagenous colitis. Prescribed therapy included oral budesonide and omeprazole, continued for eight and twelve weeks, respectively. Escitalopram was continued, with a discussion regarding changing to an alternative therapy. Based on the patient’s history of escitalopram use, this case suggests a relationship between escitalopram and microscopic colitis. Though case reports of patients diagnosed with microscopic colitis after antidepressant use are published, this case appears to be the only report of collagenous colitis without macroscopic complications following escitalopram use. This case adds further support in that antidepressants may contribute to microscopic colitis. Despite an undefined frequency of association, healthcare providers who prescribe antidepressants should be cognizant of the theorized association and understand risk factors, screening, and treatment approaches.
The Impact of Higher Than Recommended Gestational Weight Gain on Fetal Growth and Perinatal Risk Factors—The IOM Criteria Reconsidered
Authors: Kirchengast Sylvia , Fellner Josef , Haury Julia , Kraus Magdalena , Stadler Antonia , Schöllauf Teresa , Hartmann Beda
Published: January 2024

A too-high gestational weight gain, in combination with steadily increasing obesity rates among women of reproductive age, represents an enormous obstetrical problem, as obesity and high gestational weight gain are associated with enhanced fetal growth, low vital parameters, and increased cesarean section rates. This medical record-based study investigates the association patterns between too-low as well as too-high gestational weight gain, according to the 2009 Institute of Medicine (IOM) guidelines, and fetal growth, as well as birth mode and pregnancy outcome. The data of 11,755 singleton births that had taken place between 2010 and 2020 at the Public Clinic Donaustadt in Vienna, Austria, were analyzed. Birth weight, birth length, head circumference, APGAR scores, and pH values of the arterial umbilical cord blood described fetal growth as well as the vital parameters after birth. Gestational weight gain was classified as too low, recommended, or too high according to the different weight status categories of the IOM guidelines. Birth weight, birth length, and head circumference of the newborn were significantly increased (p < 0.001) among underweight, normal-weight, and overweight women who gained more weight than recommended. Among obese women, only birthweight was significantly (p < 0.001) higher among women who gained more weight than recommended. Furthermore, a too-high gestational weight gain was significantly associated with an increased risk of macrosomia and emergency cesarean sections among underweight, normal-weight, and overweight women, but not among obese ones. Obese and morbidly obese women experiencing excessive gestational weight gain showed no significantly increased risk of macrosomia or emergency cesarean section. However, among obese mothers, a too-low gestational weight gain reduced the risk of emergency cesarean sections significantly (p = 0.010). Consequently, the IOM recommendations for gestational weight gain fit only partly for pregnant women in Austria. In the case of obese and morbidly obese women, new guidelines for optimal pregnancy weight gain should be considered.
A Semantic Partition Algorithm Based on Improved K-Means Clustering for Large-Scale Indoor Areas
Authors: Shi Kegong , Yan Jinjin , Yang Jinquan
Published: January 2024

Reasonable semantic partition of indoor areas can improve space utilization, optimize property management, and enhance safety and convenience. Existing algorithms for such partitions have drawbacks, such as the inability to consider semantics, slow convergence, and sensitivity to outliers. These limitations make it difficult to have partition schemes that can match the real-world observations. To obtain proper partitions, this paper proposes an improved K-means clustering algorithm (IK-means), which differs from traditional K-means in three respects, including the distance measurement method, iterations, and stop conditions of iteration. The first aspect considers the semantics of the spaces, thereby enhancing the rationality of the space partition. The last two increase the convergence speed. The proposed algorithm is validated in a large-scale indoor scene, and the results show that it has outperformance in both accuracy and efficiency. The proposed IK-means algorithm offers a promising solution to overcome existing limitations and advance the effectiveness of indoor space partitioning algorithms. This research has significant implications for the semantic area partition of large-scale and complex indoor areas, such as shopping malls and hospitals.
Fish and Seafood Safety: Human Exposure to Toxic Metals from the Aquatic Environment and Fish in Central Asia
Authors: Zhuzzhassarova Gulnur , Azarbayjani Faranak , Zamaratskaia Galia
Published: January 2024

Toxic metals that are released into aquatic environments from natural and anthropogenic sources are absorbed by aquatic organisms and may threaten the health of both aquatic organisms and humans. Despite this, there have been limited studies on the metal concentrations in fish and humans in Central Asia. This study summarizes the presence of the toxic metals arsenic (As), mercury (Hg), cadmium (Cd), and lead (Pb) in aquatic bodies, fish, and seafood products and conducts a risk assessment. While certain areas show a notable increase in fish and seafood consumption, the overall intake in Central Asia remains below recommended levels. However, in regions with high fish consumption, there is a potential for elevated exposure to toxic metals, especially Hg. The risk of exposure to toxic metals in fish and seafood in Central Asia emerges as a significant concern. Comprehensive monitoring, regulation, and remediation efforts are imperative to ensure the safety of water sources and food consumption in the region. Public awareness campaigns and the establishment of dietary guidelines play a crucial role in minimizing the health risks associated with consumption.
An Interaction between Brain-Derived Neurotrophic Factor and Stress-Related Glucocorticoids in the Pathophysiology of Alzheimer’s Disease
Authors: Numakawa Tadahiro , Kajihara Ryutaro
Published: January 2024

Both the brain-derived neurotrophic factor (BDNF) and glucocorticoids (GCs) play multiple roles in various aspects of neurons, including cell survival and synaptic function. BDNF and its receptor TrkB are extensively expressed in neurons of the central nervous system (CNS), and the contribution of the BDNF/TrkB system to neuronal function is evident; thus, its downregulation has been considered to be involved in the pathogenesis of Alzheimer’s disease (AD). GCs, stress-related molecules, and glucocorticoid receptors (GRs) are also considered to be associated with AD in addition to mental disorders such as depression. Importantly, a growing body of evidence suggests a close relationship between BDNF/TrkB-mediated signaling and the GCs/GR system in the CNS. Here, we introduce the current studies on the interaction between the neurotrophic system and stress in CNS neurons and discuss their involvement in the pathophysiology of AD.
Antimicrobial Activity of Synthetic Enterocins A, B, P, SEK4, and L50, Alone and in Combinations, against Clostridium perfringens
Authors: García-Vela Sara , Guay Louis-David , Rahman Md Ramim Tanver , Biron Eric , Torres Carmen , Fliss Ismail
Published: January 2024

Multidrug-resistant Clostridium perfringens infections are a major threat to the poultry industry. Effective alternatives to antibiotics are urgently needed to prevent these infections and limit the spread of multidrug-resistant bacteria. The aim of the study was to produce by chemical synthesis a set of enterocins of different subgroups of class II bacteriocins and to compare their spectrum of inhibitory activity, either alone or in combination, against a panel of twenty C. perfringens isolates. Enterocins A, P, SEK4 (class IIa bacteriocins), B (unsubgrouped class II bacteriocin), and L50 (class IId leaderless bacteriocin) were produced by microwave-assisted solid-phase peptide synthesis. Their antimicrobial activity was determined by agar well diffusion and microtitration methods against twenty C. perfringens isolates and against other pathogens. The FICINDEX of different combinations of the selected enterocins was calculated in order to identify combinations with synergistic effects. The results showed that synthetic analogs of L50A and L50B were the most active against C. perfringens. These peptides also showed the broadest spectrum of activity when tested against other non-clostridial indicator strains, including Listeria monocytogenes, methicillin-resistant Staphylococcus aureus, Streptococcus suis, Streptococcus pyogenes, Enterococcus cecorum, Enterococcus faecalis, as well as Gram-negative bacteria (Campylobacter coli and Pseudomonas aeruginosa), among others. The selected synthetic enterocins were combined on the basis of their different mechanisms of action, and all combinations tested showed synergy or partial synergy against C. perfringens. In conclusion, because of their high activity against C. perfringens and other pathogens, the use of synthetic enterocins alone or as a consortium can be a good alternative to the use of antibiotics in the poultry sector.
Neuroimmune Activation and Microglia Reactivity in Female Rats Following Alcohol Dependence
Authors: Melbourne Jennifer K. , Wooden Jessica I. , Carlson Erika R. , Anasooya Shaji Chinchusha , Nixon Kimberly
Published: January 2024

The rates of alcohol use disorder among women are growing, yet little is known about how the female brain is affected by alcohol. The neuroimmune system, and specifically microglia, have been implicated in mediating alcohol neurotoxicity, but most preclinical studies have focused on males. Further, few studies have considered changes to the microglial phenotype when examining the effects of ethanol on brain structure and function. Therefore, we quantified microglial reactivity in female rats using a binge model of alcohol dependence, assessed through morphological and phenotypic marker expression, coupled with regional cytokine levels. In a time- and region-dependent manner, alcohol altered the microglial number and morphology, including the soma and process area, and the overall complexity within the corticolimbic regions examined, but no significant increases in the proinflammatory markers MHCII or CD68 were observed. The majority of cytokine and growth factor levels examined were similarly unchanged. However, the expression of the proinflammatory cytokine TNFα was increased, and the anti-inflammatory IL-10, decreased. Thus, female rats showed subtle differences in neuroimmune reactivity compared to past work in males, consistent with reports of enhanced neuroimmune responses in females across the literature. These data suggest that specific neuroimmune reactions in females may impact their susceptibility to alcohol neurotoxicity and other neurodegenerative events with microglial contributions.
Manifestation of Pathology in Animal Models of Diabetic Retinopathy Is Delayed from the Onset of Diabetes
Authors: Cubillos Samuel , Kazlauskas Andrius
Published: January 2024

Diabetic retinopathy (DR) is the most common complication that develops in patients with diabetes mellitus (DM) and is the leading cause of blindness worldwide. Fortunately, sight-threatening forms of DR develop only after several decades of DM. This well-documented resilience to DR suggests that the retina is capable of protecting itself from DM-related damage and also that accumulation of such damage occurs only after deterioration of this resilience. Despite the enormous translational significance of this phenomenon, very little is known regarding the nature of resilience to DR. Rodent models of DR have been used extensively to study the nature of the DM-induced damage, i.e., cardinal features of DR. Many of these same animal models can be used to investigate resilience because DR is delayed from the onset of DM by several weeks or months. The purpose of this review is to provide a comprehensive overview of the literature describing the use of rodent models of DR in type-1 and type-2 diabetic animals, which most clearly document the delay between the onset of DM and the appearance of DR. These readily available experimental settings can be used to advance our current understanding of resilience to DR and thereby identify biomarkers and targets for novel, prevention-based approaches to manage patients at risk for developing DR.
Insights into the Effect of Charges on Hydrogen Bonds
Authors: Chimarro-Contreras Andrea , Lopez-Revelo Yomaira , Cardenas-Gamboa Jorge , Terencio Thibault
Published: January 2024

Previous computational and experimental studies showed that charges located at the surroundings of hydrogen bonds can exert two opposite effects on them: rupture or strengthening of the hydrogen bond. This work aims to generalize the effect of charges in different hydrogen-bonded systems and to propose a coherent explanation of this effect. For these purposes, 19 systems with intra- and intermolecular hydrogen bonds were studied computationally with DFT. The FT-IR spectra of the systems were simulated, and two energy components of the hydrogen bond were studied separately to determine their variation upon the presence of a charge: charge transfer and molecular overlap. It was determined that either the breaking or strengthening of the hydrogen bond can be favored one over the other, for instance, depending on the heteroatom involved in the hydrogen bond. In addition, it is showed that the strengthening of the hydrogen bond by the presence of a charge is directly related to the decrease in charge transfer between the monomers, which is explained by an increase in molecular overlapping, suggesting a more covalent character of the interaction. The understanding of how hydrogen bonds are affected by charges is important, as it is a key towards a strategy to manipulate hydrogen bonds at convenience.
Sustained Extracellular Electrical Stimulation Modulates the Permeability of Gap Junctions in rd1 Mouse Retina with Photoreceptor Degeneration
Authors: Stürmer Sophie , Bolz Sylvia , Zrenner Eberhart , Ueffing Marius , Haq Wadood
Published: January 2024

Neurons build vast gap junction-coupled networks (GJ-nets) that are permeable to ions or small molecules, enabling lateral signaling. Herein, we investigate (1) the effect of blinding diseases on GJ-nets in mouse retinas and (2) the impact of electrical stimulation on GJ permeability. GJ permeability was traced in the acute retinal explants of blind retinal degeneration 1 (rd1) mice using the GJ tracer neurobiotin. The tracer was introduced via the edge cut method into the GJ-net, and its spread was visualized in histological preparations (fluorescent tagged) using microscopy. Sustained stimulation was applied to modulate GJ permeability using a single large electrode. Our findings are: (1) The blind rd1 retinas displayed extensive intercellular coupling via open GJs. Three GJ-nets were identified: horizontal, amacrine, and ganglion cell networks. (2) Sustained stimulation significantly diminished the tracer spread through the GJs in all the cell layers, as occurs with pharmaceutical inhibition with carbenoxolone. We concluded that the GJ-nets of rd1 retinas remain coupled and functional after blinding disease and that their permeability is regulatable by sustained stimulation. These findings are essential for understanding molecular signaling in diseases over coupled networks and therapeutic approaches using electrical implants, such as eliciting visual sensations or suppressing cortical seizures.
Small Extracellular Vesicles and Oxidative Pathophysiological Mechanisms in Retinal Degenerative Diseases
Authors: Romero Francisco J. , Diaz-Llopis Manuel , Romero-Gomez M. Inmaculada , Miranda Maria , Romero-Wenz Rebeca , Sancho-Pelluz Javier , Romero Belén , Muriach Maria , Barcia Jorge M.
Published: January 2024

This review focuses on the role of small extracellular vesicles in the pathophysiological mechanisms of retinal degenerative diseases. Many of these mechanisms are related to or modulated by the oxidative burden of retinal cells. It has been recently demonstrated that cellular communication in the retina involves extracellular vesicles and that their rate of release and cargo features might be affected by the cellular environment, and in some instances, they might also be mediated by autophagy. The fate of these vesicles is diverse: they could end up in circulation being used as markers, or target neighbor cells modulating gene and protein expression, or eventually, in angiogenesis. Neovascularization in the retina promotes vision loss in diseases such as diabetic retinopathy and age-related macular degeneration. The importance of micro RNAs, either as small extracellular vesicles’ cargo or free circulating, in the regulation of retinal angiogenesis is also discussed.
A Comparative Pharmacokinetic Study for Cysteamine-Containing Eye Drops as an Orphan Topical Therapy in Cystinosis
Authors: Csorba Anita , Katona Gábor , Budai-Szűcs Mária , Balogh-Weiser Diána , Molnár Péter , Maka Erika , Kazsoki Adrienn , Vajna Márton , Zelkó Romána , Nagy Zoltán Zsolt , Balogh György T.
Published: January 2024

Cystinosis is a low-prevalence lysosomal storage disease. The pathomechanism involves abnormal functioning of the cystinosine lysosomal cystine transporter (CTNS), causing intraliposomal accumulation of the amino acid cysteine disulfide, which crystallizes and deposits in several parts of the body. The most common ophthalmic complication of cystinosis is the deposition of “gold dust” cystine crystals on the cornea, which already occurs in infancy and leads to severe photosensitivity and dry eyes as it gradually progresses with age. In the specific treatment of cystinosis, preparations containing cysteamine (CYA) are used. The availability of commercialized eyedrops for the targeted treatment is scarce, and only Cystadrops® are commercially available with strong limitations. Thus, magistral CYA-containing compounded eyedrops (CYA-CED) could have a key role in patient care; however, a rationally designed comprehensive study on the commercialized and magistral products is still missing. This work aims to build up a comprehensive study about commercialized and magistral CYA eye drops, involving pharmacokinetic and physicochemical characterization (applying mucoadhesivity, rheology test, investigation of drug release, and parallel artificial membrane permeability assays), as well as ex vivo tests, well supported by statistical analysis.
Age-Related Macular Degeneration and Mitochondria-Associated Autoantibodies: A Review of the Specific Pathogenesis and Therapeutic Strategies
Authors: Qu Sichang , Lin Hao , Pfeiffer Norbert , Grus Franz H.
Published: January 2024

Age-related macular degeneration (AMD) is a severe retinal disease that causes irreversible visual loss and blindness in elderly populations worldwide. The pathological mechanism of AMD is complex, involving the interactions of multiple environmental and genetic factors. A poor understanding of the disease leads to limited treatment options and few effective prevention methods. The discovery of autoantibodies in AMD patients provides an opportunity to explore the pathogenesis and treatment direction of the disease. This review focuses on the mitochondria-associated autoantibodies and summarizes the functional roles of mitochondria under physiological conditions and their alterations during the pathological states. Additionally, it discusses the crosstalk between mitochondria and other organelles, as well as the mitochondria-related therapeutic strategies in AMD.
Extracellular Vesicles in the Central Nervous System: A Novel Mechanism of Neuronal Cell Communication
Authors: Filannino Francesca Martina , Panaro Maria Antonietta , Benameur Tarek , Pizzolorusso Ilaria , Porro Chiara
Published: January 2024

Cell-to-cell communication is essential for the appropriate development and maintenance of homeostatic conditions in the central nervous system. Extracellular vesicles have recently come to the forefront of neuroscience as novel vehicles for the transfer of complex signals between neuronal cells. Extracellular vesicles are membrane-bound carriers packed with proteins, metabolites, and nucleic acids (including DNA, mRNA, and microRNAs) that contain the elements present in the cell they originate from. Since their discovery, extracellular vesicles have been studied extensively and have opened up new understanding of cell–cell communication; they may cross the blood–brain barrier in a bidirectional way from the bloodstream to the brain parenchyma and vice versa, and play a key role in brain–periphery communication in physiology as well as pathology. Neurons and glial cells in the central nervous system release extracellular vesicles to the interstitial fluid of the brain and spinal cord parenchyma. Extracellular vesicles contain proteins, nucleic acids, lipids, carbohydrates, and primary and secondary metabolites. that can be taken up by and modulate the behaviour of neighbouring recipient cells. The functions of extracellular vesicles have been extensively studied in the context of neurodegenerative diseases. The purpose of this review is to analyse the role extracellular vesicles extracellular vesicles in central nervous system cell communication, with particular emphasis on the contribution of extracellular vesicles from different central nervous system cell types in maintaining or altering central nervous system homeostasis.
Nicotine Motivated Behavior in C. elegans
Authors: Salim Chinnu , Batsaikhan Enkhzul , Kan Ann Ke , Chen Hao , Jee Changhoon
Published: January 2024

To maximize the advantages offered by Caenorhabditis elegans as a high-throughput (HTP) model for nicotine dependence studies, utilizing its well-defined neuroconnectome as a robust platform, and to unravel the genetic basis of nicotine-motivated behaviors, we established the nicotine conditioned cue preference (CCP) paradigm. Nicotine CCP enables the assessment of nicotine preference and seeking, revealing a parallel to fundamental aspects of nicotine-dependent behaviors observed in mammals. We demonstrated that nicotine-elicited cue preference in worms is mediated by nicotinic acetylcholine receptors and requires dopamine for CCP development. Subsequently, we pinpointed nAChR subunits associated with nicotine preference and validated human GWAS candidates linked to nicotine dependence involved in nAChRs. Functional validation involves assessing the loss-of-function strain of the CACNA2D3 ortholog and the knock-out (KO) strain of the CACNA2D2 ortholog, closely related to CACNA2D3 and sharing human smoking phenotypes. Our orthogonal approach substantiates the functional conservation of the α2δ subunit of the calcium channel in nicotine-motivated behavior. Nicotine CCP in C. elegans serves as a potent affirmation of the cross-species functional relevance of GWAS candidate genes involved in nicotine seeking associated with tobacco abuse, providing a streamlined yet comprehensive system for investigating intricate behavioral paradigms within a simplified and reliable framework.
DNA Methylation and Chromatin Accessibility Impact Subgenome Expression Dominance in the Common Carp (Cyprinus carpio)
Authors: Yu Shuang-Ting , Zhao Ran , Sun Xiao-Qing , Hou Ming-Xi , Cao Yi-Ming , Zhang Jin , Chen Ying-Jie , Wang Kai-Kuo , Zhang Yan , Li Jiong-Tang , Wang Qi
Published: January 2024

DNA methylation and chromatin accessibility play important roles in gene expression, but their function in subgenome expression dominance remains largely unknown. We conducted comprehensive analyses of the transcriptome, DNA methylation, and chromatin accessibility in liver and muscle tissues of allotetraploid common carp, aiming to reveal the function of epigenetic modifications in subgenome expression dominance. A noteworthy overlap in differential expressed genes (DEGs) as well as their functions was observed across the two subgenomes. In the promoter and gene body, the DNA methylation level of the B subgenome was significantly different than that of the A subgenome. Nevertheless, differences in DNA methylation did not align with changes in homoeologous biased expression across liver and muscle tissues. Moreover, the B subgenome exhibited a higher prevalence of open chromatin regions and greater chromatin accessibility, in comparison to the A subgenome. The expression levels of genes located proximally to open chromatin regions were significantly higher than others. Genes with higher chromatin accessibility in the B subgenome exhibited significantly elevated expression levels compared to the A subgenome. Contrastingly, genes without accessibility exhibited similar expression levels in both subgenomes. This study contributes to understanding the regulation of subgenome expression dominance in allotetraploid common carp.
The Inhibition Effect of Epigallocatechin-3-Gallate on the Co-Aggregation of Amyloid-β and Human Islet Amyloid Polypeptide Revealed by Replica Exchange Molecular Dynamics Simulations
Authors: Li Xuhua , Zhang Yu , Yang Zhiwei , Zhang Shengli , Zhang Lei
Published: January 2024

Alzheimer’s disease and Type 2 diabetes are two epidemiologically linked diseases which are closely associated with the misfolding and aggregation of amyloid proteins amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP), respectively. The co-aggregation of the two amyloid proteins is regarded as the fundamental molecular mechanism underlying their pathological association. The green tea extract epigallocatechin-3-gallate (EGCG) has been extensively demonstrated to inhibit the amyloid aggregation of Aβ and hIAPP proteins. However, its potential role in amyloid co-aggregation has not been thoroughly investigated. In this study, we employed the enhanced-sampling replica exchange molecular dynamics simulation (REMD) method to investigate the effect of EGCG on the co-aggregation of Aβ and hIAPP. We found that EGCG molecules substantially diminish the β-sheet structures within the amyloid core regions of Aβ and hIAPP in their co-aggregates. Through hydrogen-bond, π–π and cation–π interactions targeting polar and aromatic residues of Aβ and hIAPP, EGCG effectively attenuates both inter-chain and intra-chain interactions within the co-aggregates. All these findings indicated that EGCG can effectively inhibit the co-aggregation of Aβ and hIAPP. Our study expands the potential applications of EGCG as an anti-amyloidosis agent and provides therapeutic options for the pathological association of amyloid misfolding disorders.
Transcriptome Sequencing Unveils a Molecular-Stratification-Predicting Prognosis of Sarcoma Associated with Lipid Metabolism
Authors: Hong Yuheng , Zhang Lin , Lin Weihao , Yang Yannan , Cao Zheng , Feng Xiaoli , Yu Zhentao , Gao Yibo
Published: January 2024

Sarcomas are heterogeneous connective tissue malignancies that have been historically categorized into soft tissue and bone cancers. Although multimodal therapies are implemented, many sarcoma subtypes are still difficult to treat. Lipids play vital roles in cellular activities; however, ectopic levels of lipid metabolites have an impact on tumor recurrence, metastasis, and drug resistance. Thus, precision therapies targeting lipid metabolism in sarcoma need to be explored. In this study, we performed a comprehensive analysis of molecular stratification based on lipid metabolism-associated genes (LMAGs) using both public datasets and the data of patients in our cohort and constructed a novel prognostic model consisting of squalene epoxidase (SQLE) and tumor necrosis factor (TNF). We first integrated information on gene expression profile and survival outcomes to divide TCGA sarcoma patients into high- and low-risk subgroups and further revealed the prognosis value of the metabolic signature and immune infiltration of patients in both groups, thus proposing various therapeutic recommendations for sarcoma. We observed that the low-risk sarcoma patients in the TCGA-SARC cohort were characterized by high proportions of immune cells and increased expression of immune checkpoint genes. Subsequently, this lipid metabolic signature was validated in four external independent sarcoma datasets including the CHCAMS cohort. Notably, SQLE, a rate-limiting enzyme in cholesterol biosynthesis, was identified as a potential therapeutic target for sarcoma. Knockdown of SQLE substantially inhibited cell proliferation and colony formation while promoting the apoptosis of sarcoma cells. Terbinafine, an inhibitor of SQLE, displayed similar tumor suppression capacity in vitro. The prognostic predictive model and the potential drug target SQLE might serve as valuable hints for further in-depth biological, diagnostic, and therapeutic exploration of sarcoma.
Biochemical and Transcriptome Analyses Reveal a Stronger Capacity for Photosynthate Accumulation in Low-Tillering Rice Varieties
Authors: Zhu Mingqiang , Jiang Shan , Huang Jinqiu , Li Zhihui , Xu Shuang , Liu Shaojia , He Yonggang , Zhang Zhihong
Published: January 2024

Moderate control of rice tillering and the development of rice varieties with large panicles are important topics for future high-yield rice breeding. Herein, we found that low-tillering rice varieties stopped tillering earlier and had a larger leaf area of the sixth leaf. Notably, at 28 days after sowing, the rice seedlings of the low-tillering group had an average single-culm above-ground biomass of 0.84 g, significantly higher than that of the multi-tillering group by 56.26%, and their NSC (non-structural carbohydrate) and starch contents in sheaths were increased by 43.34% and 97.75%, respectively. These results indicated that the low-tillering group of rice varieties had a stronger ability to store photosynthetic products in the form of starch in their sheaths, which was thus more beneficial for their large panicle development. The results of carbon and nitrogen metabolism analyses showed that the low-tillering group had a relatively strong carbon metabolism activity, which was more favorable for the accumulation of photosynthesis products and the following development of large panicles, while the multi-tillering group showed relatively strong nitrogen metabolism activity, which was more beneficial for the development and formation of new organs, such as tillers. Accordingly, in the low-tillering rice varieties, the up-regulated genes were enriched in the pathways mainly related to the synthesis of carbohydrates, while the down-regulated genes were mainly enriched in the nitrogen metabolism pathways. This study provides new insights into the mechanism of rice tillering regulation and promotes the development of new varieties with ideal plant types.
Immunopathology of Pulmonary Mycobacterium tuberculosis Infection in a Humanized Mouse Model
Authors: Kolloli Afsal , Kumar Ranjeet , Venketaraman Vishwanath , Subbian Selvakumar
Published: January 2024

Despite the availability of antibiotic therapy, tuberculosis (TB) is prevailing as a leading killer among human infectious diseases, which highlights the need for better intervention strategies to control TB. Several animal model systems, including mice, guinea pigs, rabbits, and non-human primates have been developed and explored to understand TB pathogenesis. Although each of these models contributes to our current understanding of host-Mycobacterium tuberculosis (Mtb) interactions, none of these models fully recapitulate the pathological spectrum of clinical TB seen in human patients. Recently, humanized mouse models are being developed to improvise the limitations associated with the standard mouse model of TB, including lack of necrotic caseation of granulomas, a pathological hallmark of TB in humans. However, the spatial immunopathology of pulmonary TB in humanized mice is not fully understood. In this study, using a novel humanized mouse model, we evaluated the spatial immunopathology of pulmonary Mtb infection with a low-dose inoculum. Humanized NOD/LtSscidIL2Rγ null mice containing human fetal liver, thymus, and hematopoietic CD34+ cells and treated with human cytokines were aerosol challenged to implant <50 pathogenic Mtb (low dose) in the lungs. At 2 and 4 weeks post infection, the tissue bacterial load, disease pathology, and spatial immunohistology were determined in the lungs, liver, spleen, and adipose tissue using bacteriological, histopathological, and immunohistochemical techniques. The results indicate that implantation of <50 bacteria can establish a progressive disease in the lungs that transmits to other tissues over time. The disease pathology in organs correspondingly increased with the bacterial load. A distinct spatial distribution of T cells, macrophages, and natural killer cells were noted in the lung granulomas. The kinetics of spatial immune cell distribution were consistent with the disease pathology in the lungs. Thus, the novel humanized model recapitulates several key features of human pulmonary TB granulomatous response and can be a useful preclinical tool to evaluate potential anti-TB drugs and vaccines.
Bafilomycin A1 Molecular Effect on ATPase Activity of Subcellular Fraction of Human Colorectal Cancer and Rat Liver
Authors: Bychkova Solomiia , Bychkov Mykola , Dordevic Dani , Vítězová Monika , Rittmann Simon K.-M. R. , Kushkevych Ivan
Published: January 2024

Bafilomycin A1 inhibits V-type H+ ATPases on the molecular level, which acidifies endo-lysosomes. The main objective of the study was to assess the effect of bafilomycin A1 on Ca2+ content, NAADP-induced Ca2+ release, and ATPase activity in rat hepatocytes and human colon cancer samples. Chlortetracycline (CTC) was used for a quantitative measure of stored calcium in permeabilized rat hepatocytes. ATPase activity was determined by orthophosphate content released after ATP hydrolysis in subcellular post-mitochondrial fraction obtained from rat liver as well as from patients’ samples of colon mucosa and colorectal cancer samples. In rat hepatocytes, bafilomycin A1 decreased stored Ca2+ and prevented the effect of NAADP on stored Ca2+. This effect was dependent on EGTA–Ca2+ buffers in the medium. Bafilomycin A1 significantly increased the activity of Ca2+ ATPases of endoplasmic reticulum (EPR), but not plasma membrane (PM) Ca2+ ATPases in rat liver. Bafilomycin A1 also prevented the effect of NAADP on these pumps. In addition, bafilomycin A1 reduced Na+/K+ ATPase activity and increased basal Mg2+ ATPase activity in the subcellular fraction of rat liver. Concomitant administration of bafilomycin A1 and NAADP enhanced these effects. Bafilomycin A1 increased the activity of the Ca2+ ATPase of EPR in the subcellular fraction of normal human colon mucosa and also in colon cancer tissue samples. In contrast, it decreased Ca2+ ATPase PM activity in samples of normal human colon mucosa and caused no changes in colon cancer. Bafilomycin A1 decreased Na+/K+ ATPase activity and increased basal Mg2+ ATPase activity in normal colon mucosa samples and in human colon cancer samples. It can be concluded that bafilomycin A1 targets NAADP-sensitive acidic Ca2+ stores, effectively modulates ATPase activity, and assumes the link between acidic stores and EPR. Bafilomycin A1 may be useful for cancer therapy.
The Postbiotic Butyrate Mitigates Gut Mucosal Disruption Caused by Acute Ethanol Exposure
Authors: Siddiqui Mohamed Tausif , Han Yingchun , Shapiro David , West Gail , Fiocchi Claudio , Cresci Gail A. M.
Published: January 2024

We aimed to test how the postbiotic butyrate impacts select gut bacteria, small intestinal epithelial integrity, and microvascular endothelial activation during acute ethanol exposure in mice and primary human intestinal microvascular endothelial cells (HIMECs). Supplementation during an acute ethanol challenge with or without tributyrin, a butyrate prodrug, was delivered to C57BL/6 mice. A separate group of mice received 3 days of clindamycin prior to the acute ethanol challenge. Upon euthanasia, blood endotoxin, cecal bacteria, jejunal barrier integrity, and small intestinal lamina propria dendritic cells were assessed. HIMECs were tested for activation following exposure to ethanol ± lipopolysaccharide (LPS) and sodium butyrate. Tributyrin supplementation protected a butyrate-generating microbe during ethanol and antibiotic exposure. Tributyrin rescued ethanol-induced disruption in jejunal epithelial barrier, elevated plasma endotoxin, and increased mucosal vascular addressin cell-adhesion molecule-1 (MAdCAM-1) expression in intestinal microvascular endothelium. These protective effects of tributyrin coincided with a tolerogenic dendritic response in the intestinal lamina propria. Lastly, sodium butyrate pre- and co-treatment attenuated the direct effects of ethanol and LPS on MAdCAM-1 induction in the HIMECs from a patient with ulcerative colitis. Tributyrin supplementation protects small intestinal epithelial and microvascular barrier integrity and modulates microvascular endothelial activation and dendritic tolerizing function during a state of gut dysbiosis and acute ethanol challenge.