bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancing Functional Ability in Chronic Nonspecific Lower Back Pain: The Impact of EMG-Guided Trunk Stabilization Exercises
Authors: Porwal Shivani , Rizvi Moattar Raza , Sharma Ankita , Ahmad Fuzail , Alshahrani Mastour Saeed , Raizah Abdullah , Shaik Abdul Rahim , Seyam Mohamed K. , Miraj Mohammad , Alkhamis Batool Abdulelah , Mukherjee Debjani , Ahmad Irshad
Published: July 2023

Background: Nonspecific lower back pain (NSLBP) is described as pain that is not caused by an identifiable, well-known disease, such as infection, tumor, osteoporosis, fracture, structural deformity, inflammatory condition, radicular syndrome, or cauda equina syndrome. Aim: The aim of this study was to determine the effect of EMG-guided trunk stabilization exercises on functional disability associated with LBP. Materials and Methods: A single-blinded pre- and post-test experimental comparative design was used for this study. Fifty individuals with chronic NSLBP were screened for inclusion criteria. Of these, forty were randomly grouped into the EMG group receiving trunk-stability exercises with electromyography biofeedback and non-EMG group receiving trunk-stabilization exercises without EMG biofeedback. Participants performed five trunk-stability exercises 3 days a week for 4 weeks. The intensity of pain, range of motion, functional disability, and balance were measured at baseline and after 4 weeks. Results: Both techniques indicated a significant effect on chronic NSLBP; however, trunk-stability exercises combined with EMG biofeedback produced better results in alleviating the intensity of pain, increasing the range of motion, and improving functional disabilities and static balance. Conclusion: The present study confirms that trunk-stability exercises with EMG biofeedback can be practiced safely, contributes to a greater boost in neuromuscular efficiency in the lumbar flexors and extensors, and is effective in modifying functional disability for patients with NSLBP.
Do Share Repurchases Crowd Out Internal Investment in South Africa?
Authors: Steenkamp Gretha , Wesson Nicolene
Published: July 2023

Researchers in developed countries have questioned whether share repurchase activity influences internal investment. The aim of this study was to investigate the relationship between share repurchases and internal investment (defined as capital expenditure, employment expenditure, and research and development) in South Africa, as little was known about this relationship in developing countries. A quantitative research methodology was followed, employing the data of South African listed companies during the 2002–2017 period. A significant negative relationship was noted between share repurchases and employment expenditure when considering all companies, while high-growth companies exhibited a significant negative relationship between share repurchases and capital expenditure. The negative relationships could indicate that companies increase share repurchases to the detriment of internal investment (especially employment). Alternatively, it may imply that share repurchase and internal investment decisions are determined simultaneously, with companies decreasing internal investment and increasing share repurchases in the absence of identifiable profitable projects (or increasing internal investment and decreasing share repurchases when growth opportunities are available). These findings could be useful to shareholders, corporate governance regulators and activists. Given the high unemployment and income inequality in South Africa, the results support a call for the improved regulation of share repurchases to ensure effective monitoring.
Tourism Support System to Utilize Virtual Reality Space Reflecting Dynamic Information in Real Time
Authors: Koga Yuro , Yamamoto Kayoko
Published: July 2023

It is important that both static and dynamic information is efficiently used to create a suitable tourism plan. However, collecting, accumulating and managing dynamic information can cost tourists time, money and energy. In the present study, an original tourism support system was designed and developed with the purpose of reducing the burden of tourists who are unfamiliar with the urban tourist destinations in particular. An original tourism planning support system and web-geographic information systems (Web-GIS) were integrated into a single system, and two original functions were implemented. The system was operated targeting Osaka City, Japan, for a period of one month. The information concerning 529 sightseeing spots was collected from tourism-related web media and then saved to the database of the system beforehand. During the operation period, a cumulative total of 160 users accessed the system. Based on the questionnaire survey results, most of the main functions were highly rated regardless of users’ travel experiences to the operation target area. Additionally, based on the access log analysis results, it was clear that the use of the system was in line with the purpose of the present study, as the number of visits to the page for the main functions were high.
Vitamin D and Diabetic Retinopathy
Authors: Gverović Antunica Antonela , Znaor Ljubo , Ivanković Mira , Puzović Velibor , Marković Irena , Kaštelan Snježana
Published: July 2023

Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors. Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are the best-known forms of vitamin D. Calcitriol (1,25-dihydroxycholecalciferol) is the active form of vitamin D, with the sun being one of its main sources. Vitamin D is synthesized in the skin by exposure to sunlight without protective factors, but care must be taken to avoid the development of sunburn. It not only plays an important role in maintaining healthy bones and immune system but has also been highlighted in numerous studies to have an influence on various diseases, including diabetic retinopathy. A large number of people suffer from vitamin D hypovitaminosis worldwide, and diagnosis is made by measuring the concentration of 25-hydroxyvitamin D (25(OH)D) in serum. Its deficiency can cause numerous diseases and, as such, supplementation is necessary. Clinical studies have proven the effectiveness of vitamin D supplementation in the treatment of diabetic retinopathy, but with a doctor’s recommendation and supervision due to possible negative side effects.
DeepSATA: A Deep Learning-Based Sequence Analyzer Incorporating the Transcription Factor Binding Affinity to Dissect the Effects of Non-Coding Genetic Variants
Authors: Ma Wenlong , Fu Yang , Bao Yongzhou , Wang Zhen , Lei Bowen , Zheng Weigang , Wang Chao , Liu Yuwen
Published: July 2023

Utilizing large-scale epigenomics data, deep learning tools can predict the regulatory activity of genomic sequences, annotate non-coding genetic variants, and uncover mechanisms behind complex traits. However, these tools primarily rely on human or mouse data for training, limiting their performance when applied to other species. Furthermore, the limited exploration of many species, particularly in the case of livestock, has led to a scarcity of comprehensive and high-quality epigenetic data, posing challenges in developing reliable deep learning models for decoding their non-coding genomes. The cross-species prediction of the regulatory genome can be achieved by leveraging publicly available data from extensively studied organisms and making use of the conserved DNA binding preferences of transcription factors within the same tissue. In this study, we introduced DeepSATA, a novel deep learning-based sequence analyzer that incorporates the transcription factor binding affinity for the cross-species prediction of chromatin accessibility. By applying DeepSATA to analyze the genomes of pigs, chickens, cattle, humans, and mice, we demonstrated its ability to improve the prediction accuracy of chromatin accessibility and achieve reliable cross-species predictions in animals. Additionally, we showcased its effectiveness in analyzing pig genetic variants associated with economic traits and in increasing the accuracy of genomic predictions. Overall, our study presents a valuable tool to explore the epigenomic landscape of various species and pinpoint regulatory deoxyribonucleic acid (DNA) variants associated with complex traits.
Blackberries and Mulberries: Berries with Significant Health-Promoting Properties
Authors: Martins Mariana S. , Gonçalves Ana C. , Alves Gilberto , Silva Luís R.
Published: July 2023

Blackberries and mulberries are small and perishable fruits that provide significant health benefits when consumed. In reality, both are rich in phytochemicals, such as phenolics and volatile compounds, and micronutrients, such as vitamins. All the compounds are well-known thanks to their medicinal and pharmacological properties, namely antioxidant, anti-inflammatory, anti-cancer, antiviral, and cardiovascular properties. Nevertheless, variables such as genotype, production conditions, fruit ripening stage, harvesting time, post-harvest storage, and climate conditions influence their nutritional composition and economic value. Given these facts, the current review focuses on the nutritional and chemical composition, as well as the health benefits, of two blackberry species (Rubus fruticosus L., and Rubus ulmifolius Schott) and one mulberry species (Morus nigra L.).
Impact of Lipid Metabolism on Macrophage Polarization: Implications for Inflammation and Tumor Immunity
Authors: Vassiliou Evros , Farias-Pereira Renalison
Published: July 2023

Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate signaling pathways that modulate macrophages’ responses to pathogens, phagocytosis, ferroptosis, and inflammation. This review focuses on lipid metabolism and macrophage functions and addresses potential molecular targets for the treatment of macrophage-related diseases. While lipogenesis is crucial for lipid accumulation and phagocytosis in M1 macrophages, M2 macrophages likely rely on fatty acid β-oxidation to utilize fatty acids as their primary energy source. Cholesterol metabolism, regulated by factors such as SREBPs, PPARs, and LXRs, is associated with the cholesterol efflux capacity and the formation of foam cells (M2-like macrophages). Foam cells, which are targets for atherosclerosis, are associated with an increase in inflammatory cytokines. Lipolysis and fatty acid uptake markers, such as CD36, also contribute to the production of cytokines. Enhancing the immune system through the inhibition of lipid-metabolism-related factors can potentially serve as a targeted approach against tumor cells. Cyclooxygenase inhibitors, which block the conversion of arachidonic acid into various inflammatory mediators, influence macrophage polarization and have generated attention in cancer research.
Alfalfa MsATG13 Confers Cold Stress Tolerance to Plants by Promoting Autophagy
Authors: Zhao Weidi , Song Jiayi , Wang Meijia , Chen Xiuxiu , Du Binghao , An Yimin , Zhang Lishuang , Wang Dan , Guo Changhong
Published: July 2023

Autophagy is a conserved cellular process that functions in the maintenance of physiological and metabolic balance. It has previously been demonstrated to improve plant tolerance to abiotic stress. Numerous autophagy–related genes (ATGs) that regulate abiotic stress have been identified, but there have been few functional studies showing how ATGs confer cold stress tolerance. The cold transcriptome data of the crown buds that experienced overwintering of the alfalfa (Medicago sativa L.) showed that MsATG13 is upregulated in response to cold stress. In the present study, we found that MsATG13 transgenic tobacco enhanced cold tolerance compared to wild–type (WT) plants. Transmission electron microscopy demonstrated that transgenic tobacco overexpressing MsATG13 formed more autophagosomes than WT plants in response to cold stress conditions. The transgenic tobacco increased autophagy levels due to upregulation of other ATGs that were necessary for autophagosome production under cold stress conditions. MsATG13 transgenic tobacco also increased the proline contents and antioxidant enzyme activities, enhancing the antioxidant defense capabilities under cold stress conditions. Furthermore, MsATG13 overexpression decreased levels of superoxide anion radicals and hydrogen peroxide under cold stress conditions. These findings demonstrate the role of MsATG13 in enhancing plant cold tolerance through modulation of autophagy and antioxidant levels.
Navigating the Blood–Brain Barrier: Challenges and Therapeutic Strategies in Breast Cancer Brain Metastases
Authors: Terceiro Lucas E. L. , Ikeogu Nnamdi M. , Lima Matheus F. , Edechi Chidalu A. , Nickel Barbara E. , Fischer Gabor , Leygue Etienne , McManus Kirk J. , Myal Yvonne
Published: July 2023

Breast cancer (BC) is the most common cancer in women, with metastatic BC being responsible for the highest number of deaths. A frequent site for BC metastasis is the brain. Brain metastasis derived from BC involves the cooperation of multiple genetic, epigenetic, angiogenic, and tumor–stroma interactions. Most of these interactions provide a unique opportunity for development of new therapeutic targets. Potentially targetable signaling pathways are Notch, Wnt, and the epidermal growth factor receptors signaling pathways, all of which are linked to driving BC brain metastasis (BCBM). However, a major challenge in treating brain metastasis remains the blood–brain barrier (BBB). This barrier restricts the access of unwanted molecules, cells, and targeted therapies to the brain parenchyma. Moreover, current therapies to treat brain metastases, such as stereotactic radiosurgery and whole-brain radiotherapy, have limited efficacy. Promising new drugs like phosphatase and kinase modulators, as well as BBB disruptors and immunotherapeutic strategies, have shown the potential to ease the disease in preclinical studies, but remain limited by multiple resistance mechanisms. This review summarizes some of the current understanding of the mechanisms involved in BC brain metastasis and highlights current challenges as well as opportunities in strategic designs of potentially successful future therapies.
The Therapeutic Potential of a Strategy to Prevent Acute Myeloid Leukemia Stem Cell Reprogramming in Older Patients
Authors: Park Moon Nyeo
Published: July 2023

Acute myeloid leukemia (AML) is the most common and incurable leukemia subtype. Despite extensive research into the disease’s intricate molecular mechanisms, effective treatments or expanded diagnostic or prognostic markers for AML have not yet been identified. The morphological, immunophenotypic, cytogenetic, biomolecular, and clinical characteristics of AML patients are extensive and complex. Leukemia stem cells (LSCs) consist of hematopoietic stem cells (HSCs) and cancer cells transformed by a complex, finely-tuned interaction that causes the complexity of AML. Microenvironmental regulation of LSCs dormancy and the diagnostic and therapeutic implications for identifying and targeting LSCs due to their significance in the pathogenesis of AML are discussed in this review. It is essential to perceive the relationship between the niche for LSCs and HSCs, which together cause the progression of AML. Notably, methylation is a well-known epigenetic change that is significant in AML, and our data also reveal that microRNAs are a unique factor for LSCs. Multiple-targeted approaches to reduce the risk of epigenetic factors, such as the administration of natural compounds for the elimination of local LSCs, may prevent potentially fatal relapses. Furthermore, the survival analysis of overlapping genes revealed that specific targets had significant effects on the survival and prognosis of patients. We predict that the multiple-targeted effects of herbal products on epigenetic modification are governed by different mechanisms in AML and could prevent potentially fatal relapses. Thus, these strategies can facilitate the incorporation of herbal medicine and natural compounds into the advanced drug discovery and development processes achievable with Network Pharmacology research.
Chios Mastic Gum: Chemical Profile and Pharmacological Properties in Inflammatory Bowel Disease: From the Past to the Future
Authors: Ottria Roberta , Xynomilakis Ornella , Casati Silvana , Abbiati Ezio , Maconi Giovanni , Ciuffreda Pierangela
Published: July 2023

Chios mastic gum, the product of the tree Pistacia lentiscus var. Chia, has been used for more than 2500 years in traditional Greek medicine for treating several diseases, thanks to the anti-inflammatory and antioxidant properties of its components. Despite the long-time use of mastic in gastroenterology and in particular in chronic-inflammation-associated diseases, to date, the literature lacks reviews regarding this topic. The aim of the present work is to summarize available data on the effects of P. lentiscus on inflammatory bowel disease. A comprehensive review of this topic could drive researchers to conduct future studies aimed at deeply investigating P. lentiscus effects and hypothesizing a mechanism of action. The present review, indeed, schematizes the possible bioactive components of mastic gum. Particular care is given to P. lentiscus var. Chia medicaments’ and supplements’ chemical compositions and their pharmacological action in inflammatory bowel disease.
Insight into the Mechanism of Interactions between the LL-37 Peptide and Model Membranes of Legionella gormanii Bacteria
Authors: Pastuszak Katarzyna , Kowalczyk Bozena , Tarasiuk Jacek , Luchowski Rafal , Gruszecki Wieslaw I. , Jurak Małgorzata , Palusinska-Szysz Marta
Published: July 2023

Legionella gormanii is a fastidious, Gram-negative bacterium known to be the etiological agent of atypical community-acquired pneumonia. The human cathelicidin LL-37 exhibits a dose-dependent bactericidal effect on L. gormanii. The LL-37 peptide at the concentration of 10 µM causes the bacteria to become viable but not cultured. The antibacterial activity of the peptide is attributed to its effective binding to the bacterial membrane, as demonstrated by the fluorescence lifetime imaging microscopy. In this study, to mimic the L. gormanii membranes and their response to the antimicrobial peptide, Langmuir monolayers were used with the addition of the LL-37 peptide to the subphase of the Langmuir trough to represent the extracellular fluid. The properties of the model membranes (Langmuir monolayers) formed by phospholipids (PL) isolated from the L. gormanii bacteria cultured on the non-supplemented (PL−choline) and choline-supplemented (PL+choline) medium were determined, along with the effect of the LL-37 peptide on the intermolecular interactions, packing, and ordering under the monolayer compression. Penetration tests at the constant surface pressure were carried out to investigate the mechanism of the LL-37 peptide action on the model membranes. The peptide binds to the anionic bacterial membranes preferentially, due to its positive charge. Upon binding, the LL-37 peptide can penetrate into the hydrophobic tails of phospholipids, destabilizing membrane integrity. The above process can entail membrane disruption and ultimately cell death. The ability to evoke such a great membrane destabilization is dependent on the share of electrostatic, hydrogen bonding and Lifshitz–van der Waals LL-37−PL interactions. Thus, the LL-37 peptide action depends on the changes in the lipid membrane composition caused by the utilization of exogenous choline by the L. gormanii.
Cue to Acid-Induced Long-Range Conformational Changes in an Antibody Preceding Aggregation: The Structural Origins of the Subpeaks in Kratky Plots of Small-Angle X-ray Scattering
Authors: Imamura Hiroshi , Honda Shinya
Published: July 2023

Antibody aggregation, followed by acid denaturation and neutralization of pH, is one of the reasons why the production of therapeutic monoclonal antibodies (mAbs) is expensive. Determining the structural details of acid-denatured antibodies is important for understanding their aggregation mechanism and for antibody engineering. Recent research has shown that monoclonal antibodies of human/humanized immunoglobulin G1 (IgG1) become smaller globules at pH 2 compared to their native structure at pH 7. This acid-denatured species is unstable at pH 7 and prone to aggregation by neutralization of pH. Small-angle X-ray scattering (SAXS) data have revealed an acid-induced reduction in the subpeaks in Kratky plot, indicating conformational changes that can lead to aggregation. The subpeaks are well resolved at pH > 3 but less pronounced at pH ≤ 2. One of the weakened subpeaks indicates loosely organized inter-region (Fab-Fab and Fab-Fc) correlations due to acid denaturation. However, the structural origin of the other subpeak (called q3 peak in this study) has not been established because its q region could represent the various inter-region, inter-domain, and intra-domain correlations in IgG1. In this study, we aimed to untangle the effects of domain–domain correlations on Kratky’s q3 peak based on the computed SAXS of the crystal structure of IgG1. The q3 peak appeared in the static structure and was more prominent in the Fc region than in the Fab or isolated domains. Further brute-force analysis indicated that longer domain–domain correlations, including the inter-region, also positively contribute to Kratky’s q3 peak. Thus, the distortion of the Fc region and a longer inter-region correlation initiate acid denaturation and aggregation.
New Evidence for Artemisia absinthium as an Alternative to Classical Antibiotics: Chemical Analysis of Phenolic Compounds, Screening for Antimicrobial Activity
Authors: Liu Zhihao , Li Xiaolin , Jin Yan , Nan Tiegui , Zhao Yuyang , Huang Luqi , Yuan Yuan
Published: July 2023

Artemisia absinthium, an important herb of the Artemisia genus, was evaluated in this study for its potential as an alternative to classical antibiotics. The antimicrobial activity of methanol extracts of A. absinthium (MEAA) was evaluated using the broth microdilution method, revealing that A. absinthium exhibited broad-spectrum antibacterial and antifungal activity. Ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF-MS) was used to analyze the chemical profile of the MEAA, with a focus on flavonoids, quinic acids, and glucaric acids. A total of 90 compounds were identified, 69 of which were described for the first time in A. absinthium. Additionally, a new class of caffeoyl methyl glucaric acids was identified. The main active compounds were quantified and screened for antimicrobial activity. A. absinthium was found to be rich in quinic acids and flavonoids. The screening for antimicrobial activity also revealed that salicylic acid, caffeic acid, casticin, and 3,4-dicaffeoylquinic acid had varying degrees of antimicrobial activity. The acute toxicity of MEAA was examined following OECD guidelines. The administration of 5000 mg/kg bw of MEAA did not result in mortality in male and female mice. Furthermore, there were no observed effects on the visceral organs or general behavior of the mice, demonstrating the good safety of MEAA. This study provides new evidence for the use of A. absinthium as an alternative to classical antibiotics in addressing the problem of bacterial resistance.
Familial Partial Lipodystrophy: Clinical Features, Genetics and Treatment in a Greek Referral Center
Authors: Kountouri Aikaterini , Korakas Emmanouil , Maratou Eirini , Ikonomidis Ignatios , Balampanis Konstantinos , Liatis Stavros , Tentolouris Nikolaos , Toulas Panagiotis , Kousathana Foteini , Giatzakis Christophoros , Dimitriadis George D. , Lambadiari Vaia
Published: July 2023

Familial partial lipodystrophy (FPLD) is a rare syndrome in which a patient’s phenotype is not merely dependent on the specific genetic mutation, but it is also defined by a combination of other demographic, environmental and genetic factors. In this prospective observational study in a Greek referral center, we enrolled 39 patients who fulfilled the clinical criteria of FPLD. A genetic analysis was conducted, which included sequence and deletion/duplication analyses of the LMNA and PPRARG genes, along with anthropometric and metabolic parameters. The treatment responses of patients who were eligible for treatment with metreleptin were evaluated at 3 and 12 months. In most of the patients, no significant changes were detected at the exon level, and any mutations that led to changes at the protein level were not associated with the lipodystrophic phenotype. On the contrary, various changes were detected at the intron level, especially in introns 7 and 10, whose clinical significance is considered unknown. In addition, treatment with metreleptin in specific FPLD patients significantly improved glycemic and lipidemic control, an effect which was sustained at the 12-month follow-up. More large-scale studies are necessary to clarify the genetic and allelic heterogeneity of the disease, along with other parameters which could predict treatment response.
Optical Flow-Based Full-Field Quantitative Blood-Flow Velocimetry Using Temporal Direction Filtering and Peak Interpolation
Authors: Meng Liangwei , Huang Mange , Feng Shijie , Wang Yiqian , Lu Jinling , Li Pengcheng
Published: July 2023

The quantitative measurement of the microvascular blood-flow velocity is critical to the early diagnosis of microvascular dysfunction, yet there are several challenges with the current quantitative flow velocity imaging techniques for the microvasculature. Optical flow analysis allows for the quantitative imaging of the blood-flow velocity with a high spatial resolution, using the variation in pixel brightness between consecutive frames to trace the motion of red blood cells. However, the traditional optical flow algorithm usually suffers from strong noise from the background tissue, and a significant underestimation of the blood-flow speed in blood vessels, due to the errors in detecting the feature points in optical images. Here, we propose a temporal direction filtering and peak interpolation optical flow method (TPIOF) to suppress the background noise, and improve the accuracy of the blood-flow velocity estimation. In vitro phantom experiments and in vivo animal experiments were performed to validate the improvements in our new method.
Untargeted Multiomics Approach Coupling Lipidomics and Metabolomics Profiling Reveals New Insights in Diabetic Retinopathy
Authors: Ancel Patricia , Martin Jean Charles , Doukbi Elisa , Houssays Marie , Gascon Pierre , Righini Maud , Matonti Frédéric , Svilar Ljubica , Valmori Marie , Tardivel Catherine , Venteclef Nicolas , Julla Jean Baptiste , Gautier Jean François , Resseguier Noémie , Dutour Anne , Gaborit Bénédicte
Published: July 2023

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus (DM) which is the main cause of vision loss in the working-age population. Currently known risk factors such as age, disease duration, and hemoglobin A1c lack sufficient efficiency to distinguish patients with early stages of DR. A total of 194 plasma samples were collected from patients with type 2 DM and DR (moderate to proliferative (PDR) or control (no or mild DR) matched for age, gender, diabetes duration, HbA1c, and hypertension. Untargeted lipidomic and metabolomic approaches were performed. Partial-least square methods were used to analyze the datasets. Levels of 69 metabolites and 85 lipid species were found to be significantly different in the plasma of DR patients versus controls. Metabolite set enrichment analysis indicated that pathways such as metabolism of branched-chain amino acids (methylglutaryl carnitine p = 0.004), the kynurenine pathway (tryptophan p < 0.001), and microbiota metabolism (p-Cresol sulfate p = 0.004) were among the most enriched deregulated pathways in the DR group. Moreover, Glucose-6-phosphate (p = 0.001) and N-methyl-glutamate (p < 0.001) were upregulated in DR. Subgroup analyses identified a specific signature associated with PDR, macular oedema, and DR associated with chronic kidney disease. Phosphatidylcholines (PCs) were dysregulated, with an increase of alkyl-PCs (PC O-42:5 p < 0.001) in DR, while non-ether PCs (PC 14:0–16:1, p < 0.001; PC 18:2–14:0, p < 0.001) were decreased in the DR group. Through an unbiased multiomics approach, we identified metabolites and lipid species that interestingly discriminate patients with or without DR. These features could be a research basis to identify new potential plasma biomarkers to promote 3P medicine.
Complete Metabolic Response to Combined Immune Checkpoint Inhibition after Progression of Metastatic Colorectal Cancer on Pembrolizumab: A Case Report
Authors: Krekeler Carolin , Wethmar Klaus , Mikesch Jan-Henrik , Kerkhoff Andrea , Menck Kerstin , Lenz Georg , Schildhaus Hans-Ulrich , Wessolly Michael , Hoffmann Matthias W. , Pascher Andreas , Asmus Inga , Wardelmann Eva , Bleckmann Annalen
Published: July 2023

DNA mismatch repair deficient (dMMR) and microsatellite instable (MSI) metastatic colorectal cancer (mCRC) can be successfully treated with FDA- and EMA-approved immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab (as single agents targeting the anti-programmed cell death protein-1 (PD-1)) or combinations of a PD-1 inhibitor with ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-targeting antibody. The best treatment strategy beyond progression on single-agent ICI therapy remains unclear. Here, we present the case of a 63-year-old male with Lynch-syndrome-associated, microsatellite instability-high (MSI-H) mCRC who achieved a rapid normalization of his tumor markers and a complete metabolic remission (CMR), currently lasting for ten months, on sequential ICI treatment with the combination of nivolumab and ipilimumab followed by nivolumab maintenance therapy after progression on single-agent anti-PD-1 ICI therapy. The therapy was well-tolerated, and no immune-related adverse events occurred. To the best of our knowledge, this is the first case of a sustained metabolic complete remission in an MSI-H mCRC patient initially progressing on single-agent anti-PD-1 therapy. Thus, dMMR mCRC patients might benefit from sequential immune checkpoint regimens even with long-term responses. However, further sophistication of clinical algorithms for treatment beyond progression on single-agent ICI therapy in MSI-mCRC is urgently needed.
Recovery of Phosphate(V) Ions from Water and Wastewater Using Chitosan-Based Sorbents Modified—A Literature Review
Authors: Wujcicki Łukasz , Kluczka Joanna
Published: July 2023

Over the past two decades, there has been increasing interest in the use of low-cost and effective sorbents in water treatment. Hybrid chitosan sorbents are potential materials for the adsorptive removal of phosphorus, which occurs in natural waters mainly in the form of orthophosphate(V). Even though there are numerous publications on this topic, the use of such sorbents in industrial water treatment and purification is limited and controversial. However, due to the explosive human population growth, the ever-increasing global demand for food has contributed to the consumption of phosphorus compounds and other biogenic elements (such as nitrogen, potassium, or sodium) in plant cultivation and animal husbandry. Therefore, the recovery and reuse of phosphorus compounds is an important issue to investigate for the development and maintenance of a circular economy. This paper characterizes the problem of the presence of excess phosphorus in water reservoirs and presents methods for the adsorptive removal of phosphate(V) from water matrices using chitosan composites. Additionally, we compare the impact of modifications, structure, and form of chitosan composites on the efficiency of phosphate ion removal and adsorption capacity. The state of knowledge regarding the mechanism of adsorption is detailed, and the results of research on the desorption of phosphates are described.
Genome-Wide Profiling of Endogenous Single-Stranded DNA Using the SSiNGLe-P1 Method
Authors: Xu Dongyang , Huang Yu , Luo Lingcong , Tang Lu , Lu Meng , Cao Huifen , Wang Fang , Diao Yong , Lyubchenko Liudmila , Kapranov Philipp
Published: July 2023

Endogenous single-stranded DNA (essDNA) can form in a mammalian genome as the result of a variety of molecular processes and can both play important roles inside the cell as well as have detrimental consequences to genome integrity, much of which remains to be fully understood. Here, we established the SSiNGLe-P1 approach based on limited digestion by P1 endonuclease for high-throughput genome-wide identification of essDNA regions. We applied this method to profile essDNA in both human mitochondrial and nuclear genomes. In the mitochondrial genome, the profiles of essDNA provide new evidence to support the strand-displacement model of mitochondrial DNA replication. In the nuclear genome, essDNA regions were found to be enriched in certain types of functional genomic elements, particularly, the origins of DNA replication, R-loops, and to a lesser degree, in promoters. Furthermore, interestingly, many of the essDNA regions identified by SSiNGLe-P1 have not been annotated and thus could represent yet unknown functional elements.
Water-Deficit Stress in the Epiphytic Elkhorn Fern: Insight into Photosynthetic Response
Authors: Oliwa Jakub , Skoczowski Andrzej , Rut Grzegorz , Kornaś Andrzej
Published: July 2023

Progressive climate changes cause disturbance of water relations in tropical rainforests, where epiphytic ferns are an important element of biodiversity. In these plants, the efficiency of photosynthesis is closely related to the efficiency of water transport. In addition, due to the lack of contact with the soil, epiphytes are extremely susceptible to water-deficit stress. The aim of this experiment was to determine the response of the photosynthetic apparatus of Platycerium bifurcatum to a 6-week water deficit. The hydration and pigment composition of leaves were determined using reflectance spectroscopy and epifluorescence microscopy. Chlorophyll a fluorescence kinetics parameters, fluorescence induction curves (OJIP), low-temperature fluorescence curves at 77 K and proline concentration were analyzed at seven time points. After a decrease in leaf hydration by 10–15%, there were disturbances in the oxidation–reduction balance, especially in the initial photochemical reactions, a rapid decrease in plant vitality (PI) and significant fluctuations in chlorophyll a fluorescence parameters. The relative size of PSI antenna structures compared to PSII decreased in the following weeks of water deficit. Changes in photochemical reactions were accompanied by a decrease in gross photosynthesis and an increase in proline concentration. Changes in the functioning of photosynthesis light phase and the pigment composition of leaves are related to the resistance of elkhorn fern to long-term water deficit.
Drought-Stress-Related Reprogramming of Gene Expression in Barley Involves Differential Histone Modifications at ABA-Related Genes
Authors: Ost Charlotte , Cao Hieu Xuan , Nguyen Thuy Linh , Himmelbach Axel , Mascher Martin , Stein Nils , Humbeck Klaus
Published: July 2023

Plants respond to drought by the major reprogramming of gene expression, enabling the plant to survive this threatening environmental condition. The phytohormone abscisic acid (ABA) serves as a crucial upstream signal, inducing this multifaceted process. This report investigated the drought response in barley plants (Hordeum vulgare, cv. Morex) at both the epigenome and transcriptome levels. After a ten-day drought period, during which the soil water content was reduced by about 35%, the relative chlorophyll content, as well as the photosystem II efficiency of the barley leaves, decreased by about 10%. Furthermore, drought-related genes such as HvS40 and HvA1 were already induced compared to the well-watered controls. Global ChIP-Seq analysis was performed to identify genes in which histones H3 were modified with euchromatic K4 trimethylation or K9 acetylation during drought. By applying stringent exclusion criteria, 129 genes loaded with H3K4me3 and 2008 genes loaded with H3K9ac in response to drought were identified, indicating that H3K9 acetylation reacts to drought more sensitively than H3K4 trimethylation. A comparison with differentially expressed genes enabled the identification of specific genes loaded with the euchromatic marks and induced in response to drought treatment. The results revealed that a major proportion of these genes are involved in ABA signaling and related pathways. Intriguingly, two members of the protein phosphatase 2C family (PP2Cs), which play a crucial role in the central regulatory machinery of ABA signaling, were also identified through this approach.
Interaction, Insensitivity and Thermal Conductivity of CL-20/TNT-Based Polymer-Bonded Explosives through Molecular Dynamics Simulation
Authors: Li Shenshen , Li Qiaoli , Xiao Jijun
Published: July 2023

Binders mixed with explosives to form polymer-bonded explosives (PBXs) can reduce the sensitivity of the base explosive by improving interfacial interactions. The interface formed between the binder and matrix explosive also affects the thermal conductivity. Low thermal conductivity may result in localized heat concentration inside the PBXs, causing the detonation of the explosive. To investigate the binder–explosive interfacial interactions and thermal conductivity, PBXs with polyurethane as the binder and 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane/2,4,6-trinitrotoluene (CL-20/TNT) co-crystal as the matrix explosive were investigated through molecular dynamics (MD) simulations and reverse non-equilibrium molecular dynamics (rNEMD) simulation. The analysis of the pair correlation function revealed that there are hydrogen bonding interactions between Estane5703 and CL-20/TNT. The length of the trigger bonds was adopted as a theoretical criterion of sensitivity, and the effect of polymer binders on the sensibility of PBXs was correlated by analyzing the interfacial trigger bonds and internal trigger bonds of PBXs for the first time. The results indicated that the decrease in sensitivity of CL-20/TNT mainly comes from the CL-20/TNT contact with Estane5703. Therefore, the sensitivity of CL-20/TNT-based PBXs can be further reduced by increasing the contact area between CL-20/TNT and Estane5703. The thermal conductivity of PBXs composed of Estane5703 and CL-20/TNT (0 0 1), (0 1 0) and (1 0 0) crystal planes, respectively, were calculated through rNEMD simulations, and the results showed that only the addition of Estane5703 to the (1 0 0) crystal plane can improve the thermal conductivity of PBX100.
Ligand-Dependent Intramolecular Motion of Native Nicotinic Acetylcholine Receptors Determined in Living Myotube Cells via Diffracted X-ray Tracking
Authors: Oishi Koichiro , Nagamori Mayu , Kashino Yasuhiro , Sekiguchi Hiroshi , Sasaki Yuji C. , Miyazawa Atsuo , Nishino Yuri
Published: July 2023

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that play an important role in signal transduction at the neuromuscular junction (NMJ). Movement of the nAChR extracellular domain following agonist binding induces conformational changes in the extracellular domain, which in turn affects the transmembrane domain and opens the ion channel. It is known that the surrounding environment, such as the presence of specific lipids and proteins, affects nAChR function. Diffracted X-ray tracking (DXT) facilitates measurement of the intermolecular motions of receptors on the cell membranes of living cells, including all the components involved in receptor function. In this study, the intramolecular motion of the extracellular domain of native nAChR proteins in living myotube cells was analyzed using DXT for the first time. We revealed that the motion of the extracellular domain in the presence of an agonist (e.g., carbamylcholine, CCh) was restricted by an antagonist (i.e., alpha-bungarotoxin, BGT).
Raman Spectroscopy Combined with Malaria Protein for Early Capture and Recognition of Broad-Spectrum Circulating Tumor Cells
Authors: Liu Xinning , Zhang Yidan , Li Xunrong , Xu Jian , Zhao Chenyang , Yang Jinbo
Published: July 2023

Early identification of tumors can significantly reduce the mortality rate. Circulating tumor cells (CTCs) are a type of tumor cell that detaches from the primary tumor and circulates through the bloodstream. Monitoring CTCs may allow the early identification of tumor progression. However, due to their rarity and heterogeneity, the enrichment and identification of CTCs is still challenging. Studies have shown that Raman spectroscopy could distinguish CTCs from metastatic cancer patients. VAR2CSA, a class of malaria proteins, has a strong broad-spectrum binding effect on various tumor cells and is a promising candidate biomarker for cancer detection. Here, recombinant malaria VAR2CSA proteins were synthesized, expressed, and purified. After confirming that various types of tumor cells can be isolated from blood by recombinant malaria VAR2CSA proteins, we further proved that the VAR2CSA combined with Raman spectroscopy could be used efficiently for tumor capture and type recognition using A549 cell lines spiked into the blood. This would allow the early screening and detection of a broad spectrum of CTCs. Finally, we synthesized and purified the malaria protein fusion antibody and confirmed its in vitro tumor-killing activity. Herein, this paper exploits the theoretical basis of a novel strategy to capture, recognize, and kill broad-spectrum types of CTCs from the peripheral blood.
Shedding Light on Skin Autoimmunity: More than Just Skin Deep
Authors: Li Philip Hei , Lau Chak-sing
Published: July 2023

Our skin is the largest organ of the body and the foremost defensive barrier against the external environment [...]
A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease
Authors: Esteban-Martos Alvaro , Brokate-Llanos Ana Maria , Real Luis Miguel , Melgar-Locatelli Sonia , de Rojas Itziar , Castro-Zavala Adriana , Bravo Maria Jose , Mañas-Padilla Maria del Carmen , García-González Pablo , Ruiz-Galdon Maximiliano , Pacheco-Sánchez Beatriz , Polvillo Rocío , Rodriguez de Fonseca Fernando , González Irene , Castilla-Ortega Estela , Muñoz Manuel J. , Rivera Patricia , Reyes-Engel Armando , Ruiz Agustin , Royo Jose Luis
Published: July 2023

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer’s disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aβ1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin’s effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.
Irisin: A Possible Marker of Adipose Tissue Dysfunction in Obesity
Authors: Tomasello Laura , Pitrone Maria , Guarnotta Valentina , Giordano Carla , Pizzolanti Giuseppe
Published: July 2023

Adipose tissue (AT) secretes pro- and anti-inflammatory cytokines involved in AT homeostasis, including tumor necrosis factor-α (TNFα) and irisin. The functionality of AT is based on a regulated equilibrium between adipogenesis and extracellular matrix (ECM) remodeling. We investigated the contributions of adipose progenitors (ASCs) and adipocytes (AMCs) to TNFα-induced ECM remodeling and a possible implication of irisin in AT impairment in obesity. ASCs and AMCs were exposed to TNFα treatment and nuclear factor–kappa (NF-kB) pathway was investigated: Tissue Inhibitor of Metalloproteinase (TIMP-1), Twist Family Transcription Factor 1 (TWIST-1), and peroxisome proliferator-activated receptor-γ (PPARγ) expression levels were analyzed. The proteolytic activity of matrix metalloproteinases (MMPs) -2 and -9 was analyzed by zymography, and the irisin protein content was measured by ELISA. In inflamed AMCs, a TIMP-1/TWIST-1 imbalance leads to a drop in PPARγ. Adipogenesis and lipid storage ability impairment come with local tissue remodeling due to MMP-9 overactivation. In vitro and ex vivo measurements confirm positive correlations among inflammation, adipose secreting irisin levels, and circulating irisin levels in patients with visceral obesity. Our findings identify the NF-kB downstream effectors as molecular initiators of AT dysfunction and suggest irisin as a possible AT damage and obesity predictive factor.
Local Administration of Minocycline Improves Nerve Regeneration in Two Rat Nerve Injury Models
Authors: Guillemot-Legris Owein , Girmahun Gedion , Shipley Rebecca J. , Phillips James B.
Published: July 2023

Peripheral nerve injuries are quite common and often require a surgical intervention. However, even after surgery, patients do not often regain satisfactory sensory and motor functions. This, in turn, results in a heavy socioeconomic burden. To some extent, neurons can regenerate from the proximal nerve stump and try to reconnect to the distal stump. However, this regenerating capacity is limited, and depending on the type and size of peripheral nerve injury, this process may not lead to a positive outcome. To date, no pharmacological approach has been used to improve nerve regeneration following repair surgery. We elected to investigate the effects of local delivery of minocycline on nerve regeneration. This molecule has been studied in the central nervous system and was shown to improve the outcome in many disease models. In this study, we first tested the effects of minocycline on SCL 4.1/F7 Schwann cells in vitro and on sciatic nerve explants. We specifically focused on the Schwann cell repair phenotype, as these cells play a central role in orchestrating nerve regeneration. Finally, we delivered minocycline locally in two different rat models of nerve injury, a sciatic nerve transection and a sciatic nerve autograft, demonstrating the capacity of local minocycline treatment to improve nerve regeneration.