bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal Disorders Associated with Waldenström Macroglobulinaemia, IgM MGUS and IgM-Producing B-Cell Lymphoproliferative Disorders
Authors: Pratt Guy , Giles Hannah V. , Pinney Jennifer H.
Published: June 2023

Renal disorders are uncommonly associated with IgM MGUS and Waldenström macroglobulinaemia (WM). Data are limited to large case series that suggest that related renal involvement occurs in 5% of patients with WM. Although uncommon, there is a much greater variety of renal pathologies associated with WM and IgM MGUS than that seen in patients with multiple myeloma, where cast nephropathy predominates. In WM, uncommonly direct infiltration of the renal system by lymphoma or cast nephropathy with a high light-chain level can occur. AL amyloidosis can present with nephrotic syndrome as a feature with IgM MGUS or WM. Cryoglobulinaemia and light-chain deposition disease are other important potential causes of renal impairment with IgM MGUS and WM. There are other rarer monoclonal gammopathy of renal significance (MGRS) conditions characterised by typically isolated kidney disease that are causally related to a B-cell or plasma-cell clonal disorder usually in a precancerous MGUS state, although in some renal pathologies, the association is less clear. Central to the majority of these diagnoses is the need for an accurate renal histological diagnosis, and management requires close joint working of renal and haematology teams.
From Fresh to Dried Lavender Flower: Changes in Phytochemical Profile According to Drying Method
Authors: Caser Matteo , Falla Nicole Mélanie , Demasi Sonia , Scariot Valentina
Published: June 2023

Lavandula angustifolia Mill. is a part of the Lamiaceae family, which includes aromatic plants used in perfumery, manufactory, food, ornamental, and medicinal sectors. Both fresh and dried lavender flowers can be exploited in different ways; however, post-harvest treatments such as drying processes can help maintain the flowers’ properties for a longer period. This study analyzed fresh (F) and dried lavender flower ultrasound-assisted extracts, comparing two different drying methods, i.e., heat-pump drying (HP) and hot-air drying (HA), to assess potential differences in their effect on the phytochemical composition (total phenolic content, total anthocyanin content, and phenolic profile) and antioxidant activity (FRAP, DPPH, and ABTS assays) of flowers, focusing on three lavender selections from north-western Alps (i.e., Susa, Stura, and Tanaro). Results showed that HP-dried flowers are to be preferred over HA-dried flowers, as they contain +66.73% of phenolics and +62.2% of anthocyanins, and they have higher antioxidant activity (from 60.32% to 284.3% more according to the assay). HP-dried flowers, particularly those from the Tanaro selection, showed also higher values in the relative antioxidant capacity index (RACI) and the global antioxidant score (GAS), ranking together with the fresh flowers. Nine bioactive compounds out of thirteen were detected by means of HPLC, seven in F (caffeic acid, hyperoside, quercetin, ellagic acid, catechin, epicatechin, and dehydroascorbic acid), four in HA (ferulic acid, hyperoside, quercitrin, and epicatechin), and two in HP (caffeic acid and hyperoside). The higher temperatures used in HA probably promoted oxidative and biochemical reactions that led to the presence and increase in these compounds. However, many other phenolic compounds may contribute to the antioxidant power of lavender extracts. Overall, HP resulted in an effective and sustainable method for drying lavender flowers and may have interesting applications to obtain final products richer in bioactive compounds and antioxidant activity to be used in the functional food industry.
Biological and Catalytic Properties of Selenoproteins
Authors: Chaudière Jean
Published: June 2023

Selenocysteine is a catalytic residue at the active site of all selenoenzymes in bacteria and mammals, and it is incorporated into the polypeptide backbone by a co-translational process that relies on the recoding of a UGA termination codon into a serine/selenocysteine codon. The best-characterized selenoproteins from mammalian species and bacteria are discussed with emphasis on their biological function and catalytic mechanisms. A total of 25 genes coding for selenoproteins have been identified in the genome of mammals. Unlike the selenoenzymes of anaerobic bacteria, most mammalian selenoenzymes work as antioxidants and as redox regulators of cell metabolism and functions. Selenoprotein P contains several selenocysteine residues and serves as a selenocysteine reservoir for other selenoproteins in mammals. Although extensively studied, glutathione peroxidases are incompletely understood in terms of local and time-dependent distribution, and regulatory functions. Selenoenzymes take advantage of the nucleophilic reactivity of the selenolate form of selenocysteine. It is used with peroxides and their by-products such as disulfides and sulfoxides, but also with iodine in iodinated phenolic substrates. This results in the formation of Se-X bonds (X = O, S, N, or I) from which a selenenylsulfide intermediate is invariably produced. The initial selenolate group is then recycled by thiol addition. In bacterial glycine reductase and D-proline reductase, an unusual catalytic rupture of selenium–carbon bonds is observed. The exchange of selenium for sulfur in selenoproteins, and information obtained from model reactions, suggest that a generic advantage of selenium compared with sulfur relies on faster kinetics and better reversibility of its oxidation reactions.
An Exploration of the Coherent Effects between METTL3 and NDUFA10 on Alzheimer’s Disease
Authors: Yang Lin , Pang Xinping , Guo Wenbo , Zhu Chengjiang , Yu Lei , Song Xianghu , Wang Kui , Pang Chaoyang
Published: June 2023

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized primarily by a decline in cognitive function. However, the etiopathogenesis of AD is unclear. N6-methyladenosine (m6A) is abundant in the brain, and it is interesting to explore the relationship between m6A and AD causes. In this paper, the gene expression of METTL3 and NDUFA10 were found to correlate with the Mini-mental State Examination (MMSE), which is a clinical indicator of the degree of dementia. METTL3 is involved in post-transcriptional methylation and the formation of m6A. NDUFA10 encodes the protein with NADH dehydrogenase activity and oxidoreductase activity in the mitochondrial electron transport chain. The following three characteristics were observed in this paper: 1. The lower the expression level of NDUFA10, the smaller the MMSE, and the higher the degree of dementia. 2. If the expression level of METTL3 dropped below its threshold, the patient would have a risk of AD with a probability close to 100%, suggesting a basic necessity for m6A to protect mRNA. 3. The lower the expression levels of both METTL3 and NDUFA10, the more likely the patient would suffer from AD, implying the coherence between METTL3 and NDUFA10. Regarding the above discovery, the following hypothesis is presented: METTL3 expression level is downregulated, then the m6A modification level of NDUFA10 mRNA is also decreased, thereby reducing the expression level of NDUFA10-encoded protein. Furthermore, the abnormal expression of NDUFA10 contributes to the assembly disorder of mitochondrial complex I and affects the process of the electron respiratory chain, with the consequent development of AD. In addition, to confirm the above conclusions, the AI Ant Colony Algorithm was improved to be more suitable for discovering the characteristics of AD data, and the SVM diagnostic model was applied to mine the coherent effects on AD between METTL3 and NDUFA10. In conclusion, our findings suggest that dysregulated m6A leads to altered expression of its target genes, thereby affecting AD’s development.
High Expression Levels of miR-21-5p in Younger Hospitalized COVID-19 Patients Are Associated with Mortality and Critical Disease
Authors: Bautista-Becerril Brandon , Nava-Quiroz Karol J. , Muñoz-Soria Evangelina , Camarena Ángel , Fricke-Galindo Ingrid , Buendia-Roldan Ivette , Pérez-Rubio Gloria , Chavez-Galán Leslie , Pérez-Torres Karina , Téllez-Quijada Fernanda , Márquez-García Eduardo , Moncada-Morales Angelica , Hernández-Zenteno Rafael de Jesús , Jaime-Capetillo María Esther , Falfán-Valencia Ramcés
Published: June 2023

In COVID-19, critical disease and invasive mechanical ventilation (IMV) increase the risk of death, mainly in patients over 60 years of age. Objectives: To find the relationship between miR-21-5p and miR-146a-5p in terms of the severity, IMV, and mortality in hospitalized COVID-19 patients younger than 55 years of age. Methods: The patients were stratified according to disease severity using the IDSA/WHO criteria for severe and critical COVID-19 and subclassified into critical non-survivors and critical survivors. Results: Ninety-seven severe/critical COVID-19 patients were included; 81.3% of the deceased were male and 18.8% were female. Higher expression miR-21-5p levels were associated as follows: severe vs. critical disease (p = 0.007, FC = 0.498), PaO2/FiO2 index, mild vs. severe (p = 0.027, FC = 0.558), and survivors vs. non-survivors (p = 0.03, FC = 0.463). Moreover, we identified correlations with clinical variables: CRP (rho = −0.54, p < 0.001), D-dimer (rho = −0.47, p < 0.05), related to damage in the kidney (rho = 0.60, p < 0.001), liver (rho = 0.41, p < 0.05), and lung (rho = 0.54, p < 0.001). Finally, miR-21-5p thresholds were calculated according to severity (8.191), IMV (8.191), and mortality (8.237); these values increased the risk of developing a critical disease (OR = 4.19), the need for IMV (OR = 5.63), and death (OR = 6.00). Conclusion: Increased expression levels of miR-21-5p are related to worse outcome of COVID-19 in younger hospitalized patients.
Immunomodulatory Role of Interferons in Viral and Bacterial Infections
Authors: Mertowska Paulina , Smolak Konrad , Mertowski Sebastian , Grywalska Ewelina
Published: June 2023

Interferons are a group of immunomodulatory substances produced by the human immune system in response to the presence of pathogens, especially during viral and bacterial infections. Their remarkably diverse mechanisms of action help the immune system fight infections by activating hundreds of genes involved in signal transduction pathways. In this review, we focus on discussing the interplay between the IFN system and seven medically important and challenging viruses (herpes simplex virus (HSV), influenza, hepatitis C virus (HCV), lymphocytic choriomeningitis virus (LCMV), human immunodeficiency virus (HIV), Epstein–Barr virus (EBV), and SARS-CoV coronavirus) to highlight the diversity of viral strategies. In addition, the available data also suggest that IFNs play an important role in the course of bacterial infections. Research is currently underway to identify and elucidate the exact role of specific genes and effector pathways in generating the antimicrobial response mediated by IFNs. Despite the numerous studies on the role of interferons in antimicrobial responses, many interdisciplinary studies are still needed to understand and optimize their use in personalized therapeutics.
Anti-Cancer Potential of Edible/Medicinal Mushrooms in Breast Cancer
Authors: Gariboldi Marzia Bruna , Marras Emanuela , Ferrario Nicole , Vivona Veronica , Prini Pamela , Vignati Francesca , Perletti Gianpaolo
Published: June 2023

Edible/medicinal mushrooms have been traditionally used in Asian countries either in the cuisine or as dietary supplements and nutraceuticals. In recent decades, they have aroused increasing attention in Europe as well, due to their health and nutritional benefits. In particular, among the different pharmacological activities reported (antibacterial, anti-inflammatory, antioxidative, antiviral, immunomodulating, antidiabetic, etc.), edible/medicinal mushrooms have been shown to exert in vitro and in vivo anticancer effects on several kinds of tumors, including breast cancer. In this article, we reviewed mushrooms showing antineoplastic activity again breast cancer cells, especially focusing on the possible bioactive compounds involved and their mechanisms of action. In particular, the following mushrooms have been considered: Agaricus bisporus, Antrodia cinnamomea, Cordyceps sinensis, Cordyceps militaris, Coriolus versicolor, Ganoderma lucidum, Grifola frondosa, Lentinula edodes, and Pleurotus ostreatus. We also report insights into the relationship between dietary consumption of edible mushrooms and breast cancer risk, and the results of clinical studies and meta-analyses focusing on the effects of fungal extracts on breast cancer patients.
Preparation of Thifluzamide Polylactic Acid Glycolic Acid Copolymer Microspheres and Its Effect on the Growth of Cucumber Seedlings
Authors: Li Yuanyuan , Wang Chaojie , Deng Xile , Cai Runze , Cao Lidong , Cao Chong , Zheng Li , Zhao Pengyue , Huang Qiliang
Published: June 2023

The polylactic acid-glycolic acid copolymer (PLGA) has been proven to be applicable in medicine, but there is limited research on its application and safety in the agricultural field. In this paper, thifluzamide PLGA microspheres were prepared via phacoemulsification and solvent volatilization, using the PLGA copolymer as the carrier and thifluzamide as the active component. It was found that the microspheres had good slow-release performance and fungicidal activity against Rhizoctonia solani. A comparative study was conducted to show the effect of thifluzamide PLGA microspheres on cucumber seedlings. Physiological and biochemical indexes of cucumber seedlings, including dry weight, root length, chlorophyll, protein, flavonoids, and total phenol content, indicated that the negative effect of thifluzamide on plant growth could be mitigated when it was wrapped in PLGA microspheres. This work explores the feasibility of PLGA as carriers in fungicide applications.
Inhibition of Fatty Acid Amide Hydrolase (FAAH) Regulates NF-kb Pathways Reducing Bleomycin-Induced Chronic Lung Inflammation and Pulmonary Fibrosis
Authors: Genovese Tiziana , Duranti Andrea , Monaco Francesco , Siracusa Rosalba , Fusco Roberta , Impellizzeri Daniela , D’Amico Ramona , Cordaro Marika , Cuzzocrea Salvatore , Di Paola Rosanna
Published: June 2023

The deadly interstitial lung condition known as idiopathic pulmonary fibrosis (IPF) worsens over time and for no apparent reason. The traditional therapy approaches for IPF, which include corticosteroids and immunomodulatory drugs, are often ineffective and can have noticeable side effects. The endocannabinoids are hydrolyzed by a membrane protein called fatty acid amide hydrolase (FAAH). Increasing endogenous levels of endocannabinoid by pharmacologically inhibiting FAAH results in numerous analgesic advantages in a variety of experimental models for pre-clinical pain and inflammation. In our study, we mimicked IPF by administering intratracheal bleomycin, and we administered oral URB878 at a dose of 5 mg/kg. The histological changes, cell infiltration, pro-inflammatory cytokine production, inflammation, and nitrosative stress caused by bleomycin were all reduced by URB878. Our data clearly demonstrate for the first time that the inhibition of FAAH activity was able to counteract not only the histological alteration bleomycin-induced but also the cascade of related inflammatory events.
In Cis Effect of DMPK Expanded Alleles in Myotonic Dystrophy Type 1 Patients Carrying Variant Repeats at 5′ and 3′ Ends of the CTG Array
Authors: Visconti Virginia Veronica , Macrì Elisa , D’Apice Maria Rosaria , Centofanti Federica , Massa Roberto , Novelli Giuseppe , Botta Annalisa
Published: June 2023

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disease caused by a CTG repeat expansion in the 3′-untranslated region (UTR) of DMPK gene. DM1 alleles containing non-CTG variant repeats (VRs) have been described, with uncertain molecular and clinical consequences. The expanded trinucleotide array is flanked by two CpG islands, and the presence of VRs could confer an additional level of epigenetic variability. This study aims to investigate the association between VR-containing DMPK alleles, parental inheritance and methylation pattern of the DM1 locus. The DM1 mutation has been characterized in 20 patients using a combination of SR-PCR, TP-PCR, modified TP-PCR and LR-PCR. Non-CTG motifs have been confirmed by Sanger sequencing. The methylation pattern of the DM1 locus was determined by bisulfite pyrosequencing. We characterized 7 patients with VRs within the CTG tract at 5′ end and 13 patients carrying non-CTG sequences at 3′ end of the DM1 expansion. DMPK alleles with VRs at 5’ end or 3’ end were invariably unmethylated upstream of the CTG expansion. Interestingly, DM1 patients with VRs at the 3′ end showed higher methylation levels in the downstream island of the CTG repeat tract, preferentially when the disease allele was maternally inherited. Our results suggest a potential correlation between VRs, parental origin of the mutation and methylation pattern of the DMPK expanded alleles. A differential CpG methylation status could play a role in the phenotypic variability of DM1 patients, representing a potentially useful diagnostic tool.
IL-6 and TGF-β-Secreting Adoptively-Transferred Murine Mesenchymal Stromal Cells Accelerate Healing of Psoriasis-like Skin Inflammation and Upregulate IL-17A and TGF-β
Authors: Cuesta-Gomez Nerea , Medina-Ruiz Laura , Graham Gerard J. , Campbell John D. M.
Published: June 2023

Mesenchymal stromal cells (MSC) show promise as cellular therapeutics. Psoriasis is a chronic inflammatory disease affecting the skin and the joints. Injury, trauma, infection and medications can trigger psoriasis by disrupting epidermal keratinocyte proliferation and differentiation, which activates the innate immune system. Pro-inflammatory cytokine secretion drives a T helper 17 response and an imbalance of regulatory T cells. We hypothesized that MSC adoptive cellular therapy could immunomodulate and suppress the effector T cell hyperactivation that underlies the disease. We used the imiquimod-induced psoriasis-like skin inflammation model to study the therapeutic potential of bone marrow and adipose tissue-derived MSC in vivo. We compared the secretome and the in vivo therapeutic potential of MSC with and without cytokine pre-challenge (“licensing”). The infusion of both unlicensed and licensed MSC accelerated the healing of psoriatic lesions, and reduced epidermal thickness and CD3+ T cell infiltration while promoting the upregulation of IL-17A and TGF-β. Concomitantly, the expression of keratinocyte differentiation markers in the skin was decreased. However, unlicensed MSC promoted the resolution of skin inflammation more efficiently. We show that MSC adoptive therapy upregulates the transcription and secretion of pro-regenerative and immunomodulatory molecules in the psoriatic lesion. Accelerated healing is associated with the secretion of TGF-β and IL-6 in the skin and MSC drives the production of IL-17A and restrains T-cell-mediated pathology.
Newly Isolated Virulent Salmophages for Biocontrol of Multidrug-Resistant Salmonella in Ready-to-Eat Plant-Based Food
Authors: Wójcicki Michał , Świder Olga , Średnicka Paulina , Shymialevich Dziyana , Ilczuk Tomasz , Koperski Łukasz , Cieślak Hanna , Sokołowska Barbara , Juszczuk-Kubiak Edyta
Published: June 2023

Due to irrational antibiotic stewardship, an increase in the incidence of multidrug resistance of bacteria has been observed recently. Therefore, the search for new therapeutic methods for pathogen infection treatment seems to be necessary. One of the possibilities is the utilization of bacteriophages (phages)—the natural enemies of bacteria. Thus, this study is aimed at the genomic and functional characterization of two newly isolated phages targeting MDR Salmonella enterica strains and their efficacy in salmonellosis biocontrol in raw carrot–apple juice. The Salmonella phage vB_Sen-IAFB3829 (Salmonella phage strain KKP 3829) and Salmonella phage vB_Sen-IAFB3830 (Salmonella phage strain KKP 3830) were isolated against S. I (6,8:l,-:1,7) strain KKP 1762 and S. Typhimurium strain KKP 3080 host strains, respectively. Based on the transmission electron microscopy (TEM) and whole-genome sequencing (WGS) analyses, the viruses were identified as members of tailed bacteriophages from the Caudoviricetes class. Genome sequencing revealed that these phages have linear double-stranded DNA and sizes of 58,992 bp (vB_Sen-IAFB3829) and 50,514 bp (vB_Sen-IAFB3830). Phages retained their activity in a wide range of temperatures (from −20 °C to 60 °C) and active acidity values (pH from 3 to 11). The exposure of phages to UV radiation significantly decreased their activity in proportion to the exposure time. The application of phages to the food matrices significantly reduced the level of Salmonella contamination compared to the control. Genome analysis showed that both phages do not encode virulence or toxin genes and can be classified as virulent bacteriophages. Virulent characteristics and no possible pathogen factors make examined phages feasible to be potential candidates for food biocontrol.
Evaluation of the Virulence Potential of Listeria monocytogenes through the Characterization of the Truncated Forms of Internalin A
Authors: Magagna Giulia , Gori Maria , Russini Valeria , De Angelis Veronica , Spinelli Elisa , Filipello Virginia , Tranquillo Vito Massimo , De Marchis Maria Laura , Bossù Teresa , Fappani Clara , Tanzi Elisabetta , Finazzi Guido
Published: June 2023

Listeria monocytogenes is a widespread Gram-positive pathogenic bacterium that causes listeriosis, a rather rare but severe foodborne disease. Pregnant women, infants, the elderly, and immunocompromised individuals are considered particularly at risk. L. monocytogenes can contaminate food and food-processing environments. In particular, ready-to-eat (RTE) products are the most common source associated with listeriosis. L. monocytogenes virulence factors include internalin A (InlA), a surface protein known to facilitate bacterial uptake by human intestinal epithelial cells that express the E-cadherin receptor. Previous studies have demonstrated that the presence of premature stop codon (PMSC) mutations naturally occurring in inlA lead to the production of a truncated protein correlated with attenuate virulence. In this study, 849 L. monocytogenes isolates, collected from food, food-processing plants, and clinical cases in Italy, were typed and analyzed for the presence of PMSCs in the inlA gene using Sanger sequencing or whole-genome sequencing (WGS). PMSC mutations were found in 27% of the isolates, predominantly in those belonging to hypovirulent clones (ST9 and ST121). The presence of inlA PMSC mutations in food and environmental isolates was higher than that in clinical isolates. The results reveal the distribution of the virulence potential of L. monocytogenes circulating in Italy and could help to improve risk assessment approaches.
Can Dietary Actives Affect miRNAs and Alter the Course or Prevent Colorectal Cancer?
Authors: Prendecka-Wróbel Monika , Pigoń-Zając Dominika , Sondej Daria , Grzywna Karolina , Kamińska Katarzyna , Szuta Mariusz , Małecka-Massalska Teresa
Published: June 2023

Colorectal cancer is a diet-related cancer. There is much research into the effects of nutrients on the prevention, modulation, and treatment of colorectal cancer. Researchers are trying to find a correlation between epidemiological observations indicating certain dietary components as the originator in the process of developing colorectal cancer, such as a diet rich in saturated animal fats, and dietary components that could eliminate the impact of harmful elements of the daily nutritional routine, i.e., substances such as polyunsaturated fatty acids, curcumin, or resveratrol. Nevertheless, it is very important to understand the mechanisms underlying how food works on cancer cells. In this case, microRNA (miRNA) seems to be a very significant research target. MiRNAs participate in many biological processes connected to carcinogenesis, progression, and metastasis. However, this is a field with development prospects ahead. In this paper, we review the most significant and well-studied food ingredients and their effects on various miRNAs involved in colorectal cancer.
Dual-Warhead Conjugate Based on Fibroblast Growth Factor 2 Dimer Loaded with α-Amanitin and Monomethyl Auristatin E Exhibits Superior Cytotoxicity towards Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1
Authors: Nawrocka Daria , Krzyscik Mateusz Adam , Sluzalska Katarzyna Dominika , Otlewski Jacek
Published: June 2023

Targeting fibroblast growth factor receptor 1 (FGFR1) is a promising therapeutic strategy for various cancers associated with alterations in the FGFR1 gene. In this study, we developed a highly cytotoxic bioconjugate based on fibroblast growth factor 2 (FGF2), which is a natural ligand of this receptor, and two potent cytotoxic drugs—α-amanitin and monomethyl auristatin E—with completely independent mechanistic modes of action. Utilizing recombinant DNA technology, we produced an FGF2 N- to C-end dimer that exhibited superior internalization capacity in FGFR1-positive cells. The drugs were site-specifically attached to the targeting protein using SnoopLigase- and evolved sortase A-mediated ligations. The resulting dimeric dual-warhead conjugate selectively binds to the FGFR1 and utilizes receptor-mediated endocytosis to enter the cells. Moreover, our results demonstrate that the developed conjugate exhibits about 10-fold higher cytotoxic potency against FGFR1-positive cell lines than an equimolar mixture of single-warhead conjugates. The diversified mode of action of the dual-warhead conjugate may help to overcome the potential acquired resistance of FGFR1-overproducing cancer cells to single cytotoxic drugs.
The Parallel Structure–Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands
Authors: Ericson Mark D. , Freeman Katie T. , LaVoi Travis M. , Donow Haley M. , Santos Radleigh G. , Giulianotti Marc A. , Pinilla Clemencia , Houghten Richard A. , Haskell-Luevano Carrie
Published: June 2023

The melanocortin receptors are involved in numerous physiological pathways, including appetite, skin and hair pigmentation, and steroidogenesis. In particular, the melanocortin-3 receptor (MC3R) is involved in fat storage, food intake, and energy homeostasis. Small-molecule ligands developed for the MC3R may serve as therapeutic lead compounds for treating disease states of energy disequilibrium. Herein, three previously reported pyrrolidine bis-cyclic guanidine compounds with five sites for molecular diversity (R1–R5) were subjected to parallel structure–activity relationship studies to identify the common pharmacophore of this scaffold series required for full agonism at the MC3R. The R2, R3, and R5 positions were required for full MC3R efficacy, while truncation of either the R1 or R4 positions in all three compounds resulted in full MC3R agonists. Two additional fragments, featuring molecular weights below 300 Da, were also identified that possessed full agonist efficacy and micromolar potencies at the mMC5R. These SAR experiments may be useful in generating new small-molecule ligands and chemical probes for the melanocortin receptors to help elucidate their roles in vivo and as therapeutic lead compounds.
The Role of Annexin A1 in DNA Damage Response in Placental Cells: Impact on Gestational Diabetes Mellitus
Authors: Moreli Jusciele Brogin , Santos Mayk Ricardo dos , Calderon Iracema de Mattos Paranhos , Hebeda Cristina Bichels , Farsky Sandra Helena Poliselli , Bevilacqua Estela , Oliani Sonia Maria
Published: June 2023

The functions of annexin A1 (ANXA1), which is expressed on membranes and in cytoplasmic granules, have been fully described. Nonetheless, the role of this protein in protecting against DNA damage in the nucleus is still emerging and requires further investigation. Here, we investigated the involvement of ANXA1 in the DNA damage response in placental cells. Placenta was collected from ANXA1 knockout mice (AnxA1−/−) and pregnant women with gestational diabetes mellitus (GDM). The placental morphology and ANXA1 expression, which are related to the modulation of cellular response markers in the presence of DNA damage, were analyzed. The total area of AnxA1−/− placenta was smaller due to a reduced labyrinth zone, enhanced DNA damage, and impaired base excision repair (BER) enzymes, which resulted in the induction of apoptosis in the labyrinthine and junctional layers. The placentas of pregnant women with GDM showed reduced expression of AnxA1 in the villous compartment, increased DNA damage, apoptosis, and a reduction of enzymes involved in the BER pathway. Our translational data provide valuable insights into the possible involvement of ANXA1 in the response of placental cells to oxidative DNA damage and represent an advancement in investigations into the mechanisms involved in placental biology.
Bioengineered Enzymes and Precision Fermentation in the Food Industry
Authors: Boukid Fatma , Ganeshan Seedhabadee , Wang Yingxin , Tülbek Mehmet Çağlar , Nickerson Michael T.
Published: June 2023

Enzymes have been used in the food processing industry for many years. However, the use of native enzymes is not conducive to high activity, efficiency, range of substrates, and adaptability to harsh food processing conditions. The advent of enzyme engineering approaches such as rational design, directed evolution, and semi-rational design provided much-needed impetus for tailor-made enzymes with improved or novel catalytic properties. Production of designer enzymes became further refined with the emergence of synthetic biology and gene editing techniques and a plethora of other tools such as artificial intelligence, and computational and bioinformatics analyses which have paved the way for what is referred to as precision fermentation for the production of these designer enzymes more efficiently. With all the technologies available, the bottleneck is now in the scale-up production of these enzymes. There is generally a lack of accessibility thereof of large-scale capabilities and know-how. This review is aimed at highlighting these various enzyme-engineering strategies and the associated scale-up challenges, including safety concerns surrounding genetically modified microorganisms and the use of cell-free systems to circumvent this issue. The use of solid-state fermentation (SSF) is also addressed as a potentially low-cost production system, amenable to customization and employing inexpensive feedstocks as substrate.
Systematic Review: Urine Biomarker Discovery for Inflammatory Bowel Disease Diagnosis
Authors: Baldan-Martin Montse , Chaparro María , Gisbert Javier P.
Published: June 2023

Inflammatory bowel diseases (IBDs) are chronic, heterogeneous, and inflammatory conditions mainly affecting the gastrointestinal tract. Currently, endoscopy is the gold standard test for assessing mucosal activity and healing in clinical practice; however, it is a costly, time-consuming, invasive, and uncomfortable procedure for the patients. Therefore, there is an urgent need for sensitive, specific, fast and non-invasive biomarkers for the diagnosis of IBD in medical research. Urine is an excellent biofluid for discovering biomarkers because it is non-invasive to sample. In this review, we aimed to summarize proteomics and metabolomics studies performed in both animal models of IBD and humans that identify urinary biomarkers for IBD diagnosis. Future large-scale multi-omics studies should be conducted in collaboration with clinicians, researchers, and industry to make progress toward the development of sensitive and specific diagnostic biomarkers, thereby making personalized medicine possible.
Unique Peptides of Cathelicidin-1 in the Early Detection of Mastitis—In Silico Analysis
Authors: Bourganou Maria V. , Kontopodis Evangelos , Tsangaris George Th. , Pierros Vasileios , Vasileiou Natalia G. C. , Mavrogianni Vasia S. , Fthenakis George C. , Katsafadou Angeliki I.
Published: June 2023

Based on the results of previously performed clinical studies, cathelicidin-1 has been proposed as a potential biomarker for the early diagnosis of mastitis in ewes. It has been hypothesized that the detection of unique peptides (defined as a peptide, irrespective of its length, that exists in only one protein of a proteome of interest) and core unique peptides (CUPs) (representing the shortest peptide that is unique) of cathelicidin-1 may potentially improve its identification and consequently the diagnosis of sheep mastitis. Peptides of sizes larger than those of the size of CUPs, which include consecutive or over-lapping CUPs, have been defined as ‘composite core unique peptides’ (CCUPs). The primary objective of the present study was the investigation of the sequence of cathelicidin-1 detected in ewes’ milk in order to identify its unique peptides and core unique peptides, which would reveal potential targets for accurate detection of the protein. An additional objective was the detection of unique sequences among the tryptic digest peptides of cathelicidin-1, which would improve accuracy of identification of the protein when performing targeted MS-based proteomics. The potential uniqueness of each peptide of cathelicidin-1 was investigated using a bioinformatics tool built on a big data algorithm. A set of CUPs was created and CCUPs were also searched. Further, the unique sequences in the tryptic digest peptides of cathelicidin-1 were also detected. Finally, the 3D structure of the protein was analyzed from predicted models of proteins. In total, 59 CUPs and four CCUPs were detected in cathelicidin-1 of sheep origin. Among tryptic digest peptides, there were six peptides that were unique in that protein. After 3D structure analysis of the protein, 35 CUPs were found on the core of cathelicidin-1 of sheep origin and among them, 29 were located on amino acids in regions of the protein with ‘very high’ or ‘confident’ estimates of confidence of the structure. Ultimately, the following six CUPs: QLNEQ, NEQS, EQSSE, QSSEP, EDPD, DPDS, are proposed as potential antigenic targets for cathelicidin-1 of sheep. Moreover, another six unique peptides were detected in tryptic digests and offer novel mass tags to facilitate the detection of cathelicidin-1 during MS-based diagnostics.
Novel Antidiabetic Agents and Their Effects on Lipid Profile: A Single Shot for Several Cardiovascular Targets
Authors: Piccirillo Francesco , Mastroberardino Sara , Nusca Annunziata , Frau Lorenzo , Guarino Lorenzo , Napoli Nicola , Ussia Gian Paolo , Grigioni Francesco
Published: June 2023

Type-2 diabetes mellitus (DM) represents one of the most important risk factors for cardiovascular diseases (CVD). Hyperglycemia and glycemic variability are not the only determinant of the increased cardiovascular (CV) risk in diabetic patients, as a frequent metabolic disorder associated with DM is dyslipidemia, characterized by hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol levels and a shift towards small dense low-density lipoprotein (LDL) cholesterol. This pathological alteration, also called diabetic dyslipidemia, represents a relevant factor which could promotes atherosclerosis and subsequently an increased CV morbidity and mortality. Recently, the introduction of novel antidiabetic agents, such as sodium glucose transporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), has been associated with a significant improvement in CV outcomes. Beyond their known action on glycemia, their positive effects on the CV system also seems to be related to an ameliorated lipidic profile. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs and their effects on diabetic dyslipidemia, which could explain the provided global benefit to the cardiovascular system.
Enabled Artificial Intelligence (AI) to Develop Sehhaty Wa Daghty App of Self-Management for Saudi Patients with Hypertension: A Qualitative Study
Authors: Alzahrani Adel , Gay Valerie , Alturki Ryan
Published: June 2023

(1) Background: The prevalence of uncontrolled hypertension is rising all across the world, making it a concern for public health. The usage of mobile health applications has resulted in a number of positive outcomes for the management and control of hypertension. (2) Objective: The study’s primary goal is to explain the steps to create a hypertension application (app) that considers cultural and social standards in Saudi Arabia, motivational features, and the needs of male and female Saudi citizens. (3) Methods: This study reports the emerged features and content needed to be adapted or developed in health apps for hypertension patients during an interactive qualitative analysis focus group activity with (n = 5) experts from the Saudi Ministry of Health. A gap analysis was conducted to develop an app based on a deep understanding of user needs with a patient-centred approach. (4) Results: Based on the participant’s reviews in this study, the app was easy to use and can help Saudi patients to control their hypertension, the design was interactive, motivational features are user-friendly, and there is a need to consider other platforms such as Android and Blackberry in a future version. (5) Conclusions: Mobile health apps can help Saudis change their unhealthy lifestyles. Target users, usability, motivational features, and social and cultural standards must be considered to meet the app’s aim.
Survey Results of Honey Bee Colony Losses in Winter in China (2009–2021)
Authors: Tang Jiao , Ji Congcong , Shi Wei , Su Songkun , Xue Yunbo , Xu Jinshan , Chen Xiao , Zhao Yazhou , Chen Chao
Published: June 2023

There is growing concern that massive loss of honey bees can cause serious negative effects on biodiversity and ecosystems. Surveys of colony losses have been performed worldwide to monitor the dynamic changes and health status of honey bee colonies. Here, we present the results of surveys regarding winter colony losses from 21 provinces in China from 2009 to 2021, with a total of 1,744,324 colonies managed by 13,704 beekeepers. The total colony losses were low (9.84%; 95% Confidence Interval (CI): 9.60–10.08%) but varied among years, provinces, and scales of apiaries. As little is known about the overwintering mortality of Apis cerana, in this study, we surveyed and compared the loss rates between Apis mellifera and A. cerana in China. We found colonies of A. mellifera suffered significantly lower losses than A. cerana in China. Larger apiaries resulted in higher losses in A. mellifera, whereas the opposite was observed in A. cerana. Furthermore, we used generalized linear mixed-effects models (GLMMs) to evaluate the effects of potential risk factors on winter colony losses and found that the operation size, species, migration, migration×species interaction, and queen problems were significantly related to the loss rates. New queens can increase their colony overwintering survival. Migratory beekeepers and large operations reported lower loss rates.
Sutureless and Rapid Deployment vs. Transcatheter Valves for Aortic Stenosis in Low-Risk Patients: Mid-Term Results
Authors: Muneretto Claudio , Di Bacco Lorenzo , Di Eusanio Marco , Folliguet Thierry , Rosati Fabrizio , D’Alonzo Michele , Cugola Diego , Curello Salvatore , Palacios Camila Mayorga , Baudo Massimo , Pollari Francesco , Fischlein Theodor
Published: June 2023

Background: Recent trials showed that TAVI is neither inferior nor superior to surgical aortic valve replacement. The aim of this study was to evaluate the outcomes of Sutureless and Rapid Deployment Valves (SuRD-AVR) when compared to TAVI in low surgical risk patients with isolated aortic stenosis. Methods: Data from five European Centers were retrospectively collected. We included 1306 consecutive patients at low surgical risk (EUROSCORE II < 4) who underwent aortic valve replacement by means of SuRD-AVR (n = 636) or TAVI (n = 670) from 2014 to 2019. A 1:1 nearest-neighbor propensity-score was performed, and two balanced groups of 346 patients each were obtained. The primary endpoints of the study were: 30-day mortality and 5-year overall survival. The secondary endpoint was 5-year survival freedom from major adverse cardiovascular and cerebrovascular events (MACCEs). Results: Thirty-day mortality was similar between the two groups (SuRD-AVR:1.7%, TAVI:2.0%, p = 0.779), while the TAVI group showed a significantly lower 5-year overall survival and survival freedom from MACCEs (5-year matched overall survival: SuRD-AVR: 78.5%, TAVI: 62.9%, p = 0.039; 5-year matched freedom from MACCEs: SuRD-AVR: 64.6%, TAVI: 48.7%, p = 0.004). The incidence of postoperative permanent pacemaker implantation (PPI) and paravalvular leak grade ≥ 2 (PVL) were higher in the TAVI group. Multivariate Cox Regression analysis identified PPI as an independent predictor for mortality. Conclusions: TAVI patients had a significantly lower five-year survival and survival freedom from MACCEs with a higher rate of PPI and PVL ≥ 2 when compared to SuRD-AVR.
Training Emotional Intelligence Online: An Evaluation of WEIT 2.0
Authors: Held Marco Jürgen , Fehn Theresa , Gauglitz Iris Katharina , Schütz Astrid
Published: June 2023

With the growing popularity of online courses, there is an increasing need for scientifically validated online interventions that can improve emotional competencies. We addressed this demand by evaluating an extended version of the Web-Based Emotional Intelligence Training (WEIT 2.0) program. Based on the four-branch model of emotional intelligence, WEIT 2.0 focuses on improving participants’ emotion perception and emotion regulation skills. A total of 214 participants were randomly assigned to the training group (n = 91) or a waiting list control group (n = 123) to evaluate short-term (directly after WEIT 2.0) and long-term intervention effects (8 weeks later). Two-way MANOVAs and mixed ANOVAs showed significant treatment effects for self-reported emotion perception of the self, as well as emotion regulation of the self and others, after 8 weeks. No significant treatment effects were found for self-reported emotion perception in others or for performance-based emotion perception or emotion regulation. Moderator analyses revealed no significant effects of digital affinity on training success from the pretest to the posttest. The findings suggest that components of self-reported emotional intelligence can be enhanced through WEIT 2.0, but performance-based emotional intelligence cannot. Further research is needed on the online training of emotional intelligence and the mechanisms that underlie training success.
Predictors of Carbohydrate Metabolism Disorders and Lethal Outcome in Patients after Myocardial Infarction: A Place of Glucose Level
Authors: Kononova Yulia , Abramyan Levon , Derevitskii Ilia , Babenko Alina
Published: June 2023

Background and aim: The aim of this study was to reveal statistical patterns in patients with acute myocardial infarction (AMI) that cause the development of carbohydrate metabolism disorders (CMD) (type 2 diabetes mellitus and prediabetes) and death within 5 years after AMI. Methods: 1079 patients who were treated with AMI in the Almazov National Medical Research Center were retrospectively selected for the study. For each patient, all data from electronic medical records were downloaded. Statistical patterns that determine the development of CMDs and death within 5 years after AMI were identified. To create and train the models used in this study, the classic methods of Data Mining, Data Exploratory Analysis, and Machine Learning were used. Results: The main predictors of mortality within 5 years after AMI were advanced age, low relative level of lymphocytes, circumflex artery lesion, and glucose level. Main predictors of CMDs were low basophils, high neutrophils, high platelet distribution width, and high blood glucose level. High values of age and glucose together were relatively independent predictors. With glucose level >11 mmol/L and age >70 years, the 5-year risk of death is about 40% and it rises with increasing glucose levels. Conclusion: The obtained results make it possible to predict the development of CMDs and death based on simple parameters that are easily available in clinical practice. Glucose level measured on the 1st day of AMI was among the most important predictors of CMDs and death.
MGMT Promoter Methylation: Prognostication beyond Treatment Response
Authors: Ashkan Keyoumars , Baig Mirza Asfand , Soumpasis Christos , Syrris Christoforos , Kalaitzoglou Dimitrios , Sharma Chaitanya , James Zachariah Joseph , Khoja Abbas Khizar , Ahmed Razna , Vastani Amisha , Bartram James , Chia Kazumi , Al-Salihi Omar , Swampilai Angela , Brazil Lucy , Laxton Ross , Reisz Zita , Bodi Istvan , King Andrew , Gullan Richard , Vergani Francesco , Bhangoo Ranjeev , Al-Sarraj Safa , Lavrador Jose Pedro
Published: June 2023

MGMT promoter methylation is related to the increased sensitivity of tumour tissue to chemotherapy with temozolomide (TMZ) and thus to improved patient survival. However, it is unclear how the extent of MGMT promoter methylation affects outcomes. In our study, a single-centre retrospective study, we explore the impact of MGMT promoter methylation in patients with glioblastoma who were operated upon with 5-ALA. Demographic, clinical and histology data, and survival rates were assessed. A total of 69 patients formed the study group (mean age 53.75 ± 15.51 years old). Positive 5-ALA fluorescence was noted in 79.41%. A higher percentage of MGMT promoter methylation was related to lower preoperative tumour volume (p = 0.003), a lower likelihood of 5-ALA positive fluorescence (p = 0.041) and a larger extent of resection EoR (p = 0.041). A higher MGMT promoter methylation rate was also related to improved progression-free survival (PFS) and overall survival (OS) (p = 0.008 and p = 0.006, respectively), even when adjusted for the extent of resection (p = 0.034 and p = 0.042, respectively). A higher number of adjuvant chemotherapy cycles was also related to longer PFS and OS (p = 0.049 and p = 0.030, respectively). Therefore, this study suggests MGMT promoter methylation should be considered as a continuous variable. It is a prognostic factor that goes beyond sensitivity to chemotherapy treatment, as a higher percentage of methylation is related not only to increased EoR and increased PFS and OS, but also to lower tumour volume at presentation and a lower likelihood of 5-ALA fluorescence intraoperatively.
Multitouch Options
Authors: Guillaume Tristan
Published: June 2023

In this article, the multitouch option, also called the n-touch option (or the “baseball” option when n=3) is analyzed and valued in closed form. This is a kind of barrier option that has been traded for a long time on the markets, but that does not yet admit a known valuation formula. The multitouch option sets a gradual knock-out/knock-in mechanism based on the number of times the underlying asset has crossed a predefined barrier in various time intervals before expiry. The higher the number of predefined time intervals during which the barrier has been touched, the lower the value of a knock-out contract at expiry, and conversely for a knock-in one. Multitouch options can be viewed as an extension of step barrier options, preserving the ability of the latter to adjust the exposure to risk over time, while eliminating the notorious danger of “sudden death” that holders of step barrier options are faced with. They are thus less risky and more flexible than step barrier options, and all the more so when compared to standard barrier options. This article also provides closed-form valuation of multitouch options with nonstandard features such as an outside barrier or a barrier defined as a continuous function of time.