bluuebunny/crossref_metadata_2025 huggingface dataset:
Injectable Thermoresponsive Hydrogels for Cancer Therapy: Challenges and Prospects
Authors: Tanga Sandrine , Aucamp Marique , Ramburrun Poornima
Published: May 2023

The enervating side effects of chemotherapeutic drugs have necessitated the use of targeted drug delivery in cancer therapy. To that end, thermoresponsive hydrogels have been employed to improve the accumulation and maintenance of drug release at the tumour site. Despite their efficiency, very few thermoresponsive hydrogel-based drugs have undergone clinical trials, and even fewer have received FDA approval for cancer treatment. This review discusses the challenges of designing thermoresponsive hydrogels for cancer treatment and offers suggestions for these challenges as available in the literature. Furthermore, the argument for drug accumulation is challenged by the revelation of structural and functional barriers in tumours that may not support targeted drug release from hydrogels. Other highlights involve the demanding preparation process of thermoresponsive hydrogels, which often involves poor drug loading and difficulties in controlling the lower critical solution temperature and gelation kinetics. Additionally, the shortcomings in the administration process of thermosensitive hydrogels are examined, and special insight into the injectable thermosensitive hydrogels that reached clinical trials for cancer treatment is provided.
Social, Genetics and Histopathological Factors Related to Titin (TTN) Gene Mutation and Survival in Women with Ovarian Serous Cystadenocarcinoma: Bioinformatics Analysis
Authors: Gomes Fabiana de Campos , Figueiredo Eric Renato Lima , Araújo Ediane Nunes De , Andrade Edila Monteiro De , Carneiro Carlos Diego Lisbôa , Almeida Gabriel Mácola De , Dias Helana Augusta Andrade Leal , Teixeira Lucélia Inoue Bispo , Almeida Manuela Trindade , Farias Mariusa Fernandes De , Linhares Natália Albim , Fonseca Natasha Lima Da , Pereira Yago Dos Santos , Melo-Neto João Simão de
Published: May 2023

Several factors may increase the risk of development of ovarian cancer. In this study, we investigated the relationship between social, genetic, and histopathologic factors in women with ovarian serous cystadenocarcinoma and titin (TTN) mutations, whether the TTN gene mutation may be a predictor, and its impact on mortality and survival in these patients. A total of 585 samples from patients with ovarian serous cystadenocarcinoma were collected from The Cancer Genome Atlas and PanCancer Atlas through the cBioPortal for analysis of social, genetic, and histopathological factors. Logistic regression was used to investigate whether TTN mutation could be a predictor, and the Kaplan–Meier method was applied to analyze survival time. TTN mutation frequency did not differ between age at diagnosis, tumor stage, and race, and was related to increased Buffa hypoxia score (p = 0.004), mutation count (p < 0.0001), Winter hypoxia Score (p = 0.030), nonsynonymous tumor mutation burden (TMB) (p < 0.0001), and reduced microsatellite instability sensor score (p = 0.010). The number of mutations (p < 0.0001) and winter hypoxia score (p = 0.008) were positively associated with TTN mutations, and nonsynonymous TMB (p < 0.0001) proved to be a predictor. Mutated TTN affects the score of genetic variables involved in cancer cell metabolism in ovarian cystadenocarcinoma.
Male Gonads Transplantation from Kadaknath Chicken to Chicken and Duck Surrogates
Authors: Naim Adnan , Mishra Surya Kanta , Sahoo Anjan , Nath Indra mani
Published: May 2023

Transplantation of the gonadal tissue of male and female avian species, such as chicken, onto suitable surrogates and production of live offspring has been successfully demonstrated as a strategy for the conservation and re-constitution of valuable chicken germplasm. The main objective of this study was to establish and develop the male gonadal tissue transplantation technology for the conservation of the indigenous chicken germplasm. The male gonads of the Indian native chicken breed, Kadaknath (KN), were transplanted from a day-old donor to a recipient white leghorn (WL) chicken, and Khaki Campbell (KC) ducks, as surrogates. All the surgical interventions were performed under permitted general anaesthesia, and the chicks, upon recovery, were reared with and without immunosuppressant. The recipient surrogates for the donor KN gonads were housed and reared for 10–14 weeks, and post-sacrifice, developed gonadal tissues were harvested to squeeze out the fluid to perform artificial insemination (AI). The AI-entailed fertility test using the recovered seminal extract from the transplanted KN testes from both surrogate species (KC ducks and WL males), used against KN purebred females, remained very close to the percent fertility realised from purebred KN chickens (controls). These initial results revealed from this trial study suggest definitively that, Kadaknath male gonads were readily accepted and grown inside the intra- and inter-species surrogate host, WL chicken and KC ducks, demonstrating a suitable intra- and inter-species donor-host system. Furthermore, the developed transplanted male gonads of KN chicken into the surrogates were found to have the potential to fertilise the egg and give rise to pure-line KN chicks.
A Novel Approach to Assess Balneotherapy Effects on Musculoskeletal Diseases—An Open Interventional Trial Combining Physiological Indicators, Biomarkers, and Patients’ Health Perception
Authors: Silva Jani , Martins José , Nicomédio Cristina , Gonçalves Catarina , Palito Cátia , Gonçalves Ramiro , Fernandes Paula Odete , Nunes Alcina , Alves Maria José
Published: May 2023

The present study aimed to evaluate whether a 14-day period of balneotherapy influences the inflammatory status, health-related quality of life (QoL) and quality of sleep, underlying overall health state, and clinically relevant benefits of patients with musculoskeletal diseases (MD). The health-related QoL was evaluated using the following instruments: 5Q-5D-5L, EQ-VAS, EUROHIS-QOL, B-IPQ, and HAQ-DI. The quality of sleep was evaluated by a BaSIQS instrument. Circulating levels of IL-6 and C-reactive protein (CRP) were measured by ELISA and chemiluminescent microparticle immunoassay, respectively. The smartband, Xiaomi MI Band 4, was used for real-time sensing of physical activity and sleep quality. MD patients improved the health-related QoL measured by 5Q-5D-5L (p < 0.001), EQ-VAS (p < 0.001), EUROHIS-QOL (p = 0.017), B-IPQ (p < 0.001), and HAQ-DI (p = 0.019) after balneotherapy; the sleep quality was also improved (BaSIQS, p = 0.019). Serum concentrations of IL-6 were markedly decreased after the 14-day balneotherapy (p < 0.001). No statistically significant differences were observed regarding the physical activity and sleep quality data recorded by the smartband. Balneotherapy may be an effective alternative treatment in managing the health status of MD patients, with a decrease in inflammatory states, along with positive effects on pain reduction, patient’s functionality, QoL, quality of sleep, and disability perception status.
The Effects of Neurodevelopmental Treatment-Based Trunk Control Exercise on Gross Motor Function and Trunk Control in Children with Developmental Disabilities
Authors: Park Miho , Kim Jeongseon , Yu Changseon , Lim Hyoungwon
Published: May 2023

Background: Good trunk control is essential for higher developmental stages as the trunk is activated first when movement occurs, providing stability for the head and extremities. Purpose: To determine if neurodevelopmental treatment-based trunk control exercise (NDT-TCE) is effective in improving gross motor function and trunk control in children with developmental disabilities (DD). Materials and Methods: Twenty children with developmental disabilities were randomly assigned to the NDT-TCE (12 children) and control (8 children) groups. Results: After the intervention; the NDT-TCE group showed improvement in GMFM (Gross Motor Function Measure; except for the GMFM-E dimension) and SATCo scores. The control group showed improvement in GMFM-A; B; C; and total scores; as well as static and active control of SATCo. The NDT-TCE group had a significant improvement in the GMFM B dimension and total score compared to the control group. The NDT-TCE group showed a significant improvement in static and active control of SATCo compared to the control group, but there was no significant difference in reactive control. Conclusions: The NDT-TCE intervention specifically improved GMFM-B and trunk control scores. Therefore, NDT-TCE can be applied as a trunk-focused intervention for children with DD who have difficulty controlling their trunk.
Evaluation of External Trigeminal Nerve Stimulation to Prevent Cerebral Vasospasm after Subarachnoid Hemorrhage Due to Aneurysmal Rupture: A Randomized, Double-Blind Proof-of-Concept Pilot Trial (TRIVASOSTIM Study)
Authors: Rigoard Philippe , Billot Maxime , Moens Maarten , Goudman Lisa , El-Hajj Hassan , Ingrand Pierre , Ounajim Amine , Roulaud Manuel , Page Philippe , Babin Etienne , Et Talby Mohamed , Dany Jonathan , Johnson Simona , Bataille Benoit , David Romain , Slavin Konstantin V.
Published: May 2023

Cerebral vasospasm remains the most frequent and devastating complication after subarachnoid aneurysmal hemorrhage because of secondary cerebral ischemia and its sequelae. The underlying pathophysiology involves vasodilator peptide release (such as CGRP) and nitric oxide depletion at the level of the precapillary sphincters of the cerebral (internal carotid artery network) and dural (external carotid artery network) arteries, which are both innervated by craniofacial autonomic afferents and tightly connected to the trigeminal nerve and trigemino-cervical nucleus complex. We hypothesized that trigeminal nerve modulation could influence the cerebral flow of this vascular network through a sympatholytic effect and decrease the occurrence of vasospasm and its consequences. We conducted a prospective double-blind, randomized controlled pilot trial to compare the effect of 10 days of transcutaneous electrical trigeminal nerve stimulation vs. sham stimulation on cerebral infarction occurrence at 3 months. Sixty patients treated for aneurysmal SAH (World Federation of Neurosurgical Societies scale between 1 and 4) were included. We compared the radiological incidence of delayed cerebral ischemia (DCI) on magnetic resonance imaging (MRI) at 3 months in moderate and severe vasospasm patients receiving trigeminal nerve stimulation (TNS group) vs. sham stimulation (sham group). Our primary endpoint (the infarction rate at the 3-month follow-up) did not significantly differ between the two groups (p = 0.99). Vasospasm-related infarctions were present in seven patients (23%) in the TNS group and eight patients (27%) in the sham group. Ultimately, we were not able to show that TNS can decrease the rate of cerebral infarction secondary to vasospasm occurrence. As a result, it would be premature to promote trigeminal system neurostimulation in this context. This concept should be the subject of further research.
The Influence of News Consumption Habits and Dispositional Traits on Trust in Medical Scientists
Authors: Larsen Meng Zhen , Haupt Michael R. , McMann Tiana , Cuomo Raphael E. , Mackey Tim K.
Published: May 2023

Public trust in medical institutions is essential for ensuring compliance with medical directives. However, the politicization of public health issues and the polarized nature of major news outlets suggest that partisanship and news consumption habits can influence medical trust. This study employed a survey with 858 participants and used regression analysis to assesses how news consumption habits and information assessment traits (IATs) influence trust in medical scientists. IATs included were conscientiousness, openness, need for cognitive closure (NFCC), and cognitive reflective thinking (CRT). News sources were classified on the basis of factuality and political bias. Initially, readership of liberally biased news was positively associated with medical trust (p < 0.05). However, this association disappeared when controlling for the news source’s factuality (p = 0.28), while CRT (p < 0.05) was positively associated with medical trust. When controlling for conservatively biased news sources, factuality of the news source (p < 0.05) and NFCC (p < 0.05) were positively associated with medical trust. While partisan media bias may influence medical trust, these results suggest that those who have higher abilities to assess information and who prefer more credible news sources have a greater trust in medical scientists.
Pro-Osteogenic and Anti-Inflammatory Synergistic Effect of Orthosilicic Acid, Vitamin K2, Curcumin, Polydatin and Quercetin Combination in Young and Senescent Bone Marrow-Derived Mesenchymal Stromal Cells
Authors: Giordani Chiara , Matacchione Giulia , Giuliani Angelica , Valli Debora , Scarpa Emanuele Salvatore , Antonelli Antonella , Sabbatinelli Jacopo , Giacchetti Gilberta , Sabatelli Sofia , Olivieri Fabiola , Rippo Maria Rita
Published: May 2023

During aging, bone marrow mesenchymal stromal cells (MSCs)—the precursors of osteoblasts—undergo cellular senescence, losing their osteogenic potential and acquiring a pro-inflammatory secretory phenotype. These dysfunctions cause bone loss and lead to osteoporosis. Prevention and intervention at an early stage of bone loss are important, and naturally active compounds could represent a valid help in addition to diet. Here, we tested the hypothesis that the combination of two pro-osteogenic factors, namely orthosilicic acid (OA) and vitamin K2 (VK2), and three other anti-inflammatory compounds, namely curcumin (CUR), polydatin (PD) and quercetin (QCT)—that mirror the nutraceutical BlastiMin Complex® (Mivell, Italy)—would be effective in promoting MSC osteogenesis, even of replicative senescent cells (sMSCs), and inhibiting their pro-inflammatory phenotype in vitro. Results showed that when used at non-cytotoxic doses, (i) the association of OA and VK2 promoted MSC differentiation into osteoblasts, even when cultured without other pro-differentiating factors; and (ii) CUR, PD and QCT exerted an anti-inflammatory effect on sMSCs, and also synergized with OA and VK2 in promoting the expression of the pivotal osteogenic marker ALP in these cells. Overall, these data suggest a potential role of using a combination of all of these natural compounds as a supplement to prevent or control the progression of age-related osteoporosis.
The Revolution of Animal Genomics in Forensic Sciences
Authors: Cardinali Irene , Tancredi Domenico , Lancioni Hovirag
Published: May 2023

Nowadays, the coexistence between humans and domestic animals (especially dogs and cats) has become a common scenario of daily life. Consequently, during a forensic investigation in civil or criminal cases, the biological material from a domestic animal could be considered “evidence” by law enforcement agencies. Animal genomics offers an important contribution in attacks and episodes of property destruction or in a crime scene where the non-human biological material is linked to the victim or perpetrator. However, only a few animal genetics laboratories in the world are able to carry out a valid forensic analysis, adhering to standards and guidelines that ensure the admissibility of data before a court of law. Today, forensic sciences focus on animal genetics considering all domestic species through the analysis of STRs (short tandem repeats) and autosomal and mitochondrial DNA SNPs (single nucleotide polymorphisms). However, the application of these molecular markers to wildlife seems to have gradually gained a strong relevance, aiming to tackle illegal traffic, avoid the loss of biodiversity, and protect endangered species. The development of third-generation sequencing technologies has glimmered new possibilities by bringing “the laboratory into the field”, with a reduction of both the enormous cost management of samples and the degradation of the biological material.
Multi-Faceted Role of Luteolin in Cancer Metastasis: EMT, Angiogenesis, ECM Degradation and Apoptosis
Authors: Rocchetti Maria Teresa , Bellanti Francesco , Zadorozhna Mariia , Fiocco Daniela , Mangieri Domenica
Published: May 2023

Luteolin (3′,4′,5,7-tetrahydroxyflavone), a member of the flavonoid family derived from plants and fruits, shows a wide range of biomedical applications. In fact, due to its anti-inflammatory, antioxidant and immunomodulatory activities, Asian medicine has been using luteolin for centuries to treat several human diseases, including arthritis, rheumatism, hypertension, neurodegenerative disorders and various infections. Of note, luteolin displays many anti-cancer/anti-metastatic properties. Thus, the purpose of this review consists in highlighting the relevant mechanisms by which luteolin inhibits tumor progression in metastasis, i.e., affecting epithelial-mesenchymal transition (EMT), repressing angiogenesis and lysis of extracellular matrix (ECM), as well as inducing apoptosis.
Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy
Authors: Paulhus Kelsey , Glasscock Edward
Published: May 2023

The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia type 1 (EA1) and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype–phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel’s pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype–phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.
Natural Products as the Potential to Improve Alzheimer’s and Parkinson’s Disease
Authors: Kim Sung Wook , Lee Jun Ho , Kim Bumjung , Yang Gabsik , Kim Jong Uk
Published: May 2023

Alzheimer’s disease and Parkinson’s disease are the two most common neurodegenerative diseases in the world, and their incidence rates are increasing as our society ages. This creates a significant social and economic burden. Although the exact cause and treatment methods for these diseases are not yet known, research suggests that Alzheimer’s disease is caused by amyloid precursor protein, while α-synuclein acts as a causative agent in Parkinson’s disease. The accumulation of abnormal proteins such as these can lead to symptoms such as loss of protein homeostasis, mitochondrial dysfunction, and neuroinflammation, which ultimately result in the death of nerve cells and the progression of neurodegenerative diseases. The medications currently available for these diseases only delay their progression and have many adverse effects, which has led to increased interest in developing natural products with fewer adverse effects. In this study, we selected specific keywords and thesis content to investigate natural products that are effective in treating Alzheimer’s and Parkinson’s diseases. We reviewed 16 papers on natural products and found that they showed promising mechanisms of action such as antioxidant, anti-inflammatory, and mitochondrial function improvement. Other natural products with similar properties could also be considered potential treatments for neurodegenerative diseases, and they can be consumed as part of a healthy diet rather than as medicine.
Genome-Wide Identification of the MAPK and MAPKK Gene Families in Response to Cold Stress in Prunus mume
Authors: Wen Zhenying , Li Mingyu , Meng Juan , Miao Runtian , Liu Xu , Fan Dongqing , Lv Wenjuan , Cheng Tangren , Zhang Qixiang , Sun Lidan
Published: May 2023

Protein kinases of the MAPK cascade family (MAPKKK–MAPKK–MAPK) play an essential role in plant stress response and hormone signal transduction. However, their role in the cold hardiness of Prunus mume (Mei), a class of ornamental woody plant, remains unclear. In this study, we use bioinformatic approaches to assess and analyze two related protein kinase families, namely, MAP kinases (MPKs) and MAPK kinases (MKKs), in wild P. mume and its variety P. mume var. tortuosa. We identify 11 PmMPK and 7 PmMKK genes in the former species and 12 PmvMPK and 7 PmvMKK genes in the latter species, and we investigate whether and how these gene families contribute to cold stress responses. Members of the MPK and MKK gene families located on seven and four chromosomes of both species are free of tandem duplication. Four, three, and one segment duplication events are exhibited in PmMPK, PmvMPK, and PmMKK, respectively, suggesting that segment duplications play an essential role in the expansion and evolution of P. mume and its gene variety. Moreover, synteny analysis suggests that most MPK and MKK genes have similar origins and involved similar evolutionary processes in P. mume and its variety. A cis-acting regulatory element analysis shows that MPK and MKK genes may function in P. mume and its variety’s development, modulating processes such as light response, anaerobic induction, and abscisic acid response as well as responses to a variety of stresses, such as low temperature and drought. Most PmMPKs and PmMKKs exhibited tissue-specifific expression patterns, as well as time-specific expression patterns that protect them through cold. In a low-temperature treatment experiment with the cold-tolerant cultivar P. mume ‘Songchun’ and the cold-sensitive cultivar ‘Lve’, we find that almost all PmMPK and PmMKK genes, especially PmMPK3/5/6/20 and PmMKK2/3/6, dramatically respond to cold stress as treatment duration increases. This study introduces the possibility that these family members contribute to P. mume’s cold stress response. Further investigation is warranted to understand the mechanistic functions of MAPK and MAPKK proteins in P. mume development and response to cold stress.
Multi-Omics Data Integration Reveals Key Variables Contributing to Subgingival Microbiome Dysbiosis-Induced Inflammatory Response in a Hyperglycemic Microenvironment
Authors: Lafleur Sarah , Bodein Antoine , Mbuya Malaïka Mutombo Joanna , Mathieu Alban , Joly Beauparlant Charles , Minne Xavier , Chandad Fatiha , Droit Arnaud , Houde Vanessa P.
Published: May 2023

Subgingival microbiome dysbiosis promotes the development of periodontitis, an irreversible chronic inflammatory disease associated with metabolic diseases. However, studies regarding the effects of a hyperglycemic microenvironment on host–microbiome interactions and host inflammatory response during periodontitis are still scarce. Here, we investigated the impacts of a hyperglycemic microenvironment on the inflammatory response and transcriptome of a gingival coculture model stimulated with dysbiotic subgingival microbiomes. HGF-1 cells overlaid with U937 macrophage-like cells were stimulated with subgingival microbiomes collected from four healthy donors and four patients with periodontitis. Pro-inflammatory cytokines and matrix metalloproteinases were measured while the coculture RNA was submitted to a microarray analysis. Subgingival microbiomes were submitted to 16s rRNA gene sequencing. Data were analyzed using an advanced multi-omics bioinformatic data integration model. Our results show that the genes krt76, krt27, pnma5, mansc4, rab41, thoc6, tm6sf2, and znf506 as well as the pro-inflammatory cytokines IL-1β, GM-CSF, FGF2, IL-10, the metalloproteinases MMP3 and MMP8, and bacteria from the ASV 105, ASV 211, ASV 299, Prevotella, Campylobacter and Fretibacterium genera are key intercorrelated variables contributing to periodontitis-induced inflammatory response in a hyperglycemic microenvironment. In conclusion, our multi-omics integration analysis unveiled the complex interrelationships involved in the regulation of periodontal inflammation in response to a hyperglycemic microenvironment.
The Comprehensive Analysis of Specific Proteins as Novel Biomarkers Involved in the Diagnosis and Progression of Gastric Cancer
Authors: Pawluczuk Elżbieta , Łukaszewicz-Zając Marta , Mroczko Barbara
Published: May 2023

Gastric cancer (GC) cases are predicted to rise by 2040 to approximately 1.8 million cases, while GC-caused deaths to 1.3 million yearly worldwide. To change this prognosis, there is a need to improve the diagnosis of GC patients because this deadly malignancy is usually detected at an advanced stage. Therefore, new biomarkers of early GC are sorely needed. In the present paper, we summarized and referred to a number of original pieces of research concerning the clinical significance of specific proteins as potential biomarkers for GC in comparison to well-established tumor markers for this malignancy. It has been proved that selected chemokines and their specific receptors, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), specific proteins such as interleukin 6 (IL-6) and C-reactive protein (CRP), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), as well as DNA- and RNA-based biomarkers, and c-MET (tyrosine-protein kinase Met) play a role in the pathogenesis of GC. Based on the recent scientific literature, our review indicates that presented specific proteins are potential biomarkers in the diagnosis and progression of GC as well as might be used as prognostic factors of GC patients’ survival.
Benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) and Its Bromo Derivatives: Molecular Structure and Reactivity
Authors: Chmovzh Timofey N. , Alekhina Daria A. , Kudryashev Timofey A. , Aysin Rinat R. , Korlyukov Alexander A. , Rakitin Oleg A.
Published: May 2023

Benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) (isoBBT) is a new electron-withdrawing building block that can be used to obtain potentially interesting compounds for the synthesis of OLEDs and organic solar cells components. The electronic structure and delocalization in benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole), 4-bromobenzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole), and 4,8-dibromobenzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) were studied using X-ray diffraction analysis and ab initio calculations by EDDB and GIMIC methods and were compared to the corresponding properties of benzo[1,2-c:4,5-c′]bis[1,2,5]thiadiazole (BBT). Calculations at a high level of theory showed that the electron affinity, which determines electron deficiency, of isoBBT was significantly smaller than that of BBT (1.09 vs. 1.90 eV). Incorporation of bromine atoms improves the electrical deficiency of bromobenzo-bis-thiadiazoles nearly without affecting aromaticity, which increases the reactivity of these compounds in aromatic nucleophilic substitution reactions and, on the other hand, does not reduce the ability to undergo cross-coupling reactions. 4-Bromobenzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) is an attractive object for the synthesis of monosubstituted isoBBT compounds. The goal to find conditions for the selective substitution of hydrogen or bromine atoms at position 4 in order to obtain compounds containing a (het)aryl group in this position and to use the remaining unsubstituted hydrogen or bromine atoms to obtain unsymmetrically substituted isoBBT derivatives, potentially interesting compounds for organic photovoltaic components, was not set before. Nucleophilic aromatic and cross-coupling reactions, along with palladium-catalyzed C-H direct arylation reactions for 4-bromobenzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole), were studied and selective conditions for the synthesis of monoarylated derivatives were found. The observed features of the structure and reactivity of isoBBT derivatives may be useful for building organic semiconductor-based devices.
Polyunsaturated Fatty Acids: Conversion to Lipid Mediators, Roles in Inflammatory Diseases and Dietary Sources
Authors: Harwood John L.
Published: May 2023

Polyunsaturated fatty acids (PUFAs) are important components of the diet of mammals. Their role was first established when the essential fatty acids (EFAs) linoleic acid and α-linolenic acid were discovered nearly a century ago. However, most of the biochemical and physiological actions of PUFAs rely on their conversion to 20C or 22C acids and subsequent metabolism to lipid mediators. As a generalisation, lipid mediators formed from n-6 PUFAs are pro-inflammatory while those from n-3 PUFAs are anti-inflammatory or neutral. Apart from the actions of the classic eicosanoids or docosanoids, many newly discovered compounds are described as Specialised Pro-resolving Mediators (SPMs) which have been proposed to have a role in resolving inflammatory conditions such as infections and preventing them from becoming chronic. In addition, a large group of molecules, termed isoprostanes, can be generated by free radical reactions and these too have powerful properties towards inflammation. The ultimate source of n-3 and n-6 PUFAs are photosynthetic organisms which contain Δ-12 and Δ-15 desaturases, which are almost exclusively absent from animals. Moreover, the EFAs consumed from plant food are in competition with each other for conversion to lipid mediators. Thus, the relative amounts of n-3 and n-6 PUFAs in the diet are important. Furthermore, the conversion of the EFAs to 20C and 22C PUFAs in mammals is rather poor. Thus, there has been much interest recently in the use of algae, many of which make substantial quantities of long-chain PUFAs or in manipulating oil crops to make such acids. This is especially important because fish oils, which are their main source in human diets, are becoming limited. In this review, the metabolic conversion of PUFAs into different lipid mediators is described. Then, the biological roles and molecular mechanisms of such mediators in inflammatory diseases are outlined. Finally, natural sources of PUFAs (including 20 or 22 carbon compounds) are detailed, as well as recent efforts to increase their production.
Oligomeric Alpha-Synuclein and STX-1A from Neural-Derived Extracellular Vesicles (NDEVs) as Possible Biomarkers of REM Sleep Behavior Disorder in Parkinson’s Disease: A Preliminary Cohort Study
Authors: Meloni Mario , Agliardi Cristina , Guerini Franca Rosa , Saibene Francesca Lea , Milner Anna Vera , Zanzottera Milena , Bolognesi Elisabetta , Puligheddu Monica , Figorilli Michela , Navarro Jorge , Clerici Mario
Published: May 2023

REM sleep behavior disorder (RBD) has a tighter link with synucleinopathies than other neurodegenerative disorders. Parkinson’s Disease (PD) patients with RBD have a more severe motor and cognitive impairment; biomarkers for RBD are currently unavailable. Synaptic accumulation of α-Syn oligomers and their interaction with SNARE proteins is responsible for synaptic dysfunction in PD. We verified whether oligomeric α-Syn and SNARE components in neural-derived extracellular vesicles (NDEVs) in serum could be biomarkers for RBD. Forty-seven PD patients were enrolled, and the RBD Screening Questionnaire (RBDSQ) was compiled. A cut-off score > 6 to define probable RBD (p-RBD) and probable non-RBD (p non-RBD) was used. NDEVs were isolated from serum by immunocapture, and oligomeric α-Syn and SNARE complex components VAMP-2 and STX-1 were measured by ELISA. NDEVs’ STX-1A resulted in being decreased in p-RBD compared to p non-RBD PD patients. A positive correlation between NDEVs’ oligomeric α-Syn and RBDSQ total score was found (p = 0.032). Regression analysis confirmed a significant association between NDEVs’ oligomeric α-Syn concentration and RBD symptoms (p = 0.033) independent from age, disease duration, and motor impairment severity. Our findings suggest that synuclein-mediated neurodegeneration in PD-RBD is more diffuse. NDEVs’ oligomeric α-Syn and SNARE complex components’ serum concentrations could be regarded as reliable biomarkers for the RBD-specific PD endophenotype.
Engineering an Optimal Y280-Lineage H9N2 Vaccine Strain by Tuning PB2 Activity
Authors: An Se-Hee , Hong Seung-Min , Song Jin-Ha , Son Seung-Eun , Lee Chung-Young , Choi Kang-Seuk , Kwon Hyuk-Joon
Published: May 2023

H9N2 avian influenza A viruses (AIVs) cause economic losses in the poultry industry and provide internal genomic segments for the evolution of H5N1 and H7N9 AIVs into more detrimental strains for poultry and humans. In addition to the endemic Y439/Korea-lineage H9N2 viruses, the Y280-lineage spread to Korea since 2020. Conventional recombinant H9N2 vaccine strains, which bear mammalian pathogenic internal genomes of the PR8 strain, are pathogenic in BALB/c mice. To reduce the mammalian pathogenicity of the vaccine strains, the PR8 PB2 was replaced with the non-pathogenic and highly productive PB2 of the H9N2 vaccine strain 01310CE20. However, the 01310CE20 PB2 did not coordinate well with the hemagglutinin (HA) and neuraminidase (NA) of the Korean Y280-lineage strain, resulting in a 10-fold lower virus titer compared to the PR8 PB2. To increase the virus titer, the 01310CE20 PB2 was mutated (I66M-I109V-I133V) to enhance the polymerase trimer integrity with PB1 and PA, which restored the decreased virus titer without causing mouse pathogenicity. The reverse mutation (L226Q) of HA, which was believed to decrease mammalian pathogenicity by reducing mammalian receptor affinity, was verified to increase mouse pathogenicity and change antigenicity. The monovalent Y280-lineage oil emulsion vaccine produced high antibody titers for homologous antigens but undetectable titers for heterologous (Y439/Korea-lineage) antigens. However, this defect was corrected by the bivalent vaccine. Therefore, the balance of polymerase and HA/NA activities can be achieved by fine-tuning PB2 activity, and a bivalent vaccine may be more effective in controlling concurrent H9N2 viruses with different antigenicities.
The High Level of RANKL Improves IκB/p65/Cyclin D1 Expression and Decreases p-Stat5 Expression in Firm Udder of Dairy Goats
Authors: Gao Zhen , Shao Dan , Zhao Chunrui , Liu Haokun , Zhao Xiaoe , Wei Qiang , Ma Baohua
Published: May 2023

Udder traits, influencing udder health and function, are positively correlated with lactation performance. Among them, breast texture influences heritability and impacts on the milk yield of cattle; however, there is a lack of systematic research on its underlying mechanism in dairy goats in particular. Here, we showed the structure of firm udders with developed connective tissue and smaller acini per lobule during lactation and confirmed that there were lower serum levels of estradiol (E2) and progesterone (PROG), and higher mammary expression of estrogen nuclear receptor (ER) α and progesterone receptor (PR), in dairy goats with firm udders. The results of transcriptome sequencing of the mammary gland revealed that the downstream pathway of PR, the receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) signal, participated in the formation of firm mammary glands. During the culture of goat mammary epithelial cells (GMECs), high RANKL level additions promote the Inhibitor kappaB (IκB)/p65/Cyclin D1 expression related to cell proliferation and decrease the phosphorylated signal transduction and transcription activator 5 (Stat5) expression related to milk-protein synthesis of GMECs, which is consistent with electron microscope results showing that there are fewer lactoprotein particles in the acinar cavity of a firm mammary. Furthermore, co-culturing with adipocyte-like cells for 7 d is beneficial for the acinar structure formation of GMECs, while there is a slightly negative effect of high RANKL level on it. In conclusion, the results of this study revealed the structure of firm udders structure and confirmed the serum hormone levels and their receptor expression in the mammary glands of dairy goats with firm udders. The underlying mechanism leading to firm udders and a decrease in milk yield were explored preliminarily, which provided an important foundation for the prevention and amelioration of firm udders and improving udder health and milk yield.
RNA-Seq Analysis Reveals an Essential Role of the cGMP-PKG-MAPK Pathways in Retinal Degeneration Caused by Cep250 Deficiency
Authors: Chen Chong , Rong Yu , Zhuang Youyuan , Tang Cheng , Liu Qian , Lin Peng , Li Dandan , Zhao Xinyi , Lu Fan , Qu Jia , Liu Xinting
Published: May 2023

Usher syndrome (USH) is characterised by degenerative vision loss known as retinitis pigmentosa (RP), sensorineural hearing loss, and vestibular dysfunction. RP can cause degeneration and the loss of rod and cone photoreceptors, leading to structural and functional changes in the retina. Cep250 is a candidate gene for atypical Usher syndrome, and this study describes the development of a Cep250 KO mouse model to investigate its pathogenesis. OCT and ERG were applied in Cep250 and WT mice at P90 and P180 to access the general structure and function of the retina. After recording the ERG responses and OCT images at P90 and P180, the cone and rod photoreceptors were visualised using an immunofluorescent stain. TUNEL assays were applied to observe the apoptosis in Cep250 and WT mice retinas. The total RNA was extracted from the retinas and executed for RNA sequencing at P90. Compared with WT mice, the thickness of the ONL, IS/OS, and whole retina of Cep250 mice was significantly reduced. The a-wave and b-wave amplitude of Cep250 mice in scotopic and photopic ERG were lower, especially the a-wave. According to the immunostaining and TUNEL stain results, the photoreceptors in the Cep250 retinas were also reduced. An RNA-seq analysis showed that 149 genes were upregulated and another 149 genes were downregulated in Cep250 KO retinas compared with WT mice retinas. A KEGG enrichment analysis indicated that cGMP-PKG signalling pathways, MAPK signalling pathways, edn2-fgf2 axis pathways, and thyroid hormone synthesis were upregulated, whereas protein processing in the endoplasmic reticulum was downregulated in Cep250 KO eyes. Cep250 KO mice experience a late-stage retinal degeneration that manifests as the atypical USH phenotype. The dysregulation of the cGMP-PKG-MAPK pathways may contribute to the pathogenesis of cilia-related retinal degeneration.
Hepatic Pin1 Expression, Particularly in Nuclei, Is Increased in NASH Patients in Accordance with Evidence of the Role of Pin1 in Lipid Accumulation Shown in Hepatoma Cell Lines
Authors: Kanna Machi , Nakatsu Yusuke , Yamamotoya Takeshi , Kushiyama Akifumi , Fujishiro Midori , Sakoda Hideyuki , Ono Hiraku , Arihiro Koji , Asano Tomoichiro
Published: May 2023

Our previous studies using rodent models have suggested an essential role for Pin1 in the pathogenesis of non-alcoholic steatohepatitis (NASH). In addition, interestingly, serum Pin1 elevation has been reported in NASH patients. However, no studies have as yet examined the Pin1 expression level in human NASH livers. To clarify this issue, we investigated the expression level and subcellular distribution of Pin1 in liver specimens obtained using needle-biopsy samples from patients with NASH and healthy liver donors. Immunostaining using anti-Pin1 antibody revealed the Pin1 expression level to be significantly higher, particularly in nuclei, in the livers of NASH patients than those of healthy donors. In the samples from patients with NASH, the amount of nuclear Pin1 was revealed to be negatively related to serum alanine aminotransferase (ALT), while tendencies to be associated with other serum parameters such as aspartate aminotransferase (AST) and platelet number were noted but did not reach statistical significance. Such unclear results and the lack of a significant relationship might well be attributable to our small number of NASH liver samples (n = 8). Moreover, in vitro, it was shown that addition of free fatty acids to medium induced lipid accumulation in human hepatoma HepG2 and Huh7 cells, accompanied with marked increases in nuclear Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), in accordance with the aforementioned observations in human NASH livers. In contrast, suppression of Pin1 gene expression using siRNAs attenuated the free fatty acid-induced lipid accumulation in Huh7 cells. Taken together, these observations strongly suggest that increased expression of Pin1, particularly in hepatic nuclei, contributes to the pathogenesis of NASH with lipid accumulation.
A New Opportunity for “Old” Molecules: Targeting PARP1 Activity through a Non-Enzymatic Mechanism
Authors: Iglesias Pablo , Seoane Marcos , Golán-Cancela Irene , Fraga Máximo , Arce Victor M. , Costoya Jose A.
Published: May 2023

In recent years, new therapies have been developed based on molecules that target molecular mechanisms involved in both the initiation and maintenance of the oncogenic process. Among these molecules are the poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. PARP1 has emerged as a target with great therapeutic potential for some tumor types, drawing attention to this enzyme and resulting in many small molecule inhibitors of its enzymatic activity. Therefore, many PARP inhibitors are currently in clinical trials for the treatment of homologous recombination (HR)-deficient tumors, BRCA-related cancers, taking advantage of synthetic lethality. In addition, several novel cellular functions unrelated to its role in DNA repair have been described, including post-translational modification of transcription factors, or acting through protein–protein interactions as a co-activator or co-repressor of transcription. Previously, we reported that this enzyme may play a key role as a transcriptional co-activator of an important component of cell cycle regulation, the transcription factor E2F1. Here, we show that PARP inhibitors, which interfere with its activity in cell cycle regulation, perform this without affecting its enzymatic function.
Enhanced Mouse Susceptibility to Endotoxin Shock after Plasmodium yoelii Infection Is Correlated with Increased Serum Levels of Lipopolysaccharide Soluble Receptors
Authors: Soe Pyone Pyone , Coutelier Jean-Paul
Published: May 2023

Sepsis is a common disease in sub-Saharan Africa and Asia, where malaria is also prevalent. To determine whether Plasmodium infection might enhance susceptibility to endotoxin shock, we used a mouse model of lipopolysaccharide (LPS) administration. Our results indicated that Plasmodium yoelii infection in mice strongly enhanced the susceptibility of the host to develop endotoxin shock. This increased susceptibility to endotoxin shock was correlated with a synergistic effect of Plasmodium and LPS on the secretion of Tumor Necrosis Factor (TNF). TNF contributed mostly to lethality after the dual challenge since neutralization with an anti-TNF antibody provided protection from death. Plasmodium infection also induced an enhancement of the serum levels of LPS soluble ligands, sCD14 and Lipopolysaccharide Binding Protein. In this regard, our data confirm that Plasmodium infection can profoundly modify responses to secondary bacteria challenges, resulting in dysregulated cytokine expression and pathological effects. If confirmed in humans, LPS soluble receptors might serve as markers of susceptibility to septic shock.
Ferritin Metabolism Reflects Multiple Myeloma Microenvironment and Predicts Patient Outcome
Authors: Plano Federica , Gigliotta Emilia , Corsale Anna Maria , Azgomi Mojtaba Shekarkar , Santonocito Carlotta , Ingrascì Manuela , Di Carlo Laura , Augello Antonino Elia , Speciale Maria , Vullo Candida , Rotolo Cristina , Camarda Giulia Maria , Caccamo Nadia , Meraviglia Serena , Dieli Francesco , Siragusa Sergio , Botta Cirino
Published: May 2023

Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome.
Immunological Profile of Vasospasm after Subarachnoid Hemorrhage
Authors: Romoli Michele , Giammello Fabrizio , Mosconi Maria Giulia , De Mase Antonio , De Marco Giovanna , Digiovanni Anna , Ciacciarelli Antonio , Ornello Raffaele , Storti Benedetta
Published: May 2023

Subarachnoid hemorrhage (SAH) carries high mortality and disability rates, which are substantially driven by complications. Early brain injury and vasospasm can happen after SAH and are crucial events to prevent and treat to improve prognosis. In recent decades, immunological mechanisms have been implicated in SAH complications, with both innate and adaptive immunity involved in mechanisms of damage after SAH. The purpose of this review is to summarize the immunological profile of vasospasm, highlighting the potential implementation of biomarkers for its prediction and management. Overall, the kinetics of central nervous system (CNS) immune invasion and soluble factors’ production critically differs between patients developing vasospasm compared to those not experiencing this complication. In particular, in people developing vasospasm, a neutrophil increase develops in the first minutes to days and pairs with a mild depletion of CD45+ lymphocytes. Cytokine production is boosted early on after SAH, and a steep increase in interleukin-6, metalloproteinase-9 and vascular endothelial growth factor (VEGF) anticipates the development of vasospasm after SAH. We also highlight the role of microglia and the potential influence of genetic polymorphism in the development of vasospasm and SAH-related complications.