bluuebunny/crossref_metadata_2025 huggingface dataset:
Studying Scripts of Women, Men and Suicide: Qualitative-Method Development and Findings from Nepal
Authors: Canetto Silvia Sara , Menger-Ogle Andrew D. , Subba Usha Kiran
Published: June 2023

Information about suicidal behavior in Nepal is limited. According to official records, suicide rates were high until the year 2000 and declined thereafter. Official records are considered unreliable and a gross undercounting of suicide cases, particularly female cases. Suicide research in Nepal has been mostly epidemiologic and hospital-based. Little is known about how suicide is understood by Nepali people in general—including dominant suicide attitudes and beliefs in Nepal. Suicide attitudes and beliefs, which are elements of a culture’s suicide scripts, predict actual suicidality. Drawing on suicide-script theory, we developed and used a semi-structured survey to explore Nepali beliefs about female and male suicide. The informants were adult (Mage = 28.4) university students (59% male). Female suicide was believed to be a response to the society-sanctioned oppression and abuse that women are subjected to, in their family and community. The prevention of female suicide was viewed as requiring dismantling ideologies, institutions, and customs (e.g., child marriage, dowry) that are oppressive to women, and ensuring that women are protected from violence and have equal social and economic rights and opportunities. Male suicide was believed to be a symptom of societal problems (e.g., unemployment) and of men’s psychological problems (e.g., their difficulties in managing emotions). The prevention of male suicide was viewed as requiring both societal (e.g., employment opportunities) and individual remedies (e.g., psychological counseling). This study’s findings suggest that a semi-structured survey can be a fruitful method to access the suicide scripts of cultures about which there is limited research.
Risk Factors for Falls and Fall-Related Fractures in Community-Living Older People with Pain: A Prospective Cohort Study
Authors: Hirase Tatsuya , Okubo Yoshiro , Delbaere Kim , Menant Jasmine C. , Lord Stephen R. , Sturnieks Daina L.
Published: June 2023

(1) Background: This prospective study aimed to identify predictors of falls and fall-related fractures in community-dwelling older people with pain; (2) Methods: Participants comprised 389 community-dwelling older people aged 70+ years who had musculoskeletal pain in the neck, back, hip, leg/knee and/or feet. Demographic, anthropometric, balance, mobility, cognitive function, psychological status and physical activity level measures were obtained at baseline. Falls were monitored with monthly falls calendars for 12 months. Logistic regression analyses were performed to identify predictors of falls and fall-related fractures during a 12-month follow-up; (3) Results: Of the 389 participants, 175 (45.0%) and 20 (5.1%) reported falls and fall-related fractures during the 12-month follow-up, respectively. Greater postural sway on foam, more depressive symptoms and lower physical activity levels at baseline were associated with falls during the 12-month follow-up. Slower walking speed at baseline was associated with fall-related fractures during the 12-month follow-up. These associations remained significant after adjusting for age, sex, body mass index, comorbidities and medication use; (4) Conclusions: This study suggests poor balance, low mood and a less active lifestyle are predictors of falls, and slower walking speed predicts fall-related fractures among community-dwelling older people with pain.
Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine
Authors: Maccari Rosanna , Ottanà Rosaria
Published: June 2023

Protein tyrosine phosphatase 1B (PTP1B) is an enzyme crucially implicated in aberrations of various signaling pathways that underlie the development of different human pathologies, such as obesity, diabetes, cancer, and neurodegenerative disorders. Its inhibition can prevent these pathogenetic events, thus providing a useful tool for the discovery of novel therapeutic agents. The search for allosteric PTP1B inhibitors can represent a successful strategy to identify drug-like candidates by offering the opportunity to overcome some issues related to catalytic site-directed inhibitors, which have so far hampered the development of drugs targeting this enzyme. In this context, trodusquemine (MSI-1436), a natural aminosterol that acts as a non-competitive PTP1B inhibitor, appears to be a milestone. Initially discovered as a broad-spectrum antimicrobial agent, trodusquemine exhibited a variety of unexpected properties, ranging from antidiabetic and anti-obesity activities to effects useful to counteract cancer and neurodegeneration, which prompted its evaluation in several preclinical and clinical studies. In this review article, we provide an overview of the main findings regarding the activities and therapeutic potential of trodusquemine and their correlation with PTP1B inhibition. We also included some aminosterol analogues and related structure–activity relationships that could be useful for further studies aimed at the discovery of new allosteric PTP1B inhibitors.
Intratumoral Restoration of miR-137 Plus Cholesterol Favors Homeostasis of the miR-137/Coactivator p160/AR Axis and Negatively Modulates Tumor Progression in Advanced Prostate Cancer
Authors: Pimenta Ruan , Mioshi Carolina Mie , Gonçalves Guilherme L. , Candido Patrícia , Camargo Juliana A. , Guimarães Vanessa R. , Chiovatto Caroline , Ghazarian Vitória , Romão Poliana , da Silva Karina Serafim , dos Santos Gabriel A. , Silva Iran A. , Srougi Miguel , Nahas William C. , Leite Kátia R. , Viana Nayara I. , Reis Sabrina T.
Published: June 2023

MicroRNAs (miRNAs) have gained a prominent role as biomarkers in prostate cancer (PCa). Our study aimed to evaluate the potential suppressive effect of miR-137 in a model of advanced PCa with and without diet-induced hypercholesterolemia. In vitro, PC-3 cells were treated with 50 pmol of mimic miR-137 for 24 h, and gene and protein expression levels of SRC-1, SRC-2, SRC-3, and AR were evaluated by qPCR and immunofluorescence. We also assessed migration rate, invasion, colony-forming ability, and flow cytometry assays (apoptosis and cell cycle) after 24 h of miRNA treatment. For in vivo experiments, 16 male NOD/SCID mice were used to evaluate the effect of restoring miR-137 expression together with cholesterol. The animals were fed a standard (SD) or hypercholesterolemic (HCOL) diet for 21 days. After this, we xenografted PC-3 LUC-MC6 cells into their subcutaneous tissue. Tumor volume and bioluminescence intensity were measured weekly. After the tumors reached 50 mm3, we started intratumor treatments with a miR-137 mimic, at a dose of 6 μg weekly for four weeks. Ultimately, the animals were killed, and the xenografts were resected and analyzed for gene and protein expression. The animals’ serum was collected to evaluate the lipid profile. The in vitro results showed that miR-137 could inhibit the transcription and translation of the p160 family, SRC-1, SRC-2, and SRC-3, and indirectly reduce the expression of AR. After these analyses, it was determined that increased miR-137 inhibits cell migration and invasion and impacts reduced proliferation and increased apoptosis rates. The in vivo results demonstrated that tumor growth was arrested after the intratumoral restoration of miR-137, and proliferation levels were reduced in the SD and HCOL groups. Interestingly, the tumor growth retention response was more significant in the HCOL group. We conclude that miR-137 is a potential therapeutic miRNA that, in association with androgen precursors, can restore and reinstate the AR-mediated axis of transcription and transactivation of androgenic pathway homeostasis. Further studies involving the miR-137/coregulator/AR/cholesterol axis should be conducted to evaluate this miR in a clinical context.
Routes of Albumin Overload Toxicity in Renal Tubular Epithelial Cells
Authors: Eleftheriadis Theodoros , Pissas Georgios , Golfinopoulos Spyridon , Efthymiadi Maria , Poulianiti Christina , Polyzou Konsta Maria Anna , Liakopoulos Vassilios , Stefanidis Ioannis
Published: June 2023

Besides being a marker of kidney disease severity, albuminuria exerts a toxic effect on renal proximal tubular epithelial cells (RPTECs). We evaluated whether an unfolded protein response (UPR) or DNA damage response (DDR) is elicited in RPTECs exposed to high albumin concentration. The deleterious outcomes of the above pathways, apoptosis, senescence, or epithelial-to-mesenchymal transition (EMT) were evaluated. Albumin caused reactive oxygen species (ROS) overproduction and protein modification, and a UPR assessed the level of crucial molecules involved in this pathway. ROS also induced a DDR evaluated by critical molecules involved in this pathway. Apoptosis ensued through the extrinsic pathway. Senescence also occurred, and the RPTECs acquired a senescence-associated secretory phenotype since they overproduced IL-1β and TGF-β1. The latter may contribute to the observed EMT. Agents against endoplasmic reticulum stress (ERS) only partially alleviated the above changes, while the inhibition of ROS upregulation prevented both UPR and DDR and all the subsequent harmful effects. Briefly, albumin overload causes cellular apoptosis, senescence, and EMT in RPTECs by triggering UPR and DDR. Promising anti-ERS factors are beneficial but cannot eliminate the albumin-induced deleterious effects because DDR also occurs. Factors that suppress ROS overproduction may be more effective since they could halt UPR and DDR.
Methotrexate Provokes Disparate Folate Metabolism Gene Expression and Alternative Splicing in Ex Vivo Monocytes and GM-CSF- and M-CSF-Polarized Macrophages
Authors: Muller Ittai B. , Lin Marry , Jonge Robert , Will Nico , López-Navarro Baltasar , Laken Conny van der , Struys Eduard A. , Oudejans Cees B. M. , Assaraf Yehuda G. , Cloos Jacqueline , Puig-Kröger Amaya , Jansen Gerrit
Published: June 2023

Macrophages constitute important immune cell targets of the antifolate methotrexate (MTX) in autoimmune diseases, including rheumatoid arthritis. Regulation of folate/MTX metabolism remains poorly understood upon pro-inflammatory (M1-type/GM-CSF-polarized) and anti-inflammatory (M2-type/M-CSF-polarized) macrophages. MTX activity strictly relies on the folylpolyglutamate synthetase (FPGS) dependent intracellular conversion and hence retention to MTX-polyglutamate (MTX-PG) forms. Here, we determined FPGS pre-mRNA splicing, FPGS enzyme activity and MTX-polyglutamylation in human monocyte-derived M1- and M2-macrophages exposed to 50 nmol/L MTX ex vivo. Moreover, RNA-sequencing analysis was used to investigate global splicing profiles and differential gene expression in monocytic and MTX-exposed macrophages. Monocytes displayed six–eight-fold higher ratios of alternatively-spliced/wild type FPGS transcripts than M1- and M2-macrophages. These ratios were inversely associated with a six–ten-fold increase in FPGS activity in M1- and M2-macrophages versus monocytes. Total MTX-PG accumulation was four-fold higher in M1- versus M2-macrophages. Differential splicing after MTX-exposure was particularly apparent in M2-macrophages for histone methylation/modification genes. MTX predominantly induced differential gene expression in M1-macrophages, involving folate metabolic pathway genes, signaling pathways, chemokines/cytokines and energy metabolism. Collectively, macrophage polarization-related differences in folate/MTX metabolism and downstream pathways at the level of pre-mRNA splicing and gene expression may account for variable accumulation of MTX-PGs, hence possibly impacting MTX treatment efficacy.
DNA:RNA Hybrids Are Major Dinoflagellate Minicircle Molecular Types
Authors: Kwok Alvin Chun Man , Leung Siu Kai , Wong Joseph Tin Yum
Published: June 2023

Peridinin-containing dinoflagellate plastomes are predominantly encoded in nuclear genomes, with less than 20 essential chloroplast proteins carried on “minicircles”. Each minicircle generally carries one gene and a short non-coding region (NCR) with a median length of approximately 400–1000 bp. We report here differential nuclease sensitivity and two-dimensional southern blot patterns, suggesting that dsDNA minicircles are in fact the minor forms, with substantial DNA:RNA hybrids (DRHs). Additionally, we observed large molecular weight intermediates, cell-lysate-dependent NCR secondary structures, multiple bidirectional predicted ssDNA structures, and different southern blot patterns when probed with different NCR fragments. In silico analysis suggested the existence of substantial secondary structures with inverted repeats (IR) and palindrome structures within the initial ~650 bp of the NCR sequences, in accordance with conversion event(s) outcomes with PCR. Based on these findings, we propose a new transcription-templating-translation model, which is associated with cross-hopping shift intermediates. Since dinoflagellate chloroplasts are cytosolic and lack nuclear envelope breakdown, the dynamic DRH minicircle transport could have contributed to the spatial-temporal dynamics required for photosystem repair. This represents a paradigm shift from the previous understanding of “minicircle DNAs” to a “working plastome”, which will have significant implications for its molecular functionality and evolution.
The Role of Increased Expression of Sirtuin 6 in the Prevention of Premature Aging Pathomechanisms
Authors: Dzidek Adrianna , Czerwińska-Ledwig Olga , Żychowska Małgorzata , Pilch Wanda , Piotrowska Anna
Published: June 2023

Sirtuins, in mammals, are a group of seven enzymes (SIRT1–SIRT7) involved in the post-translational modification of proteins—they are considered longevity proteins. SIRT6, classified as class IV, is located on the cell nucleus; however, its action is also connected with other regions, e.g., mitochondria and cytoplasm. It affects many molecular pathways involved in aging: telomere maintenance, DNA repair, inflammatory processes or glycolysis. A literature search for keywords or phrases was carried out in PubMed and further searches were carried out on the ClinicalTrials.gov website. The role of SIRT6 in both premature and chronological aging has been pointed out. SIRT6 is involved in the regulation of homeostasis—an increase in the protein’s activity has been noted in calorie-restriction diets and with significant weight loss, among others. Expression of this protein is also elevated in people who regularly exercise. SIRT6 has been shown to have different effects on inflammation, depending on the cells involved. The protein is considered a factor in phenotypic attachment and the migratory responses of macrophages, thus accelerating the process of wound healing. Furthermore, exogenous substances will affect the expression level of SIRT6: resveratrol, sirtinol, flavonoids, cyanidin, quercetin and others. This study discusses the importance of the role of SIRT6 in aging, metabolic activity, inflammation, the wound healing process and physical activity.
GmUFO1 Regulates Floral Organ Number and Shape in Soybean
Authors: Yu Huimin , Zhang Yaohua , Fang Junling , Yang Xinjing , Zhang Zhirui , Wang Fawei , Wu Tao , Khan Muhammad Hafeez Ullah , Bhat Javaid Akhter , Jiang Yu , Wang Yi , Feng Xianzhong
Published: June 2023

The UNUSUAL FLORAL ORGANS (UFO) gene is an essential regulatory factor of class B genes and plays a vital role in the process of inflorescence primordial and flower primordial development. The role of UFO genes in soybean was investigated to better understand the development of floral organs through gene cloning, expression analysis, and gene knockout. There are two copies of UFO genes in soybean and in situ hybridization, which have demonstrated similar expression patterns of the GmUFO1 and GmUFO2 genes in the flower primordium. The phenotypic observation of GmUFO1 knockout mutant lines (Gmufo1) showed an obvious alteration in the floral organ number and shape and mosaic organ formation. By contrast, GmUFO2 knockout mutant lines (Gmufo2) showed no obvious difference in the floral organs. However, the GmUFO1 and GmUFO2 double knockout lines (Gmufo1ufo2) showed more mosaic organs than the Gmufo1 lines, in addition to the alteration in the organ number and shape. Gene expression analysis also showed differences in the expression of major ABC function genes in the knockout lines. Based on the phenotypic and expression analysis, our results suggest the major role of GmUFO1 in the regulation of flower organ formation in soybeans and that GmUFO2 does not have any direct effect but might have an interaction role with GmUFO1 in the regulation of flower development. In conclusion, the present study identified UFO genes in soybean and improved our understanding of floral development, which could be useful for flower designs in hybrid soybean breeding.
Involvement of the Restoration of Cerebral Blood Flow and Maintenance of eNOS Expression in the Prophylactic Protective Effect of the Novel Ferulic Acid Derivative FAD012 against Ischemia/Reperfusion Injuries in Rats
Authors: Asano Takashi , Xuan Meiyan , Iwata Naohiro , Takayama Jun , Hayashi Kousuke , Kato Yosuke , Aoyama Toshiya , Sugo Hiroshi , Matsuzaki Hirokazu , Yuan Bo , Kamiuchi Shinya , Hibino Yasuhide , Sakamoto Takeshi , Okazaki Mari
Published: June 2023

Tissue plasminogen activator, aiming to restore cerebral blood flow (CBF), has been used for acute ischemic strokes in clinics; however, its narrow therapeutic time window remains a serious concern. To develop novel prophylactic drugs to alleviate cerebral ischemia/reperfusion injuries, ferulic acid derivative 012 (FAD012) was synthesized and showed comparable antioxidant properties to ferulic acid (FA) and probably possesses the potent ability to cross the blood–brain barrier. A more potent cytoprotective effect of FAD012 against H2O2-induced cytotoxicity in PC12 cells was also observed. In vivo toxicity was not observed in rats given a long-term oral administration of FAD012, indicating its good tolerability. A one-week-course oral administration of FAD012 significantly alleviated middle cerebral artery occlusion (MCAO)-induced cerebral ischemia/reperfusion injuries in rats, accompanied by the restoration of CBF and endothelial nitrogen oxide synthetase (eNOS) expression. Treatment with FAD012 significantly restored the cell viability and eNOS expression damaged by H2O2, used to mimic MCAO-triggered oxidative stress, in rat brain microvascular endothelial cells. Our findings suggested that FAD012 protected the viability of vascular endothelium and maintained eNOS expression, ultimately contributing to the restoration of CBF, and may provide a rationale for the development of FAD012 into an effective prophylactic drug for patients at high risk of stroke.
Fusarium Mycotoxins Zearalenone and Deoxynivalenol Reduce Hepatocyte Innate Immune Response after the Listeria monocytogenes Infection by Inhibiting the TLR2/NFκB Signaling Pathway
Authors: Feng Nannan , Zhong Fang , Cai Guodong , Zheng Wanglong , Zou Hui , Gu Jianhong , Yuan Yan , Zhu Guoqiang , Liu Zongping , Bian Jianchun
Published: June 2023

Zearalenone (ZEA) and deoxynivalenol (DON) are two common mycotoxins produced by the genus Fusarium and have potential immunotoxic effects that may lead to a weak immune response against bacterial infections. Listeria monocytogenes (L. monocytogenes), a food-borne pathogenic microorganism ubiquitous in the environment, actively multiplies in the liver, where hepatocytes are capable of resistance through mediated innate immune responses. At present, it is not clear if ZEA and DON affect hepatocyte immune responses to L. monocytogenes infection or the mechanisms involved. Therefore, in this study, in vivo and in vitro models were used to investigate the effects of ZEA and DON on the innate immune responses of hepatocytes and related molecules after L. monocytogenes infection. In vivo studies revealed that ZEA and DON inhibited the toll-like receptors 2 (TLR2)/nuclear factor kappa-B (NFκB) pathway in the liver tissue of L. monocytogenes-infected mice, downregulating the expression levels of Nitric oxide (NO), in the liver and repressing the immune response. In addition, ZEA and DON inhibited Lipoteichoic acid (LTA)-induced expression of TLR2 and myeloid differentiation factor 88 (MyD88) in Buffalo Rat Liver (BRL 3A) cells in vitro, downregulating the TLR2/NFκB signaling pathway and resulting in the decreased expression levels of NO, causing immunosuppressive effects. In summary, ZEA and DON can negatively regulate NO levels through TLR2/NFκB, inhibiting the innate immune responses of the liver, and aggravate L. monocytogenes infections in mouse livers.
MAPK-ERK Pathway
Authors: Park Jong-In
Published: June 2023

The name extracellular signal-regulated kinase (ERK) was first used for a cell cycle regulating Ser/Thr protein kinase cloned in mammalian cells [...]
A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis
Authors: Morris Vanessa S. , Ghazi Hanya , Fletcher Daniel M. , Guinn Barbara-ann
Published: June 2023

Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral blood. Although AML can occur at any age, the incidence peaks at age 65. The pathobiology of AML also varies with age with associated differences in incidence, as well as the frequency of cytogenetic change and somatic mutations. In addition, 5-year survival rates in paediatrics are 60–75% but fall to 5–15% in older AML patients. This systematic review aimed to determine whether the altered genes in AML affect the same molecular pathways, indifferent of patient age, and, therefore, whether patients could benefit from the repurposing drugs or the use of the same immunotherapeutic strategies across age boundaries to prevent relapse. Using a PICO framework and PRISMA-P checklist, relevant publications were identified using five literature databases and assessed against an inclusion criteria, leaving 36 articles, and 71 targets for therapy, for further analysis. QUADAS-2 was used to determine the risk of bias and perform a quality control step. We then priority-ranked the list of cancer antigens based on predefined and pre-weighted objective criteria as part of an analytical hierarchy process used for dealing with complex decisions. This organized the antigens according to their potential to act as targets for the immunotherapy of AML, a treatment that offers an opportunity to remove residual leukaemia cells at first remission and improve survival rates. It was found that 80% of the top 20 antigens identified in paediatric AML were also within the 20 highest scoring immunotherapy targets in adult AML. To analyse the relationships between the targets and their link to different molecular pathways, PANTHER and STRING analyses were performed on the 20 highest scoring immunotherapy targets for both adult and paediatric AML. There were many similarities in the PANTHER and STRING results, including the most prominent pathways being angiogenesis and inflammation mediated by chemokine and cytokine signalling pathways. The coincidence of targets suggests that the repurposing of immunotherapy drugs across age boundaries could benefit AML patients, especially when used in combination with conventional therapies. However, due to cost implications, we would recommend that efforts are focused on ways to target the highest scoring antigens, such as WT1, NRAS, IDH1 and TP53, although in the future other candidates may prove successful.
A Bioactive Compound-Loaded Zinc-Aminoclay Encapsulated, Pickering Emulsion System for Treating Acne-Inducing Microbes
Authors: Kim Seong-Hyeon , Bae In-Sun , Lee Hyun Uk , Moon Ju-Young , Lee Young-Chul
Published: June 2023

Acne is a common skin condition caused by the growth of certain bacteria. Many plant extracts have been investigated for their potential to combat acne-inducing microbes, and one such plant extract is microwave-assisted Opuntia humifusa extract (MA-OHE). The MA-OHE was loaded onto zinc-aminoclay (ZnAC) and encapsulated in a Pickering emulsion system (MA-OHE/ZnAC PE) to evaluate its therapeutic potential against acne-inducing microbes. Dynamic light scattering and scanning electron microscopy were used to characterize MA-OHE/ZnAC PE with a mean particle diameter of 353.97 nm and a PDI of 0.629. The antimicrobial effect of MA-OHE/ZnAC was evaluated against Staphylococcus aureus (S. aureus) and Cutibacterium acnes (C. acnes), which contribute to acne inflammation. The antibacterial activity of MA-OHE/ZnAC was 0.1 and 0.025 mg/mL to S. aureus and C. acnes, respectively, which were close to naturally derived antibiotics. Additionally, the cytotoxicity of MA-OHE, ZnAC, and MA-OHE/ZnAC was tested, and the results showed that they had no cytotoxic effects on cultured human keratinocytes in a range of 10–100 μg/mL. Thus, MA-OHE/ZnAC is suggested to be a promising antimicrobial agent for treating acne-inducing microbes, while MA-OHE/ZnAC PE is a potentially advantageous dermal delivery system.
Gated Calcium Ion Channel and Mutation Mechanisms in Multidrug-Resistant Tuberculosis
Authors: D’Elia John A. , Weinrauch Larry A.
Published: June 2023

A wide spectrum of Gram-positive/Gram-negative bacteria has been found resistant to a wide spectrum of antibiotics in the United States of America during the past decade. Drug-resistant tuberculosis is not yet a major threat in North/South America, Europe, and the Middle East. However, the migration of populations in times of drought, famine, and hostilities may increase the global reach of this ancient pathogen. Given an increased spread from China and India to African countries, drug-resistant Mycobacterium tuberculosis has become an emerging topic of concern for Europe and North America. Due to the dangers associated with the spread of pathogens among different populations, the World Health Organization continues to expand healthcare advisories for therapeutic approaches for both stationary and migrating populations. As much of the literature focuses on endemic to pandemic viruses, we remain concerned that other treatable communicable diseases may be ignored. One such disease is multidrug-resistant tuberculosis. We focus on molecular mechanisms that this pathogen relies upon for the development of multidrug resistance via gene mutation and the evolutionary development of new enzyme and calcium channels.
PNPLA3-I148M Variant Promotes the Progression of Liver Fibrosis by Inducing Mitochondrial Dysfunction
Authors: Gou Yusong , Wang Lifei , Zhao Jinhan , Xu Xiaoyi , Xu Hangfei , Xie Fang , Wang Yanjun , Feng Yingmei , Zhang Jing , Zhang Yang
Published: June 2023

Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is strongly associated with non-alcoholic steatohepatitis and advanced fibrosis; however, the underlying mechanisms remain largely unknown. In this study, we investigated the effect of PNPLA3-I148M on the activation of hepatic stellate cell line LX-2 and the progression of liver fibrosis. Immunofluorescence staining and enzyme-linked immunosorbent assay were used to detect lipid accumulation. The expression levels of fibrosis, cholesterol metabolism, and mitochondria-related markers were measured via real-time PCR or western blotting. Electron microscopy was applied to analyze the ultrastructure of the mitochondria. Mitochondrial respiration was measured by a Seahorse XFe96 analyzer. PNPLA3-I148M significantly promoted intracellular free cholesterol aggregation in LX-2 cells by decreasing cholesterol efflux protein (ABCG1) expression; it subsequently induced mitochondrial dysfunction characterized by attenuated ATP production and mitochondrial membrane potential, elevated ROS levels, caused mitochondrial structural damage, altered the oxygen consumption rate, and decreased the expression of mitochondrial-function-related proteins. Our results demonstrated for the first time that PNPLA3-I148M causes mitochondrial dysfunction of LX-2 cells through the accumulation of free cholesterol, thereby promoting the activation of LX-2 cells and the development of liver fibrosis.
Recognition of DNA Lesions
Authors: Timmins Joanna
Published: June 2023

The average human cell suffers from approximately 104–105 DNA lesions per day [...]
The Cleavage-Specific Tau 12A12mAb Exerts an Anti-Amyloidogenic Action by Modulating the Endocytic and Bioenergetic Pathways in Alzheimer’s Disease Mouse Model
Authors: Latina Valentina , Atlante Anna , Malerba Francesca , La Regina Federico , Balzamino Bijorn Omar , Micera Alessandra , Pignataro Annabella , Stigliano Egidio , Cavallaro Sebastiano , Calissano Pietro , Amadoro Giuseppina
Published: June 2023

Beyond deficits in hippocampal-dependent episodic memory, Alzheimer’s Disease (AD) features sensory impairment in visual cognition consistent with extensive neuropathology in the retina. 12A12 is a monoclonal cleavage specific antibody (mAb) that in vivo selectively neutralizes the AD-relevant, harmful N-terminal 20–22 kDa tau fragment(s) (i.e., NH2htau) without affecting the full-length normal protein. When systemically injected into the Tg2576 mouse model overexpressing a mutant form of Amyloid Precursor Protein (APP), APPK670/671L linked to early onset familial AD, this conformation-specific tau mAb successfully reduces the NH2htau accumulating both in their brain and retina and, thus, markedly alleviates the phenotype-associated signs. By means of a combined biochemical and metabolic experimental approach, we report that 12A12mAb downregulates the steady state expression levels of APP and Beta-Secretase 1 (BACE-1) and, thus, limits the Amyloid beta (Aβ) production both in the hippocampus and retina from this AD animal model. The local, antibody-mediated anti-amyloidogenic action is paralleled in vivo by coordinated modulation of the endocytic (BIN1, RIN3) and bioenergetic (glycolysis and L-Lactate) pathways. These findings indicate for the first time that similar molecular and metabolic retino-cerebral pathways are modulated in a coordinated fashion in response to 12A12mAb treatment to tackle the neurosensorial Aβ accumulation in AD neurodegeneration.
The Emerging Role of Autophagy-Associated lncRNAs in the Pathogenesis of Neurodegenerative Diseases
Authors: Jiang Yapei , Xu Naihan
Published: June 2023

Neurodegenerative diseases (NDDs) have become a significant global public health problem and a major societal burden. The World Health Organization predicts that NDDs will overtake cancer as the second most common cause of human mortality within 20 years. Thus, it is urgently important to identify pathogenic and diagnostic molecular markers related to neurodegenerative processes. Autophagy is a powerful process for removing aggregate-prone proteins in neurons; defects in autophagy are often associated with the pathogenesis of NDDs. Long non-coding RNAs (lncRNAs) have been suggested as key regulators in neurodevelopment; aberrant regulation of lncRNAs contributes to neurological disorders. In this review, we summarize the recent progress in the study of lncRNAs and autophagy in the context of neurodegenerative disorders, especially Alzheimer’s disease (AD) and Parkinson’s disease (PD). The information presented here should provide guidance for future in-depth investigations of neurodegenerative processes and related diagnostic molecular markers and treatment targets.
Next-Generation Sequencing and Triple-Negative Breast Cancer: Insights and Applications
Authors: Tierno Domenico , Grassi Gabriele , Scomersi Serena , Bortul Marina , Generali Daniele , Zanconati Fabrizio , Scaggiante Bruna
Published: June 2023

The poor survival of triple-negative breast cancer (TNBC) is due to its aggressive behavior, large heterogeneity, and high risk of recurrence. A comprehensive molecular investigation of this type of breast cancer using high-throughput next-generation sequencing (NGS) methods may help to elucidate its potential progression and discover biomarkers related to patient survival. In this review, the NGS applications in TNBC research are described. Many NGS studies point to TP53 mutations, immunocheckpoint response genes, and aberrations in the PIK3CA and DNA repair pathways as recurrent pathogenic alterations in TNBC. Beyond their diagnostic and predictive/prognostic value, these findings suggest potential personalized treatments in PD -L1-positive TNBC or in TNBC with a homologous recombination deficit. Moreover, the comprehensive sequencing of large genomes with NGS has enabled the identification of novel markers with clinical value in TNBC, such as AURKA, MYC, and JARID2 mutations. In addition, NGS investigations to explore ethnicity-specific alterations have pointed to EZH2 overexpression, BRCA1 alterations, and a BRCA2-delaAAGA mutation as possible molecular signatures of African and African American TNBC. Finally, the development of long-read sequencing methods and their combination with optimized short-read techniques promise to improve the efficiency of NGS approaches for future massive clinical use.
Oleoylethanolamide Treatment Modulates Both Neuroinflammation and Microgliosis, and Prevents Massive Leukocyte Infiltration to the Cerebellum in a Mouse Model of Neuronal Degeneration
Authors: Pérez-Martín Ester , Pérez-Revuelta Laura , Barahona-López Cristina , Pérez-Boyero David , Alonso José R. , Díaz David , Weruaga Eduardo
Published: June 2023

Neurodegenerative diseases involve an exacerbated neuroinflammatory response led by microglia that triggers cytokine storm and leukocyte infiltration into the brain. PPARα agonists partially dampen this neuroinflammation in some models of brain insult, but neuronal loss was not the triggering cause in any of them. This study examines the anti-inflammatory and immunomodulatory properties of the PPARα agonist oleoylethanolamide (OEA) in the Purkinje Cell Degeneration (PCD) mouse, which exhibits striking neuroinflammation caused by aggressive loss of cerebellar Purkinje neurons. Using real-time quantitative polymerase chain reaction and immunostaining, we quantified changes in pro- and anti-inflammatory markers, microglial density and marker-based phenotype, and overall leukocyte recruitment at different time points after OEA administration. OEA was found to modulate cerebellar neuroinflammation by increasing the gene expression of proinflammatory mediators at the onset of neurodegeneration and decreasing it over time. OEA also enhanced the expression of anti-inflammatory and neuroprotective factors and the Pparα gene. Regarding microgliosis, OEA reduced microglial density—especially in regions where it is preferentially located in PCD mice—and shifted the microglial phenotype towards an anti-inflammatory state. Finally, OEA prevented massive leukocyte infiltration into the cerebellum. Overall, our findings suggest that OEA may change the environment to protect neurons from degeneration caused by exacerbated inflammation.
Role of Lanthanides and Bilayer Fe2As2 in the Electronic Properties of RbLn2Fe4As4O2 (Ln = Gd, Tb, and Dy) Superconductors
Authors: Huang Yi-Na , Liu Da-Yong , Mei Hong-Ying , Han Li , Yang Huan-Ping
Published: June 2023

The superconducting transition temperatures (Tc) of RbGd2Fe4As4O2, RbTb2Fe4As4O2, and RbDy2Fe4As4O2 are 35 K, 34.7 K, and 34.3 K without doping, respectively. For the first time, we have studied the high-temperature nonmagnetic state and the low-temperature magnetic ground state of 12442 materials, RbTb2Fe4As4O2 and RbDy2Fe4As4O2, using first principles calculations and comparing them with RbGd2Fe4As4O2. We also performed a detailed study of the effects of lanthanides and bilayer Fe2As2. We predict that the ground state of RbLn2Fe4As4O2 (Ln = Gd, Tb, and Dy) is spin-density-wave-type, in-plane, striped antiferromagnets, and the magnetic moment around each Fe atom is about 2 μB. We also found that the structural differences caused by the simple ionic radius have little effect on the properties of these three materials. Different lanthanide elements themselves play a major role in the electronic properties of the materials. It can be confirmed that the effect of Gd on RbLn2Fe4As4O2 is indeed different from that of Tb and Dy, and the presence of Gd is more conducive to interlayer electron transfer. This means that Gd can transfer more electrons from the GdO layer to the FeAs layer compared to Tb and Dy. Therefore, RbGd2Fe4As4O2 has a stronger internal coupling strength of the bilayer Fe2As2 layer. This can explain why the Tc of RbGd2Fe4As4O2 is slightly higher than that of RbTb2Fe4As4O2 and RbDy2Fe4As4O2.
Investigation of Plasma-Electrolytic Processing on EDMed Austenitic Steels
Authors: Ablyaz Timur Rizovich , Shlykov Evgeny Sergeevich , Muratov Karim Ravilevich , Osinnikov Ilya Vladimirovich , Bannikov Mikhail Vladimirovich , Sidhu Sarabjeet Singh
Published: June 2023

This study investigates the effect of electrolytic plasma processing on the degree of defective layer removal from a damaged layer obtained after manufacturing operations. Electrical discharge machining (EDM) is widely accepted in modern industries for product development. However, these products may have undesirable surface defects that may require secondary operations. This work aims to study the die-sinking EDM of steel components followed by the application of plasma electrolytic polishing (PeP) to enhance the surface properties. The results showed that the decrease in the roughness of the EDMed part after PeP was 80.97%. The combined process of EDM and subsequent PeP makes it possible to obtain the desired surface finish and mechanical properties. In the case of finishing EDM processing and turning, followed by PeP processing, the fatigue life is enhanced without failure up to 109 cycles. However, the application of this combined method (EDM + PeP) requires further research to ensure consistent removal of the unwanted defective layer.
Microstructure and Recrystallization Behavior of Heating Rate-Controlled Electrolytic Capacitor Aluminum Foil under Cold Forming and Annealing
Authors: Wang Yunlei , Wu Taibin , Che Luchang , Huang Guangjie
Published: June 2023

A novel annealing process of controlled heating rate is used to produce severe cold-formed aluminum plates, which are processed into aluminum foil and mainly used for high-voltage electrolytic capacitor anodes. The experiment in this study focused on various aspects such as microstructure, recrystallization behavior, grain size, and grain boundary characteristics. The results revealed a comprehensive influence of cold-rolled reduction rate, annealing temperature, and heating rate on recrystallization behavior and grain boundary characteristics during the annealing process. The heating rate applied plays a crucial role in controlling the recrystallization process and the subsequent grain growth, which ultimately determines whether or not the grains will become larger. In addition, as the annealing temperature rises, the recrystallized fraction increases and the grains size decreases; conversely, the recrystallized fraction decreases as the heating rate increases. When the annealing temperature remains constant, the recrystallization fraction increases with a greater deformation degree. Once complete recrystallization occurs, the grain will undergo secondary growth and may even subsequently become coarser. If the deformation degree and annealing temperature remain constant, the increased heating rate will result in a lower recrystallization fraction. This is due to the inhibition of recrystallization, and most of the aluminum sheet even remains in a deformed state before recrystallization. This kind of microstructure evolution, grain characteristic revelation, and recrystallization behavior regulation can provide effective help for enterprise engineers and technicians to guide the production of capacitor aluminum foil to a certain extent, so as to improve the quality of aluminum foil and increase the electric storage performance.
The Design and Development of Woven Textile Solar Panels
Authors: Abeywickrama Neranga , Kgatuke Matholo , Marasinghe Kalana , Nashed Mohamad Nour , Oliveira Carlos , Shahidi Arash M. , Dias Tilak , Hughes-Riley Theodore
Published: June 2023

Over the past few years, alternative power supplies to either supplement or replace batteries for electronic textile and wearable applications have been sought, with the development of wearable solar energy harvesting systems gaining significant interest. In a previous publication the authors reported a novel concept to craft a yarn capable of harvesting solar energy by embedding miniature solar cells within the fibers of a yarn (solar electronic yarns). The aim of this publication is to report the development of a large-area textile solar panel. This study first characterized the solar electronic yarns, and then analyzed the solar electronic yarns once woven into double cloth woven textiles; as part of this study, the effect of different numbers of covering warp yarns on the performance of the embedded solar cells was explored. Finally, a larger woven textile solar panel (510 mm × 270 mm) was constructed and tested under different light intensities. It was observed that a PMAX = 335.3 ± 22.4 mW of energy could be harvested on a sunny day (under 99,000 lux lighting conditions).
Development of Al-Mg2Si Alloy Hybrid Surface Composites by Friction Stir Processing: Mechanical, Wear, and Microstructure Evaluation
Authors: Raja R. , Shanmugam Ragavanantham , Jannet Sabitha , Kumar G. B. Veeresh , Venkateshwaran N. , Naresh K. , Ramoni Monsuru
Published: June 2023

Surface composites are viable choices for various applications in the aerospace and automotive industries. Friction Stir Processing (FSP) is a promising method for fabricating surface composites. Aluminum Hybrid Surface Composites (AHSC) are fabricated using the FSP to strengthen a hybrid mixture prepared with equal parts of Boron carbide (B4C), Silicon Carbide (SiC), and Calcium Carbonate (CaCO3) particles. Different hybrid reinforcement weight percentages (reinforcement content of 5% (T1), 10% (T2), and 15% (T3)) were used in fabricating AHSC samples. Furthermore, different mechanical tests were performed on hybrid surface composite samples with different weight percentages of the reinforcements. Dry sliding wear assessments were performed in standard pin-on-disc apparatus as per ASTM G99 guidelines to estimate wear rates. The presence of reinforcement contents and dislocation behavior was investigated using Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) studies. The results indicated that the Ultimate Tensile Strength (UTS) of sample T3 exhibited 62.63% and 15.17% higher than that of samples T1 and T2, respectively, while the Elongation (%) of T3 exhibited 38.46% and 15.38% lower than that of samples T1 and T2, respectively. Moreover, it was found that the hardness of sample T3 increased in the stir zone compared to samples T1 and T2, owing to its higher brittle response. The higher brittle response of sample T3 compared to samples T1 and T2 was confirmed by the higher value of Young’s modulus and the lower value of Elongation (%).
Microwave Synthesis of Poly(Acrylic) Acid-Coated Magnetic Nanoparticles as Draw Solutes in Forward Osmosis
Authors: Vohl Sabina , Ban Irena , Drofenik Miha , Buksek Hermina , Gyergyek Sašo , Petrinic Irena , Hélix-Nielsen Claus , Stergar Janja
Published: June 2023

Polyacrylic acid (PAA)-coated magnetic nanoparticles (MNP@PAA) were synthesized and evaluated as draw solutes in the forward osmosis (FO) process. MNP@PAA were synthesized by microwave irradiation and chemical co-precipitation from aqueous solutions of Fe2+ and Fe3+ salts. The results showed that the synthesized MNPs have spherical shapes of maghemite Fe2O3 and superparamagnetic properties, which allow draw solution (DS) recovery using an external magnetic field. Synthesized MNP, coated with PAA, yielded an osmotic pressure of ~12.8 bar at a 0.7% concentration, resulting in an initial water flux of 8.1 LMH. The MNP@PAA particles were captured by an external magnetic field, rinsed in ethanol, and re-concentrated as DS in repetitive FO experiments with deionized water as a feed solution (FS). The osmotic pressure of the re-concentrated DS was 4.1 bar at a 0.35% concentration, resulting in an initial water flux of 2.1 LMH. Taken together, the results show the feasibility of using MNP@PAA particles as draw solutes.
Evaluation of the Fresh Properties of Cement Pastes: Part I—Response Models Applied to Changes in the One-Variable-at-a-Time Method
Authors: Maia Lino
Published: June 2023

The workability of cement-based materials is one of the features that makes these construction materials the most used worldwide. Measuring and understanding how cement-based constituent materials affect fresh properties depends on the experimental plans. The experimental plans deal with the constituent materials used, the tests carried out, and the run of experiments. Here, the fresh properties (workability) of cement-based pastes are evaluated based on the diameter in the mini-slump test and the time in the Marsh funnel test being measured. This overall study is composed of two parts. In Part I, tests were carried out on several cement-based paste compositions incorporating distinct constituent materials. The effects of the distinct constituent materials on the workability were analyzed. Furthermore, this work deals with an approach to the run of experiments. A typical run of experiments was applied, with basic sets of mixed compositions being studied by only changing one input parameter at a time. This approach used in Part I is faced with a more scientific approach applied in Part II of the work where, based on the design of experiments, multiple input parameters were changed at a time. This work showed that a basic run of experiments is quick and easy to apply and leads to results for simple analyses; conversely, it lacks information for advanced analyses and scientific conclusions. The tests carried out included studies on the effect on the workability caused by changes in the limestone filler content, the type of cement, the water-to-cement ratio, distinct superplasticizers, and shrinkage-reducing admixture.