bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of the CDK7 Gene, Coding for the Catalytic Subunit of the Cyclin-Dependent Kinase (CDK)-Activating Kinase (CAK) and General Transcription Factor II H, by the Trans-Activator Protein Tax of Human T-Cell Leukemia Virus Type-1
Authors: Shirasawa Mashiro , Nakajima Rinka , Zhou Yaxuan , Zhao Lin , Fikriyanti Mariana , Iwanaga Ritsuko , Bradford Andrew P. , Kurayoshi Kenta , Araki Keigo , Ohtani Kiyoshi
Published: August 2024

Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). The trans-activator protein Tax of HTLV-1 plays crucial roles in leukemogenesis by promoting proliferation of virus-infected cells through activation of growth-promoting genes. However, critical target genes are yet to be elucidated. We show here that Tax activates the gene coding for cyclin-dependent kinase 7 (CDK7), the essential component of both CDK-activating kinase (CAK) and general transcription factor TFIIH. CAK and TFIIH play essential roles in cell cycle progression and transcription by activating CDKs and facilitating transcriptional initiation, respectively. Tax induced CDK7 gene expression not only in human T-cell lines but also in normal peripheral blood lymphocytes (PHA-PBLs) along with increased protein expression. Tax stimulated phosphorylation of CDK2 and RNA polymerase II at sites reported to be mediated by CDK7. Tax activated the CDK7 promoter through the NF-κB pathway, which mainly mediates cell growth promotion by Tax. Knockdown of CDK7 expression reduced Tax-mediated induction of target gene expression and cell cycle progression. These results suggest that the CDK7 gene is a crucial target of Tax-mediated trans-activation to promote cell proliferation by activating CDKs and transcription.
Structural Variations Identified in Patients with Autism Spectrum Disorder (ASD) in the Chinese Population: A Systematic Review of Case-Control Studies
Authors: Chair Sek-Ying , Chow Ka-Ming , Chan Cecilia Wai-Ling , Chan Judy Yuet-Wa , Law Bernard Man-Hin , Waye Mary Miu-Yee
Published: August 2024

Autistic spectrum disorder (ASD) is a neurodevelopmental disability characterised by the impairment of social interaction and communication ability. The alarming increase in its prevalence in children urged researchers to obtain a better understanding of the causes of this disease. Genetic factors are considered to be crucial, as ASD has a tendency to run in families. In recent years, with technological advances, the importance of structural variations (SVs) in ASD began to emerge. Most of these studies, however, focus on the Caucasian population. As a populated ethnicity, ASD shall be a significant health issue in China. This systematic review aims to summarise current case-control studies of SVs associated with ASD in the Chinese population. A list of genes identified in the nine included studies is provided. It also reveals that similar research focusing on other genetic backgrounds is demanded to manifest the disease etiology in different ethnic groups, and assist the development of accurate ethnic-oriented genetic diagnosis.
Medium- and Long-Term Effects of COVID-19 in a Population of Patients Admitted to the Intensive Care Unit: Cognitive and Psychological Sequelae and Quality of Life Six Months and One Year after Discharge
Authors: Lavolpe Sara , Beretta Natascia , Bonaldi Sofia , Tronci Stefano , Albano Giovanni , Bombardieri Emilio , Merlo Paola
Published: August 2024

Most researchers have assessed cognitive functions in post-COVID-19 patients by means of screening tools and found cognitive sequelae in addition to anxiety, stress, depression, and a reduced quality of life (QoL). This study was aimed at investigating cognitive and psychological sequelae in patients admitted to the intensive care unit (ICU) six months (t6) and one year (t12) after discharge from the hospital, the impact of critical illness on well-being and QoL, and the protective role of cognitive reserve (CR). Twenty-three ICU patients underwent an extensive neuropsychological test battery at t6 and t12; a healthy control group underwent the same evaluation. Patient scores were compared with control scores: patients reported significantly lower scores in visual–spatial functions, both at t6 (U = 122; p = 0.033) and at t12 (U = 70; p = 0.003), and higher levels of anxiety (U = 126; p = 0.043) and depression (U = 97; p = 0.005) at t6; the levels of anxiety decreased at t12, while only depression symptoms persisted (U = 99.5; p = 0.025). Regarding the QoL, patients obtained lower scores in the physical component of QoL, both at t6 (U = 72; p = 0.008) and at t12 (U = 56.5; p = 0.005). Few and moderate correlations emerged between isolated cognitive functions and CR and the length of hospital stay. The results suggest a prevalent visual–spatial involvement, the medium- and long-term persistence of psychological sequelae, and a reduced QoL in ICU patients.
Biological Control of Streptomyces Species Causing Common Scabs in Potato Tubers in the Yaqui Valley, Mexico
Authors: Montoya-Martínez Amelia C. , Chávez-Luzanía Roel Alejandro , Olguín-Martínez Ana Isabel , Ruíz-Castrejón Abraham , Moreno-Cárdenas Jesús Daniel , Esquivel-Chávez Fabiola , Parra-Cota Fannie I. , de los Santos-Villalobos Sergio
Published: August 2024

Potatoes (Solanum tuberosum L.) represent an important food in the country’s gastronomy due to their cost, nutritional contribution, and versatility. However, many plant diseases such as the common scab—caused by Streptomyces species—reduce its yield and quality. This study aims to determine Streptomyces species being the causal agent of common scabs in a commercial potato field in the Yaqui Valley, Mexico, while identifying Bacillus strains as a biological control method to mitigate the impact of this disease under field conditions. Thus, three Streptomyces strains were selected from symptomatic samples, and then they were morphologically and molecularly (through sequencing recA and rpoB genes) identified as Streptomyces caniscabiei. After pathogenicity tests, the three strains were found to be pathogenic to potato tubers. In screening assays to identify biocontrol bacteria, strain TSO2T (Bacillus cabrialesii subsp. tritici) and TE3T_UV25 (Bacillus subtilis) had the best in vitro biocontrol effect against S. caniscabiei. Then, a field experiment (1 ha per treatment), under commercial conditions, was carried out to analyze the effectivity of these biocontrol bacteria to mitigate the common scabs on potato crops. After four months, the inoculation of this bacterial consortium decreased common scab incidence from 31% to 21% and increased the potato yield up to almost 5 tons/ha vs. the un-inoculated treatment. These findings demonstrate the effectiveness of the studied bacterial consortium as a potential biological control strategy to control common scabs of potato caused by Streptomyces caniscabiei, as well as increase the potato yield in the Yaqui Valley, Mexico.
Household Compositions and Substance Use among Young Adults in the U.S.
Authors: Han Beth , Tomoyasu Naomi , Einstein Emily B. , Jones Christopher M. , Compton Wilson M.
Published: August 2024

Background: Adults aged 21–29 have the highest past-month prevalence of tobacco, alcohol, and illicit drug use in the U.S. Currently, young adults often delay traditional adulthood milestones (e.g., marriage and childbearing), which may impact their household composition and substance use. Methods: We examined how the past-month prevalence of eight mutually exclusive substance use outcomes varied by household composition among young adults using the 2016–2019 National Surveys on Drug Use and Health (NSDUH) data. Bivariable and multivariable multinomial logistic regression analyses were applied. Results: Among young adults residing with their children, the most common household composition was residing with children and a spouse/partner (16.6%, 95% CI = 16.5–16.8%). Among those residing without children, common household compositions included residing with parents (22.8%, 95% CI = 22.2–23.4%) and residing only with a spouse/partner (17.9%, 95% CI = 17.6–18.3%). Past-month prevalence of binge alcohol, tobacco, and illicit drug use varied by household composition. Residing only with children and a spouse/partner was associated with a low prevalence of most examined substance use patterns. Across household compositions, those residing solely with unrelated individuals had the highest adjusted prevalence of tobacco, drug, and binge alcohol use (13.8%, 95% CI = 12.5–15.1%). Conclusions: The prevalence of substance use patterns among U.S. young adults varies by household composition. Those residing solely with unrelated individuals had the highest prevalence of tobacco, binge alcohol, and drug use. The presence of a young adult’s own children and a spouse/partner is associated with a lower prevalence of most examined substance use patterns. As household compositions continue to diversify, targeted substance use prevention/treatment strategies may be needed.
The Associations among Cyberbullying Victimization and Chinese and American Adolescents’ Mental Health Issues: The Protective Role of Perceived Parental and Friend Support
Authors: Wright Michelle F.
Published: August 2024

Researchers have focused on identifying factors that may mitigate the negative consequences associated with cyberbullying victimization. A significant factor that has received considerable attention is perceived social support from parents and friends and its potential to reduce the risk of cyberbullying victimization and the associated negative mental health issues. However, the buffering effects of perceived social support from parents and friends on the longitudinal relationships among cyberbullying victimization, depression, subjective health complaints, and self-harm have been less explored, particularly in cross-cultural contexts. To address this gap, the present study examined the role of perceived social support from parents and friends in buffering against depression, subjective health complaints, and self-harm, measured one year later, associated with cyberbullying victimization among 463 Chinese (49% female) and 445 American (52% female) eighth graders (ages 13–15). They completed self-report questionnaires on cyberbullying victimization, perceived social support from parents and friends, and mental health (i.e., depression, subjective health complaints, self-harm). One year later, they completed the same mental health questionnaires. The findings revealed no differences in reports of perceived support from parents, but greater reports of social support from friends for American adolescents when compared to Chinese adolescents. High levels of perceived social support from parents were associated with a stronger negative relationship between cyberbullying victimization, depression, subjective health complaints, and self-harm for both Chinese and American adolescents, with these effects being more pronounced for Chinese adolescents, while opposite patterns were found for American adolescents and perceived social support from friends. These results are discussed in the context of cultural values and how these values shape the role of adults in adolescents’ lives.
School Health Promotion, the Body Mass Index z-Score, and Psychosocial Health in Primary Schools of the Netherlands
Authors: Vonk Lisanne , Eekhout Iris , Huijts Tim , Levels Mark , Jansen Maria
Published: August 2024

Childhood overweight and psychosocial issues remain significant public health concerns. Schools worldwide implement health promotion programs to address these issues and to support the physical and psychosocial health of children. However, more insight is needed into the relation between these health-promoting programs and the Body Mass Index (BMI) z-score and psychosocial health of children, while taking into account how school factors might influence this relation. Therefore, we examined whether the variation between primary schools regarding the BMI z-score and psychosocial health of students could be explained by school health promotion, operationalized as Healthy School (HS) certification, general school characteristics, and the school population; we also examined to what extent the characteristics interact. The current study had a repeated cross-sectional design. Multilevel analyses were performed to calculate the variation between schools, and to examine the association between HS certification and our outcomes. Existing data of multiple school years on 1698 schools were used for the BMI z-score and on 841 schools for psychosocial health. The school level explained 2.41% of the variation in the BMI z-score and 2.45% of the variation in psychosocial health, and differences were mostly explained by parental socioeconomic status. Additionally, HS certification was associated with slightly lower BMI z-scores, but not with psychosocial health. Therefore, obtaining HS certification might contribute to the better physical health of primary school students in general. This might indicate that HS certification also relates to healthier lifestyles in primary schools, but further research should examine this.
shRNA-Targeting Caspase-3 Inhibits Cell Detachment Induced by Pemphigus Vulgaris Autoantibodies in HaCaT Cells
Authors: Pacheco-Tovar Deyanira , Pacheco-Tovar María-Guadalupe , Saavedra-Alonso Santiago , Zapata-Benavides Pablo , Torres-del-Muro Felipe-de-Jesús , Bollain-y-Goytia Juan-José , Herrera-Esparza Rafael , Rodríguez-Padilla Cristina , Avalos-Díaz Esperanza
Published: August 2024

Pemphigus is an autoimmune disease that affects the skin and mucous membranes, induced by the deposition of pemphigus IgG, which mainly targets desmogleins 1 and 3 (Dsg1 and 3). This autoantibody causes steric interference between Dsg1 and 3 and the loss of cell adhesion, producing acantholysis. This molecule and its cellular effects are clinically reflected as intraepidermal blistering. Pemphigus vulgaris-IgG (PV-IgG) binding involves p38MAPK-signaling-dependent caspase-3 activation. The present work assessed the in vitro effect of PV-IgG on the adherence of HaCaT cells dependent on caspase-3. PV-IgG induced cell detachment and apoptotic changes, as demonstrated by annexin fluorescent assays. The effect of caspase-3 induced by PV-IgG was suppressed in cells pre-treated with caspase-3-shRNA, and normal IgG (N-IgG) as a control had no relevant effects on the aforementioned parameters. The results demonstrated that shRNA reduces caspase-3 expression, as measured via qRT-PCR and via Western blot and immunofluorescence, and increases cell adhesion. In conclusion, shRNA prevented in vitro cell detachment and the late effects of apoptosis induced by PV-IgG on HaCaT cells, furthering our understanding of the molecular role of caspase-3 cell adhesion dependence in pemphigus disease.
Genetic Variants in the TBC1D2B Gene Are Associated with Ramon Syndrome and Hereditary Gingival Fibromatosis
Authors: Kularbkaew Thatphicha , Thongmak Tipaporn , Sandeth Phan , Durward Callum S. , Vittayakittipong Pichai , Duke Paul , Iamaroon Anak , Kintarak Sompid , Intachai Worrachet , Ngamphiw Chumpol , Tongsima Sissades , Jatooratthawichot Peeranat , Cox Timothy C. , Ketudat Cairns James R. , Kantaputra Piranit
Published: August 2024

Ramon syndrome (MIM 266270) is an extremely rare genetic syndrome, characterized by gingival fibromatosis, cherubism-like lesions, epilepsy, intellectual disability, hypertrichosis, short stature, juvenile rheumatoid arthritis, and ocular abnormalities. Hereditary or non-syndromic gingival fibromatosis (HGF) is also rare and considered to represent a heterogeneous group of disorders characterized by benign, slowly progressive, non-inflammatory gingival overgrowth. To date, two genes, ELMO2 and TBC1D2B, have been linked to Ramon syndrome. The objective of this study was to further investigate the genetic variants associated with Ramon syndrome as well as HGF. Clinical, radiographic, histological, and immunohistochemical examinations were performed on affected individuals. Exome sequencing identified rare variants in TBC1D2B in both conditions: a novel homozygous variant (c.1879_1880del, p.Glu627LysfsTer61) in a Thai patient with Ramon syndrome and a rare heterozygous variant (c.2471A>G, p.Tyr824Cys) in a Cambodian family with HGF. A novel variant (c.892C>T, p.Arg298Cys) in KREMEN2 was also identified in the individuals with HGF. With support from mutant protein modeling, our data suggest that TBC1D2B variants contribute to both Ramon syndrome and HGF, although variants in additional genes might also contribute to the pathogenesis of HGF.
The Impact of High-Fructose Diet and Co-Sensitization to House Dust Mites and Ragweed Pollen on the Modulation of Airway Reactivity and Serum Biomarkers in Rats
Authors: Zimbru Răzvan-Ionuț , Zimbru Elena-Larisa , Ordodi Valentin-Laurențiu , Bojin Florina-Maria , Crîsnic Daniela , Grijincu Manuela , Mirica Silvia-Nicoleta , Tănasie Gabriela , Georgescu Marius , Huțu Ioan , Haidar Laura , Păunescu Virgil , Panaitescu Carmen
Published: August 2024

The topic of ragweed pollen (RW) versus house dust mites (HDMs) has often been deliberated, but the increasing incidence of co-sensitization between them has been scarcely addressed. Utilizing Sprague Dawley rats, we explored the effects of co-sensitization with the combination of HDMs and RW pollen extracts in correlation with high-fructose diet (HFrD) by in vitro tracheal reactivity analysis in isolated organ bath and biological explorations. Our findings unveiled interrelated connections between allergic asthma, dyslipidemia, and HFrD-induced obesity, shedding light on their compounding role through inflammation. The increased CRP values and airway hyperresponsiveness to the methacholine challenge suggest a synergistic effect of obesity on amplifying the existing inflammation induced by asthma. One of the major outcomes is that the co-sensitization to HDMs and RW pollen led to the development of a severe allergic asthma phenotype in rats, especially in those with HFrD. Therefore, the co-sensitization to these allergens as well as the HFrD may play a crucial role in the modulation of systemic inflammation, obesity, and airway reactivity.
The Discovery of a Specific CKIP-1 Ligand for the Potential Treatment of Disuse Osteoporosis
Authors: Wei Yange , Wu Bo , Liu Mingqiu , Cui Chun-Ping
Published: August 2024

Bone homeostasis relies on the delicate balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. The casein kinase 2 interacting protein-1 (CKIP-1), a specific CK2α subunit-interacting protein, has been documented as one of the crucial negative regulators of bone formation. CKIP-1 siRNA therapy has constraints that limit its use in clinical applications. Therefore, it is necessary to explore effective targeting strategies for CKIP-1. In this study, we observed an upregulation of CKIP-1 protein expression in the microgravity environment, while its ubiquitination levels decreased. We further investigated the interaction between CKIP-1 and VHL and found that VHL enhanced CKIP-1 degradation through the ubiquitylation–proteasome system (UPS). Additionally, we discovered a small molecule ligand, named C77, through DNA-encoded library (DEL) screening, which binds to CKIP-1 both in vivo and in vitro, as confirmed by Surface Plasmon Resonance (SPR) and the Cellular Thermal shift assay (CETSA), respectively. Our findings demonstrated the potential of VHL and C77 as guiding factors in the development of CKIP-1-based Proteolysis-Targeting Chimeras (PROTACs), which could be future therapeutic interventions in disuse osteoporosis.
Antagonistic Strain Bacillus velezensis JZ Mediates the Biocontrol of Bacillus altitudinis m-1, a Cause of Leaf Spot Disease in Strawberry
Authors: Zhang Li , Liu Zirui , Pu Yilei , Zhang Boyuan , Wang Boshen , Xing Linman , Li Yuting , Zhang Yingjun , Gu Rong , Jia Feng , Li Chengwei , Liu Na
Published: August 2024

Biofertilizers are environmentally friendly compounds that can enhance plant growth and substitute for chemically synthesized products. In this research, a new strain of the bacterium Bacillus velezensis, designated JZ, was isolated from the roots of strawberry plants and exhibited potent antagonistic properties against Bacillus altitudinis m-1, a pathogen responsible for leaf spot disease in strawberry. The fermentation broth of JZ exerted an inhibition rate of 47.43% against this pathogen. Using an optimized acid precipitation method, crude extracts of lipopeptides from the JZ fermentation broth were obtained. The crude extract of B. velezensis JZ fermentation broth did not significantly disrupt the cell permeability of B. altitudinis m-1, whereas it notably reduced the Ca2+-ATPase activity on the cell membrane and markedly elevated the intracellular reactive oxygen species (ROS) concentration. To identify the active compounds within the crude extract, QTOF-MS/MS was employed, revealing four antimicrobial compounds: fengycin, iturin, surfactin, and a polyene antibiotic known as bacillaene. The strain JZ also produced various plant-growth-promoting substances, such as protease, IAA, and siderophore, which assists plants to survive under pathogen infection. These findings suggest that the JZ strain holds significant potential as a biological control agent against B. altitudinis, providing a promising avenue for the management of plant bacterial disease.
Matrine Suppresses Arsenic-Induced Malignant Transformation of SV-HUC-1 Cells via NOX2
Authors: Wang Lanfei , Qiu Nianfeng , Tong Suyuan , Yu Yan , Xi Shuhua , Wang Fei
Published: August 2024

Arsenic (As) has been classified as a carcinogen for humans. There is abundant evidence indicating that arsenic increases the risk of bladder cancer among human populations. However, the underlying mechanisms have yet to be fully understood and elucidated. NADPH oxidases (NOXs) are the main enzymes for ROS production in the body. NADPH Oxidase 2 (NOX2), which is the most distinctive and ubiquitously expressed subunit of NOXs, can promote the formation and development of tumors. The utilization of NOX2 as a therapeutic target has been proposed to modulate diseases resulting from the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Matrine has been reported to exhibit various pharmacological effects, including anti-inflammatory, antifibrotic, antitumor, and analgesic properties. However, it has not been reported whether matrine can inhibit malignant transformation induced by arsenic in uroepithelial cells through NOX2. We have conducted a series of experiments using both a sub-chronic NaAsO2 exposure rat model and a long-term NaAsO2 exposure cell model. Our findings indicate that arsenic significantly increases cell proliferation, migration, and angiogenesis in vivo and in vitro. Arsenic exposure resulted in an upregulation of reactive oxygen species (ROS), NOX2, and NLRP3 inflammasome expression. Remarkably, both in vivo and in vitro, the administration of matrine demonstrated a significant improvement in the detrimental impact of arsenic on bladder epithelial cells. This was evidenced by the downregulation of proliferation, migration, and angiogenesis, as well as the expression of the NOX2 and NLRP3 inflammasomes. Collectively, these findings indicate that matrine possesses the ability to reduce NOX2 levels and inhibit the transformation of bladder epithelial cells.
Blackberry Juice Fermented with Two Consortia of Lactic Acid Bacteria and Isolated Whey: Physicochemical and Antioxidant Properties during Storage
Authors: Lugo-Zarate Liliana , Delgado-Olivares Luis , Cruz-Cansino Nelly del Socorro , González-Olivares Luis Guillermo , Castrejón-Jiménez Nayeli Shantal , Estrada-Luna Diego , Jiménez-Osorio Angélica Saraí
Published: August 2024

Fermenting fruit juices with lactic acid bacteria (LAB) is a sustainable method to enhance fruit harvests and extend shelf life. This study focused on blackberries, rich in antioxidants with proven health benefits. In this research, we examined the effects of fermentation (48 h at 37 °C) at 28 days on whey-supplemented (WH, 1:1) blackberry juice (BJ) inoculated with two LAB mixtures. Consortium 1 (BJWH/C1) included Levilactobacillus brevis, Lactiplantibacillus plantarum, and Pediococcus acidilactici, while consortium 2 (BJWH/C2) comprised Lacticaseibacillus casei and Lacticaseibacillus rhamnosus. All of the strains were previously isolated from aguamiel, pulque, and fermented milk. Throughout fermentation and storage, several parameters were evaluated, including pH, lactic acid production, viscosity, stability, reducing sugars, color, total phenolic content, anthocyanins, and antioxidant capacity. Both consortia showed a significant increase in LAB count (29–38%) after 16 h. Sample BJWH/C2 demonstrated the best kinetic characteristics, with high regression coefficients (R2 = 0.97), indicating a strong relationship between lactic acid, pH, and fermentation/storage time. Despite some fluctuations during storage, the minimum LAB count remained at 9.8 log CFU/mL, and lactic acid content increased by 95%, with good storage stability. Notably, sample BJWH/C2 increased the total phenolic content during storage. These findings suggest that adding whey enhances biomass and preserves physicochemical properties during storage.
Mineralocorticoid Receptor Signaling in Peripheral Blood Cells in Patients with Multiple Sclerosis
Authors: Küstermann Franziska , Busse Kathy , Orthgieß Johannes , Stoppe Muriel , Haars Sarah , Then Bergh Florian
Published: August 2024

Multiple sclerosis (MS) is associated with alterations in neuroendocrine function, primarily the hypothalamic–pituitary–adrenal axis, including lower expression of the glucocorticoid receptor (GR) and its target genes in peripheral blood mononuclear cells (PBMC) or full blood. We previously found reduced mineralocorticoid receptor (MR) expression in MS patients’ peripheral blood. MS is being treated with a widening variety of disease-modifying treatments (DMT), some of which have similar efficacy but different mechanisms of action; body-fluid biomarkers to support the choice of the optimal initial DMT and/or to indicate an unsatisfactory response before clinical activity are unavailable. Using cell culture of volunteers’ PBMCs and subsequent gene expression analysis (microarray and qPCR validation), we identified the mRNA expression of OTUD1 to represent MR signaling. The MR and MR target gene expression levels were then measured in full blood samples. In 119 MS (or CIS) patients, the expression of both MR and OTUD1 was lower than in 42 controls. The expression pattern was related to treatment, with the MR expression being particularly low in patients treated with fingolimod. While MR signaling may be involved in the therapeutic effects of some disease-modifying treatments, MR and OTUD1 expression can complement the neuroendocrine assessment of MS disease course. If confirmed, such assessment may support clinical decision-making.
Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
Authors: Papini Nadia , Giussani Paola , Tringali Cristina
Published: August 2024

Metformin is a widely employed drug in type 2 diabetes. In addition to warranting good short- and long-term glycemic control, metformin displays many intriguing properties as protection against cardiovascular and neurodegenerative diseases, anti-tumorigenic and longevity promotion. In addition to being a low-cost drug, metformin is generally well tolerated. However, despite the enthusiastic drive to aliment these novel studies, many contradictory results suggest the importance of better elucidating the complexity of metformin action in different tissues/cells to establish its possible employment in neurodegenerative diseases. This review summarises recent data identifying lysosomal-dependent processes and lysosomal targets, such as endosomal Na+/H+ exchangers, presenilin enhancer 2 (PEN2), the lysosomal pathway leading to AMP-activated protein kinase (AMPK) activation, and the transcription factor EB (TFEB), modulated by metformin. Lysosomal dysfunctions resulting in autophagic and lysosomal acidification and biogenesis impairment appear to be hallmarks of many inherited and acquired neurodegenerative diseases. Lysosomes are not yet seen as a sort of cellular dump but are crucial in determining key signalling paths and processes involved in the clearance of aggregated proteins. Thus, the possibility of pharmacologically modulating them deserves great interest. Despite the potentiality of metformin in this context, many additional important issues, such as dosing, should be addressed in the future.
Preliminary Studies about Valorization of Acmella oleracea Bioactive Content in Modern Dermato-Cosmetic Applications to Combat Skin Oxidative Stress
Authors: Turcov Delia , Trifan Adriana , Puitel Adrian Catalin , Cimpoesu Ramona , Zbranca-Toporas Anca , Maxim Claudia , Suteu Daniela , Barna Ana Simona
Published: August 2024

The development of products with skin-protective effects has been driven by the increasing incidence of skin diseases that are exacerbated by increasing pollution, urbanization, poor living, working, fatigue, dietary habits, and general treatment. The ability of antioxidants to protect the skin from oxidative stress and its effects makes them one of the most important ingredients in today’s cosmetics. This article aims first to characterize the plant extracts obtained from Acmella oleracea (A. oleracea) and then to evaluate the preliminary criteria for a new marketed product: the stability, antioxidant activity, and in vitro behavior of certain serums based on A. oleracea plant extract and hyaluronic acid. The extracts were obtained by liquid–solid extraction methods (maceration (M), ultrasound-assisted extraction (UEA), and a combined method between these two (UEA + M) using an aqueous solution of ethyl alcohol as the extraction solvent. The determination of the amounts of compounds with antioxidant activity highlighted the fact that the extract obtained from the whole plant of A. oleracea using maceration in conditions of S/L = 1:30, 20 days, and an extraction solvent percentage of 50% led to obtaining the highest amount of polyphenols (30.42 μg GAE/g), while using the combined UAE + M method under conditions of S/L = 1:30, 6 min + 20 days, and 50% extraction solvent led to obtaining the highest amount of flavonoids (32.88 mg QE/g). The tests performed on dermato-cosmetic serums based on the plant extract and multimolecular hyaluronic acid (HA) (1 HA with HMW—1.0 mDa–1.6 mDa; HA with LMW—10 kDa–200 kDa; and HA OLIGO, MW < 10 kDa) led to the conclusion that they exhibit structural stability, good shear behavior revealing a satisfactory texture, and high physical stability during storage. These results encourage the transition to in-depth testing, both microbiological and dermatological, as a final step in the consideration of a new commercial product.
Opposite Contractile Effects of Amphetamine-Related Hallucinogenic Drugs in the Isolated Human Atrium
Authors: Neumann Joachim , Hofmann Britt , Gergs Ulrich
Published: August 2024

The present study examined three hallucinogenic amphetamine derivatives, namely, 2,5-dimethoxy-4-iodoamphetamine (DOI) as well as 2,5-dimethoxy-4-methylamphetamine (DOM) and 4-methylmethcathinone (mephedrone). The objective of this study was to test the hypothesis that DOI, DOM, and mephedrone would increase the contractile force in isolated human atrial preparations in a manner similar to amphetamine. To this end, we measured contractile force under isometric conditions in electrically stimulated (1 Hz) human atrial preparations obtained during open surgery. DOI and DOM alone or in the presence of isoprenaline reduced the contractile force concentration-dependently in human atrial preparations. These negative inotropic effects of DOM and DOI were not attenuated by 10 µM atropine. However, mephedrone increased the contractile force in human atrial preparations in a concentration- and time-dependent manner. Furthermore, these effects were attenuated by the subsequent addition of 10 µM propranolol or pretreatment with 10 µM cocaine in the organ bath. Therefore, it can be concluded that amphetamine derivatives may exert opposing effects on cardiac contractile force. The precise mechanism by which DOI and DOM exert their negative inotropic effects remains unknown at present. The cardiac effects of mephedrone are probably due to the release of cardiac noradrenaline.
Nucleic Acid Armor: Fortifying RNA Therapeutics through Delivery and Targeting Innovations for Immunotherapy
Authors: Jiang Yi , Jiang Bolong , Wang Zhenru , Li Yuxi , Cheung James Chung Wai , Yin Bohan , Wong Siu Hong Dexter
Published: August 2024

RNA is a promising nucleic acid-based biomolecule for various treatments because of its high efficacy, low toxicity, and the tremendous availability of targeting sequences. Nevertheless, RNA shows instability and has a short half-life in physiological environments such as the bloodstream in the presence of RNAase. Therefore, developing reliable delivery strategies is important for targeting disease sites and maximizing the therapeutic effect of RNA drugs, particularly in the field of immunotherapy. In this mini-review, we highlight two major approaches: (1) delivery vehicles and (2) chemical modifications. Recent advances in delivery vehicles employ nanotechnologies such as lipid-based nanoparticles, viral vectors, and inorganic nanocarriers to precisely target specific cell types to facilitate RNA cellular entry. On the other hand, chemical modification utilizes the alteration of RNA structures via the addition of covalent bonds such as N-acetylgalactosamine or antibodies (antibody–oligonucleotide conjugates) to target specific receptors of cells. The pros and cons of these technologies are enlisted in this review. We aim to review nucleic acid drugs, their delivery systems, targeting strategies, and related chemical modifications. Finally, we express our perspective on the potential combination of RNA-based click chemistry with adoptive cell therapy (e.g., B cells or T cells) to address the issues of short duration and short half-life associated with antibody–oligonucleotide conjugate drugs.
Use of Guazuma ulmifolia Lam. Stem Bark Extracts to Prevent High-Fat Diet Induced Metabolic Disorders in Mice
Authors: Rodrigues Elisana Lima , Santana Lidiani Figueiredo , Nascimento Valter Aragão do , Arakaki Marcel Asato , Cardoso Claudia Andréa Lima , Filiú Wander Fernando de Oliveira , Guimarães Rita de Cássia Avellaneda , Hiane Priscila Aiko , Freitas Karine de Cássia
Published: August 2024

This study aimed to evaluate the effects of supplementation with ethanolic and aqueous extracts from the bark of the stem of Guazuma ulmifolia in mice submitted to a high-fat diet as well as to evaluate the chemical composition of these extracts. The chemical composition and antioxidant potential was evaluated in aqueous and ethanolic extracts of the stem bark. The in vivo test consisted of evaluating the effects of the aqueous and ethanolic extracts of the stem bark on C57BL/6 mice receiving a high-fat diet. The animals were evaluated for weight gain, feed consumption, visceral adiposity, serum, and inflammatory and hormonal parameters. The results of the chemical analyses corroborate those obtained by the literature, which reported gallocatechin, epigallocatechin and epigallocatechin gallate. Compared with the ethanolic extract, the aqueous extract showed greater antioxidant capacity. Both extracts resulted in lower feed consumption in the animals, but they did not influence weight gain or visceral adiposity and resulted in varied changes in the lipid profile. In addition, they did not influence glucose tolerance, insulin sensitivity, or fasting blood glucose. Furthermore, the leptin levels increased, which may have contributed to satiety, but this was shown to have a negative impact on other inflammatory and hormonal parameters. Therefore, under the conditions of this study, the biologically active compounds present in the plant species Guazuma ulmifolia were not able to contribute to the treatment of metabolic changes related to the consumption of a high-fat diet.
Bacterial Production of CDKL5 Catalytic Domain: Insights in Aggregation, Internal Translation and Phosphorylation Patterns
Authors: Colarusso Andrea , Lauro Concetta , Canè Luisa , Cozzolino Flora , Tutino Maria Luisa
Published: August 2024

Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase involved in human brain development and functioning. Mutations in CDKL5, especially in its catalytic domain, cause a severe developmental condition named CDKL5 deficiency disorder. Nevertheless, molecular studies investigating the structural consequences of such mutations are still missing. The CDKL5 catalytic domain harbors different sites of post-translational modification, such as phosphorylations, but their role in catalytic activity, protein folding, and stability has not been entirely investigated. With this work, we describe the expression pattern of the CDKL5 catalytic domain in Escherichia coli demonstrating that it predominantly aggregates. However, the use of solubility tags, the lowering of the expression temperature, the manual codon optimization to overcome an internal translational start, and the incubation of the protein with K+ and MgATP allow the collection of a soluble catalytically active kinase. Interestingly, the resulting protein exhibits hypophosphorylation compared to its eukaryotic counterpart, proving that bacteria are a useful tool to achieve almost unmodified CDKL5. Posing questions about the CDKL5 autoactivation mechanism and the determinants for its stability, this research provides a valuable platform for comparative biophysical studies between bacterial and eukaryotic-expressed proteins, contributing to our understanding of neurodevelopmental disorders associated with CDKL5 dysfunction.
Role and Regulatory Mechanism of circRNA_14820 in the Proliferation and Differentiation of Goat Skeletal Muscle Satellite Cells
Authors: Yang Pu , Li Xuelong , Liu Chengli , Han Yanguo , E Guangxin , Huang Yongfu
Published: August 2024

Skeletal muscle satellite cells (SMSCs), a type of myogenic stem cell, play a pivotal role in postnatal muscle regeneration and repair in animals. Circular RNAs (circRNAs) are a distinct class of non-coding RNA molecules capable of regulating muscle development by modulating gene expression, acting as microRNAs, or serving as protein decoys. In this study, we identified circ_14820, an exonic transcript derived from adenosine triphosphatase family protein 2 (ATAD2), through initial RNA-Seq analysis. Importantly, overexpression of circ_14820 markedly enhanced the proliferation of goat SMSCs while concomitantly suppressing their differentiation. Moreover, circ_14820 exhibited predominant localization in the cytoplasm of SMSCs. Subsequent small RNA and mRNA sequencing of circ_14820-overexpressing SMSCs systematically elucidated the molecular regulatory mechanisms associated with circ_14820. Our preliminary findings suggest that the circ_14820-miR-206-CCND2 regulatory axis may govern the development of goat SMSCs. These discoveries contribute to a deeper understanding of circRNA-mediated mechanisms in regulating skeletal muscle development, thereby advancing our knowledge of muscle biology.
Suppressive Effect of Black Soldier Fly Larvae Frass on Fusarium Wilt Disease in Tomato Plants
Authors: Arabzadeh Ghazaleh , Delisle-Houde Maxime , Vandenberg Grant W. , Deschamps Marie-Hélène , Dorais Martine , Derome Nicolas , Tweddell Russell J.
Published: August 2024

This study investigated the effect of black soldier fly larvae (BSFL) frass derived from BSFL reared on a diet composed of fruit/vegetable/bakery/brewery residues (FVBB diet) and on the Gainesville diet (GV diet) on the development of tomato (Solanum lycopersicum) Fusarium wilt caused by Fusarium oxysporum f. sp. lycopersici (FOL). Tomato plants were grown in a substrate inoculated with FOL that was amended (10%, v:v) or not (control) with either a commercial compost, pasteurized (70 °C for 1 h) frass from BSFL reared on a FVBB diet, non-pasteurized frass from BSFL reared on a FVBB diet, pasteurized frass from BSFL reared on the GV diet, or non-pasteurized frass from BSFL reared on the GV diet. The results show that frass from BSFL reared on the GV diet, irrespective of pasteurization, inhibited FOL root colonization and reduced the severity of tomato Fusarium wilt to a far greater extent than frass from BSFL reared on a FVBB diet and commercial compost made of peat, seaweed, and shrimps. This study suggests that BSFL frass, depending on the larval rearing diet, has the potential to serve as a pasteurized or non-pasteurized soil amendment with prophylactic properties against FOL in tomato plants, opening new avenues of research for the valorization of BSFL frass.
Extrinsic and Intrinsic Competition between Chouioa cunea Yang and Tetrastichus septentrionalis (Hymenoptera: Eulophidae), Two Pupal Parasitoids of the Fall Webworm, Hyphantria cunea (Lepidoptera: Erebidae)
Authors: Li Zhixin , Yang Liyuan , Ma Xi , Liu Xudan , Cheng Yiran , Sun Shouhui
Published: August 2024

The endoparasitoids Chouioa cunea Yang and Tetrastichus septentrionalis Yang (Hymenoptera: Eulophidae) are both gregarious pupal parasitoids of the fall webworm, Hyphantria cunea (Drury) (Lepidoptera: Erebidae). In order to analyze the competitive interactions between both parasitoids exploiting H. cunea, we assessed both extrinsic and intrinsic competition. The search time, oviposition duration, and oviposition frequency were used as evaluation criteria for extrinsic competition. The number of survival days, female ratio, and number of parasitoids emerging from the host were used as evaluation criteria for intrinsic competition. The results indicated that both parasitoid species were able to parasitize hosts that were already parasitized by competitors. The first released species consistently emerged as the superior competitor in multiparasitized hosts. Both parasitoid release orders and time intervals between oviposition affect the competition of parasitoids and the parasitic efficiency. The results emphasize the parasitic abilities of both parasitoid species and provide a basis for future research on competition mechanisms and biological control of H. cunea.
Robotic versus Mini-Laparoscopic Colposacropexy to Treat Pelvic Organ Prolapse: A Retrospective Observational Cohort Study and a Medicolegal Perspective
Authors: Billone Valentina , Gullo Giuseppe , Perino Girolamo , Catania Erika , Cucinella Gaspare , Ganduscio Silvia , Vassiliadis Alessandra , Zaami Simona
Published: August 2024

Background: POP (pelvic organ prolapse) involves the descent of one or more pelvic organs downwards with or without protrusion from the vaginal opening, caused by the relaxation and weakening of ligaments, connective tissue, and pelvic muscles. Such an outcome negatively impacts the quality of life. The gold standard procedure for repairing apical compartment prolapse is colposacropexy (CS) to secure the anterior and posterior walls of the vagina to the anterior longitudinal sacral ligament, located anteriorly to the sacral promontory, using a mesh. Several surgical approaches are feasible. Laparotomic or minimally invasive methods, including laparoscopic or robotic ones, can restore the horizontal axis of the vagina and typically involve concomitant hysterectomy. Methods: This study is based on 80 patients who underwent CS at Palermo’s Ospedali Riuniti Villa Sofia-Cervello from 2019 to 2023. Women aged 35–85 at the time of surgery were divided into two groups: 40 patients underwent mini-laparoscopic surgery, and 40 patients underwent robotic surgery. The following parameters were accounted for: demographic data (initials of name and surname, age), preoperative clinical diagnosis, date of surgery, surgical procedure performed, estimated intraoperative blood loss, duration of surgical intervention, length of hospital stay, postoperative pain assessed at 24 h using the VAS scale, and any complications occurring in the postoperative period. Mini-laparoscopic CS (Minilap) and robotic CS (Rob) were then compared in terms of outcomes. Results: In the Minilap group, 11 patients out of 40 had a preoperative diagnosis of vaginal vault prolapse. The average age in this group was 61.6. Five of these patients had isolated cystocele, while the rest presented vaginal stump prolapse linked to cystocele, rectocele, or both. The remaining 29 patients in the Minilap group had a preoperative diagnosis of uterovaginal prolapse, also associated with cystocele, rectocele, or both, or isolated in nine cases. In the Rob group (average age: 60.1), 13 patients were diagnosed with vaginal prolapse (isolated or associated with cystocele), while the remaining 27 had a diagnosis of uterovaginal prolapse. In the Minilap group, the average procedure duration was 123.3 min, shorter than the Rob group (160.1 min). Conclusions: The data collected throughout this prospective study point to the mini-laparoscopic approach as being preferable over the robotic one in terms of surgical procedure length, intraoperative blood loss, postoperative pain, and aesthetic outcome. Hospital stay duration and post operative complication rates were similar for both groups. The innovative and ever-progressing nature of such procedures calls for novel standards prioritizing patient care as well as medicolegal viability.
Efficacy and Safety of Immune Checkpoint Inhibitor Combination Therapy for Dysphagia in Patients with Advanced Esophageal Cancer
Authors: Nakayama Yurika , Ando Takayuki , Takagi Hiroaki , Motoo Iori , Ueda Yuko , Sakumura Miho , Kajiura Shinya , Takahashi Saeko , Shimada Seitaro , Takashima Yusuke , Fujinami Haruka , Ogawa Kohei , Tamura Hotaka , Hosokawa Ayumu , Yasuda Ichiro
Published: August 2024

Background/Objectives: Recently, pembrolizumab plus 5-fluorouracil and cisplatin (FP), nivolumab plus FP, and nivolumab plus ipilimumab have become the first-line treatments for patients with advanced esophageal cancer. However, the treatment efficacy in primary tumors has not been reported. We assessed the outcomes of these treatments in advanced esophageal cancer, specifically focusing on esophageal dysphagia improvements and the primary tumor response. Methods: This retrospective study was conducted between October 2021 and November 2023. We investigated 23 patients with esophageal cancer and dysphagia who received an immune checkpoint inhibitor (ICI) plus FP or nivolumab plus ipilimumab. Results: The median progression-free survival (PFS) was 10.6 months (95% confidence interval [CI]: 9.0–12.5), and the median overall survival was not reached (95%CI: 13.0–NA). Improvement in dysphagia was observed in 19/23 (82.6%) patients, with a median time to improvement of 26 days (range: 15–77 days) and a median dysphagia PFS of 12.6 months (range: 8.1–NA months). Ten patients experienced immune-related adverse events (irAEs): seven had interstitial pneumonia, and three had thyroid dysfunction, pituitary dysfunction, and rash, respectively. Conclusions: Although there was a high frequency of irAEs, ICI for esophageal cancer achieved high response rates and prolonged survival. The observed improvement in dysphagia suggests the potential efficacy of the treatment against primary tumors.