Search Results (131)

Aging in females affects the ovaries before any other organ. This has a significant impact on women’s health. Aging results in the gradual depletion of ovarian follicles and a decline in oocyte quality. Studies have shown that cellular changes within ovaries manifest before the depletion of ovarian follicles. To understand the molecular mechanisms underlying these changes, we conducted a comprehensive analysis of gene expression changes in aging mouse ovaries. When RNA sequencing data from 6-month-old mice were compared to those from 12-month-old mice, we identified numerous differentially expressed genes, as well as transcript variants. Transcript variants arise from alternative transcription start sites (TSSs) and alternative pre-mRNA processing. Therefore, we further analyzed a specific set of regulators for these cellular processes. Our findings indicate that ovarian aging alters the expression of epigenetic regulators (ERs) and transcription factors (TFs) that are involved in alternative TSS usage. Ovarian aging also affects the expression of RNA-binding proteins (RBPs) and spliceosome components (SPs), which are essential for pre-mRNA processing. We noticed that variations in transcript variants were more pronounced than those found through gene expression analysis. While 8% of the known TFs and ERs were differentially expressed at the gene level, this increased to 30% at the transcript variant level. Similarly, 3% of the known RBPs but no known SPs were differentially expressed at the gene level, while this increased to 30% at the transcript variant level. These observations highlight the importance of focusing on transcript variants and their functions in aging research, as they may provide insight into the underlying biological processes involved. Full article

Background/objectives: The COVID-19 pandemic affected cancer care globally. Our objective was to analyze the demographic and clinical characteristics of kidney cancer (KC) patients between the pre-COVID-19 and COVID-19 periods. We also aimed to assess how KC was discovered—incidentally or symptomatically—and identify factors predicting the mode of discovery and advanced-stage disease. Methods: This retrospective study analyzed data from 400 patients aged 18 years or older diagnosed with kidney cancer (KC) at a large regional Hungarian clinical center during two time periods: the pre-COVID-19 period (1 January 2019 to 15 March 2020) and the COVID-19 period (16 March 2020 to 13 May 2021). Demographic and clinical information, including the mode of cancer discovery, was collected for all patients. Results: During the pandemic, monthly kidney cancer diagnoses declined by 10.3%. The proportion of female patients rose significantly from 31.9% to 42.9% (p = 0.023). Incidental tumor detection decreased from 82.4% to 72.4% (p = 0.018), while symptomatic presentation increased from 14.2% to 19.4%, although not significantly (p = 0.166). Non-incidental detection was associated with a 3.42-fold increase in odds of advanced cancer pre-pandemic and a 2.03-fold increase during the pandemic. Symptomatic presentation raised these odds by 4.51 and 2.76 times, respectively. Conclusions: Our study revealed changes in kidney cancer detection during the pandemic, including a rise in the proportion of female patients and a decline in case numbers, likely due to reduced incidental findings. Non-incidental discovery and symptom presence remained predictors of advanced-stage disease, although the odds were lower. Various factors—such as changes in healthcare access and gender-related differences in health-seeking behavior—may possibly explain these changes. Our findings support the critical role of incidental detection in high-risk populations. Full article

Background: Over the last two decades, a fair number of echocardiographic studies have investigated the influence of metabolic dysfunction-associated steatotic liver disease (MASLD) on myocardial strain and strain rate parameters assessed by speckle tracking echocardiography (STE) in individuals without overt heart disease, reporting not univocal results. We aimed at analyzing the main findings of these studies. Methods: All studies examining conventional echoDoppler parameters by transthoracic echocardiography (TTE) and left ventricular (LV) mechanics [LV-global longitudinal strain (GLS), LV-global strain rate in systole (GSRs), in early diastole (GSRe) and late diastole (GSRl)] by STE in MASLD patients without known heart disease vs. healthy individuals, were searched on PubMed, Embase and Scopus databases. The primary endpoint was to quantify the effect of MASLD on LV-GLS in individuals without overt cardiac disease. Continuous data [LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and left ventricular ejection fraction (LVEF)] were pooled as the standardized mean difference (SMD) comparing MASLD cohorts with healthy controls. Results: A total of 11 studies were included, totaling 1348 MASLD patients and 6098 healthy controls. Overall, MASLD showed a medium effect on LV-GLS (SMD −0.6894; 95%CI −0.895, −0.472, p < 0.001) and LV-GLSRs (SMD −0.753; 95%CI −1.501, −0.006, p = 0.048), a large effect on LV-GLSRe (SMD −0.837; 95%CI −1.662, −0.012, p = 0.047) and a small and not statistically significant effect on LV-GLSRl (SMD −0.375; 95%CI −1.113, 0.363, p = 0.319) and LVEF (SMD −0.134; 95%CI −0.285, 0.017, p = 0.083). The overall I² statistic was 86.4%, 89.4%, 90.9%, 89.6% and 72.5% for LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and LVEF studies, respectively, indicating high between-study heterogeneity. Egger’s test for LV-GLS studies gave a p value of 0.11, 0.26, 0.40, 0.32 and 0.42 for LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and LVEF studies, respectively, thus excluding publication bias. Meta-regression analysis excluded any correlation between potential confounders and LV-GLS in MASLD individuals (all p > 0.05). Sensitivity analysis confirmed the robustness of study results. Conclusions: MASLD has a medium effect on LV-GLS, independently of demographics, anthropometrics and the cardiovascular disease burden. STE analysis may allow early detection of subclinical LV systolic dysfunction in MASLD patients, potentially identifying those who may develop heart failure later in life. Full article

The proliferation of trophoblast stem (TS) cells and their differentiation into multiple lineages are pivotal for placental development and functions. Various transcription factors (TFs), such as CDX2, EOMES, GATA3, TFAP2C, and TEAD4, along with their binding sites and cis-regulatory elements, have been studied for their roles in trophoblast cells. While previous studies have primarily focused on individual enhancer regions in trophoblast development and differentiation, recent attention has shifted towards investigating the role of super-enhancers (SEs) in different trophoblast cell lineages. SEs are clusters of regulatory elements enriched with transcriptional regulators, forming complex gene regulatory networks via differential binding patterns and the synchronized stimulation of multiple target genes. Although the exact role of SEs remains unclear, they are commonly found near master regulator genes for specific cell types and are implicated in the transcriptional regulation of tissue-specific stem cells and lineage determination. Additionally, super-enhancers play a crucial role in regulating cellular growth and differentiation in both normal development and disease pathologies. This review summarizes recent advances on SEs’ role in placental development and the pathophysiology of placental diseases, emphasizing the potential for identifying SE-driven networks in the placenta to provide valuable insights for developing therapeutic strategies to address placental dysfunctions. Full article

Background/Objectives: Nisin A, an antimicrobial peptide produced by Lactococcus lactis, primarily shows antimicrobial activity against Gram-positive bacteria, with efficacy increased when used in combination with an antimicrobial drug. On the other hand, oral candidiasis, caused by Candida, occurs in immunocompromised patients and requires antifungal therapy. However, antifungal drug-resistant Candida strains are increasing worldwide, leading to serious problems. Methods: To examine the effects of nisin A against Candida species, we investigated the combined effects of nisin A and antifungal drugs on the growth and viability of Candida strains. Results: While nisin A alone had no antifungal effect, together with amphotericin (AMPH), it showed synergistic effects towards C. albicans, as well as the non-albican strains C. glabrata, C tropicalis, and C. parapsilosis in checkerboard assay results. Furthermore, nisin A with miconazole (MCZ) or micafungin (MCFG) demonstrated a synergistic or additive effect on those strains. Cell viability assay results showed that nisin A enhanced the fungicidal activity of AMPH against both C. albicans and C. glabrata. Biofilm reduction assays showed that nisin A with AMPH, MCZ, or MCFG inhibited biofilm activity against C. albicans as compared with each antifungal drug alone. Finally, nisin A with AMPH, MCZ, or MCFG resulted in a reduced minimum inhibitory concentration of those antifungal drugs against clinically isolated C. albicans and C. glabrata.Conclusions: When used in combination with nisin A, the antifungal drug dosage can be lowered, thus helping to prevent adverse side effects and the emergence of drug-resistant oral Candida species. Full article

Most eukaryotic genes express more than one mature mRNA, defined as transcript variants. This complex phenomenon arises from various mechanisms, such as using alternative transcription start sites and alternative post-transcriptional processing events. The resulting transcript variants can lead to synthesizing proteins that possess distinct functional domains or may even generate noncoding RNAs, each with unique roles in cellular processes. The generation of these transcript variants is not merely a random occurrence; it is cell-type specific and varies with developmental stages, aging processes, or pathogenesis of diseases. This highlights the biological significance of transcript variants in regulating gene expression and their potential impact on cellular functionality. Despite the biological importance, investigating transcript variants has been hampered by challenges associated with detecting their expression. This review article addresses the advancements in molecular techniques in detecting transcript variants. Traditional methods such as RT-PCR and RT-qPCR can easily detect known transcript variants using primers that target unique exons associated with the variants. Other techniques like RACE-PCR and hybridization-based methods, including Northern blotting, RNase protection assays, and microarrays, have also been utilized to detect transcript variants. Nevertheless, RNA sequencing (RNA-Seq) has emerged as a powerful technique for identifying transcript variants, especially those with previously unknown sequences. The effectiveness of RNA sequencing in transcript variant detection depends on the specific sequencing approach and the precision of data analysis. By understanding the strengths and weaknesses of each laboratory technique, researchers can develop more effective strategies for detecting mRNA transcript variants. This ability will be crucial for our comprehensive understanding of gene regulation and the implications of transcript diversity in various biological contexts. Full article

Background: Respiratory syncytial virus (RSV) is a common cause of acute respiratory infection (ARI). The risk of severe RSV outcomes is higher among older adults (OAs) and individuals with chronic diseases (high risk, HR). AS01_E-adjuvanted RSV preFusion protein 3 OA vaccine (adjuvanted RSVPreF3 OA is approved for the prevention of lower respiratory tract disease [LRTD] due to RSV in OAs). The objective of this study was to assess the potential public health impact of an RSV vaccination program using adjuvanted RSVPreF3 OA in adults ≥75 years (y) and HR adults ≥60 y in Italy. Methods: A static multi-cohort Markov model was used to estimate the number of RSV cases and associated health outcomes projected in adults ≥75 y and HR adults ≥60 y with no RSV vaccination or with a single dose of adjuvanted RSVPreF3 OA. Epidemiological, healthcare resource use and cost data were obtained from the scientific literature. Vaccine efficacy and waning inputs were based on results from the AReSVi-006 phase III clinical trial. Several scenarios for vaccine coverage were explored. Results: Assuming the target vaccination rate for influenza vaccination in Italy (75%), the model predicted that vaccinating Italian adults ≥75 y and the HR population ≥ 60 y with adjuvanted RSVPreF3 OA would reduce the number of RSV-LRTD events by 43%, leading to a reduction in associated emergency department visits, hospitalizations, complications, deaths, and direct healthcare costs over a 3-year period. Conclusions: The vaccination of Italians aged ≥ 75 y and HR individuals aged ≥ 60 y using the adjuvanted RSVPreF3 OA vaccine has the potential to offer substantial public health benefits by reducing the burden of RSV disease. Full article

The objective of the study was to examine the relationship between rumination time and various parameters related to eating and locomotion, including other chews, eating chews, eating time, drinking gulps, bolus counts, chews per minute, activity, and activity change, utilizing RumiWatch technology. The RumiWatch noseband sensor (RWS; ITIN + HOCH GmbH, Feeding Technology, Liestal, Switzerland) was utilized to record time and frequency related to rumination, eating, and movement behaviors. The RumiWatch system (RWS) was put into operation from 1 June 2023 to 30 June 2023. The first two weeks, from 1 June to 14 June 2023 at 7 a.m., served as a period for the cows to acclimate to the RWS, acting as an adjustment phase. Monitoring activities with the RWS commenced on 7 a.m. and lasted until the end of the month, 30 June 2023, with data being recorded daily on an hourly basis. Our findings indicate a significant negative correlation between rumination time and other activity time (r = −0.50), which represents the duration cows allocate to behaviors outside of eating, chewing cud, or distinct movement activities. Additionally, a significant negative correlation was observed between rumination time and eating time (r = −0.54). Furthermore, we observed strong positive correlations with rumination chews (r = 0.84) and bolus (r = 0.75). A weaker positive correlation was found with chews per minute (r = 0.29), while no significant correlation was detected with drinking gulps (r = 0.10). Based on our findings, we recommend the implementation of the RumiWatch System for monitoring rumination and feeding behaviors in lactating dairy cattle. This technology provides valuable insights into cow health and welfare, enabling early detection of potential health issues and improving herd management practices. Full article

Gene expression or gene regulation studies often assume one gene expresses one mRNA. However, contrary to the conventional idea, a single gene in mammalian cells can express multiple transcript variants translated into several different proteins. The transcript variants are generated through transcription from alternative start sites and alternative post-transcriptional processing of the precursor mRNA (pre-mRNA). In addition, gene mutations and RNA editing further enhance the diversity of the transcript variants. The transcript variants can encode proteins with various domains, expanding the functional repertoire of a single gene. Some transcript variants may not encode proteins but function as non-coding RNAs and regulate gene expression. The expression level of the transcript variants may vary between cell types or within the same cells under different biological conditions. Transcript variants are characteristic of cell differentiation in a particular tissue, and the variants may play a key role in normal development and aging. Studies also reported that some transcript variants may have roles in disease pathogenesis. The biological significances urge studying the complexity of gene expression at the transcript level. This article updates the molecular basis of transcript variants in mammalian cells, including the formation mechanisms and potential roles in host biology. Gaining insight into the transcript variants will not only identify novel mechanisms of gene regulation but also unravel the role of the variants in health and disease. Full article

Background/objectives: The goal of this investigation was to compare the time to biopsy (TBI) and time to treatment (TTI) for head and neck squamous cell carcinoma (HNSCC) patients before and during the COVID-19 pandemic and to examine the effect of demographic and clinical characteristics on these intervals. Methods: Our retrospective study at a large regional Hungarian cancer center analyzed data from patients aged 18 or older diagnosed with HNSCC between 1 January 2017 and 15 March 2020 (pre-COVID-19 period) and 16 March 2020 to 13 May 2021 (COVID-19 period). We calculated the time from initial physician contact to biopsy (TBI) and from biopsy to treatment initiation (TTI) and performed descriptive and exploratory statistical analyses. Results: The median TBI decreased significantly (6 vs. 3 days; p = 0.008), while the median TTI was not affected significantly (28 vs. 29 days; p = 0.972) pre-pandemic and during the pandemic, respectively. Residence in a village was linked to a significant reduction in median TBI during the pandemic (p = 0.000), coinciding with a higher proportion of rural patients diagnosed with oral cavity/oropharyngeal cancers during the pandemic (50.3% pre-pandemic vs. 67.4% during pandemic, p = 0.044). Median TTI decreased significantly during the pandemic for patients with laryngeal tumors (27.5 vs. 18.5 days; p = 0.012). Conclusions: Our study, one of a few from this region, provides insights into HNSCC patient waiting times. Improvement in TBI likely resulted from the availability of telemedicine, reduced diagnostic demands from non-cancer patients, and an increased incidence of oral cavity/oropharyngeal cancer among rural patients. Full article

We analyzed the transcriptome data of wildtype and estrogen receptor β knockout (Erβ^KO) rat ovaries during the early postnatal period and detected remarkable changes in epigenetic regulators and transcription factors. Compared with postnatal day (PD) 4.5 ovaries, PD 6.5 wildtype ovaries possessed 581 differentially expressed downstream transcripts (DEDTs), including 17 differentially expressed epigenetic regulators (DEERs) and 23 differentially expressed transcription factors (DETFs). Subsequently, compared with PD 6.5 ovaries, PD 8.5 wildtype ovaries showed 920 DEDTs, including 24 DEERs and 68 DETFs. The DEDTs, DEERs, and DETFs in wildtype ovaries represented the gene expression during primordial follicle activation and the gradual development of primary follicles of first-wave origin because the second-wave follicles remained dormant during this developmental period. When we compared the transcriptome data of age-matched Erβ^KO ovaries, we observed that PD 6.5 Erβ^KO ovaries had 744 DEDTs compared with PD 4.5 ovaries, including 46 DEERs and 55 DETFs. The loss of ERβ rapidly activated the primordial follicles of both first- and second-wave origin on PD 6.5 and showed a remarkable increase in DEDTs (744 vs. 581). However, compared with PD 6.5 ovaries, PD 8.5 Erβ^KO ovaries showed only 191 DEDTs, including 8 DEERs and 10 DETFs. This finding suggests that the PD 8.5 Erβ^KO ovaries did not undergo remarkable ovarian follicle activation greater than that had already occurred in PD 6.5 Erβ^KO ovaries. The results also showed that the numbers of DEERs and DETFs were associated with increased changes in DEDTs; the greater the number of DEERs or DETFs, the larger the number of DEDTs. In addition to the quantitative differences in DEERs and DETFs between the wildtype and Erβ^KO ovaries, the differentially expressed regulators showed distinct patterns. We identified that 17 transcripts were tied to follicle assembly, 6 to follicle activation, and 12 to steroidogenesis. Our observations indicate that a loss of ERβ dysregulates the epigenetic regulators and transcription factors in Erβ^KO ovaries, which disrupts the downstream genes in ovarian follicles and increases follicle activation. Further studies are required to clarify if ERβ directly or indirectly regulates DEDTs, including DEERs and DETFs, during the neonatal development of rat ovarian follicles. Full article

Objectives: This study aimed to determine the positive predictive value of our NMD Suspicion Criteria in the diagnosis of NMDs. Other clinical factors routinely examined in our voice and swallowing examinations were also investigated to see if they had a significant association with the diagnosis of NMDs. Methods: This study retrospectively investigated the medical charts of patients who visited our Voice and Swallowing outpatient clinic between 2013 and 2022. Patients with previously diagnosed NMDs were excluded from the analysis. Among the remaining patients, we included those that were referred to neurologists for further evaluation due to suspicion of having an NMD based on the NMD Suspicion Criteria. The patients were then divided into groups according to the status of their diagnosis within 2 years of referral as “diagnosed”, “denied”, or “observed”. These three groups of patients were then compared according to the following clinical findings; velopharyngeal insufficiency (VPI), tongue atrophy, impaired tongue movement, dysarthria, vocal fold mobility impairment, dysphagia, involuntary movement, gait disturbances, weight loss, and a sense of fatigue in order to see if they were significantly associated with the diagnosis of NMDs. Results: Of 3769 outpatients without a confirmed diagnosis of NMDs, 37 were referred to neurologists for suspected NMDs, and 19 (51%) were diagnosed with NMDs. VPI and impaired tongue movement were significant diagnostic factors for NMDs (p = 0.014, 0.033). VPI during speech (p = 0.045) was more strongly associated with the diagnosis of NMDs than VPI during swallowing (p = 0.076). Fatigue was a significant related factor for other diseases (non-NMDs) causing Voice and Swallowing problems (p = 0.049). Conclusions: In the outpatient clinic setting, suspicion of NMD should be raised, particularly when VPI and impaired tongue movement are observed, prompting a thorough assessment of velopharyngeal closure during both speech and swallowing. Full article

This study investigated the effect of combining radiation with an angiogenesis inhibitor and vascular disrupting agent on tumor response and systemic toxicity. CDF1 mice with 200 mm³ foot implanted C3H mammary carcinomas were treated with TNP-470 (100 mg/kg every second day for 2 weeks; s.c.) and combretastatin A-4 phosphate (CA4P; 1 × 250 mg/kg, i.p.). Radiation (230-kV X-rays) was locally administered to tumors of restrained non-anesthetized mice. Response was tumor growth delay and change in mouse body weight. Radiation induced changes in serum levels of 10 cytokines up to 72-h after irradiation were measured using a Luminex assay. The results showed that TNP-470 (100 mg/kg × 7) or CA4P (250 mg/kg × 1) significantly (Student’s t-test; p < 0.05) inhibited tumor growth; the greatest effect when these two drugs were combined. TNP-470 and CA4P, alone or together, also significantly enhanced tumor response to radiation. No systemic toxicity occurred with drugs administered alone or in combination, but toxicity was observed when TNP-470 was combined with radiation. Serum cytokine levels only showed a significant transient increase in IL-6 1-h after irradiating. In conclusion, combining different acting vascular targeting agents with radiation increased anti-tumor activity. However, this benefit may sometimes be associated with a radiation-induced inflammatory response increasing systemic toxicity. Full article

Organic compounds with antibacterial and antiparasitic properties are gaining significance for biomedical applications. This study focuses on the solvent-free synthesis (green synthesis) of 1,4-naphthoquinone or 2,3-dichloro-1,4-naphthoquinone with different phenylamines using silica gel as an acid solid support. The study also includes in silico PASS predictions and the discovery of antibacterial and antiparasitic properties of phenylaminonaphthoquinone derivatives 1–12, which can be further applied in drug discovery and development. These activities were discussed in terms of molecular descriptors such as hydrophobicity, molar refractivity, and half-wave potentials. The in vitro antimicrobial potential of the synthesized compounds 1–12 was evaluated against a panel of six bacterial strains (three Gram-positive: Staphylococcus aureus, Proteus mirabilis, and Enterococcus faecalis; and three Gram-negative bacteria: Escherichia coli, Salmonella typhimurium, and Klebsiella pneumoniae). Six compounds (1, 3, 5, 7, 10, and 11) showed better activity toward S. aureus with MIC values between 3.2 and 5.7 μg/mL compared to cefazolin (MIC = 4.2 μg/mL) and cefotaxime (MIC = 8.9 μg/mL), two cephalosporin antibiotics. Regarding in vitro antiplasmodial activity, compounds 1 and 3 were the most active against the Plasmodium falciparum strain 3D7 (chloroquine-sensitive), displaying IC₅₀ values of 0.16 and 0.0049 μg/mL, respectively, compared to chloroquine (0.33 μg/mL). In strain FCR-3 (chloroquine-resistant), most of the compounds showed good activity, with compounds 3 (0.12 μg/mL) and 11 (0.55 μg/mL) being particularly noteworthy. Additionally, docking studies were used to better rationalize the action and prediction of the binding modes of these compounds. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed. Full article

We report on two mechanisms of angularly selective enhanced screening in the solid vortex phase of extremely layered superconductors with tilted columnar defects (CDs). We study Bi₂Sr₂CaCu₂O_8+δ samples with different densities of CD tilted 45° from the c-axis, and conduct local ac Hall magnetometry measurements, probing the sustainable current of the vortex system. We reveal two types of maxima in sustainable current for particular directions, detected as dips in the magnetic transmittivity of the vortex system. First, for a smaller number of vortices than of defects, an enhancement of screening is detected at an angular location ${\Theta }_{\mathrm{dip}}^1$∼45° for H applied close to the direction of CD. For a larger number of vortices than of CD, ${\Theta }_{\mathrm{dip}}^1$ decreases towards the $ab$-plane direction upon warming. Second, a pair of additional dips in transmittivity are detected at angles ${\Theta }_{dip}^2$ closer to, and quite symmetric with, the $ab$-plane. These two types of angularly selective enhanced screening reveal the effective pinning by tilted CD even for the composite vortex lattices nucleated in tilted fields in Bi₂Sr₂CaCu₂O_8+δ. Full article