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Tobacco Induced Diseases 2024The e-cigarette market is large and diverse. Traditional smoking cessation trials involving a control group and a 6-month observation period are an inefficient...
INTRODUCTION
The e-cigarette market is large and diverse. Traditional smoking cessation trials involving a control group and a 6-month observation period are an inefficient methodology for testing the multiple treatment options e-cigarettes provide for harm reduction in cigarette smokers. We determined when product substitution occurred in the e-cigarette provision arm of an e-cigarette substitution trial for cigarette smokers who were not interested in quitting.
METHODS
We conducted a secondary analysis of 120 cigarette smokers with severe mental illness (recruitment 2017-2020) who were given disposable e-cigarettes for 8 weeks and assessed at weeks 0 (t0), 2, 4, 6, and 8. We explored product substitution through visit-to-visit correlations in change in product use, then developed a dual process growth model for cigarette and e-cigarette use to test the association between increases in e-cigarette use and concurrent decreases in cigarettes smoked.
RESULTS
Mean age of the participants was 45.9 years, and 42.7% smoked ≥20 cigarettes per day. Almost all product substitution occurred between t0 and t2. For the average smoker (18 cigarettes per day), t2 cigarette frequency decreased by 0.39 (95% CI: -0.56 - -0.22) cigarettes for each additional e-cigarette session. There was effect modification (p=0.033), such that baseline light smokers (<10 cigarettes/day) had no significant decrease in t2 cigarette frequency, regardless of their initial increase in e-cigarette use, while heavy smokers (38 cigarettes/day) switched products nearly on a one-to-one basis.
CONCLUSIONS
In this study, most product substitution occurred early, and heavier smokers had larger t2 decreases in cigarettes/day with increased e-cigarette use. If confirmed with replication studies, the findings could suggest establishment of a novel outcome for e-cigarette studies - early product substitution - and support the value of short-term comparative effectiveness trials that compare multiple potentially lower harm tobacco products.
CLINICAL TRIAL REGISTRATION
The study was registered on the official website of ClinicalTrials.gov.
IDENTIFIER
ID NCT03050853.
PubMed: 38873183
DOI: 10.18332/tid/189220 -
Water Research X May 2024The impacts of climate change on hydrology underscore the urgency of understanding watershed hydrological patterns for sustainable water resource management. The...
The impacts of climate change on hydrology underscore the urgency of understanding watershed hydrological patterns for sustainable water resource management. The conventional physics-based fully distributed hydrological models are limited due to computational demands, particularly in the case of large-scale watersheds. Deep learning (DL) offers a promising solution for handling large datasets and extracting intricate data relationships. Here, we propose a DL modeling framework, incorporating convolutional neural networks (CNNs) to efficiently replicate physics-based model outputs at high spatial resolution. The goal was to estimate groundwater head and surface water depth in the Sabgyo Stream Watershed, South Korea. The model datasets consisted of input variables, including elevation, land cover, soil type, evapotranspiration, rainfall, and initial hydrological conditions. The initial conditions and target data were obtained from the fully distributed hydrological model HydroGeoSphere (HGS), whereas the other inputs were actual measurements in the field. By optimizing the training sample size, input design, CNN structure, and hyperparameters, we found that CNNs with residual architectures (ResNets) yielded superior performance. The optimal DL model reduces computation time by 45 times compared to the HGS model for monthly hydrological estimations over five years (RMSE 2.35 and 0.29 m for groundwater and surface water, respectively). In addition, our DL framework explored the predictive capabilities of hydrological responses to future climate scenarios. Although the proposed model is cost-effective for hydrological simulations, further enhancements are needed to improve the accuracy of long-term predictions. Ultimately, the proposed DL framework has the potential to facilitate decision-making, particularly in large-scale and complex watersheds.
PubMed: 38872710
DOI: 10.1016/j.wroa.2024.100228 -
Frontiers in Aging Neuroscience 2024The observational association between cathepsin and Parkinson's disease (PD) has been partially explored in previous research. However, the causal relationship remains...
OBJECTIVE
The observational association between cathepsin and Parkinson's disease (PD) has been partially explored in previous research. However, the causal relationship remains unclear. In this study, our objective is to investigate the causal link between cathepsin and PD using Mendelian randomization (MR) analysis and elucidate the underlying mechanisms governing their interaction.
METHODS
Utilizing bidirectional two-sample MR and multivariable MR, we systematically investigates the causal relationship between nine cathepsins and PD. The data pertaining to cathepsins were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project, while data related to PD were sourced from versions R9 and R10 of the FinnGen database. The primary analytical method utilized was the inverse variance weighted (IVW), with MR analysis initially conducted using PD data from R9, complemented by a series of sensitivity analyses. Subsequently, replication analysis was performed on the R10 dataset, and meta-analysis were employed to merge the findings from both datasets. To explore potential mechanisms by which Cathepsins may impact PD, MR analyses were performed on significant Cathepsins with alpha-synuclein. MR analysis and colocalization analysis were conducted on expression quantitative trait loci (eQTL) data of gene related to alpha-synuclein with PD data.
RESULT
Forward MR analyses revealed more cathepsin B (CTSB) associated with less PD risk (OR = 0.898, 95%CI: 0.834-0.966, = 0.004), while more cathepsin H (CTSH) (OR = 1.076, 95%CI: 1.007-1.149, = 0.029) and more cathepsin S (CTSS) (OR = 1.076, 95%CI: 1.007-1.150, = 0.030) associated with increasing PD risk. Meta-analyses validated these associations. Multivariate MR Results were consistent with those before adjustment. No significant results were observed in bidirectional MR analysis. In the investigation of the underlying mechanism, our findings demonstrate that CTSB significantly reduces the levels of alpha-synuclein (OR = 0.909, 95%CI: 0.841-0.983, = 0.017). Concurrently, a genetically determined positive correlation between alpha-synuclein and PD is illuminated by both eQTL MR and colocalization analysis.
CONCLUSION
In conclusion, this MR study yields robust evidence suggesting an association between elevated levels of CTSB and reduced PD risk, mediated by the downregulation of alpha-synuclein levels. Conversely, higher levels of CTSH and CTSS are associated with an increased risk of PD. These findings offer novel insights into the pathophysiological mechanisms of PD and identify potential drug targets for disease prevention and treatment warranting further clinical investigations.
PubMed: 38872630
DOI: 10.3389/fnagi.2024.1394807 -
Cell Host & Microbe Jun 2024Aspects of how Burkholderia escape the host's intrinsic immune response to replicate in the cell cytosol remain enigmatic. Here, we show that Burkholderia has evolved...
Aspects of how Burkholderia escape the host's intrinsic immune response to replicate in the cell cytosol remain enigmatic. Here, we show that Burkholderia has evolved two mechanisms to block the activity of Ring finger protein 213 (RNF213)-mediated non-canonical ubiquitylation of bacterial lipopolysaccharide (LPS), thereby preventing the initiation of antibacterial autophagy. First, Burkholderia's polysaccharide capsule blocks RNF213 association with bacteria and second, the Burkholderia deubiquitylase (DUB), TssM, directly reverses the activity of RNF213 through a previously unrecognized esterase activity. Structural analysis provides insight into the molecular basis of TssM esterase activity, allowing it to be uncoupled from its isopeptidase function. Furthermore, a putative TssM homolog also displays esterase activity and removes ubiquitin from LPS, establishing this as a virulence mechanism. Of note, we also find that additional immune-evasion mechanisms exist, revealing that overcoming this arm of the host's immune response is critical to the pathogen.
Topics: Ubiquitination; Lipopolysaccharides; Humans; Burkholderia; Bacterial Proteins; Esterases; Immune Evasion; Ubiquitin-Protein Ligases; Host-Pathogen Interactions; Autophagy; Virulence
PubMed: 38870903
DOI: 10.1016/j.chom.2024.04.012 -
PloS One 2024This paper presents the initial exploration of the free radical scavenging capabilities of peptides derived from protein hydrolysates (PPH) obtained from Zingiber...
A novel peptide derived from Zingiber cassumunar rhizomes exhibits anticancer activity against the colon adenocarcinoma cells (Caco-2) via the induction of intrinsic apoptosis signaling.
This paper presents the initial exploration of the free radical scavenging capabilities of peptides derived from protein hydrolysates (PPH) obtained from Zingiber cassumunar rhizomes (Phlai). To replicate the conditions of gastrointestinal digestion, a combination of pepsin and pancreatin proteolysis was employed to generate these hydrolysates. Subsequently, the hydrolysate underwent fractionation using molecular weight cut-off membranes at 10, 5, 3, and 0.65 kDa. The fraction with a molecular weight less than 0.65 kDa exhibited the highest levels ABTS, DPPH, FRAP, and NO radical scavenging activity. Following this, RP-HPLC was used to further separate the fraction with a molecular weight less than 0.65 kDa into three sub-fractions. Among these, the F5 sub-fraction displayed the most prominent radical-scavenging properties. De novo peptide sequencing via quadrupole-time-of-flight-electron spin induction-mass spectrometry identified a pair of novel peptides: Asp-Gly-Ile-Phe-Val-Leu-Asn-Tyr (DGIFVLNY or DY-8) and Ile-Pro-Thr-Asp-Glu-Lys (IPTDEK or IK-6). Database analysis confirmed various properties, including biological activity, toxicity, hydrophilicity, solubility, and potential allergy concerns. Furthermore, when tested on the human adenocarcinoma colon (Caco-2) cell line, two synthetic peptides demonstrated cellular antioxidant activity in a concentration-dependent manner. These peptides were also assessed using the FITC Annexin V apoptosis detection kit with PI, confirming the induction of apoptosis. Notably, the DY-8 peptide induced apoptosis, upregulated mRNA levels of caspase-3, -8, and -9, and downregulated Bcl-2, as confirmed by real-time quantitative polymerase chain reaction (RT-qPCR). Western blot analysis indicated increased pro-apoptotic Bax expression and decreased anti-apoptotic Bcl-2 expression in Caco-2 cells exposed to the DY-8 peptide. Molecular docking analysis revealed that the DY-8 peptide exhibited binding affinity with Bcl-2, Bcl-xL, and Mcl-1, suggesting potential utility in combating colon cancer as functional food ingredients.
Topics: Humans; Apoptosis; Rhizome; Caco-2 Cells; Signal Transduction; Peptides; Colonic Neoplasms; Zingiberaceae; Adenocarcinoma; Antineoplastic Agents; Free Radical Scavengers
PubMed: 38870120
DOI: 10.1371/journal.pone.0304701 -
Heliyon Jun 2024Anti-SARS-CoV-2 and immunomodulatory drugs are important for treating clinically severe patients with respiratory distress symptoms. Alpha- and gamma-mangostins (AM and...
BACKGROUND
Anti-SARS-CoV-2 and immunomodulatory drugs are important for treating clinically severe patients with respiratory distress symptoms. Alpha- and gamma-mangostins (AM and GM) were previously reported as potential 3C-like protease (3CL) and Angiotensin-converting enzyme receptor 2 (ACE2)-binding inhibitors .
OBJECTIVE
We aimed to evaluate two active compounds, AM and GM, from for their antivirals against SARS-CoV-2 in live virus culture systems and their cytotoxicities using standard methods. Also, we aimed to prove whether 3CL and ACE2 neutralization were major targets and explored whether any additional targets existed.
METHODS
We tested the translation and replication efficiencies of SARS-CoV-2 in the presence of AM and GM. Initial and subgenomic translations were evaluated by immunofluorescence of SARS-CoV-2 3CL and N expressions at 16 h after infection. The viral genome was quantified and compared with the untreated group. We also evaluated the efficacies and cytotoxicities of AM and GM against four strains of SARS-CoV-2 (wild-type B, B.1.167.2, B.1.36.16, and B.1.1.529) in Vero E6 cells. The potential targets were evaluated using cell-based anti-attachment, time-of-drug addition, 3CL activities, and ACE2-binding using a surrogated viral neutralization test (sVNT). Moreover, additional targets were explored using combinatorial network-based interactions and Chemical Similarity Ensemble Approach (SEA).
RESULTS
AM and GM reduced SARS-CoV-2 3CL and N expressions, suggesting that initial and subgenomic translations were globally inhibited. AM and GM inhibited all strains of SARS-CoV-2 at EC of 0.70-3.05 μM, in which wild-type B was the most susceptible strain (EC 0.70-0.79 μM). AM was slightly more efficient in the variants (EC 0.88-2.41 μM), resulting in higher selectivity indices (SI 3.65-10.05), compared to the GM (EC 0.94-3.05 μM, SI 1.66-5.40). GM appeared to be more toxic than AM in both Vero E6 and Calu-3 cells. Cell-based anti-attachment and time-of-addition suggested that the potential molecular target could be at the post-infection. 3CL activity and ACE2 binding were interfered with in a dose-dependent manner but were insufficient to be a major target. Combinatorial network-based interaction and chemical similarity ensemble approach (SEA) suggested that fatty acid synthase (FASN), which was critical for SARS-CoV-2 replication, could be a target of AM and GM.
CONCLUSION
AM and GM inhibited SARS-CoV-2 with the highest potency at the wild-type B and the lowest at the B.1.1.529. Multiple targets were expected to integratively inhibit viral replication in cell-based system.
PubMed: 38867992
DOI: 10.1016/j.heliyon.2024.e31987 -
Translational Psychiatry Jun 2024Depression is a prevalent and incapacitating condition with a significant impact on global morbidity and mortality. Although the immune system's role in its pathogenesis...
Depression is a prevalent and incapacitating condition with a significant impact on global morbidity and mortality. Although the immune system's role in its pathogenesis is increasingly recognized, there is a lack of comprehensive understanding regarding the involvement of innate and adaptive immune cells. To address this gap, we conducted a multicenter case-control study involving 121 participants matched for sex and age. These participants had either an active (or current) major depressive episode (MDE) (39 cases) or a remitted MDE (40 cases), including individuals with major depressive disorder or bipolar disorder. We compared these 79 patients to 42 healthy controls (HC), analyzing their immunological profiles. In blood samples, we determined the complete cell count and the monocyte subtypes and lymphocyte T-cell populations using flow cytometry. Additionally, we measured a panel of cytokines, chemokines, and neurotrophic factors in the plasma. Compared with HC, people endorsing a current MDE showed monocytosis (p = 0.001), increased high-sensitivity C-reactive protein (p = 0.002), and erythrocyte sedimentation rate (p = 0.003), and an altered proportion of specific monocyte subsets. CD4 lymphocytes presented increased median percentages of activation markers CD69 (p = 0.007) and exhaustion markers PD1 (p = 0.013) and LAG3 (p = 0.014), as well as a higher frequency of CD4CD25FOXP3 regulatory T cells (p = 0.003). Additionally, patients showed increased plasma levels of sTREM2 (p = 0.0089). These changes are more likely state markers, indicating the presence of an ongoing inflammatory response during an active MDE. The Random Forest model achieved remarkable classification accuracies of 83.8% for MDE vs. HC and 70% for differentiating active and remitted MDE. Interestingly, the cluster analysis identified three distinct immunological profiles among MDE patients. Cluster 1 has the highest number of leukocytes, mainly given by the increment in lymphocyte count and the lowest proinflammatory cytokine levels. Cluster 3 displayed the most robust inflammatory pattern, with high levels of TNFα, CX3CL1, IL-12p70, IL-17A, IL-23, and IL-33, associated with the highest level of IL-10, as well as β-NGF and the lowest level for BDNF. This profile is also associated with the highest absolute number and percentage of circulating monocytes and the lowest absolute number and percentage of circulating lymphocytes, denoting an active inflammatory process. Cluster 2 has some cardinal signs of more acute inflammation, such as elevated levels of CCL2 and increased levels of proinflammatory cytokines such as IL-1β, IFNγ, and CXCL8. Similarly, the absolute number of monocytes is closer to a HC value, as well as the percentage of lymphocytes, suggesting a possible initiation of the inflammatory process. The study provides new insights into the immune system's role in MDE, paving the ground for replication prospective studies targeting the development of diagnostic and prognostic tools and new therapeutic targets.
Topics: Humans; Female; Male; Case-Control Studies; Depressive Disorder, Major; Adult; Immunophenotyping; Middle Aged; Cytokines; Monocytes; Bipolar Disorder; Inflammation; Antigens, CD; Flow Cytometry
PubMed: 38866753
DOI: 10.1038/s41398-024-02902-2 -
Cell Death & Disease Jun 2024Full-length p53 (p53α) plays a pivotal role in maintaining genomic integrity and preventing tumor development. Over the years, p53 was found to exist in various... (Review)
Review
Full-length p53 (p53α) plays a pivotal role in maintaining genomic integrity and preventing tumor development. Over the years, p53 was found to exist in various isoforms, which are generated through alternative splicing, alternative initiation of translation, and internal ribosome entry site. p53 isoforms, either C-terminally altered or N-terminally truncated, exhibit distinct biological roles compared to p53α, and have significant implications for tumor development and therapy resistance. Due to a lack of part and/or complete C- or N-terminal domains, ectopic expression of some p53 isoforms failed to induce expression of canonical transcriptional targets of p53α like CDKN1A or MDM2, even though they may bind their promoters. Yet, p53 isoforms like Δ40p53α still activate subsets of targets including MDM2 and BAX. Furthermore, certain p53 isoforms transactivate even novel targets compared to p53α. More recently, non-canonical functions of p53α in DNA repair and of different isoforms in DNA replication unrelated to transcriptional activities were discovered, amplifying the potential of p53 as a master regulator of physiological and tumor suppressor functions in human cells. Both regarding canonical and non-canonical functions, alternative p53 isoforms frequently exert dominant negative effects on p53α and its partners, which is modified by the relative isoform levels. Underlying mechanisms include hetero-oligomerization, changes in subcellular localization, and aggregation. These processes ultimately influence the net activities of p53α and give rise to diverse cellular outcomes. Biological roles of p53 isoforms have implications for tumor development and cancer therapy resistance. Dysregulated expression of isoforms has been observed in various cancer types and is associated with different clinical outcomes. In conclusion, p53 isoforms have expanded our understanding of the complex regulatory network involving p53 in tumors. Unraveling the mechanisms underlying the biological roles of p53 isoforms provides new avenues for studies aiming at a better understanding of tumor development and developing therapeutic interventions to overcome resistance.
Topics: Humans; Tumor Suppressor Protein p53; Protein Isoforms; Neoplasms; Animals; Drug Resistance, Neoplasm; Proto-Oncogene Proteins c-mdm2
PubMed: 38866752
DOI: 10.1038/s41419-024-06783-7 -
The Journal of Cell Biology Aug 2024CDC7 kinase is crucial for DNA replication initiation and is involved in fork processing and replication stress response. Human CDC7 requires the binding of either DBF4...
CDC7 kinase is crucial for DNA replication initiation and is involved in fork processing and replication stress response. Human CDC7 requires the binding of either DBF4 or DRF1 for its activity. However, it is unclear whether the two regulatory subunits target CDC7 to a specific set of substrates, thus having different biological functions, or if they act redundantly. Using genome editing technology, we generated isogenic cell lines deficient in either DBF4 or DRF1: these cells are viable but present signs of genomic instability, indicating that both can independently support CDC7 for bulk DNA replication. Nonetheless, DBF4-deficient cells show altered replication efficiency, partial deficiency in MCM helicase phosphorylation, and alterations in the replication timing of discrete genomic regions. Notably, we find that CDC7 function at replication forks is entirely dependent on DBF4 and not on DRF1. Thus, DBF4 is the primary regulator of CDC7 activity, mediating most of its functions in unperturbed DNA replication and upon replication interference.
Topics: DNA Replication; Humans; Cell Cycle Proteins; Protein Serine-Threonine Kinases; Phosphorylation; Genomic Instability; Adaptor Proteins, Signal Transducing; DNA-Binding Proteins
PubMed: 38865090
DOI: 10.1083/jcb.202402144 -
Antimicrobial Agents and Chemotherapy Jun 2024Islatravir (ISL) is a deoxyadenosine analog that inhibits HIV-1 reverse transcription by multiple mechanisms. Lenacapavir (LEN) is a novel capsid inhibitor that inhibits...
Islatravir (ISL) is a deoxyadenosine analog that inhibits HIV-1 reverse transcription by multiple mechanisms. Lenacapavir (LEN) is a novel capsid inhibitor that inhibits HIV-1 at multiple stages throughout the viral life cycle. ISL and LEN are being investigated as once-weekly combination oral therapy for the treatment of HIV-1. Here, we characterized ISL and LEN to assess combinatorial antiviral activity, cytotoxicity, and the potential for interactions between the two compounds. Bliss analysis revealed ISL with LEN demonstrated additive inhibition of HIV-1 replication, with no evidence of antagonism across the range of concentrations tested. ISL exhibited potent antiviral activity against variants encoding known LEN resistance-associated mutations (RAMs) with or without the presence of M184V, an ISL RAM in reverse transcriptase (RT) . Static resistance selection experiments were conducted with ISL and LEN alone and in combination, initiating with either wild-type virus or virus containing the M184I RAM in RT to further assess their barrier to the emergence of resistance. The combination of ISL with LEN more effectively suppressed viral breakthrough at lower multiples of the compounds' IC (half-maximal inhibitory concentration) values and fewer mutations emerged with the combination compared to either compound on its own. The known pathways for development of resistance with ISL and LEN were not altered, and no novel single mutations emerged that substantially reduced susceptibility to either compound. The lack of antagonism and cross-resistance between ISL and LEN support the ongoing evaluation of the combination for treatment of HIV-1.
PubMed: 38864613
DOI: 10.1128/aac.00334-24