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The Journal of Biological Chemistry Jun 2024Aberrant regulation of signal transduction pathways can adversely derail biological processes for tissue development. One such process is the embryonic eyelid closure...
Aberrant regulation of signal transduction pathways can adversely derail biological processes for tissue development. One such process is the embryonic eyelid closure that is dependent on the Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1). Map3k1 knockout in mice results in defective eyelid closure and an autosomal recessive eye-open at birth phenotype. We have shown that in utero exposure to dioxin, a persistent environmental toxicant, induces the same eye defect in Map3k1 heterozygous but not wild type pups. Here we explore the mechanisms of the Map3k1 (gene) and dioxin (environment) interactions (GxE) underlying defective eyelid closure. We show that, acting through the Aryl Hydrocarbon Receptor (AHR), dioxin activates Epidermal Growth Factor Receptor (EGFR) signaling, which in turn depresses MAP3K1-dependent Jun N-terminal Kinase (JNK) activity. The dioxin mediated JNK repression is moderate but is exacerbated by Map3k1 heterozygosity. Therefore, dioxin exposed Map3k1 embryonic eyelids have a marked reduction of JNK activity, accelerated differentiation and impeded polarization in the epithelial cells. Knocking out Ahr or Egfr in eyelid epithelium attenuates the open-eye defects in dioxin-treated Map3k1 pups, whereas knockout of Jnk1 and S1pr that encodes the Sphigosin-1-phosphate (S1P) receptors upstream of the MAP3K1-JNK pathway potentiates the dioxin toxicity. Our novel findings show that the crosstalk of AHR, EGFR and S1P-MAP3K1-JNK pathways determines the outcome of dioxin exposure. Thus, gene mutations targeting these pathways are potential risk factors for the toxicity of environmental chemicals.
PubMed: 38897570
DOI: 10.1016/j.jbc.2024.107486 -
JMIR Public Health and Surveillance Jun 2024Exposure risk was shown to have affected individual susceptibility and the epidemic spread of COVID-19. The dynamics of risk by and across exposure settings alongside...
BACKGROUND
Exposure risk was shown to have affected individual susceptibility and the epidemic spread of COVID-19. The dynamics of risk by and across exposure settings alongside the variations following the implementation of social distancing interventions are understudied.
OBJECTIVE
This study aims to examine the population's trajectory of exposure risk in different settings and its association with SARS-CoV-2 infection across 3 consecutive Omicron epidemic waves in Hong Kong.
METHODS
From March to June 2022, invitation letters were posted to 41,132 randomly selected residential addresses for the recruitment of households into a prospective population cohort. Through web-based monthly surveys coupled with email reminders, a representative from each enrolled household self-reported incidents of SARS-CoV-2 infections, COVID-19 vaccination uptake, their activity pattern in the workplace, and daily and social settings in the preceding month. As a proxy of their exposure risk, the reported activity trend in each setting was differentiated into trajectories based on latent class growth analyses. The associations of different trajectories of SARS-CoV-2 infection overall and by Omicron wave (wave 1: February-April; wave 2: May-September; wave 3: October-December) in 2022 were evaluated by using Cox proportional hazards models and Kaplan-Meier analysis.
RESULTS
In total, 33,501 monthly responses in the observation period of February-December 2022 were collected from 5321 individuals, with 41.7% (2221/5321) being male and a median age of 46 (IQR 34-57) years. Against an expanding COVID-19 vaccination coverage from 81.9% to 95.9% for 2 doses and 20% to 77.7% for 3 doses, the cumulative incidence of SARS-CoV-2 infection escalated from <0.2% to 25.3%, 32.4%, and 43.8% by the end of waves 1, 2, and 3, respectively. Throughout February-December 2022, 52.2% (647/1240) of participants had worked regularly on-site, 28.7% (356/1240) worked remotely, and 19.1% (237/1240) showed an assorted pattern. For daily and social settings, 4 and 5 trajectories were identified, respectively, with 11.5% (142/1240) and 14.6% (181/1240) of the participants gauged to have a high exposure risk. Compared to remote working, working regularly on-site (adjusted hazard ratio [aHR] 1.47, 95% CI 1.19-1.80) and living in a larger household (aHR 1.12, 95% CI 1.06-1.18) were associated with a higher risk of SARS-CoV-2 infection in wave 1. Those from the highest daily exposure risk trajectory (aHR 1.46, 95% CI 1.07-2.00) and the second highest social exposure risk trajectory (aHR 1.52, 95% CI 1.18-1.97) were also at an increased risk of infection in waves 2 and 3, respectively, relative to the lowest risk trajectory.
CONCLUSIONS
In an infection-naive population, SARS-CoV-2 transmission was predominantly initiated at the workplace, accelerated in the household, and perpetuated in the daily and social environments, as stringent restrictions were scaled down. These patterns highlight the phasic shift of exposure settings, which is important for informing the effective calibration of targeted social distancing measures as an alternative to lockdown.
Topics: Humans; COVID-19; Hong Kong; Prospective Studies; Male; Female; Adult; Middle Aged; SARS-CoV-2; Cohort Studies
PubMed: 38896447
DOI: 10.2196/51498 -
Cancer Research Communications Jun 2024Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma (PDAC)....
Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma (PDAC). However, the mechanistic link with established drivers of this disease remains in part elusive. Here, using a new genetically-engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of PDAC development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared to the KrasG12D only expressing mice. Analysis of the mechanism using RNA-seq demonstrate higher levels of GLI2 targets, particularly tumor growth promoting genes including Ccnd1, N-Myc and Bcl2, in KrasG12D mutant cells. Further, ChIP-seq studies showed that in these cells KrasG12D increases the levels of H3K4me3 at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression.
PubMed: 38896052
DOI: 10.1158/2767-9764.CRC-23-0464 -
BioRxiv : the Preprint Server For... Jun 2024Depletion or inhibition of core stress granule proteins, G3BP1 in mammals and TIAR-2 in , increases axon regeneration in injured neurons that show spontaneous...
Depletion or inhibition of core stress granule proteins, G3BP1 in mammals and TIAR-2 in , increases axon regeneration in injured neurons that show spontaneous regeneration. Inhibition of G3BP1 by expression of its acidic or 'B-domain' accelerates axon regeneration after nerve injury bringing a potential therapeutic intervention to promote neural repair in the peripheral nervous system. Here, we asked if G3BP1 inhibition is a viable strategy to promote regeneration in the injured mammalian central nervous system where axons do not regenerate spontaneously. G3BP1 B-domain expression was found to promote axon regeneration in both the mammalian spinal cord and optic nerve. Moreover, a cell permeable peptide to a subregion of G3BP1's B-domain (rodent G3BP1 amino acids 190-208) accelerated axon regeneration after peripheral nerve injury and promoted the regrowth of reticulospinal axons into the distal transected spinal cord through a bridging peripheral nerve graft. The rodent and human G3BP1 peptides promoted axon growth from rodent and human neurons cultured on permissive substrates, and this function required alternating Glu/Asp-Pro repeats that impart a unique predicted tertiary structure. These studies point to G3BP1 granules as a critical impediment to CNS axon regeneration and indicate that G3BP1 granule disassembly represents a novel therapeutic strategy for promoting neural repair after CNS injury.
PubMed: 38895344
DOI: 10.1101/2024.06.07.597743 -
Materials (Basel, Switzerland) Jun 2024Surface treatment of implants facilitates osseointegration, with nanostructured surfaces exhibiting accelerated peri-implant bone regeneration. This study compared...
Surface treatment of implants facilitates osseointegration, with nanostructured surfaces exhibiting accelerated peri-implant bone regeneration. This study compared bone-to-implant contact (BIC) in implants with hydroxyapatite (HA), sand-blasted and acid-etched (SLA), and SLA with calcium (Ca)-coated (XPEED) surfaces. Seventy-five disk-shaped grade 4 Ti specimens divided into three groups were prepared, with 16 implants per group tested in New Zealand white rabbits. Surface characterization was performed using X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), digital microscopy, and a contact angle analyzer. Cell viability, proliferation, and adhesion were assessed using MC3T3-E1 cells. Apatite formation was evaluated using modified simulated body fluid (m-SBF) incubation. After 4 weeks of healing, the outcomes reviewed were BIC, bone area (BA), removal torque tests, and histomorphometric evaluation. A microstructure analysis revealed irregular pores across all groups, with the XPEED group exhibiting a nanostructured Ca-coated surface. Surface characterization showed a crystalline CaTiO layer on XPEED surfaces, with evenly distributed Ca penetrating the implants. All surfaces provided excellent environments for cell growth. The XPEED and SLA groups showed significantly higher cell density and viability with superior osseointegration than HA ( < 0.05); XPEED exhibited the highest absorbance values. Thus, XPEED surface treatment improved implant performance, biocompatibility, stability, and osseointegration.
PubMed: 38893971
DOI: 10.3390/ma17112707 -
Cancers May 2024In breast cancer, epithelial-mesenchymal transition (EMT) is positively associated with programmed death ligand 1 (PD-L1) expression and immune escape, and TWIST1...
In breast cancer, epithelial-mesenchymal transition (EMT) is positively associated with programmed death ligand 1 (PD-L1) expression and immune escape, and TWIST1 silences ERα expression and induces EMT and cancer metastasis. However, how TWIST1 regulates PD-L1 and immune evasion is unknown. This study analyzed TWIST1 and PD-L1 expression in breast cancers, investigated the mechanism for TWIST1 to regulate PD-L1 transcription, and assessed the effects of TWIST1 and PD-L1 in cancer cells on cytotoxic CD8+ T cells. Interestingly, TWIST1 expression is correlated with high-level PD-L1 expression in ERα-negative breast cancer cells. The overexpression and knockdown of TWIST1 robustly upregulate and downregulate PD-L1 expression, respectively. TWIST1 binds to the PD-L1 promoter and recruits the TIP60 acetyltransferase complex in a BRD8-dependent manner to transcriptionally activate PD-L1 expression, which significantly accelerates the exhaustion and death of the cytotoxic CD8+ T cells. Accordingly, knockdown of TWIST1 or BRD8 or inhibition of PD-L1 significantly enhances the tumor antigen-specific CD8+ T cells to suppress the growth of breast cancer cells. These results demonstrate that TWIST1 directly induces PD-L1 expression in ERα-negative breast cancer cells to promote immune evasion. Targeting TWIST1, BRD8, and/or PD-L1 in ERα-negative breast cancer cells with TWIST1 expression may sensitize CD8+ T-cell-mediated immunotherapy.
PubMed: 38893094
DOI: 10.3390/cancers16111973 -
International Journal of Molecular... Jun 2024Melanoma is the fifth most common cancer in the United States. Conventional drug discovery methods are inherently time-consuming and costly, which imposes significant...
Melanoma is the fifth most common cancer in the United States. Conventional drug discovery methods are inherently time-consuming and costly, which imposes significant limitations. However, the advent of Artificial Intelligence (AI) has opened up new possibilities for simulating and evaluating numerous drug candidates, thereby mitigating the requisite time and resources. In this context, normalizing flow models by employing machine learning techniques to create new molecular structures holds promise for accelerating the discovery of effective anticancer therapies. This manuscript introduces , a novel AI model designed to generate new molecular entities with potential therapeutic value in cancer treatment. It has been trained on the NCI-60 dataset, encompassing thousands of molecules tested across 60 tumour cell lines, with an emphasis on the melanoma SK-MEL-28 cell line. The model successfully generated new molecules with predicted improved efficacy in inhibiting tumour growth while being synthetically feasible. This represents a significant advancement over conventional generative models, which often produce molecules that are challenging or impossible to synthesize. Furthermore, has also been utilized to optimize molecules known for their efficacy in clinical melanoma treatments. This led to the creation of novel molecules with a predicted enhanced likelihood of effectiveness against melanoma, currently undocumented on PubChem.
Topics: Humans; Antineoplastic Agents; Artificial Intelligence; Melanoma; Cell Line, Tumor; Drug Discovery; Machine Learning
PubMed: 38892374
DOI: 10.3390/ijms25116186 -
International Journal of Molecular... May 2024The rhizobacterial strain BJ3 showed 16S rDNA sequence similarity to species within the genus. Its complete genome sequence revealed a 97% match with and uncovered...
The rhizobacterial strain BJ3 showed 16S rDNA sequence similarity to species within the genus. Its complete genome sequence revealed a 97% match with and uncovered gene clusters essential for plant-growth-promoting traits (PGPTs). These clusters include genes responsible for producing indole acetic acid (IAA), osmolytes, non-ribosomal peptides (NRPS), volatile organic compounds (VOCs), siderophores, lipopolysaccharides, hydrolytic enzymes, and spermidine. Additionally, the genome contains genes for nitrogen fixation and phosphate solubilization, as well as a gene encoding 1-aminocyclopropane-1-carboxylate (ACC) deaminase. The treatment with BJ3 enhanced root architecture, boosted vegetative growth, and accelerated early flowering in . Treated seedlings also showed increased lignin production and antioxidant capabilities, as well as notably increased tolerance to water deficit and high salinity. An RNA-seq transcriptome analysis indicated that BJ3 treatment significantly activated genes related to immunity induction, hormone signaling, and vegetative growth. It specifically activated genes involved in the production of auxin, ethylene, and salicylic acid (SA), as well as genes involved in the synthesis of defense compounds like glucosinolates, camalexin, and terpenoids. The expression of AP2/ERF transcription factors was markedly increased. These findings highlight BJ3's potential to produce various bioactive metabolites and its ability to activate auxin, ethylene, and SA signaling in , positioning it as a new strain that could significantly improve plant growth, stress resilience, and immune function.
Topics: Burkholderia; Arabidopsis; Stress, Physiological; Plant Development; Indoleacetic Acids; Gene Expression Regulation, Plant; Genomics; Plant Growth Regulators; Plant Roots; Ethylenes
PubMed: 38892282
DOI: 10.3390/ijms25116091 -
International Journal of Molecular... May 2024Global warming poses a threat to plant survival, impacting growth and agricultural yield. Protein turnover, a critical regulatory mechanism balancing protein synthesis...
Global warming poses a threat to plant survival, impacting growth and agricultural yield. Protein turnover, a critical regulatory mechanism balancing protein synthesis and degradation, is crucial for the cellular response to environmental changes. We investigated the effects of elevated temperature on proteome dynamics in seedlings using N-stable isotope labeling and ultra-performance liquid chromatography-high resolution mass spectrometry, coupled with the algorithm. Analyzing different cellular fractions from plants grown under 22 °C and 30 °C growth conditions, we found significant changes in the turnover rates of 571 proteins, with a median 1.4-fold increase, indicating accelerated protein dynamics under thermal stress. Notably, soluble root fraction proteins exhibited smaller turnover changes, suggesting tissue-specific adaptations. Significant turnover alterations occurred with redox signaling, stress response, protein folding, secondary metabolism, and photorespiration, indicating complex responses enhancing plant thermal resilience. Conversely, proteins involved in carbohydrate metabolism and mitochondrial ATP synthesis showed minimal changes, highlighting their stability. This analysis highlights the intricate balance between proteome stability and adaptability, advancing our understanding of plant responses to heat stress and supporting the development of improved thermotolerant crops.
Topics: Arabidopsis; Seedlings; Arabidopsis Proteins; Isotope Labeling; Nitrogen Isotopes; Proteome; Algorithms; Proteomics; Temperature; Heat-Shock Response
PubMed: 38892074
DOI: 10.3390/ijms25115882 -
International Journal of Molecular... May 2024Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA)...
Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA) compound ([At]PSMA-5) exhibited excellent tumor growth suppression in a xenograft model. We conducted preclinical biodistribution and toxicity studies for the first-in-human clinical trial. [At]PSMA-5 was administered to both normal male ICR mice ( = 85) and cynomolgus monkeys ( = 2). The mice were divided into four groups for the toxicity study: 5 MBq/kg, 12 MBq/kg, 35 MBq/kg, and vehicle control, with follow-ups at 1 day ( = 10 per group) and 14 days ( = 5 per group). Monkeys were observed 24 h post-administration of [At]PSMA-5 (9 MBq/kg). Blood tests and histopathological examinations were performed at the end of the observation period. Blood tests in mice indicated no significant myelosuppression or renal dysfunction. However, the monkeys displayed mild leukopenia 24 h post-administration. Despite the high accumulation in the kidneys and thyroid, histological analysis revealed no abnormalities. On day 1, dose-dependent single-cell necrosis/apoptosis was observed in the salivary glands of mice and intestinal tracts of both mice and monkeys. Additionally, tingible body macrophages in the spleen and lymph nodes indicated phagocytosis of apoptotic B lymphocytes. Cortical lymphopenia (2/10) in the thymus and a decrease in the bone marrow cells (9/10) were observed in the 35 MBq/kg group in mice. These changes were transient, with no irreversible toxicity observed in mice 14 days post-administration. This study identified no severe toxicities associated with [At]PSMA-5, highlighting its potential as a next-generation targeted alpha therapy for prostate cancer. The sustainable production of At using a cyclotron supports its applicability for clinical use.
Topics: Animals; Male; Prostatic Neoplasms; Mice; Tissue Distribution; Mice, Inbred ICR; Astatine; Alpha Particles; Humans; Macaca fascicularis; Glutamate Carboxypeptidase II; Radiopharmaceuticals
PubMed: 38891856
DOI: 10.3390/ijms25115667