Ultradian Rest-activity Rhythms Induced by Quinpirole in Mice Using Wavelet Analysis.

Objective: Ultradian rhythms are biological rhythms with periods of a few seconds to a few hours. Along with circadian rhythms, ultradian rhythms influence human physiology. However, such rhythms have not been studied as intensively as circadian rhythms. This study aimed to identify ultradian rest-activity rhythms induced by the dopamine D2/D3 agonist quinpirole in mice. Methods: We used 10 mice from the Institute of Cancer Research. Quinpirole was administered at a dose of 0.5 mg/kg. We assessed free rest-activity using infrared detectors and conducted wavelet analysis to measure the period and its variation. We also used the paired t test to compare ultradian rhythm patterns. Results: Quinpirole did not significantly change total 24-hour locomotor activity (p = 0.065). However, it significantly increased locomotor activity during the dark phase (p = 0.001) and decreased it during the light phase (p = 0.016). In the continuous wavelet transform analysis, the mean period was 5.618 hours before quinpirole injection and 4.523 hours after injection. The period showed a significant decrease (p = 0.040), while the variation remained relatively consistent before and after quinpirole injection. Conclusion: This study demonstrated ultradian rest-activity rhythms induced by quinpirole using wavelet analysis. Quinpirole-induced ultradian rhythms exhibited rapid oscillations with shortened periods and increased activity during the dark phase. To better understand these changes in ultradian rhythms caused by quinpirole, it is essential to compare them with the effects of other psychopharmacological agents. Furthermore, investigating the pharmacological impact on ultradian rest-activity rhythms may have valuable applications in clinical studies.

The Pigmentation of Blue Light Is Mediated by Both Melanogenesis Activation and Autophagy Inhibition through OPN3-TRPV1.

Blue light, a high-energy radiation in the visible light spectrum, was recently reported to induce skin pigmentation. In this study, we investigated the involvement of TRPV1-mediated signaling along with OPN3 in blue light-induced melanogenesis as well as its signaling pathway. Operating downstream target of OPN3 in blue light-induced melanogenesis, blue light activated TRPV1 and upregulated its expression, resulting in calcium influx. Calcium ion induced the activation of calcium/calmodulin-dependent protein kinase II and MAPK. It also downregulated clusterin expression, leading to the nuclear translocation of PAX3, ultimately affecting melanin synthesis. In addition, blue light interfered with autophagy-mediated regulation of melanosomes by decreasing not only the interaction between clusterin and LC3B but the expression of activating transcription factor family. These findings demonstrate that the pigmenting effects of blue light are mediated by calcium/calmodulin-dependent protein kinase II- and MAPK-mediated signaling as well as clusterin-dependent inhibition of autophagy through OPN3-TRPV1-calcium influx, suggesting, to our knowledge, a previously unreported signaling pathway through which blue light regulates melanocyte biology. Furthermore, these results suggest that TRPV1 and clusterin could be potential therapeutic targets for blue light-induced pigmentation due to prolonged exposure to blue light.

Tetrachloroethylene exposure and neurobehavioral performance among children living near multiple contamination sites.

BACKGROUND: Tetrachloroethylene (PCE) is a known neurotoxicant mainly observed in populations with high level occupational exposure. Health effects of low-level community exposure are poorly understood. This study evaluated PCE exposure and neurobehavioral performance in 6 to 11-year-old children living in a community with multiple PCE contamination sites. METHODS: This cross-sectional study recruited eighty-nine children who attended public schools in Martinsville, Indiana. PCE was measured in exhaled breath using proton transfer reaction mass spectrometry. Children were classified into three exposure groups: 'Level 1' (≤ 0.75 µg/m3), 'Level 2' (>0.75-1.90 µg/m3), and 'Level 3' (>1.90 µg/m3). A battery of tests assessed children's neurobehavioral performance related to their cognition, behavior, and academic achievement and a questionnaire collected demographic and exposure characteristics. Adjusted regression models estimated associations of PCE exposure with neurobehavioral outcomes. RESULTS: Seventy-three participants completed data collection. The average scores for all participants on the Fluid, Total, Early Childhood Composites, Behavioral Symptoms Index, and Math Computation were significantly lower than standard scores of normative sample, with 30 % of participants having one or more scores two standard deviations worse than the standard scores. Compared to children having the lowest PCE exposure, significant inverse associations were identified for PCE exposure with Fluid Composite for Level 2 (ß = -12.0 (95 % CI = -23.4, -0.6)) and Level 3 (-12.2 (-23.4, -1.0)) exposure groups, Total Composite for Level 2 (-10.1 (-19.2, -1.1)) and Level 3 (-11.8 (-20.4, -3.2)) exposure groups, and Early Childhood Composite for Level 3 exposure group (-11.0 (-18.7, -3.4)). CONCLUSIONS: This study identified associations of PCE in exhaled breath with lower cognitive functioning, problem-solving abilities, and adaptive functioning in children. Mainly, working memory, episodic memory, processing speed, and executive function-cognitive flexibility were associated with PCE exposure. These results underscore the need for further investigations, considering the impact of low-level environmental exposure on children's neurobehavioral outcomes.

Structural and biochemical investigation into stable FGF2 mutants with novel mutation sites and hydrophobic replacements for surface-exposed cysteines.

Fibroblast growth factor 2 (FGF2) is an attractive biomaterial for pharmaceuticals and functional cosmetics. To improve the thermo-stability of FGF2, we designed two mutants harboring four-point mutations: FGF2-M1 (D28E/C78L/C96I/S137P) and FGF2-M2 (D28E/C78I/C96I/S137P) through bioinformatics, molecular thermodynamics, and molecular modeling. The D28E mutation reduced fragmentation of the FGF2 wild type during preparation, and the substitution of a whale-specific amino acid, S137P, enhanced the thermal stability of FGF2. Surface-exposed cysteines that participate in oligomerization through intermolecular disulfide bond formation were substituted with hydrophobic residues (C78L/C78I and C96I) using the in silico method. High-resolution crystal structures revealed at the atomic level that the introduction of mutations stabilizes each local region by forming more favorable interactions with neighboring residues. In particular, P137 forms CH-π interactions with the side chain indole ring of W123, which seems to stabilize a ß-hairpin structure, containing a heparin-binding site of FGF2. Compared to the wild type, both FGF2-M1 and FGF2-M2 maintained greater solubility after a week at 45 °C, with their Tm values rising by ~ 5 °C. Furthermore, the duration for FGF2-M1 and FGF2-M2 to reach 50% residual activity at 45 °C extended to 8.8- and 8.2-fold longer, respectively, than that of the wild type. Interestingly, the hydrophobic substitution of surface-exposed cysteine in both FGF2 mutants makes them more resistant to proteolytic cleavage by trypsin, subtilisin, proteinase K, and actinase than the wild type and the Cys → Ser substitution. The hydrophobic replacements can influence protease resistance as well as oligomerization and thermal stability. It is notable that hydrophobic substitutions of surface-exposed cysteines, as well as D28E and S137P of the FGF2 mutants, were designed through various approaches with structural implications. Therefore, the engineering strategies and structural insights adopted in this study could be applied to improve the stability of other proteins.

Age- and ethnic-driven molecular and clinical disparity of East Asian breast cancers.

BACKGROUND: Breast cancer (BC) is a complex disease with profound genomic aberrations. However, the underlying molecular disparity influenced by age and ethnicity remains elusive. METHODS: In this study, we aimed to investigate the molecular properties of 843 primary and metastatic BC patients enrolled in the K-MASTER program. By categorizing patients into two distinct age subgroups, we explored their unique molecular properties. Additionally, we leveraged large-scale genomic data from the TCGA and MSK-IMPACT studies to examine the ethnic-driven molecular and clinical disparities. RESULTS: We observed a high prevalence of PI3KCA mutations in K-MASTER HER2 + tumors, particularly in older patients. Moreover, we identified increased mutation rates in DNA damage response molecules, including ARID1A, MSH6, and MLH1. The K-MASTER patients were mainly comprised of triple-negative breast cancer (TNBC) and HER2-positive tumors, while the TCGA and MSK-IMPACT cohorts exhibited a predominance of hormone receptor-positive (HR +) subtype tumors. Importantly, GATA3 mutations were less frequently observed in East Asian patients, which correlated with poor clinical outcomes. In addition to characterizing the molecular disparities, we developed a gradient-boosting multivariable model to identify a new molecular signature that could predict the therapeutic response to platinum-based chemotherapy. CONCLUSIONS: Our findings collectively provide unprecedented insights into the significance of age and ethnicity on the molecular and clinical characteristics of BC patients.

Vitamin B12 Deficiency Manifesting As Pancytopenia, Lymphadenopathy, and Fever: A Clinical Mimic of Hematologic Malignancies.

Pancytopenia is a complex medical condition characterized by decreased levels of red blood cells (RBCs), white blood cells (WBCs), and platelets (PLTs). It can arise from impaired production, peripheral destruction, or a combination of both. The causes of pancytopenia range from reversible factors like infections and medication reactions to irreversible conditions. Vitamin B12 deficiency is a notable reversible cause that can take years to manifest in adults due to stored reserves. However, deficiencies caused by impaired absorption, especially due to the lack of intrinsic factors (IFs), can lead to rapid deterioration within two to five years. A healthy 39-year-old male with an athletic lifestyle presented with symptoms such as dizziness, nausea, vomiting, palpitations, and fainting over a few days. These symptoms were preceded by weeks of persistent body aches, headaches, weakness, daily fevers, chills, and night sweats. Vital signs were stable. The physical examination revealed conjunctival pallor and lymphadenopathy in the submandibular and superficial cervical regions. Initial blood tests showed normocytic anemia (Hgb 4.9, MCV 80), leukopenia (2.99), thrombocytopenia (142), and elevated liver enzymes (AST 199, ALT 96, and total bilirubin of 2.04). The peripheral smear showed tear-drop cells and hypochromic cells. The initial impression was hematologic malignancy, including but not limited to leukemia, lymphoma, or myelofibrosis given clinical findings such as B-symptoms like night sweats, neck lymphadenopathy, and subjective daily fever, along with pancytopenia. The patient received a bolus of normal saline and a transfusion of two units of packed RBCs. CT scans of the chest, abdomen, and pelvis showed no adenopathy or splenomegaly. Although initial clinical assessment pointed toward a potential hematologic malignancy, comprehensive testing, including SPEP, reticulocyte count/fraction, serum folate, and serum vitamin B12, revealed only severe vitamin B12 deficiency, with a level of less than 150, with the presence of IF antibodies. Treatment involved intensive in-patient vitamin B12 injections followed by a detailed outpatient regimen. The patient completed a daily dose of vitamin B12 injections for seven consecutive days, followed by weekly injections for the next four weeks. Subsequent laboratory results demonstrated an increase in WBC count to 8.39, Hgb level to 13.2, and PLT count of 249, indicating a continued positive response to the vitamin B12 replacement therapy. In summary, pancytopenia poses a diagnostic challenge that demands careful evaluation of patient data and comprehensive testing. Vitamin B12 deficiency, which encompasses pernicious anemia (PA), is among the reversible factors to consider. This aspect holds significance before opting for more invasive measures like a bone marrow biopsy. Nutritional deficiencies need to be considered first as differentials in pancytopenia, even in the absence of typical signs of vitamin B12 deficiency (like macrocytosis and hypersegmented neutrophils) and in the presence of compelling clinical indications pointing to a hematologic malignancy.

Evaluation of tetrachloroethylene (PCE) and its degradation products in human exhaled breath and indoor air in a community setting.

Tetrachloroethylene (PCE) is a widely utilized volatile chemical in industrial applications, including dry cleaning and metal degreasing. Exposure to PCE potentially presents a significant health risk to workers as well as communities near contamination sites. Adverse health effects arise not only from PCE, but also from PCE degradation products, such as trichloroethylene (TCE) and vinyl chloride (VC). PCE, TCE, and VC can contaminate water, soil, and air, leading to exposure through multiple pathways, including inhalation, ingestion, and dermal contact. This study focused on a community setting in Martinsville, Indiana, a working-class Midwestern community in the United States, where extensive PCE contamination has occurred due to multiple contamination sites (referring to 'plumes'), including a Superfund site. Utilizing proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS), PCE, TCE, and VC concentrations were measured in the exhaled breath of 73 residents from both within and outside the plume areas. PCE was detected in 66 samples, TCE in 26 samples, and VC in 68 samples. Our results revealed a significant positive correlation between the concentrations of these compounds in exhaled breath and indoor air (Pearson correlation coefficients: PCE = 0.75, TCE = 0.71, and VC = 0.89). This study confirms the presence of PCE and its degradation products in exhaled breath in a community exposure investigation, demonstrating the potential of using exhaled breath analysis in monitoring exposure to environmental contaminants. This study showed the feasibility of utilizing PTR-TOF-MS in community investigations to assess exposure to PCE and its degradation products by measuring these compounds in exhaled breath and indoor air.

Rapid and High-Density Antibody Immobilization Using Electropolymerization of Pyrrole for Highly Sensitive Immunoassay.

Polypyrrole (Ppy) is a biologically compatible polymer that is used as a matrix, in which drugs and enzymes can be incorporated by doping. Here, we suggest an inventive application of Ppy as a biorecognition film encapsulated with an antibody (Ab) as an alternative strategy for the on-site multistep functionalization of thiol-based self-assembled monolayers. The fabrication steps of the recognition films were followed by dropping pyrrole and Ab mixed solutions onto the electrode and obtaining a thin film by direct current electropolymerization. The efficiency of Ab immobilization was studied by using fluorescence microscopy and electrochemical (EC) methods. Finally, the Ab density was increased and immobilized in 1 min, and the sensing performance as an EC immunosensor was demonstrated using α-fetoprotein with a limit of detection of 3.13 pg/mL and sensing range from 1 pg/mL to 100 ng/mL. This study demonstrates the potential for electrochemical functionalization of biomolecules with high affinity and rapidity.

The Role of Extracellular Vesicles in Pandemic Viral Infections.

Extracellular vesicles (EVs), of diverse origin and content, are membranous structures secreted by a broad range of cell types. Recent advances in molecular biology have highlighted the pivotal role of EVs in mediating intercellular communication, facilitated by their ability to transport a diverse range of biomolecules, including proteins, lipids, DNA, RNA and metabolites. A striking feature of EVs is their ability to exert dual effects during viral infections, involving both proviral and antiviral effects. This review explores the dual roles of EVs, particularly in the context of pandemic viruses such as HIV-1 and SARS-CoV-2. On the one hand, EVs can enhance viral replication and exacerbate pathogenesis by transferring viral components to susceptible cells. On the other hand, they have intrinsic antiviral properties, including activation of immune responses and direct inhibition of viral infection. By exploring these contrasting functions, our review emphasizes the complexity of EV-mediated interactions in viral pathogenesis and highlights their potential as targets for therapeutic intervention. The insights obtained from investigating EVs in the context of HIV-1 and SARS-CoV-2 provide a deeper understanding of viral mechanisms and pathologies, and offer a new perspective on managing and mitigating the impact of these global health challenges.

Efficient recovery and recycling/upcycling of precious metals using hydrazide-functionalized star-shaped polymers.

There is a growing demand for adsorption technologies for recovering and recycling precious metals (PMs) in various industries. Unfortunately, amine-functionalized polymers widely used as metal adsorbents are ineffective at recovering PMs owing to their unsatisfactory PM adsorption performance. Herein, a star-shaped, hydrazide-functionalized polymer (S-PAcH) is proposed as a readily recoverable standalone adsorbent with high PM adsorption performance. The compact chain structure of S-PAcH containing numerous hydrazide groups with strong reducibility promotes PM adsorption by enhancing PM reduction while forming large, collectable precipitates. Compared with previously reported PM adsorbents, commercial amine polymers, and reducing agents, S-PAcH exhibited significantly higher adsorption capacity, selectivity, and kinetics toward three PMs (gold, palladium, and platinum) with model, simulated, and real-world feed solutions. The superior PM recovery performance of S-PAcH was attributed to its strong reduction capability combined with its chemisorption mechanism. Moreover, PM-adsorbed S-PAcH could be refined into high-purity PMs via calcination, directly utilized (upcycled) as catalysts for dye reduction, or regenerated for reuse, demonstrating its high practical feasibility. Our proposed PM adsorbents would have a tremendous impact on various industrial sectors from the perspectives of environmental protection and sustainable development.

Molecular characterization of positively selected genes contributing aquatic adaptation in marine mammals.

BACKGROUND: Marine mammals, which have evolved independently into three distinct lineages, share common physiological features that contribute to their adaptation to the marine environment. OBJECTIVE: To identify positively selected genes (PSGs) for adaptation to the marine environment using available genomic data from three taxonomic orders: cetaceans, pinnipeds, and sirenians. METHODS: Based on the genomes within each group of Artiodactyla, Carnivora and Afrotheria, we performed selection analysis using the branch-site model in CODEML. RESULTS: Based on the branch-site model, 460, 614, and 359 PSGs were predicted for the cetaceans, pinnipeds, and sirenians, respectively. Functional enrichment analysis indicated that genes associated with hemostasis were positively selected across all lineages of marine mammals. We observed positive selection signals for the hemostasis and coagulation-related genes plasminogen activator, urokinase (PLAU), multimerin 1 (MMRN1), gamma-glutamyl carboxylase (GGCX), and platelet endothelial aggregation receptor 1 (PEAR1). Additionally, we found out that the sodium voltage-gated channel alpha subunit 9 (SCN9A), serine/arginine repetitive matrix 4 (SRRM4), and Ki-ras-induced actin-interacting protein (KRAP) are under positive selection pressure and are associated with cognition, neurite outgrowth, and IP3-mediated Ca2 + release, respectively. CONCLUSION: This study will contribute to our understanding of the adaptive evolution of marine mammals by providing information on a group of candidate genes that are predicted to influence adaptation to aquatic environments, as well as their functional characteristics.

Exploring novel immunotherapy biomarker candidates induced by cancer deformation.

Triple-negative breast cancer (TNBC) demands urgent attention for the development of effective treatment strategies due to its aggressiveness and limited therapeutic options [1]. This research is primarily focused on identifying new biomarkers vital for immunotherapy, with the aim of developing tailored treatments specifically for TNBC, such as those targeting the PD-1/PD-L1 pathway. To achieve this, the study places a strong emphasis on investigating Ig genes, a characteristic of immune checkpoint inhibitors, particularly genes expressing Ig-like domains with altered expression levels induced by "cancer deformation," a condition associated with cancer malignancy. Human cells can express approximately 800 Ig family genes, yet only a few Ig genes, including PD-1 and PD-L1, have been developed into immunotherapy drugs thus far. Therefore, we investigated the Ig genes that were either upregulated or downregulated by the artificial metastatic environment in TNBC cell line. As a result, we confirmed the upregulation of approximately 13 Ig genes and validated them using qPCR. In summary, our study proposes an approach for identifying new biomarkers applicable to future immunotherapies aimed at addressing challenging cases of TNBC where conventional treatments fall short.

In vitro Fertilization Outcomes of Frozen-thawed Embryo Transfer with Hatched Blastocysts versus with Hatching Blastocysts.

This study aimed to elucidate the effect of hatching status on in vitro fertilization (IVF) outcomes in frozen-thawed blastocyst transfer cycles. Frozen-thawed embryo transfer (FET) cycles performed at a single fertility center between 2016 and 2021 were retrospectively assessed. Analyses were restricted to 6,821 frozen-thawed blastocyst transfers in women aged 24-47 years. For optimal comparability, double embryo transfer (ET) cycles consisting of one hatching and one hatched blastocyst were excluded. The implantation and pregnancy rates were evaluated and compared between the hatching and hatched blastocyst transfer groups based on patients' age (<38 vs. ≥38 years), blastocyst grade (good vs. bad grade), and the number of transferred embryos (single ET vs. double ET). Hatched blastocyst transfer was associated with higher implantation and clinical pregnancy rates in the single ET group (15.7% and 15.6%, respectively; p<0.001). The transfer of two hatched blastocysts had higher implantation and clinical pregnancy rates compared to the transfer of two hatching blastocysts (19.5% and 20.4%, respectively; p<0.001) in the double ET group. In the hatched blastocyst transfer group, the clinical pregnancy and implantation rates were higher, regardless of each woman's age and embryo quality. The IVF treatment outcomes were improved when the blastocysts were hatched during FET cycles. Hence, hatched blastocyst transfer in FET cycles could be considered a superior method in IVF practice.

Diagnostic value of 18F-FDG PET/CT versus diffusion-weighted MRI in detection of residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal squamous cell carcinoma: A prospective study.

BACKGROUND: Despite advances in treatment, residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal squamous cell carcinoma (SCC) remain a challenge in clinical management and require accurate and timely detection for optimal salvage therapy. This study aimed to compare the diagnostic value of Fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) in detecting residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal SCC. METHODS: A prospective study was conducted on 30 patients who presented with new symptoms after definitive (chemo) radiotherapy for laryngeal (n = 21) and hypopharyngeal (n = 9) carcinoma. Both 18F-FDG PET/CT and DW-MRI were performed and histopathologic analysis served as the standard of reference. RESULTS: Histopathology showed 20 patients as positive and 10 as negative for tumors. 18F-FDG PET/CT detected all tumors correctly but was falsely positive in one case. DW-MRI detected tumors in 18 out of 20 positive patients and correctly excluded tumors in all negative patients. The sensitivity and specificity of 18F-FDG PET/CT were 100% and 90%, respectively, while the values for DW-MRI were 90% and 100%, respectively. CONCLUSIONS: The study concludes that 18F-FDG PET/CT is slightly superior to DW-MRI in detecting residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal SCC. The combined use of 18F-FDG PET/CT and DW-MRI can potentially improve specificity in therapy response evaluation.

GPT-4 Performance for Neurologic Localization.

Background and Objectives: In health care, large language models such as Generative Pretrained Transformers (GPTs), trained on extensive text datasets, have potential applications in reducing health care disparities across regions and populations. Previous software developed for lesion localization has been limited in scope. This study aims to evaluate the capability of GPT-4 for lesion localization based on clinical presentation. Methods: GPT-4 was prompted using history and neurologic physical examination (H&P) from published cases of acute stroke followed by questions for clinical reasoning with answering for "single or multiple lesions," "side," and "brain region" using Zero-Shot Chain-of-Thought and Text Classification prompting. GPT-4 output on 3 separate trials for each of 46 cases was compared with imaging-based localization. Results: GPT-4 successfully processed raw text from H&P to generate accurate neuroanatomical localization and detailed clinical reasoning. Performance metrics across trial-based analysis for specificity, sensitivity, precision, and F1-score were 0.87, 0.74, 0.75, and 0.74, respectively, for side; 0.94, 0.85, 0.84, and 0.85, respectively, for brain region. Class labels within the brain region were similarly high for all regions except the cerebellum and were also similar when considering all 3 trials to examine metrics by case. Errors were due to extrinsic causes-inadequate information in the published cases, and intrinsic causes-failures of logic or inadequate knowledge base. Discussion: This study reveals capabilities of GPT-4 in the localization of acute stroke lesions, showing a potential future role as a clinical tool in neurology.

Anti-pollutant effect of oleic acid against urban particulate matter is mediated via regulation of AhR- and TRPV1-mediated signaling in vitro.

Urban Particulate Matter (UPM) induces skin aging and inflammatory responses by regulating skin cells through the transient receptor potential vanilloid 1 (TRPV1). Although oleic acid, an unsaturated free fatty acid (FFA), has some functional activities, its effect on UPM-induced skin damage has not been elucidated. Here, we investigated signaling pathways on how oleic acid is involved in attenuating UPM induced cell damage. UPM treatment increased XRE-promoter luciferase activity and increased translocation of AhR to the nucleus, resulting in the upregulation of CYP1A1 gene. However, oleic acid treatment attenuated the UPM effects on AhR signaling. Furthermore, while UPM induced activation of TRPV1 and MAPKs signaling which activated the downstream molecules NFκB and AP-1, these effects were reduced by cotreatment with oleic acid. UPM-dependent generation of reactive oxygen species (ROS) and reduction of cellular proliferation were also attenuated by the treatment of oleic acid. These data reveal that cell damage induced by UPM treatment occurs through AhR signaling and TRPV1 activation which in turn activates ERK and JNK, ultimately inducing NFκB and AP-1 activation. These effects were reduced by the cotreatment of oleic acid on HaCaT cells. These suggest that oleic acid reduces UPM-induced cell damage through inhibiting both the AhR signaling and activation of TRPV1 and its downstream molecules, leading to a reduction of pro-inflammatory cytokine and recovery of cell proliferation.

Human Motor Neurons Elicit Pathological Hallmarks of ALS and Reveal Potential Biomarkers of the Disease in Response to Prolonged IFNγ Exposure.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder marked by progressive motor neuron degeneration and muscle denervation. A recent transcriptomic study integrating a wide range of human ALS samples revealed that the upregulation of p53, a downstream target of inflammatory stress, is commonly detected in familial and sporadic ALS cases by a mechanism linked to a transactive response DNA-binding protein 43 (TDP-43) dysfunction. In this study, we show that prolonged interferon-gamma (IFNγ) treatment of human induced pluripotent stem cell-derived spinal motor neurons results in a severe cytoplasmic aggregation of TDP-43. TDP-43 dysfunction resulting from either IFNγ exposure or an ALS-associated TDP-43 mutation was associated with the activation of the p53 pathway. This was accompanied by the hyperactivation of neuronal firing, followed by the complete loss of their electrophysiological function. Through a comparative single-cell transcriptome analysis, we have identified significant alterations in ALS-associated genes in motor neurons exposed to IFNγ, implicating their direct involvement in ALS pathology. Interestingly, IFNγ was found to induce significant levels of programmed death-ligand 1 (PD-L1) expression in motor neurons without affecting the levels of any other immune checkpoint proteins. This finding suggests a potential role of excessive PD-L1 expression in ALS development, given that PD-L1 was recently reported to impair neuronal firing ability in mice. Our findings suggest that exposing motor neurons to IFNγ could directly derive ALS pathogenesis, even without the presence of the inherent genetic mutation or functional glia component. Furthermore, this study provides a comprehensive list of potential candidate genes for future immunotherapeutic targets with which to treat sporadic forms of ALS, which account for 90% of all reported cases.

The complete chloroplast genome sequence of the North American sclerophyllous evergreen shrub, Quercus turbinella (Fagaceae).

Quercus turbinella (section Quercus; Fagaceae) is an evergreen shrub characteristic in central Arizona and it concerns one of the most abundant and economically important genera of Quercus in the Northern Hemisphere. Here, we have sequenced the complete chloroplast genome to provide insight into the phylogenetic relationship of Q. turbinella. The whole genome is 161,208 bp in length with two inverted repeat regions of 25,827 bp each, which separate a large single-copy region of 90,552 bp and a small single-copy region of 19,002 bp. A total of 136 genes were annotated, including 88 protein-coding genes, eight ribosomal RNAs, and 40 transfer RNAs. The result of the maximum-likelihood phylogenetic analysis strongly suggested that Quercus turbinella had a close relationship to Quercus macrocarpa with strong bootstrap support.

Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma.

Approximately 50% of Merkel cell carcinoma (MCC) patients facing this highly aggressive skin cancer initially respond positively to PD-1-based immunotherapy. Nevertheless, the recurrence of MCC post-immunotherapy emphasizes the pressing need for more effective treatments. Recent research has highlighted Cyclin-dependent kinases 4 and 6 (CDK4/6) as pivotal cell cycle regulators gaining prominence in cancer studies. This study reveals that the CDK4/6 inhibitor, palbociclib can enhance PD-L1 gene transcription and surface expression in MCC cells by activating HIF2α. Inhibiting HIF2α with TC-S7009 effectively counteracts palbociclib-induced PD-L1 transcription and significantly intensifies cell death in MCC. Simultaneously, co-targeting CDK4/6 and HIF2α boosts ROS levels while suppressing SLC7A11, a key regulator of cellular redox balance, promoting ferroptosis- a form of immunogenic cell death linked to iron. Considering the rising importance of immunogenic cell death in immunotherapy, this strategy holds promise for improving future MCC treatments, markedly increasing immunogenic cell death various across various MCC cell lines, thus advancing cancer immunotherapy.