The Impact of Surgical Delay in Primary Cutaneous Melanoma: A Systematic Review.

BACKGROUND AND OBJECTIVES: The prognosis of patients diagnosed with melanoma is highly dependent on staging, early detection, and early intervention. In this systematic review, the authors aimed to investigate the impact of surgical delay (time between diagnostic biopsy and definitive surgical excision) on melanoma-specific outcomes. MATERIAL AND METHODS: A systematic review was conducted from Embase (1974-present), MEDLINE (1946-present), Cochrane Central Register of Controlled Trials (2005-present), Scopus, and Web of Science. A total of 977 studies were included for review after removal of duplicates. A total of 10 studies were included for final analysis. RESULTS: In total, 70% (7/10) of the studies found that longer wait times between initial biopsy and surgical intervention are correlated with lower overall survival. Among the 9 studies that reported overall survival as a percentage, the median and SD overall survival was 82% ± 5.87. CONCLUSION: There is evidence that prolonged surgical delay in patients diagnosed with Stage I cutaneous melanoma is associated with worsened overall mortality, whereas the effect of surgical delay on overall mortality in Stages II and III melanomas is uncertain. Future prospective studies and randomized clinical trials are needed to better define the appropriate surgical wait times between biopsy and surgical treatment.

The synergism of Lactobacillaceae, inulin, polyglucose, and aerobic exercise ameliorates hyperglycemia by modulating the gut microbiota community and the metabolic profiles in db/db mice.

This study aimed to assess the impact of Lactobacillaceae (L or H represents a low or high dose), inulin (I), and polydextrose (P) combined with aerobic exercise (A) on the composition of the gut microbiota and metabolic profiles in db/db mice. After a 12-week intervention, LIP, LIPA, and HIPA groups exhibited significant improvements in hyperglycemia, glucose tolerance, insulin resistance, inflammatory response, and short-chain fatty acid (SCFA) and blood lipid levels compared to type 2 diabetes mice (MC). After treatment, the gut microbiota composition shifted favorably in the treatment groups which significantly increased the abundance of beneficial bacteria, such as Bacteroides, Blautia, Akkermansia, and Faecalibaculum, and significantly decreased the abundance of Proteus. Metabolomics analysis showed that compared to the MC group, the contents of 5-hydroxyindoleacetic acid, 3-hydroxysebacic acid, adenosine monophosphate (AMP), xanthine and hypoxanthine were significantly decreased, while 3-ketosphinganine, sphinganine, and sphingosine were significantly increased in the LIP and LIPA groups, respectively. Additionally, LIP and LIPA not only improved sphingolipid metabolism and purine metabolism pathways but also activated AMP-activated protein kinase to promote ß-oxidation by increasing the levels of SCFAs. Faecalibaculum, Blautia, Bacteroides, and Akkermansia exhibited positive correlations with sphingosine, 3-ketosphinganine, and sphinganine, and exhibited negative correlations with hypoxanthine, xanthine and AMP. Faecalibaculum, Blautia, Bacteroides, and Akkermansia may have the potential to improve sphingolipid metabolism and purine metabolism pathways. These findings suggest that the synergism of Lactobacillaceae, inulin, polydextrose, and aerobic exercise provides a promising strategy for the prevention and management of type 2 diabetes.

The paradox of the safer cigarette: understanding the pulmonary effects of electronic cigarettes.

Electronic cigarette (e-cigarette) use continues to rise globally. E-cigarettes have been presented as safer alternatives to combustion cigarettes that can mitigate the harm associated with tobacco products; however, the degree to which e-cigarette use itself can lead to morbidity and mortality is not fully defined. Herein we describe how e-cigarettes function; discuss the current knowledge of the effects of e-cigarette aerosol on lung cell cytotoxicity, inflammation, anti-pathogen immune response, mucociliary clearance, oxidative stress, DNA damage, carcinogenesis, matrix remodeling, and airway hyperresponsiveness; and summarize the impact on lung diseases, including COPD, respiratory infection, lung cancer, and asthma. We highlight how the inclusion of nicotine or flavoring compounds in e-liquids can impact lung toxicity. Finally, we consider the paradox of the safer cigarette - the toxicities of e-cigarettes that can mitigate their potential to serve as a harm reduction tool in the fight against traditional cigarettes, and we summarize the research needed in this under-investigated area.

Dual-role transcription factors stabilize intermediate expression levels.

Precise control of gene expression levels is essential for normal cell functions, yet how they are defined and tightly maintained, particularly at intermediate levels, remains elusive. Here, using a series of newly developed sequencing, imaging, and functional assays, we uncover a class of transcription factors with dual roles as activators and repressors, referred to as condensate-forming level-regulating dual-action transcription factors (TFs). They reduce high expression but increase low expression to achieve stable intermediate levels. Dual-action TFs directly exert activating and repressing functions via condensate-forming domains that compartmentalize core transcriptional unit selectively. Clinically relevant mutations in these domains, which are linked to a range of developmental disorders, impair condensate selectivity and dual-action TF activity. These results collectively address a fundamental question in expression regulation and demonstrate the potential of level-regulating dual-action TFs as powerful effectors for engineering controlled expression levels.

Free fatty acid receptor 4 in cardiac myocytes ameliorates ischemic cardiomyopathy.

Aims: Free fatty acid receptor 4 (Ffar4) is a receptor for long-chain fatty acids that attenuates heart failure driven by increased afterload. Recent findings suggest that Ffar4 prevents ischemic injury in brain, liver, and kidney, and therefore, we hypothesized that Ffar4 would also attenuate cardiac ischemic injury. Methods and Results: Using a mouse model of ischemia-reperfusion (I/R), we found that mice with systemic deletion of Ffar4 (Ffar4KO) demonstrated impaired recovery of left ventricular systolic function post-I/R with no effect on initial infarct size. To identify potential mechanistic explanations for the cardioprotective effects of Ffar4, we performed bulk RNAseq to compare the transcriptomes from wild-type (WT) and Ffar4KO infarcted myocardium 3-days post-I/R. In the Ffar4KO infarcted myocardium, gene ontology (GO) analyses revealed augmentation of glycosaminoglycan synthesis, neutrophil activation, cadherin binding, extracellular matrix, rho signaling, and oxylipin synthesis, but impaired glycolytic and fatty acid metabolism, cardiac repolarization, and phosphodiesterase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated impaired AMPK signaling and augmented cellular senescence in the Ffar4KO infarcted myocardium. Interestingly, phosphodiesterase 6c (PDE6c), which degrades cGMP, was the most upregulated gene in the Ffar4KO heart. Further, the soluble guanylyl cyclase stimulator, vericiguat, failed to increase cGMP in Ffar4KO cardiac myocytes, suggesting increased phosphodiesterase activity. Finally, cardiac myocyte-specific overexpression of Ffar4 prevented systolic dysfunction post-I/R, defining a cardioprotective role of Ffa4 in cardiac myocytes. Conclusions: Our results demonstrate that Ffar4 in cardiac myocytes attenuates systolic dysfunction post-I/R, potentially by attenuating oxidative stress, preserving mitochondrial function, and modulation of cGMP signaling.

RT-QuIC detection of chronic wasting disease prion in platelet samples of white-tailed deer.

BACKGROUND: Chronic wasting disease (CWD) is a prion disease of captive and free-ranging cervids. Currently, a definitive diagnosis of CWD relies on immunohistochemistry detection of PrPSc in the obex and retropharyngeal lymph node (RPLN) of the affected cervids. For high-throughput screening of CWD in wild cervids, RPLN samples are tested by ELISA followed by IHC confirmation of positive results. Recently, real-time quacking-induced conversion (RT-QuIC) has been used to detect CWD positivity in various types of samples. To develop a blood RT-QuIC assay suitable for CWD diagnosis, this study evaluated the assay sensitivity and specificity with and without ASR1-based preanalytical enrichment and NaI as the main ionic component in assay buffer. RESULTS: A total of 23 platelet samples derived from CWD-positive deer (ELISA + /IHC +) and 30 platelet samples from CWD-negative (ELISA-) deer were tested. The diagnostic sensitivity was 43.48% (NaCl), 65.22% (NaI), 60.87% (NaCl-ASR1) or 82.61% (NaI-ASR1). The diagnostic specificity was 96.67% (NaCl), 100% (NaI), 100% (NaCl-ASR1), or 96.67% (NaI-ASR1). The probability of detecting CWD prion in platelet samples derived from CWD-positive deer was 0.924 (95% CRI: 0.714, 0.989) under NaI-ASR1 experimental condition and 0.530 (95% CRI: 0.156, 0.890) under NaCl alone condition. The rate of amyloid formation (RFA) was greatest under the NaI-ASR1 condition at 10-2 (0.01491, 95% CRI: 0.00675, 0.03384) and 10-3 (0.00629, 95% CRI: 0.00283, 0.01410) sample dilution levels. CONCLUSIONS: Incorporation of ASR1-based preanalytical enrichment and NaI as the main ionic component significantly improved the sensitivity of CWD RT-QuIC on deer platelet samples. Blood test by the improved RT-QuIC assay may be used for antemortem and postmortem diagnosis of CWD.

Design and Usability of an Open-Source, Low-Cost Flexible Laryngoscope for Resource-Limited Settings.

Importance: Endoscopes are paramount to the practice of otolaryngology. To provide physicians in low-middle-income countries with adequate tools to treat otolaryngologic problems, it is necessary to create a low-cost sustainable option. Objective: To describe the design and usability of an open-source, low-cost flexible laryngoscope that addresses the lack of affordable and accessible methods for otolaryngologic visualization in resource-limited settings. Design, Setting, and Participants: This quality improvement study used a mixed-methods approach, including a technical description of device design as well as quantitative and qualitative survey evaluation of device usability. Engineering involved device design, sourcing or manufacturing individual components, fabricating a prototype, and iterative testing. Key assumptions and needs for the device were identified in collaboration with otolaryngologists in Zimbabwe, and designed and simulated by biomedical engineers in a US university laboratory. Board-certified otolaryngologists at a single US university hospital trialed a completed prototype on simulated airways between May 2023 and June 2023. Main Outcomes and Measures: Technical details on the design of the device are provided. Otolaryngologist gave feedback on device characteristics, maneuverability, and visualization using the System Usability Scale, a customized Likert-scale questionnaire (5-point scale), and semistructured interviews. Results: A functional prototype meeting requirements was completed consisting of a distal-chip camera, spring bending tip, handle housing the control mechanism and electronics, and flexible polyether block amide-coated silicone sheath housing the camera and control wires; an external monitor provided real-time visualization and ability to store data. A total of 14 otolaryngologists participated in the device review. The mean (SD) System Usability Scale score was 88.93 (10.08), suggesting excellent usability. The device was rated highly for ease of set up, physical attributes, image quality, and functionality. Conclusions and Relevance: This quality improvement study described the design of a novel open-source low-cost flexible laryngoscope that external review with otolaryngologists suggests was usable and feasible in various resource-limited environments. Future work is needed to translate the model into a clinical setting.

Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma.

Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of antigens. In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface antigens that could be targeted by antibodies and chimeric antigen receptor-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas) and 9166 normal tissue samples (from the Genotype-Tissue Expression project), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative antigens. Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.

Increased Diabetes Complications in a Mouse Model of Oxidative Stress Due to 'Mismatched' Mitochondrial DNA.

Associations between chronic diabetes complications and mitochondrial dysfunction represent a subject of major importance, given the diabetes pandemic and high personal and socioeconomic costs of diabetes and its complications. Modelling diabetes complications in inbred laboratory animals is challenging due to incomplete recapitulation of human features, but offer mechanistic insights and preclinical testing. As mitochondrial-based oxidative stress is implicated in human diabetic complications, herein we evaluate diabetes in a unique mouse model that harbors a mitochondrial DNA from a divergent mouse species (the 'xenomitochondrial mouse'), which has mild mitochondrial dysfunction and increased oxidative stress. We use the streptozotocin-induced diabetes model with insulin supplementation, with 20-weeks diabetes. We compare C57BL/6 mice and the 'xenomitochondrial' mouse, with measures of heart and kidney function, histology, and skin oxidative stress markers. Compared to C57BL/6 mice, the xenomitochondrial mouse has increased diabetic heart and kidney damage, with cardiac dysfunction, and increased cardiac and renal fibrosis. Our results show that mitochondrial oxidative stress consequent to divergent mtDNA can worsen diabetes complications. This has implications for novel therapeutics to counter diabetes complications, and for genetic studies of risk, as mtDNA genotypes may contribute to clinical outcomes.

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis.

BACKGROUND: Rheumatic heart disease is the major cause of valvular heart disease in developing nations. Endothelial cells (ECs) are considered crucial contributors to rheumatic heart disease, but greater insight into their roles in disease progression is needed. METHODS: We used a Cdh5-driven EC lineage-tracing approach to identify and track ECs in the K/B.g7 model of autoimmune valvular carditis. Single-cell RNA sequencing was used to characterize the EC populations in control and inflamed mitral valves. Immunostaining and conventional histology were used to evaluate lineage tracing and validate single-cell RNA-sequencing findings. The effects of VEGFR3 (vascular endothelial growth factor receptor 3) and VEGF-C (vascular endothelial growth factor C) inhibitors were tested in vivo. The functional impact of mitral valve disease in the K/B.g7 mouse was evaluated using echocardiography. Finally, to translate our findings, we analyzed valves from human patients with rheumatic heart disease undergoing mitral valve replacements. RESULTS: Lineage tracing in K/B.g7 mice revealed new capillary lymphatic vessels arising from valve surface ECs during the progression of disease in K/B.g7 mice. Unsupervised clustering of mitral valve single-cell RNA-sequencing data revealed novel lymphatic valve ECs that express a transcriptional profile distinct from other valve EC populations including the recently identified PROX1 (Prospero homeobox protein 1)+ lymphatic valve ECs. During disease progression, these newly identified lymphatic valve ECs expand and upregulate a profibrotic transcriptional profile. Inhibiting VEGFR3 through multiple approaches prevented expansion of this mitral valve lymphatic network. Echocardiography demonstrated that K/B.g7 mice have left ventricular dysfunction and mitral valve stenosis. Valve lymphatic density increased with age in K/B.g7 mice and correlated with worsened ventricular dysfunction. Importantly, human rheumatic valves contained similar lymphatics in greater numbers than nonrheumatic controls. CONCLUSIONS: These studies reveal a novel mode of inflammation-associated, VEGFR3-dependent postnatal lymphangiogenesis in murine autoimmune valvular carditis, with similarities to human rheumatic heart disease.

Sulfur dioxide in the mid-infrared transmission spectrum of WASP-39b.

The recent inference of sulfur dioxide (SO2) in the atmosphere of the hot (approximately 1,100 K), Saturn-mass exoplanet WASP-39b from near-infrared JWST observations1-3 suggests that photochemistry is a key process in high-temperature exoplanet atmospheres4. This is because of the low (<1 ppb) abundance of SO2 under thermochemical equilibrium compared with that produced from the photochemistry of H2O and H2S (1-10 ppm)4-9. However, the SO2 inference was made from a single, small molecular feature in the transmission spectrum of WASP-39b at 4.05 µm and, therefore, the detection of other SO2 absorption bands at different wavelengths is needed to better constrain the SO2 abundance. Here we report the detection of SO2 spectral features at 7.7 and 8.5 µm in the 5-12-µm transmission spectrum of WASP-39b measured by the JWST Mid-Infrared Instrument (MIRI) Low Resolution Spectrometer (LRS)10. Our observations suggest an abundance of SO2 of 0.5-25 ppm (1σ range), consistent with previous findings4. As well as SO2, we find broad water-vapour absorption features, as well as an unexplained decrease in the transit depth at wavelengths longer than 10 µm. Fitting the spectrum with a grid of atmospheric forward models, we derive an atmospheric heavy-element content (metallicity) for WASP-39b of approximately 7.1-8.0 times solar and demonstrate that photochemistry shapes the spectra of WASP-39b across a broad wavelength range.

Association between high-density lipoprotein cholesterol and lumbar bone mineral density in Chinese: a large cross-sectional study.

BACKGROUND: The association between lipid and bone metabolism, particularly the role of high-density lipoprotein cholesterol (HDL-C) in regulating bone mineral density (BMD), is of significant interest. Despite numerous studies, findings on this relationship remain inconclusive, especially since evidence from large, sexually diverse Chinese populations is sparse. This study, therefore, investigates the correlation between HDL-C and lumbar BMD in people of different genders using extensive population-based data from physical examinations conducted in China. METHODS: Data from a cross-sectional survey involving 20,351 individuals aged > = 20 years drawn from medical records of health check-ups at the Health Management Centre of the Henan Provincial People's Hospital formed the basis of this study. The primary objective was to determine the correlation between HDL-C levels and lumbar BMD across genders. The analysis methodology included demographic data analysis, one-way ANOVA, subgroup analyses, multifactorial regression equations, smoothed curve fitting, and threshold and saturation effect analyses. RESULTS: Multifactorial regression analysis revealed a significant inverse relationship between HDL-C levels and lumbar BMD in both sexes, controlling for potential confounders (Male: ß = -8.77, 95% CI -11.65 to -5.88, P < 0.001; Female: ß = -4.77, 95% CI -8.63 to -0.90, P = 0.015). Subgroup and threshold saturation effect analyses indicated a stronger association in males, showing that increased HDL-C correlates with reduced lumbar BMD irrespective of age and body mass index (BMI). The most significant effect was observed in males with BMI > 28 kg/m2 and HDL-C > 1.45 mmol/L and in females with a BMI between 24 and 28 kg/m2. CONCLUSION: Elevated HDL-C is associated with decreased bone mass, particularly in obese males. These findings indicate that individuals with high HDL-C levels should receive careful clinical monitoring to mitigate osteoporosis risk. TRIAL REGISTRATION: The research protocol received ethics approval from the Ethics Committee at Beijing Jishuitan Hospital, in conformity with the Declaration of Helsinki guidelines (No. 2015-12-02). These data are a contribution of the China Health Quantitative CT Big Data Research team, registered at clinicaltrials.gov (code: NCT03699228).

ChIPr: accurate prediction of cohesin-mediated 3D genome organization from 2D chromatin features.

The three-dimensional genome organization influences diverse nuclear processes. Here we present Chromatin Interaction Predictor (ChIPr), a suite of regression models based on deep neural networks, random forest, and gradient boosting to predict cohesin-mediated chromatin interaction strength between any two loci in the genome. The predictions of ChIPr correlate well with ChIA-PET data in four cell lines. The standard ChIPr model requires three experimental inputs: ChIP-Seq signals for RAD21, H3K27ac, and H3K27me3 but works well with just RAD21 signal. Integrative analysis reveals novel insights into the role of CTCF motif, its orientation, and CTCF binding on cohesin-mediated chromatin interactions.

Associations between alcohol use disorder polygenic score and remission in participants from high-risk families and the Indiana Biobank.

BACKGROUND: In the United States, ~50% of individuals who meet criteria for alcohol use disorder (AUD) during their lifetimes do not remit. We previously reported that a polygenic score for AUD (PGSAUD ) was positively associated with AUD severity as measured by DSM-5 lifetime criterion count, and AUD severity was negatively associated with remission. Thus, we hypothesized that PGSAUD would be negatively associated with remission. METHODS: Individuals of European (EA) and African ancestry (AA) from the Collaborative Study on the Genetics of Alcoholism (COGA) who met lifetime criteria for AUD, and two EA cohorts ascertained for studies of liver diseases and substance use disorders from the Indiana Biobank were included. In COGA, 12-month remission was defined as any period of ≥12 consecutive months without meeting AUD criteria except craving and was further categorized as abstinent and non-abstinent. In the Indiana Biobank, remission was defined based on ICD codes and could not be further distinguished as abstinent or non-abstinent. Sex and age were included as covariates. COGA analyses included additional adjustment for AUD severity, family history of remission, and AUD treatment history. RESULTS: In COGA EA, PGSAUD was negatively associated with 12-month and non-abstinent remission (p ≤ 0.013, ßs between -0.15 and -0.10) after adjusting for all covariates. In contrast to the COGA findings, PGSAUD was positively associated with remission (p = 0.004, ß = 0.28) in the Indiana Biobank liver diseases cohort but not in the Indiana Biobank substance use disorder cohort (p = 0.17, ß = 0.15). CONCLUSIONS: PGSAUD was negatively associated with 12-month and non-abstinent remission in COGA EA, independent of behavioral measures of AUD severity and family history of remission. The discrepant results in COGA and the Indiana Biobank could reflect different ascertainment strategies: the Indiana Biobank participants were older and had higher rates of liver disease, suggesting that these individuals remitted due to alcohol-related health conditions that manifested in later life.

Aging-disturbed FUS phase transition impairs hematopoietic stem cells by altering chromatin structure.

ABSTRACT: Aged hematopoietic stem cells (HSCs) exhibit compromised reconstitution capacity. The molecular mechanisms behind this phenomenon are not fully understood. Here, we observed that the expression of FUS is increased in aged HSCs, and enforced FUS recapitulates the phenotype of aged HSCs through arginine-glycine-glycine-mediated aberrant FUS phase transition. By using Fus-gfp mice, we observed that FUShigh HSCs exhibit compromised FUS mobility and resemble aged HSCs both functionally and transcriptionally. The percentage of FUShigh HSCs is increased upon physiological aging and replication stress, and FUSlow HSCs of aged mice exhibit youthful function. Mechanistically, FUShigh HSCs exhibit a different global chromatin organization compared with FUSlow HSCs, which is observed in aged HSCs. Many topologically associating domains (TADs) are merged in aged HSCs because of the compromised binding of CCCTC-binding factor with chromatin, which is invoked by aberrant FUS condensates. It is notable that the transcriptional alteration between FUShigh and FUSlow HSCs originates from the merged TADs and is enriched in HSC aging-related genes. Collectively, this study reveals for the first time that aberrant FUS mobility promotes HSC aging by altering chromatin structure.

Coupled atmospheric chemistry, radiation, and dynamics of an exoplanet generate self-sustained oscillations.

Nonlinearity in photochemical systems is known to allow self-sustained oscillations, but they have received little attention in studies of planetary atmospheres. Here, we present a unique, self-oscillatory solution for ozone chemistry of an exoplanet from a numerical simulation using a fully coupled, three-dimensional (3D) atmospheric chemistry-radiation-dynamics model. Forced with nonvarying stellar insolation and emission flux of nitric oxide (NO), atmospheric ozone abundance oscillates by a factor of thirty over a multidecadal timescale. As such self-oscillations can only occur with biological nitrogen fixation contributing to NO emission, we propose that they are a unique class of biosignature. The resulting temporal variability in the atmospheric spectrum is potentially observable. Our results underscore the importance of revisiting the spectra of exoplanets over multidecadal timescales to characterizing the atmospheric chemistry of exoplanets and searching for exoplanet biosignatures. There are also profound implications for comparative planetology and the evolution of the atmospheres of terrestrial planets in the solar system and beyond. Fully coupled, 3D atmospheric chemistry-radiation-dynamics models can reveal new phenomena that may not exist in one-dimensional models, and hence, they are powerful tools for future planetary atmospheric research.

Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma.

Background: Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter-and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of neoantigens. Results: In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface neoantigens that could be targeted by antibodies and chimeric antigen receptor (CAR)-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas [TCGA]) and 9,166 normal tissue samples (from the Genotype-Tissue Expression project [GTEx]), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN , which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative neoantigens. Conclusions: Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.