Photocatalytic doping of organic semiconductors.

Chemical doping is an important approach to manipulating charge-carrier concentration and transport in organic semiconductors (OSCs)1-3 and ultimately enhances device performance4-7. However, conventional doping strategies often rely on the use of highly reactive (strong) dopants8-10, which are consumed during the doping process. Achieving efficient doping with weak and/or widely accessible dopants under mild conditions remains a considerable challenge. Here, we report a previously undescribed concept for the photocatalytic doping of OSCs that uses air as a weak oxidant (p-dopant) and operates at room temperature. This is a general approach that can be applied to various OSCs and photocatalysts, yielding electrical conductivities that exceed 3,000 S cm-1. We also demonstrate the successful photocatalytic reduction (n-doping) and simultaneous p-doping and n-doping of OSCs in which the organic salt used to maintain charge neutrality is the only chemical consumed. Our photocatalytic doping method offers great potential for advancing OSC doping and developing next-generation organic electronic devices.

Non-equilibrium transport in polymer mixed ionic-electronic conductors at ultrahigh charge densities.

Conducting polymers are mixed ionic-electronic conductors that are emerging candidates for neuromorphic computing, bioelectronics and thermoelectrics. However, fundamental aspects of their many-body correlated electron-ion transport physics remain poorly understood. Here we show that in p-type organic electrochemical transistors it is possible to remove all of the electrons from the valence band and even access deeper bands without degradation. By adding a second, field-effect gate electrode, additional electrons or holes can be injected at set doping states. Under conditions where the counterions are unable to equilibrate in response to field-induced changes in the electronic carrier density, we observe surprising, non-equilibrium transport signatures that provide unique insights into the interaction-driven formation of a frozen, soft Coulomb gap in the density of states. Our work identifies new strategies for substantially enhancing the transport properties of conducting polymers by exploiting non-equilibrium states in the coupled system of electronic charges and counterions.

Global analysis of gene expression in response to double trisomy loquat (Eriobotrya japonica).

Aneuploidy generally has severe phenotypic consequences. However, the molecular basis for this has been focused on single chromosomal dosage changes. It is not clear how the karyotype of complex aneuploidies affects gene expression. Here, we identified six different double-trisomy loquat strains from Q24 progenies of triploid loquat. The differences and similarities of the transcriptional responses of different double trisomy loquat strains were studied systematically via RNA-seq. The global modulation of gene expression indicated that both cis and trans-effects coordinately regulated gene expression in aneuploid loquat to some extent, and this coordinated regulation was determined by different gene functional groups. Aneuploidy can induce specific transcriptional responses on loquat chromosomes. The differentially expressed genes exhibited regional gene expression dysregulation domains along chromosomes. Furthermore, Aneuploidy could also promote the expression of genes with moderate and high in loquats. Our results provide new insights into the genome-wide transcriptional effects of karyotypes with complex aneuploidies.

Fibroblast activation protein inhibitor positron emission tomography imaging in muscles of patients with idiopathic inflammatory myopathy.

OBJECTIVES: Mesenchymal stromal cells in muscles participate in regeneration following muscle injury. This study explored the potential of [18F]fibroblast activation protein inhibitor (FAPI)-42 positron emission tomography (PET) targeting mesenchymal stromal cells to evaluate disease activity of idiopathic inflammatory myopathy (IIM). METHODS: Patients with IIM (n = 26) were prospectively included and underwent [18F]FAPI-42 PET/CT and whole-body MRI between January 2023 and July 2023. Patients with malignancies were retrospectively included in the control group and only underwent [18F]FAPI-42 PET/CT (n = 28). [18F]FAPI-42 PET/CT images were evaluated using for avid-FAPI uptake and the target-to-background ratio (TBR). Whole-body MRI was evaluated for oedema, fatty infiltration, and atrophy in 42 muscles in the IIM group. The global FAPI- and MRI-derived parameters were calculated for each. PATIENT: . Clinical assessment of disease activity and muscle strength were collected. RESULTS: Patients with IIM had significantly higher global FAPI-avid muscle ratios (0.68 [interquartile range (IQR): 0.45, 0.79] vs 0.06 [IQR: 0, 0.11], p< 0.001) and global muscle TBR (2.26 [IQR: 1.71, 2.75] vs 1.23 [IQR: 1.02, 1.52], p< 0.001) compared with controls. In the IIM group, the median TBR was higher in muscles with oedema than in those without (2.44 [IQR: 1.46, 3.27] vs 1.31 [IQR: 0.95, 1.99], p< 0.001). Global FAPI-avid muscle ratios significantly correlated with global oedema score (r = 0.833), muscle strength (r=-0.649), serum creatine kinase (r = 0.456), and disease activity index (r = 0.495-0.621). CONCLUSION: Increased [18F]FAPI-42 uptake was associated with muscle oedema in IIM. FAPI-derived parameters correlated with IIM disease activity. [18F]FAPI-42 is a promising PET tracer for evaluating IIM disease activity.

Head-to-head comparison between [68Ga]Ga-DOTA-NOC and [18F]DOPA PET/CT in a diverse cohort of patients with pheochromocytomas and paragangliomas.

PURPOSE: To compare the detection ability of 68Ga-labelled DOTA-l-Nal3-octreotide ([68Ga]Ga-DOTA-NOC) and 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]DOPA) in patients with phaeochromocytomas and paragangliomas (PPGLs) of different origins and gene mutations, such as germline succinate dehydrogenase complex genes (SDHx). METHODS: Eighty-five patients with histopathologically confirmed PPGLs who underwent both [68Ga]Ga-DOTA-NOC and [18F]DOPA PET/CT from March 2017 to June 2023 were enrolled in this retrospective study. For comparative analyses, PPGLs were classified as phaeochromocytoma (PCC), sympathetic paraganglioma (sPGL), and head/neck paraganglioma (HNPGL). Detection rates were analyzed on per-patient and per-lesion bases and compared using the Chi-square/Fischer's exact test. RESULTS: Among 85 patients with PPGLs (48 males; 43 years ± 17 [SD]), the patient-based detection rates of [68Ga]Ga-DOTA-NOC and [18F]DOPA PET/CT were 87.1% (74/85) and 89.4% (76/85), respectively (p = 0.634), and the lesion-based detection rates were 80.8% (479/593) and 71.2% (422/593), respectively (p < 0.001). Only one patient with a recurrent PCC presented double-negative imaging, while 66 patients exhibited double-positive imaging. The remaining patients were either [68Ga]Ga-DOTA-NOC-negative/[18F]DOPA-positive (n = 10) or [68Ga]Ga-DOTA-NOC-positive/[18F]DOPA-negative (n = 8). In subgroup analyses, [68Ga]Ga-DOTA-NOC PET/CT detected significantly more metastases of sPGL (91.1%, 236/259) and SDHx-related PPGL (89.6%, 86/96) than [18F]DOPA PET/CT (48.6%[126/259] and 50.0%[48/96], respectively; both p < 0.001). However, [18F]DOPA showed significantly higher detection rates of PCC in both primary/recurrent and metastatic lesions (94.3%[50/53] vs. 62.3%[33/53] and 87.9%[174/198] vs. 69.2%[137/198], respectively; both p < 0.001). Regarding metastases in different organs, [68Ga]Ga-DOTA-NOC PET/CT detected more lesions than [18F]DOPA PET/CT in bone (96.2%[176/183] vs. 66.1%[121/183]; p < 0.001) and lymph nodes (82.0%[73/89] vs. 53.9%[48/89]; p < 0.001) but less lesions in peritoneum (20%[4/20] vs. 100%[20/20]; p < 0.001). CONCLUSION: [68Ga]Ga-DOTA-NOC and [18F]DOPA are complementary in diagnosing PPGL under the appropriate clinical setting. [68Ga]Ga-DOTA-NOC should be considered as the ideal first-line tracer for detecting metastases of sPGL and SDHx-related tumours, whereas [18F]DOPA may be the optimal tracer for evaluating non-SDHx-related PCC, especially in detecting primary lesions and monitoring recurrence.

zDHHC20-driven S-palmitoylation of CD80 is required for its costimulatory function.

CD80 is a transmembrane glycoprotein belonging to the B7 family, which has emerged as a crucial molecule in T cell modulation via the CD28 or CTLA4 axes. CD80-involved regulation of immune balance is a finely tuned process and it is important to elucidate the underlying mechanism for regulating CD80 function. In this study we investigated the post-translational modification of CD80 and its biological relevance. By using a metabolic labeling strategy, we found that CD80 was S-palmitoylated on multiple cysteine residues (Cys261/262/266/271) in both the transmembrane and the cytoplasmic regions. We further identified zDHHC20 as a bona fide palmitoyl-transferase determining the S-palmitoylation level of CD80. We demonstrated that S-palmitoylation protected CD80 protein from ubiquitination degradation, regulating the protein stability, and ensured its accurate plasma membrane localization. The palmitoylation-deficient mutant (4CS) CD80 disrupted these functions, ultimately resulting in the loss of its costimulatory function upon T cell activation. Taken together, our results describe a new post-translational modification of CD80 by S-palmitoylation as a novel mechanism for the regulation of CD80 upon T cell activation.

Palmitoyltransferase ZDHHC3 is essential for the oncogenic activity of PML/RARα in acute promyelocytic leukemia.

The oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα) is critical for acute promyelocytic leukemia (APL). PML/RARα initiates APL by blocking the differentiation and increasing the self-renewal of leukemic cells. The standard clinical therapies all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which induce PML/RARα proteolysis, have dramatically improved the prognosis of APL patients. However, the emergence of mutations conferring resistance to ATRA and ATO has created challenges in the treatment of APL patients. Exploring pathways that modulate the oncogenic activity of PML/RARα could help develop novel therapeutic strategies for APL, particularly for drug-resistant APL. Herein, we demonstrated for the first time that palmitoylation of PML/RARα was a critical determinant of its oncogenic activity. PML/RARα palmitoylation was found to be catalyzed mainly by the palmitoyltransferase ZDHHC3. Mechanistically, ZDHHC3-mediated palmitoylation regulated the oncogenic transcriptional activity of PML/RARα and APL pathogenesis. The knockdown or overexpression of ZDHHC3 had respective effects on the expression of proliferation- and differentiation-related genes. Consistently, the depletion or inhibition of ZDHHC3 could significantly arrest the malignant progression of APL, particularly drug-resistant APL, whereas ZDHHC3 overexpression appeared to have a promoting effect on the malignant progression of APL. Thus, our study not only reveals palmitoylation as a novel regulatory mechanism that modulates PML/RARα oncogenic activity but also identifies ZDHHC3 as a potential therapeutic target for APL, including drug-resistant APL.

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Associations of the planetary health diet index (PHDI) with asthma: the mediating role of body mass index.

BACKGROUND: Given the global shifts in environmental conditions and dietary habits, understanding the potential impact of dietary factors and body mass index (BMI) on respiratory diseases, including asthma, is paramount. Investigating these relationships can contribute to the formulation of more effective prevention strategies. The Planetary Health Diet Index (PHDI), a dietary scoring system that balances human health with environmental sustainability, underscores the importance of increasing the consumption of plant-based foods while reducing the intake of red meat, sugar, and highly processed foods. The objective of this study was to assess the association between PHDI and the prevalence of asthma and the mediation effect of BMI in a US general population. METHODS: This study utilized data from 32,388 participants in the National Health and Nutrition Examination Survey (NHANES) spanning from 2005 to 2018. Multivariate logistic regression and weighted quantile sum (WQS) regressions were employed to investigate the association between PHDI, individual nutrients, and asthma. Restricted cubic spline (RCS) analysis explored the linear or non-linear relationship between PHDI and asthma. Interaction analyses were conducted on subgroups to validate the findings. Mediation analysis was performed to examine the effect of BMI on the relationship between PHDI and asthma. RESULTS: There was a significant negative association between PHDI and asthma. After adjusting for covariates, for every 10-point increase in PHDI, there was a 4% decrease in the prevalence of asthma (P = 0.025). Moreover, as PHDI increased, there was a trend towards lower asthma prevalence (P for trend < 0.05). WQS analyses showed consistent associations (OR = 0.93, 95%CI: 0.88, 0.98), with Fiber, Vitamin C, and Protein significant factors. The dose-response curve indicated a linear association between PHDI and asthma, with higher PHDI associated with lower asthma prevalence. Additionally, BMI is significantly positively associated with asthma (P < 0.001), and BMI decreases as the PHDI increases (ß = -0.64, P < 0.001). Mediation analysis indicates that BMI significantly mediates the relationship between PHDI and asthma, with a mediation proportion of 33.85% (P < 0.001). CONCLUSION: The results of this study show a strong negative correlation between PHDI and the prevalence of asthma. In addition, BMI mediated this negative relationship.

The role of quantitative tumor burden based on [68 Ga]Ga-DOTA-NOC PET/CT in well-differentiated neuroendocrine tumors: beyond prognosis.

PURPOSE: We aimed to elucidate the role of quantitative tumor burden based on PET/CT of somatostatin receptors in well-differentiated neuroendocrine tumors (NETs). METHODS: This study enrolled patients with [68 Ga]Ga-DOTA-NOC PET/CT-positive advanced NETs who did not receive medical treatment prior to PET/CT. Tumor burden was calculated using methods based on the background threshold and relative fixed threshold values (30%, 40%, and 50%). The prognostic value of the measured tumor burden in reference to overall survival (OS) and progression-free survival (PFS) on treatment with octreotide long-acting repeatable (LAR) was assessed using Cox regression analysis, Harrell's C-index, and survival analysis. A classification and regression tree (CART) was used to determine the optimal threshold for tumor burden. RESULTS: A total of 204 patients were included. Somatostatin receptor-expressing tumor volume (SRETV) and liver SRETV derived from a relative fixed threshold of 30% (SRETV30 and liver SRETV30) were statistically significantly associated with OS (C-index: 0.802 [95% confidence interval (CI), 0.658-0.946] and 0.806 [95% CI, 0.664-0.948], respectively). Extrahepatic tumor burden was not correlated with OS (hazard ratio: 0.617, 95% CI: 0.241-1.574, P = 0.312). Among 155 patients with non-functional NETs with a ki-67 index of ≤ 10%, those with a high SRETV30 (P = 0.016) or high liver SRETV30 (P = 0.014) showed statistically significantly worse PFS on treatment with octreotide LAR. Patients receiving a higher dose of octreotide LAR normalized by SRETV30 or liver SRETV30 (a normalized dose or a liver normalized dose) showed prolonged PFS on treatment with octreotide LAR and a prolonged OS. CONCLUSION: Quantitative tumor burden based on [68 Ga]Ga-DOTA-NOC PET/CT was correlated with OS and PFS in patients with non-functional NETs with a ki-67 index of ≤ 10% who received octreotide LAR. Calculating normalized and liver normalized doses may help in selecting the starting dose of octreotide LAR.