Characterization of Metabolic Patterns in Mouse Oocytes during Meiotic Maturation.

Well-balanced and timed metabolism is essential for making a high-quality egg. However, the metabolic framework that supports oocyte development remains poorly understood. Here, we obtained the temporal metabolome profiles of mouse oocytes during in vivo maturation by isolating large number of cells at key stages. In parallel, quantitative proteomic analyses were conducted to bolster the metabolomic data, synergistically depicting the global metabolic patterns in oocytes. In particular, we discovered the metabolic features during meiotic maturation, such as the fall in polyunsaturated fatty acids (PUFAs) level and the active serine-glycine-one-carbon (SGOC) pathway. Using functional approaches, we further identified the key targets mediating the action of PUFA arachidonic acid (ARA) on meiotic maturation and demonstrated the control of epigenetic marks in maturing oocytes by SGOC network. Our data serve as a broad resource on the dynamics occurring in metabolome and proteome during oocyte maturation.

Stratifying TAD boundaries pinpoints focal genomic regions of regulation, damage, and repair.

Advances in chromatin mapping have exposed the complex chromatin hierarchical organization in mammals, including topologically associating domains (TADs) and their substructures, yet the functional implications of this hierarchy in gene regulation and disease progression are not fully elucidated. Our study delves into the phenomenon of shared TAD boundaries, which are pivotal in maintaining the hierarchical chromatin structure and regulating gene activity. By integrating high-resolution Hi-C data, chromatin accessibility, and DNA double-strand breaks (DSBs) data from various cell lines, we systematically explore the complex regulatory landscape at high-level TAD boundaries. Our findings indicate that these boundaries are not only key architectural elements but also vibrant hubs, enriched with functionally crucial genes and complex transcription factor binding site-clustered regions. Moreover, they exhibit a pronounced enrichment of DSBs, suggesting a nuanced interplay between transcriptional regulation and genomic stability. Our research provides novel insights into the intricate relationship between the 3D genome structure, gene regulation, and DNA repair mechanisms, highlighting the role of shared TAD boundaries in maintaining genomic integrity and resilience against perturbations. The implications of our findings extend to understanding the complexities of genomic diseases and open new avenues for therapeutic interventions targeting the structural and functional integrity of TAD boundaries.

Genome sequences and population genomics reveal climatic adaptation and genomic divergence between two closely related sweetgum species.

Understanding the genetic basis of population divergence and adaptation is an important goal in population genetics and evolutionary biology. However, the relative roles of demographic history, gene flow, and/or selective regime in driving genomic divergence, climatic adaptation, and speciation in non-model tree species are not yet fully understood. To address this issue, we generated whole-genome resequencing data of Liquidambar formosana and L. acalycina, which are broadly sympatric but altitudinally segregated in the Tertiary relict forests of subtropical China. We integrated genomic and environmental data to investigate the demographic history, genomic divergence, and climatic adaptation of these two sister species. We inferred a scenario of allopatric species divergence during the late Miocene, followed by secondary contact during the Holocene. We identified multiple genomic islands of elevated divergence that mainly evolved through divergence hitchhiking and recombination rate variation, likely fostered by long-term refugial isolation and recent differential introgression in low-recombination genomic regions. We also found some candidate genes with divergent selection signatures potentially involved in climatic adaptation and reproductive isolation. Our results contribute to a better understanding of how late Tertiary/Quaternary climatic change influenced speciation, genomic divergence, climatic adaptation, and introgressive hybridization in East Asia's Tertiary relict flora. In addition, they should facilitate future evolutionary, conservation genomics, and molecular breeding studies in Liquidambar, a genus of important medicinal and ornamental values.

Dual-specificity phosphatase 5-mediated fatty acid oxidation promotes Mycobacterium bovis BCG -induced inflammatory responses.

Mycobacterium tuberculosis (Mtb) reprograms FAs metabolism of macrophages during infection and affects inflammatory reaction eventually, however, the mechanism remains poorly understood. Here we show that Mycobacterium bovis (BCG) induces DUSP5 expression through TLR2-MAPKs signaling pathway and promotes fatty acid oxidation (FAO). Silencing DUSP5 by adeno-associated virus vector (AAV) ameliorates lung injury and DUSP5 knockdown reduces the expression of IL-1ß, IL-6 and inactivated NF-κB signaling in BCG-infected macrophages. Of note, DUSP5 specific siRNA increases the content of free fatty acids (FFAs) and triglyceride (TG), but represses the expression of FAO associated enzymes such as CPT1A and PPARα, suggesting DUSP5 mediated FAO during BCG infection. Moreover, Inhibiting FAO by pharmacological manner suppresses IL-1ß, IL-6, TNF-α expression and relieves lung damage. Taken together, our data indicates DUSP5 mediates FAO reprogramming and promotes inflammatory response to BCG infection.

TMEM16A inhibits autophagy and promotes the invasion of hypopharyngeal squamous cell carcinoma through mTOR pathway.

Previous studies have indicated that transmembrane protein 16A (TMEM16A) plays a crucial role in the pathogenesis and progression of various tumors by influencing multiple signaling pathways. However, the role of TMEM16A in regulating autophagy via the mammalian target of rapamycin (mTOR) pathway and its impact on the development of hypopharyngeal squamous cell carcinoma (HSCC) remain unclear. Immunohistochemistry and western blotting were used to assess the expression of TMEM16A in HSCC tissues and metastatic lymph nodes. Manipulation of TMEM16A expression levels was achieved in the FaDu cell line through overexpression or knockdown, followed by assessment of its biological effects using cell colony formation, wound healing, transwell and invasion assays. Additionally, apoptosis and autophagy-related proteins, as well as autophagosome formation, were evaluated through western blotting, transmission electron microscopy and immunofluorescence following TMEM16A knockdown or overexpression in FaDu cells. Our study revealed significantly elevated levels of TMEM16A in both HSCC tissues and metastatic lymph nodes compared with normal tissues. In vitro experiments demonstrated that silencing TMEM16A led to a notable suppression of HSCC cell proliferation, invasion and migration. Furthermore, TMEM16A silencing effectively inhibited tumor growth in xenografted mice. Subsequent investigations indicated that knockdown of TMEM16A in HSCC cells could suppress mTOR activation, thereby triggering autophagic cell death by upregulating sequestosome-1 (SQSTM1/P62) and microtubule-associated protein light chain 3 II (LC3II). This study highlights the crucial role of TMEM16A in modulating autophagy in HSCC, suggesting its potential as a therapeutic target for the treatment of this malignancy.

Evaluation of a novel PET tracer [18F]-Florbetazine for Alzheimer's disease diagnosis and ß-amyloid deposition quantification.

[18F]-Florbetazine ([18F]-92) is a selective PET tracer for ß-amyloid (Aß) depositions with a novel diaryl-azine scaffold to reduce lipophilicity and to achieve higher gray-to-white matter contrast. We aimed to assess its diagnostic value in Alzheimer's disease (AD) and pharmacokinetics characteristics in human subjects. METHODS: Six healthy controls (HCs) and nine AD patients underwent dynamic PET examination with [18F]-Florbetazine and a structural MRI scan. The time-activity-curves (TACs) for volumes of interest (VOIs) in cerebral cortex, cerebellar cortex and cerebral white matter was depicted and their standardized uptake value ratios (SUVRs) with cerebellar cortex as reference were compared between HCs and AD patients. The cerebral gray-to-white matter SUV ratio (GWR) was also calculated. RESULTS: In HCs, radioactivities in the cerebral cortex VOIs were homogeneously low and at the same level as in cerebellar cortex, while in AD patients, cortical VOIs expected to contain Aß exhibited high radioactivity. Cerebral cortex SUVRs remain relatively low in HCs while keep increasing along with time in AD patients. After 15 min, the cerebral cortex SUVRs became significant higher in AD patients compared to HCs with 100 % discrimination accuracy. In AD patients, GWR remained over 1.3 for all time intervals and visual inspection showed lower uptake in cerebral white matter compared to cerebral cortex. CONCLUSION: [18F]-Florbetazine PET showed high uptake on Aß plaques and high gray-to-white contrast in AD patients that are favorable in visual read. [18F]-Florbetazine can be potentially used for detection and quantification of Aß depositions in the living human brain.

P2X7 receptor of olfactory bulb microglia plays a pathogenic role in stress-related depression in mice with allergic rhinitis.

The aim of this study was to explore the role and mechanism of the olfactory bulb (OB) microglial P2X7 receptor (P2X7R) in allergic rhinitis (AR)-related depression, with the objective of identifying a potential clinical target. An AR mouse model was induced using ovalbumin (OVA), while chronic stress was employed to induce depression. The study used P2X7R-specific antagonists and OB microglia-specific P2X7R knockdown mice as crucial tools. The results showed that mice in the OVA + stress group exhibited more pronounced depressive-like phenotypes. Furthermore, there was an observed increase in microglial activation in the OB, followed by a rise in the level of inflammation. The pharmacological inhibition of P2X7R significantly mitigated the depression-like phenotype and the OB inflammatory response in OVA + stress mice. Notably, the specific knockdown of microglial P2X7R in the OB resulted in a similar effect, possibly linked to the regulation of IL-1ß via the "ATP-P2X7R-Caspase 1" axis. These findings collectively demonstrate that microglial P2X7R in the OB acts as a direct effector molecule in AR-related depression, and its inhibition may offer a novel strategy for clinical prevention and treatment.

Understanding the nose-brain axis and its role in related diseases: A conceptual review.

The nose-brain axis (NBA), a critical component of the body-brain axis, not only serves as a drug transport route for the treatment of brain diseases but also mediates changes such as neuroimmune disorders, which may be an important mechanism in the occurrence and development of some nasal or brain diseases. Despite its importance, there are substantial gaps that remain in our understanding of the characteristics of NBA-mediated diseases and of the cellular and molecular mechanisms underlying the bidirectional NBA crosstalk. These gaps have limited the translational application of NBA-related research findings to some extent. Therefore, this review aims to address the conceptual framework of NBA and highlight its values in representative diseases by combining existing literature with new research results from our group. We hope that this paper will provide a basis for further in-depth research in this field, and facilitate the clinical translation of NBA.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Predicting amyloid-PET and clinical conversion in apolipoprotein E ε3/ε3 non-demented individuals with multidimensional factors.

The apolipoprotein E (APOE) ε4 is a well-established risk factor of amyloid-ß (Aß) in Alzheimer's disease (AD). However, because of the high prevalence of APOE ε3, there may be a large number of people with APOE ε3/ε3 who are non-demented and have Aß pathology. There are limited studies on assessing Aß status and clinical conversion in the APOE ε3/ε3 non-demented population. Two hundred and ninety-three non-demented individuals with APOE ε3/ε3 from ADNI database were divided into Aß-positron emission tomography (Aß-PET) positivity (+) and Aß-PET negativity (-) groups using cut-off value of >1.11. Stepwise regression searched for a single or multidimensional clinical variables for predicting Aß-PET (+), and the receiver operating characteristic curve (ROC) assessed the accuracy of the predictive models. The Cox regression model explored the risk factors associated with clinical conversion to mild cognitive impairment (MCI) or AD. The results showed that the combination of sex, education, ventricle and white matter hyperintensity (WMH) volume can accurately predict Aß-PET status in cognitively normal (CN), and the combination of everyday cognition study partner total (EcogSPTotal) score, age, plasma p-tau 181 and WMH can accurately predict Aß-PET status in MCI individuals. EcogSPTotal score were independent predictors of clinical conversion to MCI or AD. The findings may provide a non-invasive and effective tool to improve the efficiency of screening Aß-PET (+), accelerate and reduce costs of AD trial recruitment in future secondary prevention trials or help to select patients at high risk of disease progression in clinical trials.

A self-amplifying loop of TP53INP1 and P53 drives oxidative stress-induced apoptosis of bone marrow mesenchymal stem cells.

Bone marrow mesenchymal stem cell (BMSC) transplantation is a promising regenerative therapy; however, the survival rate of BMSCs after transplantation is low. Oxidative stress is one of the main reasons for the high apoptosis rate of BMSCs after transplantation, so there is an urgent need to explore the mechanism of oxidative stress-induced apoptosis of BMSCs. Our previous transcriptome sequencing results suggested that the expression of P53-induced nuclear protein 1 (TP53INP1) and the tumor suppressor P53 (P53) was significantly upregulated during the process of oxidative stress-induced apoptosis of BMSCs. The present study further revealed the role and mechanism of TP53INP1 and P53 in oxidative stress-induced apoptosis in BMSCs. Overexpression of TP53INP1 induced apoptosis of BMSCs, knockdown of TP53INP1 alleviated oxidative stress apoptosis of BMSCs. Under oxidative stress conditions, P53 is regulated by TP53INP1, while P53 can positively regulate the expression of TP53INP1, so the two form a positive feedback loop. To clarify the mechanism of feedback loop formation. We found that TP53INP1 inhibited the ubiquitination and degradation of P53 by increasing the phosphorylation level of P53, leading to the accumulation of P53 protein. P53 can act on the promoter of the TP53INP1 gene and increase the expression of TP53INP1 through transcriptional activation. This is the first report on a positive feedback loop formed by TP53INP1 and P53 under oxidative stress. The present study clarified the formation mechanism of the positive feedback loop. The TP53INP1-P53 positive feedback loop may serve as a potential target for inhibiting oxidative stress-induced apoptosis in BMSCs.

A 3-Year Survival Update from a Phase 2 Study of Paclitaxel Plus Cisplatin and 5-Fuorouracil Induction Chemotherapy for Locally Advanced Borderline-Resectable Esophageal Squamous Cell Carcinoma: The NEOCRTEC-1601 Clinical Trial.

BACKGROUND: This study updated 3-year analyses to further characterize the impact of docetaxel, cisplatin, and fluorouracil (TPF) chemotherapy followed by surgery. METHODS: This study was a single-center phase 2 clinical trial. Patients with a diagnosis of borderline resectable esophageal squamous cell carcinoma (BR-ESCC) because of the primary tumor or bulky lymph node that potentially invaded adjacent organs were eligible. The treatment started with TPF chemotherapy followed by surgery if the cancer was resectable, or by concurrent chemoradiation if it was unresectable. This updated report presents the 3-year overall survival (OS) and progression-free survival (PFS) rates. RESULTS: Surgery was performed for 27 patients (57.4%), and R0 resection was confirmed in 25 patients (53.2%). Pathologic complete response was confirmed in four patients (8.5%). The median follow-up time for the surviving patients was 44.8 months (range, 3.4-74.6 months). The median OS for all the patients was 41.9 months (95% confidence interval [CI], 18.6-65.3 months), with a median PFS of 38.7 months (95% CI, 23.5-53.9 months). The 3-year survival rate for all the patients was 54.4%. The 3-year survival rate for the R0 patients was 65.4%. CONCLUSION: Long-term follow-up evaluation confirmed that TPF followed by surgery is feasible and promising in terms of survival for BR-ESCC patients. Trial Registration ClinicalTrials.gov identifer: NCT02976909.

Evaluation of the safety, biodistribution, dosimetry of [18F]AlF-NOTA-LM3 and head-to-head comparison with [68Ga]Ga-DOTATATE in patients with well-differentiated neuroendocrine tumors: an interim analysis of a prospective trial.

PURPOSE: 18F-labelled somatostatin receptor (SSTR) analogs offer several advantages over 68Ga in terms of yield, cost, spatial resolution and detection rate. This study presents an interim analysis of a prospective trial designed to assess the safety, biodistribution and dosimetry of [18F]AlF-NOTA-LM3, and compare its diagnostic efficacy and clinical management outcomes with [68Ga]Ga-DOTATATE or [68Ga]Ga-NODAGA-LM3 in patients with well-differentiated NETs. METHODS: Twenty-one patients with histologically confirmed well-differentiated neuroendocrine tumors (G1 and G2) were prospectively recruited. The first eight patients underwent serial PET scans at 5, 15, 30, 45, 60, and 120 min after [18F]AlF-NOTA-LM3 injection to assess biodistribution and dosimetry. The remaining patients underwent whole-body PET/CT scans. [18F]AlF-NOTA-LM3 and [68Ga]Ga-DOTATATE PET/CT were done within a week, with a minimum 24-hour interval between the two scans. Focal uptake above the surrounding background activity and could not be explained by physiologic uptake was considered lesions of NETs. Lesion number, tumor uptake, and tumor-to-background ratio (TBR) were compared. In patients with discrepant findings, the size of the smallest lesions (measured on coregistered CT) detected on [68Ga]Ga-DOTATATE and [18F]AlF-NOTA-LM3 was compared. RESULTS: [18F]AlF-NOTA-LM3 was safe and well-tolerated. Physiological uptake of [18F]AlF-NOTA-LM3 was significantly lower than that of [68Ga]Ga-DOTATATE in abdominal organs and bone marrow, but higher in blood pool and lung. The mean effective dose was 0.024 ± 0.014 mSv/MBq. [18F]AlF-NOTA-LM3 detected significantly more liver lesions (457 vs. 291, P = 0.006) and lymph node lesions (30 vs. 22, P = 0.011) compared to [68Ga]Ga-DOTATATE. The tumor uptake was comparable, but TBR was significantly higher with [18F]AlF-NOTA-LM3 for lesions from all sites except for the duodenum. The size of the minimum liver lesions (0.54 ± 0.15 vs. 1.01 ± 0.49, P<0.001) and lymph node lesions (0.50 ± 0.19 vs. 1.26 ± 0.86, P = 0.024) detected on [18F]ALF-NOTA-LM3 were significantly smaller than those detected on [68Ga]Ga-DOTATATE. CONCLUSION: [18F]AlF-NOTA-LM3 shows favorable biodistribution, higher spatial resolution and superior performance than [68Ga]Ga-DOTATATE in detecting liver and lymph node metastases, with higher TBR. Notably, it is the first SSTR analog to show superiority in detecting lymph node lesions when compared to [68Ga]Ga-DOTATATE. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT06056362.

P2X7 receptor of microglia in olfactory bulb mediates the pathogenesis of olfactory dysfunction in a mouse model of allergic rhinitis.

The pathogenesis of allergic rhinitis (AR)-related olfactory dysfunction (OD) remains unknown. Inhibiting microglial response in olfactory bulb (OB) can ameliorate AR-related OD, but no precise targets have been available. In this study, we established a mouse model of ovalbumin (OVA)-induced AR and combined with the application of P2X7 receptor (P2X7R)-specific antagonists and cell culture in conditioned medium to investigate the role and mechanism of OB microglial P2X7R in AR-related OD. Serum IgE and IL-5 levels determined via ELISA and federated the number of nose-scratching to affirm the success of OVA-induced AR mouse model. Buried food pellet test was used to evaluate the olfactory function of mice. The changes of IBA1, GFAP, P2X7R, IL-1ß, IL-1Ra, and CASPASE 1 were detected by quantitative polymerase chain reaction and western blotting. The levels of adenosine triphosphate (ATP) were determined by the commercialized kit. The morphological changes of microglia were assessed using immunofluorescence staining and Sholl analysis. Findings showed that AR-related OD was associated with OB microglia-mediated imbalance between IL-1ß and IL-1Ra. Treatment with BBG improved the olfactory function in AR mice with restoring the balance between IL-1ß and IL-1Ra. In vitro, the conditioned medium obtained after HNEpC treatment with Der p1 could activate HMC3 to arise inflammatory reaction basing on "ATP-P2X7R-Caspase 1" axis, while inhibition of its P2X7R suppressed the reaction. In brief, microglial P2X7R in OB is a direct effector molecule in AR-related OD and inhibition of it may be a new strategy for the treatment of AR-related OD.

Phase II study of SOXIRI (S-1/oxaliplatin/irinotecan) chemotherapy in patients with unresectable pancreatic ductal adenocarcinoma.

BACKGROUND: To provide data on the safety and efficacy of a combination chemotherapy regimen consisting of S-1, oxaliplatin, and irinotecan (SOXIRI) as a first-line therapy in unresectable pancreatic ductal adenocarcinoma (UPDA) patients. METHODS: Patients with UPDA and no prior treatment chemotherapy in the UPDA setting were enrolled. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival (PFS) and adverse events. Patients received 80 mg/m2 S-1 twice a day for 2 weeks in an alternate-day administration cycle, 85 mg/m2 oxaliplatin on Day 1, and 150 mg/m2 irinotecan on Day 1 of a 2-week cycle. RESULTS: In these 62 enrolled patients, the ORR was 27.4 %, median OS was 12.1 months, and median PFS was 6.5 months. Major grade 3 or 4 toxicity included neutropenia (22.3 %), leucopenia (16.1 %), nausea (9.7 %), vomiting (9.7 %), thrombocytopenia (6.5 %), anorexia (8.5 %), anemia (4.8 %), and diarrhea (1.6 %). No treatment-related deaths occurred. In addition, the analysis of 32 patients suffering pain revealed that the rate of pain relief was 34.4 %. CONCLUSION: SOXIRI might be a standard regimen with an acceptable toxicity profile and favorable efficacy for use as chemotherapy in patients with UPDA.

Phase I, first-in-human study of XTR004, a novel 18F-labeled tracer for myocardial perfusion PET: Biodistribution, radiation dosimetry, pharmacokinetics, and safety after a single injection at rest.

OBJECTIVES: This study assessed the imaging characteristics, pharmacokinetics and safety of XTR004, a novel 18F-labeled Positron Emission Tomography (PET) myocardial perfusion imaging tracer, after a single injection at rest in humans. METHODS: Eleven healthy subjects (eight men and three women) received intravenous XTR004 (239-290 megabecquerel [MBq]). Safety profiles were monitored on the dosing day and three follow-up visits. Multiple whole-body PET scans were conducted over 4.7 h to evaluate biodistribution and radiation dosimetry. Blood and urine samples collected for 7.25 h were metabolically corrected to characterize pharmacokinetics. RESULTS: In the first 0-12 min PET images of ten subjects, liver (26.81 ± 4.01), kidney (11.43 ± 2.49), lung (6.75 ± 1.76), myocardium (4.72 ± 0.67) and spleen (3.1 ± 0.84) exhibited the highest percentage of the injected dose (%ID). Myocardial uptake of XTR004 in the myocardium initially reached 4.72 %ID and 7.06 g/mL, and negligibly changed within an hour (Δ: 7.20%, 5.95%). The metabolically corrected plasma peaked at 2.5 min (0.0013896 %ID/g) and halved at 45.2 min. Whole-body effective dose was 0.0165 millisievert (mSv)/MBq. Cumulative urine excretion was 8.18%. Treatment-related adverse events occurred in seven out of eleven subjects (63.6%), but no severe adverse event was reported. CONCLUSIONS: XTR004 demonstrated a favorable safety profile, rapid, high, and stable myocardial uptake and excellent potential for PET myocardial perfusion imaging (MPI). Further exploration of XTR004 PET MPI for detecting myocardial ischemia is warranted.

Pharmacologically significant constituents collectively responsible for anti-sepsis action of XueBiJing, a Chinese herb-based intravenous formulation.

Sepsis, a life-threatening health issue, lacks effective medicine targeting the septic response. In China, treatment combining the intravenous herbal medicine XueBiJing with conventional procedures reduces the 28-day mortality of critically ill patients by modulating septic response. In this study, we identified the combined active constituents that are responsible for the XueBiJing's anti-sepsis action. Sepsis was induced in rats by cecal ligation and puncture (CLP). The compounds were identified based on their systemic exposure levels and anti-sepsis activities in CLP rats that were given an intravenous bolus dose of XueBiJing. Furthermore, the identified compounds in combination were assessed, by comparing with XueBiJing, for levels of primary therapeutic outcome, pharmacokinetic equivalence, and pharmacokinetic compatibility. We showed that a total of 12 XueBiJing compounds, unchanged or metabolized, circulated with significant systemic exposure in CLP rats that received XueBiJing. Among these compounds, hydroxysafflor yellow A, paeoniflorin, oxypaeoniflorin, albiflorin, senkyunolide I, and tanshinol displayed significant anti-sepsis activities, which involved regulating immune responses, inhibiting excessive inflammation, modulating hemostasis, and improving organ function. A combination of the six compounds, with the same respective doses as in XueBiJing, displayed percentage survival and systemic exposure in CLP rats similar to those by XueBiJing. Both the combination and XueBiJing showed high degrees of pharmacokinetic compatibility regarding interactions among the six active compounds and influences of other circulating XueBiJing compounds. The identification of XueBiJing's pharmacologically significant constituents supports the medicine's anti-sepsis use and provides insights into a polypharmacology-based approach to develop medicines for effective sepsis management.

Impact of compound warm and wet events on dengue fever infection in South and Southeast Asian countries.

BACKGROUND: Multiple studies have reported the profound influence of various climate factors on dengue fever infection, while the effects of joint exposure to warm and wet environment, a condition favouring dengue vectors, on disease transmission were less evaluated. This study aims to investigate the impact of various compound temperature, rainfall, and relative humidity exposures on dengue fever infection in the South and Southeast Asia regions. METHODS: Weekly dengue fever surveillance data from 2012 to 2020 were collected from 48 locations in four countries named Singapore (1 location), Sri Lanka (15 locations), Malaysia (9 locations), and Thailand (23 locations, with 11 locations having different study periods). The distributed lag non-linear models were built to assess the impacts of compound temperature, rainfall, and relative humidity exposures on dengue fever infection risks. RESULTS: A total of 1,359,993 dengue fever cases were reported with 9.33%, 24.02%, 48.73%, and 17.91% cases contributed by Singapore, Sri Lanka, Malaysia, and Thailand, respectively. Compared to non-warm-non-wet, compound warm-wet was associated with an increased dengue risk (RR:1.32, 95% CI:1.21-1.44). Compared to moderate temperature-humidity, warm-wet environment was also associated with an increase in dengue risk (RR:1.37, 95% CI:1.22-1.55). In comparison to weeks with moderate temperature-rainfall, warm-wet weeks was linked to an elevated dengue risk (RR:1.39, 95% CI:1.27-1.52), whereas cold-dry weather would significantly reduce the infection risk (RR:0.70, 95% CI:0.62-0.80). Modification effects showed that the hot effect on dengue infection was more pronounced under higher humidity, while the impact of rainfall increased with warmer temperature. CONCLUSION: Warm-wet events were associated with an increased dengue fever risk, while the infection risk would decline in cold-dry environment, and modification effects exist among exposures. Findings from this study highlight the importance of considering joint temperature, humidity, and rainfall dependency of dengue fever infection in disease prevention and control.

Lightweight Single Image Super-Resolution via Efficient Mixture of Transformers and Convolutional Networks.

In this paper, we propose a Local Global Union Network (LGUN), which effectively combines the strengths of Transformers and Convolutional Networks to develop a lightweight and high-performance network suitable for Single Image Super-Resolution (SISR). Specifically, we make use of the advantages of Transformers to provide input-adaptation weighting and global context interaction. We also make use of the advantages of Convolutional Networks to include spatial inductive biases and local connectivity. In the shallow layer, the local spatial information is encoded by Multi-order Local Hierarchical Attention (MLHA). In the deeper layer, we utilize Dynamic Global Sparse Attention (DGSA), which is based on the Multi-stage Token Selection (MTS) strategy to model global context dependencies. Moreover, we also conduct extensive experiments on both natural and satellite datasets, acquired through optical and satellite sensors, respectively, demonstrating that LGUN outperforms existing methods.

Brain response in allergic rhinitis: Profile and proposal.

In addition to typical nasal symptoms, patients with allergic rhinitis (AR) will further lead to symptoms related to brain function such as hyposmia, anxiety, depression, cognitive impairment, memory loss, etc., which seriously affect the quality of life of patients and bring a heavy burden to the patient's family and society. Some scholars have speculated that there may be potential "nose-brain communication" mechanism in AR that rely on neuro-immunity. This mechanism plays an important role in AR-associated brain response process. However, no study has directly demonstrated which neural circuits will change in the connection between the nose and brain during the onset of AR, and the mechanism which underlines this question is also lack. Focusing on the topic of "nose-brain communication", this paper systematically summarizes the latest research progress between AR and related brain responses and discusses the mechanism of AR-related neurological phenotypes. Hope new diagnostic and therapeutic targets to ameliorate the brain function-related symptoms and improve the quality of life of AR patients will be developed.