Psychological first aid in operation for military healthcare providers : a study on pre-deployment training.

INTRODUCTION: During operational missions, while the management of physical injuries in the field remains the priority, the identification of operational incapacity of psychological origin is necessary as it is equally crucial for the safety of the individual, the group and the mission. The French Military Health Service has developed a Psychological First Aid Training in Operation (PFATO) course based on relational simulations, for military service members. The aim is to identify the early signs of psychological distress in a comrade and to adopt an adapted and protective attitude. PFATO training is also offered to healthcare providers. METHODS: We conducted a descriptive cross-sectional study using a self-administered online questionnaire which was sent after deployment to all physicians or nurses trained in PFATO between July 2019 and July 2021 (n=80). The main objective of our work was to evaluate the relevance of this awareness training among physicians and nurses and to identify specific complementary expectations in operational psychiatry for this population. RESULTS: We obtained a response rate of 55%. Significantly, 21.62% of participants used PFATO during their last deployment and another 20% observed a team member using PFATO. The circumstances of use as reported by participants included acute stress related to combat, conflict with hierarchy or comrades, and suicidal crisis. Among those who used PFATO, the training helped 87.5% of them to identify signs of psychological distress and 100% of them to assist combatants . All respondents stressed the added value of practical simulations during PFATO education. Moreover, this study also makes it possible to identify adaptations needed to optimize this module for healthcare providers. CONCLUSION: The results suggest the value for healthcare provider of training in first-response psychological care using relational simulation based on the model of raising awareness about PFATO.

Poly-ADP-ribosylation dynamics, signaling, and analysis.

ADP-ribosylation is a reversible post-translational modification that plays a role as a signaling mechanism in various cellular processes. This modification is characterized by its structural diversity, highly dynamic nature, and short half-life. Hence, it is tightly regulated at many levels by cellular factors that fine-tune its formation, downstream signaling, and degradation that together impacts cellular outcomes. Poly-ADP-ribosylation is an essential signaling mechanism in the DNA damage response that mediates the recruitment of DNA repair factors to sites of DNA damage via their poly-ADP-ribose (PAR)-binding domains (PBDs). PAR readers, encoding PBDs, convey the PAR signal to mediate cellular outcomes that in some cases can be dictated by PAR structural diversity. Several PBD families have been identified, each with variable PAR-binding affinity and specificity, that also recognize and bind to distinct parts of the PAR chain. PARylation signaling has emerged as an attractive target for the treatment of specific cancer types, as the inhibition of PAR formation or degradation can selectively eliminate cancer cells with specific DNA repair defects and can enhance radiation or chemotherapy response. In this review, we summarize the key players of poly-ADP-ribosylation and its regulation and highlight PBDs as tools for studying PARylation dynamics and the expanding potential to target PARylation signaling in cancer treatment.

mInsc coordinates Par3 and NuMA condensates for assembly of the spindle orientation machinery in asymmetric cell division.

As a fundamental process governing the self-renewal and differentiation of stem cells, asymmetric cell division is controlled by several conserved regulators, including the polarity protein Par3 and the microtubule-associated protein NuMA, which orchestrate the assembly and interplay of the Par3/Par6/mInsc/LGN complex at the apical cortex and the LGN/Gαi/NuMA/Dynein complex at the mitotic spindle to ensure asymmetric segregation of cell fate determinants. However, this model, which is well-supported by genetic studies, has been challenged by evidence of competitive interaction between NuMA and mInsc for LGN. Here, the solved crystal structure of the Par3/mInsc complex reveals that mInsc competes with Par6ß for Par3, raising questions about how proteins assemble overlapping targets into functional macromolecular complexes. Unanticipatedly, we discover that Par3 can recruit both Par6ß and mInsc by forming a dynamic condensate through phase separation. Similarly, the phase-separated NuMA condensate enables the coexistence of competitive NuMA and mInsc with LGN in the same compartment. Bridge by mInsc, Par3/Par6ß and LGN/NuMA condensates coacervate, robustly enriching all five proteins both in vitro and within cells. These findings highlight the pivotal role of protein condensates in assembling multi-component signalosomes that incorporate competitive protein-protein interaction pairs, effectively overcoming stoichiometric constraints encountered in conventional protein complexes.

Protease activated receptor-1 regulates mixed lineage kinase-3 to drive triple-negative breast cancer tumorigenesis.

Triple-negative breast cancer (TNBC) is difficult to treat breast cancer subtype due to lack or insignificant expressions of targetable estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Therefore, finding a targetable protein or signaling pathway in TNBC would impact patient care. Here, we report that a member of the Mixed Lineage Kinase (MLK) family, MLK3, is an effector of G-protein-coupled protease-activated receptors 1 (PAR1) and targeting MLK3 by a small-molecule inhibitor prevented PAR1-mediated TNBC tumorigenesis. In silico and immunohistochemistry analysis of human breast tumors showed overexpression of PAR1 and MLK3 in TNBC tumors. Treating α-thrombin and PAR1 agonist increased MLK3 and JNK activities and induced cell migration in TNBC cells. The PAR1 positive/high (PAR1+/hi) population of TNBC cells showed aggressive tumor phenotype with increased MLK3 signaling. Moreover, combined inhibition of the PAR1 and MLK3 mitigated the TNBC tumor burden in preclinical TNBC models. Our data suggests that activation of the PAR1-MLK3 axis promotes TNBC tumorigenesis. Therefore, combinatorial therapy targeting MLK3 and PAR1 could effectively reduce TNBC tumor burden.

[Measurement and evaluation of personal attenuation rating before and after the training of the noise-exposed workers wearing foam earplugs].

Objective: To measure and compare the difference of personal attenuation rating (PAR) of the workers wearing foam earplugs before and after the training, and to evaluate the effect of ear protector wearing training on the noise protection. Methods: In February 2023, 94 workers exposed to noise in a machinery manufacturing factory were selected as subjects. The production noise in the workplace was measured and subjects were trained to wear earplugs. The PAR values of wearing 3M 1110 foam test earplugs were measured and recorded before and after the training by using the fit testing of hearing protection device. The differences between the actual PAR values with nominal values and the noise attenuation values in related standards were compared, and the protective effect of hearing protection device before and after training was evaluated. Results: The average age of the subjects was (36.76±11.48) years old, the average length of service was (16.34±11.64) years, and the average exposure time to noise was (15.67±11.64) years. The noise detection results of the subjects' posts were ranged from 80.1 to 94.3 dB (A). The results of subjects wore 3M 1110 foam test earplugs for fit testing showed that the binaural PAR value after training was (19.3±6.4) dB (A), which was significantly higher than that before training (11.1±7.4) dB (A) (t=13.31, P<0.001). After training, 11 people (11.70%) could reach the corrected noise reduction value (NRR value), 26 people (27.66%) could reach the standard of single noise reduction value (SNR value) ×0.6, and 84 people (89.36%) could reach the standard of (NRR-7) /2. The under protection rate of hearing protectors after training (7.45%) was significantly lower than that before training (45.74%), and the difference of different protection levels before and after training was statistically significant (χ(2)=40.83, P<0.001) . Conclusion: It is suggested that enterprises should use the fit testing instead of nominal value estimation to evaluate the noise reduction effect of hearing protection device. Special training on the selection and use of hearing protection device should be strengthened, so as to ensure that workers wear them correctly and improve the protective effect of hearing protection device.

Novel heterozygous variant of ADPRHL2 causes pathogenic variation in CONDSIAS.

Adprhl2 (OMIM: 610624) mutation associated stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS, OMIM: 618170) is a sporadic neurodegenerative disease with poor prognosis. ADPRHL2 encodes ADP-ribosylhydrolase 3 (ARH3), which participates in ADP-ribosylation to remove poly-ADP ribose (PAR). We found a new compound heterozygous mutation in the ADPRHL2 gene c.580C > T (p.Gln194Ter) and c.803-1G > A in a 30-month-old boy, who showed gait instability, abnormal EEG, and developmental delay after respiratory infection. He died of convulsions 4 months after onset. By constructing a mutant plasmid and using Western blot to detect the expression of ARH3 and PAR, it was demonstrated that the ADPRHL2 gene c.580C > T (p.Gln194Ter) and c.803-1G > A is pathogenic according to ACMG guidelines.

Naringenin alleviates bone cancer pain via NF-κB/uPA/PAR2 pathway in mice.

PURPOSE: This investigation aims to explore the protective role of Naringenin (Nar) in bone cancer pain (BCP) via TNF-α-mediated NF-κB/uPA/PAR2 pathway. METHODS: BCP model was manipulated by the injection of LL2 cells into femur of mice. The levels of TNF-α and uPA in bone tissue and serum were studied by ELISA. The expressions of PAR2, PKC-γ, PKA and TRPV1 were determined by qPCR and western blot. Levels of p-IKKß, IKKß, p-p65, p65 were determined by western blot. Levels of p-p65 and uPA in bone tissue were studied by immunohistochemistry. Behavior tests in this investigation included paw withdrawal latency (PWL) and the paw withdrawal threshold (PWT). Radiological analysis and micro-CT were used to study bone structure. The lesions of bone tissue were determined by HE staining. The Dorsal root ganglia (DRG) isolated from mice were used to determine the level of PAR2 pathway. RESULTS: Naringenin improved the BCP-induced bone damage based on the increases of BV/TV, Conn. D, BMD and BMC and the decrease of bone destruction score. Naringenin repressed the reductions of PWT and PWL in BCP mice. Naringenin decreased the levels of PAR2, PKC-γ, PKA and TRPV1 of DRG and reduced the levels of p-IKKß, p-p65, and uPA in serum and bone tissue in BCP. Importantly, naringenin suppressed the enhancement of TNF-α in serum and bone tissue in BCP mice. CONCLUSION: Naringenin alleviated pain sensitization and bone damage of mice with BCP via TNF-α-mediated NF-κB/uPA/PAR2 pathway. We demonstrated a novel pathway for anti-BCP treatment with naringenin.

Nuclear PKM2 binds pre-mRNA at folded G-quadruplexes and reveals their gene regulatory role.

Nuclear localization of the metabolic enzyme PKM2 is widely observed in various cancer types. We identify nuclear PKM2 as a non-canonical RNA-binding protein (RBP) that specifically interacts with folded RNA G-quadruplex (rG4) structures in precursor mRNAs (pre-mRNAs). PKM2 occupancy at rG4s prevents the binding of repressive RBPs, such as HNRNPF, and promotes the expression of rG4-containing pre-mRNAs (the "rG4ome"). We observe an upregulation of the rG4ome during epithelial-to-mesenchymal transition and a negative correlation of rG4 abundance with patient survival in different cancer types. By preventing the nuclear accumulation of PKM2, we could repress the rG4ome in triple-negative breast cancer cells and reduce migration and invasion of cancer cells in vitro and in xenograft mouse models. Our data suggest that the balance of folded and unfolded rG4s controlled by RBPs impacts gene expression during tumor progression.

Recombinant hirudin and PAR-1 regulate macrophage polarisation status in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a malignant tumour. Although some standard therapies have been established to improve the cure rate, they remain ineffective for specific individuals. Therefore, it is meaningful to find more novel therapeutic approaches. Macrophage polarisation is extensively involved in the process of tumour development. Recombinant hirudin (rH) affects macrophages and has been researched frequently in clinical trials lately. Our article validated the regulatory role of rH in macrophage polarisation and the mechanism of PAR-1 by collecting clinical samples and subsequently establishing a cellular model to provide a scientifically supported perspective for discovering new therapeutic approaches. METHOD: We assessed the expression of macrophage polarisation markers, cytokines and PAR-1 in clinical samples. We established a cell model by co-culture with THP-1 and OCI-Ly10 cell. We determined the degree of cell polarisation and expression of validation cytokines by flow cytometry, ELISA, and RT-qPCR to confirm the success of the cell model. Subsequently, different doses of rH were added to discover the function of rH on cell polarisation. We confirmed the mechanism of PAR-1 in macrophage polarisation by transfecting si-PAR-1 and pcDNA3.1-PAR-1. RESULTS: We found higher expression of M2 macrophage markers (CD163 + CMAF+) and PAR-1 in 32 DLBCL samples. After inducing monocyte differentiation into M0 macrophages and co-culturing with OCI-Ly10 lymphoma cells, we found a trend of these expressions in the cell model consistent with the clinical samples. Subsequently, we discovered that rH promotes the polarisation of M1 macrophages but inhibits the polarisation of M2 macrophages. We also found that PAR-1 regulates macrophage polarisation, inhibiting cell proliferation, migration, invasion and angiogenic capacity. CONCLUSION: rH inhibits macrophage polarisation towards the M2 type and PAR-1 regulates polarisation, proliferation, migration, invasion, and angiogenesis of DLBCL-associated macrophages.

Spatial phytoplankton community structure revealed by photosynthetic pigments in the tropical estuarine-coastal zone (Bangladesh).

To explore the variation of phytoplankton community along the Bakkhali river estuary and its adjacent coastal water in the north of the Bay of Bengal, total Chl-a (TChl-a) concentrations and group-specific photosynthetic pigments were investigated during April 2017. Distinct spatial distribution was observed in temperature, turbidity and nutrient concentrations as well as in TChl-a concentrations, showing a seaward decreasing pattern. The different distribution of phytoplankton pigments and functional groups along the gradients was also observed. Chlorophyll-b and zeaxanthin showed their highest abundance in the turbid riverine water, while alloxanthin and prasinoxanthin dominated in the coastal water. High concentrations of fucoxanthin, peridinin and hex-fucoxanthin were associated with high-light availability and showed a seaward increasing trend. Three phytoplankton groups can be classified: the riverine group (chlorophytes and cyanobacteria), the coastal group (cryptophytes and prasinophytes) and the offshore group (diatoms, dinoflagellate and haptophytes_type 6). The predominance of cryptophytes (avg. 48%) over diatoms (avg. 28%) was basically influenced by the scarcity of nitrogen and silicate relative to phosphate. Not only availability of nutrients, the photosynthetically active radiation also plays a key role in regulating TChl-a, photosynthetic pigments and functional groups in this tropical estuarine-coastal zone.

IL-6/STAT3 signaling pathway induces prostate apoptosis response protein-4(PAR-4) to stimulate malignant behaviors of hepatocellular carcinoma cells.

INTRODUCTION AND OBJECTIVES: Prostate apoptosis response protein-4 (PAR-4) is considered a tumor suppressor. However, the role of PAR-4 in hepatocellular carcinoma (HCC) has rarely been reported. The study explores the role of PAR-4 in the malignant behaviors of HCC cells. MATERIALS AND METHODS: TCGA database was applied to analyze the expression of PAR-4 in HCC. Evaluated PAR-4 relationship with clinical parameters and prognosis by tissue microarray; expression of STAT3, p-STAT3, Src and Ras was detected by Western blotting or laser confocal microscopy. Cell scratch and flow cytometry assays were used to observe IL-6 regulation of the malignant behaviors of HCC cells. The tumorigenic potential of HCC cells in vivo was evaluated in a nude mouse tumor model. RESULTS: Analysis indicated that the expression of PAR-4 in HCC tissues was significantly higher than that in normal liver tissues; and PAR-4 interacted with STAT3. KEGG analysis showed that PAR-4 plays a role in the Janus kinase (JAK)/STAT signaling pathway. The positive expression rate of PAR-4 in HCC tissues was significantly higher than that in adjacent tissues. Positive correlation between IL-6 and PAR-4 expression in the HCC tissues. Exogenous IL-6 significantly promoted the proliferation and migration of HCC cells and up-regulated the expression of PAR-4 and p-STAT3 in HCC cells. Interference of the expression of PAR-4 could reduce the malignant behaviors of HCC cells and inhibit tumorigenesis in a nude mouse tumor model. CONCLUSIONS: PAR-4 expression is positively correlated with HCC; PAR-4 promotes malignant behavior of HCC cells mediated by the IL-6/STAT3 signaling pathway.

BET Inhibition Rescues Acinar-Ductal-Metaplasia and Ciliogenesis and Ameliorates Chronic Pancreatitis-Driven Changes in Mice with Loss of the Polarity Protein Par3.

BACKGROUND & AIMS: The apical-basal polarity of pancreatic acinar cells is essential for maintaining tissue architecture. However, the mechanisms by which polarity proteins regulate acinar pancreas injury and regeneration are poorly understood. METHODS: Cerulein-induced pancreatitis was induced in mice with conditional deletion of the polarity protein Par3 in the pancreas. The impact of Par3 loss on pancreas injury and regeneration was assessed by histologic analyses and transcriptional profiling by RNA sequencing. Mice were pretreated with the bromodomain and extraterminal domain (BET) inhibitor JQ1 before cotreatment with cerulein to determine the effect of BET inhibition on pancreas injury and regeneration. RESULTS: Initially, we show that Par3 is increased in acinar-ductal metaplasia (ADM) lesions present in human and mouse chronic pancreatitis specimens. Although Par3 loss disrupts tight junctions, Par3 is dispensable for pancreatogenesis. However, with aging, Par3 loss results in low-grade inflammation, acinar degeneration, and pancreatic lipomatosis. Par3 loss exacerbates acute pancreatitis-induced injury and chronic pancreatitis-induced acinar cell loss, promotes pancreatic lipomatosis, and prevents regeneration. Par3 loss also results in suppression of chronic pancreatitis-induced ADM and primary ciliogenesis. Notably, targeting BET proteins attenuates chronic pancreatitis-induced loss of primary cilia and promotes ADM in mice lacking pancreatic Par3. Targeting BET proteins also attenuates cerulein-induced acinar cell loss and enhances recovery of acinar cell mass and body weight of mice lacking pancreatic Par3. CONCLUSIONS: Combined, this study demonstrates how Par3 restrains chronic pancreatitis-induced changes in the pancreas and identifies a potential role for BET inhibitors to attenuate pancreas injury and facilitate regeneration.

PAR1 Activation, via LMBR1/BMP Axis, Promotes the Osteogenesis of Periodontal Ligament Stem Cells (PDLSCs) and Alleviates the Inhibitory Effect of Sodium Butyrate on PDLSCs Osteogenesis.

BACKGROUND: Periodontitis is the leading cause of tooth loss and can exacerbate various systemic inflammatory conditions. Periodontal ligament stem cells (PDLSCs) stand out as prominent and favorable candidates for promoting periodontal tissue regeneration. This study aimed to investigate whether the protease-activated receptor type 1 (PAR1) can mitigate the sodium butyrate (NaB)-induced PDLSCs osteogenesis inhibition and unravel the underlying mechanism. METHODS: Public datasets from the Gene Expression Omnibus (GEO) were utilized to analyze differentially expressed genes (DEGs) in periodontitis and subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. PDLSCs were cultured normally in control medium (CM) as the negative control or in osteogenic medium (OM) to induce osteogenesis. PAR1 was either activated or suppressed using a selective agonist or antagonist (OM+agonist and OM+antagonist). The evaluation of PDLSCs osteogenesis was based on the levels of osteogenesis-related markers, including runt-related transcription factor 2 (RUNX2), osterix (OSX), osteocalcin (OCN), and osteopontin (OPN), alkaline phosphatase (ALP) activity, and calcium concentration. Additionally, cell proliferation and osteogenic differentiation were measured through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Alizarin Red Staining. To determine the PAR1 targeting the limb development membrane protein 1 (LMBR1)/bone morphogenetic protein (BMP) pathway, LMBR1 was upregulated through cell transfection and BMP2 was inhibited using the selective inhibitor Noggin protein. Finally, NaB was introduced into PDLSCs to investigate the effect on NaB-induced inhibition of PDLSCs osteogenesis. RESULTS: PAR1, RUNX2, OSX, OCN, OPN, proliferation, ALP activity, calcium concentration, osteogenic differentiation, BMP2, and BMP4 exhibited significant increases in PDLSCs cultured in OM (p < 0.01). These parameters were further elevated by PAR1 agonist and conversely reduced by PAR1 antagonist (p < 0.01). Conversely, LMBR1 was decreased in PDLSCs cultured in OM (p < 0.001), with further reduction induced by PAR1 agonist and a reverse increase observed with PAR1 antagonist (p < 0.001). OE-LMBR1 transfection successfully elevated LMBR1 levels, subsequently inhibiting BMP2 and BMP4 (p < 0.001). Meanwhile, the Noggin protein effectively suppressed BMP2 and BMP4 (p < 0.001). All observed osteogenesis-related changes were reversed by the increased LMBR1 or inhibition of the BMP pathway (p < 0.001). Furthermore, NaB suppressed osteogenesis-related changes in OM-cultured PDLSCs (p < 0.001), and these effects were entirely reversed by PAR1 agonist (p < 0.001). Conversely, the increased LMBR1 or inhibited BMP pathway disrupted the osteogenesis reversion induced by PAR1 agonist (p < 0.001). CONCLUSION: The activation of PAR1, through suppressing LMBR1 signaling and activating BMP pathway, demonstrates the ability to enhance the osteogenesis of PDLSCs and mitigate the inhibitory effects on PDLSCs osteogenesis caused by NaB.

Gestodene, a novel positive allosteric modulator of PAR1, enhances PAR1-mediated human platelet aggregation.

Background: Protease-activated receptor 1 (PAR1) is expressed in human platelets and can be activated by low concentrations of thrombin. Vorapaxar, a selective antagonist of PAR1, inhibits thrombin-induced calcium mobilization in human platelet, which is associated with an increased risk of bleeding. Conversely, the administration of a positive allosteric modulator (PAM) of PAR1 may pose a substantial risk of thrombosis due to inducing excessive platelet activation. In this study, we discovered a novel PAM of PAR1 and investigated the effect of enhanced PAR1 activation by PAM of PAR1 on platelet activation. Methods: To find PAMs of PAR1, a cell-based screen was performed in HT29 cells, and finally, gestodene, an oral contraceptive drug (OC), was identified as a novel PAM of PAR1. The mechanism of action of gestodene and its effects on platelet activation were investigated in human megakaryocytic leukemia cell line MEG-01 cells and human platelet. Results: Gestodene enhanced both thrombin- and PAR1-activating peptide (AP)-induced intracellular calcium levels in a dose-dependent manner without altering PAR2 and PAR4 activity. Gestodene significantly increased PAR1-AP-induced internalization of PAR1 and phosphorylation of ERK1/2, and the enhancing effects were significantly blocked by vorapaxar. Furthermore, gestodene potently increased PAR1-AP induced morphological changes in MEG-01 cells. Remarkably, in human blood, gestodene exerted a robust augmentation of PAR1-AP-induced platelet aggregation, and vorapaxar effectively attenuated the gestodene-induced enhancement of platelet aggregation mediated by PAR1. Conclusion: Gestodene is a selective PAM of PAR1 and suggest one possible mechanism for the increased risk of venous thromboembolism associated with OCs containing gestodene.

Hepatocyte-independent PAR1-biased signaling controls liver pathology in experimental obesity.

BACKGROUND: Protease-activated receptor-1 (PAR1) has emerged as an important link between coagulation and the complications of obesity including metabolic dysfunction-associated steatotic liver disease (MASLD). PAR1 is expressed by various cells and cleaved by different proteases to generate unique tethered agonists that activate distinct signaling pathways. Mice expressing PAR1 with an R41Q mutation have disabled canonical thrombin-mediated signaling, whereas R46Q mice express PAR1 resistant to noncanonical signaling by activated protein C. METHODS: Mice with whole body and hepatocyte-selective PAR1 deficiency as well as PAR1 R41Q and R46Q mice were fed a high-fat diet (HFD) to induce MASLD. RESULTS: HFD-fed R41Q mice displayed reduced hepatic steatosis and liver/body weight ratio. In contrast, HFD-fed R46Q mice displayed increased relative liver weight and hepatic steatosis alongside increased serum alanine aminotransferase activity. Surprisingly, despite the distinct impact of PAR1 mutations on steatosis, selective deletion of PAR1 in hepatocytes had no impact. To evaluate a viable PAR1-targeted approach, mice with HFD-induced obesity were treated with the allosteric PAR1 modulator NRD-21, which inhibits canonical PAR1 inflammatory signaling but promotes PAR1 protective, noncanonical anti-inflammatory signaling. NRD-21 treatment reduced plasma tumor necrosis factor-alpha, serum alanine aminotransferase activity, hepatic steatosis, and insulin resistance (Homeostatic Model Assessment for Insulin Resistance) but increased plasma active glucagon-like peptide-1. CONCLUSION: The results suggest that nonhepatocellular canonical PAR1 cleavage drives MASLD in obese mice and provide translational proof-of-concept that selective pharmacologic modulation of PAR1 yields multiple metabolic benefits in experimental obesity.

Corrigendum: YKL-40 promotes chemokine expression following drug-induced liver injury via TF-PAR1 pathway in mice.

[This corrects the article DOI: 10.3389/fphar.2023.1205062.].

Automatic segmentation of high-risk clinical target volume and organs at risk in brachytherapy of cervical cancer with a convolutional neural network.

PURPOSE: This study aimed to design an autodelineation model based on convolutional neural networks for generating high-risk clinical target volumes and organs at risk in image-guided adaptive brachytherapy for cervical cancer. MATERIALS AND METHODS: A novel SERes-u-net was trained and tested using CT scans from 98 patients with locally advanced cervical cancer who underwent image-guided adaptive brachytherapy. The Dice similarity coefficient, 95th percentile Hausdorff distance, and clinical assessment were used for evaluation. RESULTS: The mean Dice similarity coefficients of our model were 80.8%, 91.9%, 85.2%, 60.4%, and 82.8% for the high-risk clinical target volumes, bladder, rectum, sigmoid, and bowel loops, respectively. The corresponding 95th percentile Hausdorff distances were 5.23mm, 4.75mm, 4.06mm, 30.0mm, and 20.5mm. The evaluation results revealed that 99.3% of the convolutional neural networks-generated high-risk clinical target volumes slices were acceptable for oncologist A and 100% for oncologist B. Most segmentations of the organs at risk were clinically acceptable, except for the 25% sigmoid, which required significant revision in the opinion of oncologist A. There was a significant difference in the clinical evaluation of convolutional neural networks-generated high-risk clinical target volumes between the two oncologists (P<0.001), whereas the score differences of the organs at risk were not significant between the two oncologists. In the consistency evaluation, a large discrepancy was observed between senior and junior clinicians. About 40% of SERes-u-net-generated contours were thought to be better by junior clinicians. CONCLUSION: The high-risk clinical target volumes and organs at risk of cervical cancer generated by the proposed convolutional neural networks model can be used clinically, potentially improving segmentation consistency and efficiency of contouring in image-guided adaptive brachytherapy workflow.

Significance of MRI-based radiomics in predicting pathological complete response to neoadjuvant chemoradiotherapy of locally advanced rectal cancer: A narrative review.

Neoadjuvant chemoradiotherapy is the standard treatment for patients with locally advanced rectal cancers owing to its ability to downstage primary tumours. Some patients can achieve pathological complete response after neoadjuvant therapy, and can adopt a "watch and wait" treatment strategy to avoid overtreatment. Therefore, it is essential to develop strategies for predicting responses to neoadjuvant therapy. Radiomics has shown great potential in extracting tumour features from high-throughput medical images for the construction of mathematics models for predicting the effects of anticancerous therapies. Herein, we explored MRI-based radiomics and found that it can predict responses of locally advanced rectal cancers to chemoradiation. Efficient radiomics model allow early-stage prediction of the effect of neoadjuvant chemoradiotherapy on locally advanced rectal cancers. It helps clinicians to make informed therapeutic decisions. In this review, we discuss the workflow of radiomics, and summarize the clinical application of MRI-based radiomics in predicting pathological complete response to neoadjuvant chemoradiotherapy of locally advanced rectal cancer.

Remote sensing estimates of global sea surface nitrate: Methodology and validation.

Information about sea surface nitrate (SSN) concentrations is crucial for estimating oceanic new productivity and for carbon cycle studies. Due to the absence of optical properties in SSN and the intricate relationships with environmental factors affecting spatiotemporal dynamics, developing a more representative and widely applicable remote sensing inversion algorithm for SSN is challenging. Most methods for the remote estimation of SSN are based on data-driven neural networks or deep learning and lack mechanistic descriptions. Since fitting functions between the SSN and sea surface temperature (SST), mixed layer depth (MLD), and chlorophyll (Chl) content have been established for the open ocean, it is important to include the remote sensing indicator photosynthetically active radiation (PAR), which is critical in nitrate biogeochemical processes. In this study, we employed an algorithm for estimating the monthly average SSN on a global 1° by 1° resolution grid; this algorithm relies on the empirical relationship between the World Ocean Atlas 2018 (WOA18) monthly interpolated climatology of nitrate in each 1° × 1° grid and the estimated monthly SST and PAR datasets from Moderate Resolution Imaging Spectroradiometer (MODIS) and MLD from the Hybrid Coordinate Ocean Model (HYCOM). These results indicated that PAR potentially affects SSN. Furthermore, validation of the SSN model with measured nitrate data from different months and locations for the years 2018-2023 yielded a high prediction accuracy (N = 12,846, R2 = 0.93, root mean square difference (RMSE) = 3.12 µmol/L, and mean absolute error (MAE) = 2.22 µmol/L). Further independent validation and sensitivity tests demonstrated the validity of the algorithm for retrieving SSN.

Proteolytic bacteria expansion during colitis amplifies inflammation through cleavage of the external domain of PAR2.

Imbalances in proteolytic activity have been linked to the development of inflammatory bowel diseases (IBD) and experimental colitis. Proteases in the intestine play important roles in maintaining homeostasis, but exposure of mucosal tissues to excess proteolytic activity can promote pathology through protease-activated receptors (PARs). Previous research implicates microbial proteases in IBD, but the underlying pathways and specific interactions between microbes and PARs remain unclear. In this study, we investigated the role of microbial proteolytic activation of the external domain of PAR2 in intestinal injury using mice expressing PAR2 with a mutated N-terminal external domain that is resistant to canonical activation by proteolytic cleavage. Our findings demonstrate the key role of proteolytic cleavage of the PAR2 external domain in promoting intestinal permeability and inflammation during colitis. In wild-type mice expressing protease-sensitive PAR2, excessive inflammation leads to the expansion of bacterial taxa that cleave the external domain of PAR2, exacerbating colitis severity. In contrast, mice expressing mutated protease-resistant PAR2 exhibit attenuated colitis severity and do not experience the same proteolytic bacterial expansion. Colonization of wild-type mice with proteolytic PAR2-activating Enterococcus and Staphylococcus worsens colitis severity. Our study identifies a previously unknown interaction between proteolytic bacterial communities, which are shaped by inflammation, and the external domain of PAR2 in colitis. The findings should encourage new therapeutic developments for IBD by targeting excessive PAR2 cleavage by bacterial proteases.