Systemic immune profiling of Omicron-infected subjects inoculated with different doses of inactivated virus vaccine.

SARS-CoV-2 primary strain-based vaccination exerts a protective effect against Omicron variants-initiated infection, symptom occurrence, and disease severity in a booster-dependent manner. Yet, the underlying mechanisms remain unclear. During the 2022 Omicron outbreak in Shanghai, we enrolled 122 infected adults and 50 uninfected controls who had been unvaccinated or vaccinated with two or three doses of COVID-19 inactive vaccines and performed integrative analysis of 41-plex CyTOF, RNA-seq, and Olink on their peripheral blood samples. The frequencies of HLA-DRhi classical monocytes, non-classical monocytes, and Th1-like Tem tended to increase, whereas the frequency of Treg was reduced by booster vaccine, and they influenced symptom occurrence in a vaccine dose-dependent manner. Intercorrelation and mechanistic analysis suggested that the booster vaccination induced monocytic training, which would prime monocytic activation and maturation rather than differentiating into myeloid-derived suppressive cells upon Omicron infections. Overall, our study provides insights into how booster vaccination elaborates protective immunity across SARS-CoV-2 variants.

Successful Immune Reconstitution in a Patient with a TYK2 Deficiency after Allogeneic Stem Cell Transplantation from Unrelated Donors.

A boy with primary immunodeficiency, caused by a tyrosine kinase 2 (TYK2) mutation, presented with immune defects and a lifelong history of severe infections. Our aim was to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) could restore the patient's immune defenses and reduce susceptibility to infection. In the absence of a suitable HLA-matched blood relative to act as a donor, the patient received an allogeneic HSCT from unrelated donors. The patient's clinical data were analyzed in the Children's Hospital of Chongqing Medical University (Chongqing, China) before transplantation and during the 4-year follow-up period using a combination of western blotting (e.g., TYK2 and STAT levels), qRT-PCR (e.g., T cell receptor rearrangement excision circles, kappa deletion element recombination circles, and TYK2 transcript levels), and flow cytometry (e.g., lymphocyte subpopulations and CD107α secretion). We found that HSCT significantly reduced the incidence of severe infections, restored normal TKY2 levels, and reversed defects such as impaired JAK/STAT signaling in response to interferon-α or interleukin-10 treatment. Although the patient did not develop acute graft-versus-host disease (GVHD) after transplantation, he did experience chronic GVHD symptoms in a number of organs, which were effectively managed. Our findings suggest that HSCT is a feasible strategy for reconstituting the immune system in TYK2-deficient patients; however, the factors associated with GVHD and autoimmune thyroiditis development in TYK2-deficient patients undergoing HSCT warrant further investigation.

Fluoxetine Successfully Treats Intracranial Enterovirus E18 Infection in a Patient with CD79a Deficiency Arising from Segmental Uniparental Disomy of Chromosome 19.

The pre BCR complex plays a crucial role in B cell production, and its successful expression marks the B cell differentiation from the pro-B to pre-B. The CD79a and CD79b mutations, encoding Igα and Igß respectively, have been identified as the cause of autosomal recessive agammaglobulinemia (ARA). Here, we present a case of a patient with a homozygous CD79a mutation, exhibiting recurrent respiratory infections, diarrhea, growth and development delay, unique facial abnormalities and microcephaly, as well as neurological symptoms including tethered spinal cord, sacral canal cyst, and chronic enteroviral E18 meningitis. Complete blockade of the early B cell development in the bone marrow of the patient results in the absence of peripheral circulating mature B cells. Whole exome sequencing revealed a Loss of Heterozygosity (LOH) of approximately 19.20Mb containing CD79a on chromosome 19 in the patient. This is the first case of a homozygous CD79a mutation caused by segmental uniparental diploid (UPD). Another key outcome of this study is the effective management of long-term chronic enteroviral meningitis using a combination of intravenous immunoglobulin (IVIG) and fluoxetine. This approach offers compelling evidence of fluoxetine's utility in treating enteroviral meningitis, particularly in immunocompromised patients.

Qualitative Immunoglobulin Deficiency Causes Bacterial Infections in Patients with STAT1 Gain-of-Function Mutations.

PURPOSES: STAT1 is a transduction and transcriptional regulator that functions within the classical JAK/STAT pathway. In addition to chronic mucocutaneous candidiasis, bacterial infections are a common occurrence in patients with STAT1 gain-of-function (GOF) mutations. These patients often exhibit skewing of B cell subsets; however, the impact of STAT1-GOF mutations on B cell-mediated humoral immunity remains largely unexplored. It is also unclear whether these patients with IgG within normal range require regular intravenous immunoglobulin (IVIG) therapy. METHODS: Eleven patients (harboring nine different STAT1-GOF mutations) were enrolled. Reporter assays and immunoblot analyses were performed to confirm STAT1 mutations. Flow cytometry, deep sequencing, ELISA, and ELISpot were conducted to assess the impact of STAT1-GOF on humoral immunity. RESULTS: All patients exhibited increased levels of phospho-STAT1 and total STAT1 protein, with two patients carrying novel mutations. In vitro assays showed that these two novel mutations were GOF mutations. Three patients with normal total IgG levels received regular IVIG infusions, resulting in effective control of bacterial infections. Four cases showed impaired affinity and specificity of pertussis toxin-specific antibodies, accompanied by reduced generation of class-switched memory B cells. Patients also had a disrupted immunoglobulin heavy chain (IGH) repertoire, coupled with a marked reduction in the somatic hypermutation frequency of switched Ig transcripts. CONCLUSION: STAT1-GOF mutations disrupt B cell compartments and skew IGH characteristics, resulting in impaired affinity and antigen-specificity of antibodies and recurrent bacterial infections. Regular IVIG therapy can control these infections in patients, even those with normal total IgG levels.

Strategy for Comprehensive Detection and Annotation of Gut Microbiota-Related Metabolites Based on Liquid Chromatography-High-Resolution Mass Spectrometry.

Gut microbiota, widely populating the mammalian gastrointestinal tract, plays an important role in regulating diverse pathophysiological processes by producing bioactive molecules. Extensive detection of these molecules contributes to probing microbiota function but is limited by insufficient identification of existing analytical methods. In this study, a systematic strategy was proposed to detect and annotate gut microbiota-related metabolites on a large scale. A pentafluorophenyl (PFP) column-based liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method was first developed for high-coverage analysis of gut microbiota-related metabolites, which was verified to be stable and robust with a wide linearity range, high sensitivity, satisfactory recovery, and repeatability. Then, an informative database integrating 968 knowledge-based microbiota-related metabolites and 282 sample-sourced ones defined by germ-free (GF)/antibiotic-treated (ABX) models was constructed and subsequently used for targeted extraction and annotation in biological samples. Using pooled feces, plasma, and urine of mice for demonstration application, 672 microbiota-related metabolites were annotated, including 21% neglected by routine nontargeted peak detection. This strategy serves as a useful tool for the comprehensive capture of the intestinal flora metabolome, contributing to our deeper understanding of microbe-host interactions.

Assessing the efficiency of eligibility criteria for low-dose computed tomography lung screening in China according to current guidelines.

BACKGROUND: Evidence from observational studies indicates that lung cancer screening (LCS) guidelines with high rates of lung cancer (LC) underdiagnosis, and although current screening guidelines have been updated and eligibility criteria for screening have been expanded, there are no studies comparing the efficiency of LCS guidelines in Chinese population. METHODS: Between 2005 and 2022, 31,394 asymptomatic individuals were screened using low-dose computed tomography (LDCT) at our institution. Demographic data and relevant LC risk factors were collected. The efficiency of the LCS for each guideline criteria was expressed as the efficiency ratio (ER). The inclusion rates, eligibility rates, LC detection rates, and ER based on the different eligibility criteria of the four guidelines were comparatively analyzed. The four guidelines were as follows: China guideline for the screening and early detection of lung cancer (CGSL), the National Comprehensive Cancer Network (NCCN), the United States Preventive Services Task Force (USPSTF), and International Early Lung Cancer Action Program (I-ELCAP). RESULTS: Of 31,394 participants, 298 (155 women, 143 men) were diagnosed with LC. For CGSL, NCCN, USPSTF, and I-ELCAP guidelines, the eligibility rates for guidelines were 13.92%, 6.97%, 6.81%, and 53.46%; ERe for eligibility criteria were 1.46%, 1.64%, 1.51%, and 1.13%, respectively; and for the inclusion rates, they were 19.0%, 9.5%, 9.3%, and 73.0%, respectively. LCs which met the screening criteria of CGSL, NCCN, USPSTF, and I-ELCAP guidelines were 29.2%, 16.4%, 14.8%, and 86.6%, respectively. The age and smoking criteria for CGSL were stricter, hence resulting in lower rates of LC meeting the screening criteria. The CGSL, NCCN, and USPSTF guidelines showed the highest underdiagnosis in the 45-49 age group (17.4%), while the I-ELCAP guideline displayed the highest missed diagnosis rate (3.0%) in the 35-39 age group. Males and females significantly differed in eligibility based on the criteria of the four guidelines (P < 0.001). CONCLUSIONS: The I-ELCAP guideline has the highest eligibility rate for both males and females. But its actual efficiency ratio for those deemed eligible by the guideline was the lowest. Whereas the NCCN guideline has the highest ERe value for those deemed eligible by the guideline.

Photoactuators Based on Plastically Flexible α-Cyanostilbene Molecular Crystals Driven by the Solid-State [2+2] Cycloaddition Reaction.

Organic photomechanical molecular crystals are promising candidates for photoactuators, which have potential applications as smart materials in various fields. However, it is still challenging to fabricate photomechanical molecular crystals with flexibility because most of the molecular crystals are brittle and the mechanism of flexible crystals remains controversial. Here, a plastically flexible α-cyanostilbene crystal has been synthesized that can undergo solid-state [2+2] cycloaddition reaction under violet or UV irradiation and exhibits excellent photomechanical bending properties. A hook-shaped crystal can lift 0.7 mg object upward by 1.5 cm, which proves its potential for application as photoactuators. When complex with the agarose polymer, the molecules will be in the form of macroscopic crystals, which can drive the composite films to exhibit excellent photomechanical bending performance. Upon irradiation with UV light, the composite film can quickly lift 18.0 mg object upward by 0.3 cm. The results of this work may facilitate the application of macroscale crystals as photoactuators.

In silico analysis of intestinal microbial instability and symptomatic markers in mice during the acute phase of severe burns.

BACKGROUND: Severe burns may alter the stability of the intestinal flora and affect the patient's recovery process. Understanding the characteristics of the gut microbiota in the acute phase of burns and their association with phenotype can help to accurately assess the progression of the disease and identify potential microbiota markers. METHODS: We established mouse models of partial thickness deep III degree burns and collected faecal samples for 16 S rRNA amplification and high throughput sequencing at two time points in the acute phase for independent bioinformatic analysis. RESULTS: We analysed the sequencing results using alpha diversity, beta diversity and machine learning methods. At both time points, 4 and 6 h after burning, the Firmicutes phylum content decreased and the content of the Bacteroidetes phylum content increased, showing a significant decrease in the Firmicutes/Bacteroidetes ratio compared to the control group. Nine bacterial genera changed significantly during the acute phase and occupied the top six positions in the Random Forest significance ranking. Clustering results also clearly showed that there was a clear boundary between the communities of burned and control mice. Functional analyses showed that during the acute phase of burn, gut bacteria increased lipoic acid metabolism, seleno-compound metabolism, TCA cycling, and carbon fixation, while decreasing galactose metabolism and triglyceride metabolism. Based on the abundance characteristics of the six significantly different bacterial genera, both the XGboost and Random Forest models were able to discriminate between the burn and control groups with 100% accuracy, while both the Random Forest and Support Vector Machine models were able to classify samples from the 4-hour and 6-hour burn groups with 86.7% accuracy. CONCLUSIONS: Our study shows an increase in gut microbiota diversity in the acute phase of deep burn injury, rather than a decrease as is commonly believed. Severe burns result in a severe imbalance of the gut flora, with a decrease in probiotics and an increase in microorganisms that trigger inflammation and cognitive deficits, and multiple pathways of metabolism and substance synthesis are affected. Simple machine learning model testing suggests several bacterial genera as potential biomarkers of severe burn phenotypes.

High-resolution self-corrected single-pixel imaging through dynamic and complex scattering media: erratum.

We correct typographical errors in our paper [Opt. Express31, 23027 (2023)10.1364/OE.489808]. The corrections have no influence on the results and conclusions of the original paper.

High-resolution ghost imaging through complex scattering media via a temporal correction: erratum.

We correct a typographical error in our Letter [Opt. Lett.47, 3692 (2022)10.1364/OL.463897]. The corrections have no influence on the results and conclusions of the original Letter.

Magnetic Resonance Elastography of Anterior Mediastinal Tumors.

BACKGROUND: Preoperative differentiation of the types of mediastinal tumors is essential. Magnetic resonance (MR) elastography potentially provides a noninvasive method to assess the classification of mediastinal tumor subtypes. PURPOSE: To evaluate the use of MR elastography in anterior mediastinal masses and to characterize the mechanical properties of tumors of different subtypes. STUDY TYPE: Prospective. SUBJECTS: 189 patients with anterior mediastinal tumors (AMTs) confirmed by histopathology (62 thymomas, 53 thymic carcinomas, 57 lymphomas, and 17 germ cell tumors). FIELD STRENGTH/SEQUENCE: A gradient echo-based 2D MR elastography sequence and a diffusion-weighted imaging (DWI) sequence at 3.0 T. ASSESSMENT: Stiffness and apparent diffusion coefficients (ADC) were measured in AMTs using MR elastography-derived elastograms and DWI-derived ADC maps, respectively. The aim of this study is to identify whether MR elastography can differentiate between the histological subtypes of ATMs. STATISTICAL TESTS: One-way analysis of variance (ANOVA), two-way ANOVA, Pearson's linear correlation coefficient (r), receiver operating characteristic (ROC) curve analysis; P < 0.05 was considered significant. RESULTS: Lymphomas had significantly lower stiffness than other AMTs (4.0 ± 0.63 kPa vs. 4.8 ± 1.39 kPa). The mean stiffness of thymic carcinomas was significantly higher than that of other AMTs (5.6 ± 1.41 kPa vs. 4.2 ± 0.94 kPa). Using a cutoff value of 5.0 kPa, ROC analysis showed that lymphomas could be differentiated from other AMTs with an accuracy of 59%, sensitivity of 97%, and specificity of 38%. Using a cutoff value of 5.1 kPa, thymic carcinomas could be differentiated from other AMTs with an accuracy of 84%, sensitivity of 67%, and specificity of 90%. However, there was an overlap in the stiffness values of individual thymomas (4.2 ± 0.71; 3.9-4.5), thymic carcinomas (5.6 ± 1.41; 5.0-6.1), lymphomas (4.0 ± 0.63; 3.8-4.2), and germ cell tumors (4.5 ± 1.79; 3.3-5.6). DATA CONCLUSION: MR elastography-derived stiffness may be used to evaluate AMTs of various histologies. TECHNICAL EFFICACY: Stage 2.

Hydration Mechanism and Its Effect on the Solubility of Aripiprazole.

PROPOSE: The propose is to investigate the reasons for the insolubility of Form III in water and to explore the mechanism of the hydration process of Form III. METHODS: The conformational and cohesive energies of Form III and Form H1 were calculated using Gaussian 16 and Crystal Explorer 17. Gaussian 16 and Multiwfn 3.8 was used to calculate the molecular surface electrostatic potential of Form III and Form H1 and to calculate the energies of the stronger intermolecular interactions in the crystal structure. The behaviors of Form III in water were simulated using Gromacs 2020.6. Finally, the hydration process from Form III to Form H1 was monitored in situ using Raman spectroscopy. RESULTS: The conformational energies of Form III and H1 are almost the same. The cohesion energy of Form H1 is much larger than that of Form III because both number of hydrogen bonds and van der Waals interactions are higher in the Form H1. During the simulation, the supercell of APZ form a supramolecular cluster. Several molecules manually dismantled from the cluster spontaneously combine to form new molecular clusters. Both increases in temperature and external energy input accelerate the hydration process. CONCLUSIONS: More hydrogen bonds and strong van der Waals interactions in Form H1 lead to a greater stability. The overall decrease in polarity and the strong binding effect on APZ molecule clusters due to intermolecular interactions lead to the water insolubility of Form III. The hydration process from Form III to Form H1 follows a novel, dandelion sowing-like hydration mechanism.

Novel Pharmaceutical Cocrystals of Tegafur: Synthesis, Performance, and Theoretical Studies.

PURPOSE: Tegafur (TF) is one of the most important clinical antitumor drugs with poor water solubility, severely reducing its bioavailability. This work develops new cocrystals to improve the solubility of TF and systematically investigates the intermolecular interactions to provide new insights into the formation of cocrystal and changes in physicochemical properties. METHOD: In this paper, two new 1:1 cocrystals of TF with 2,4 dihydroxybenzoic acid (2,4HBA) and p-nitrophenol (PNP) were synthesized. The cocrystal products were identified and characterized by various solid state analysis techniques. And the high performance liquid chromatography (HPLC) was conducted to determine the solubility and dissolution rate of TF and cocrystals. Moreover, the quantum chemistry calculations of crystal structure provided theoretical support for the results. RESULT: Compared with pure TF, the solubility and dissolution rate of TF-2,4HBA is significantly increased in a pH 6.8 buffer at 37°C. Under accelerated storage conditions (40°C, 75% RH), all cocrystal exhibits excellent stability over 8 weeks. Hirshfeld surface (HS) analysis, atoms in molecules (AIM) analysis, interaction region indicator (IRI) analysis, molecular electrostatic potential surface (MEPS) analysis and frontier molecular orbital (HOMO-LUMO) analysis were integrated to understand the hydrogen bonding interaction more comprehensively. The simulation results are in good agreement with the experimental data. The results show that the analysis of physical and chemical properties of TF-PNP cocrystal and TF crystal by quantum chemistry method is reliable at molecular level. CONCLUSION: These results are helpful to provide guiding methods in the cocrystal development and theoretical study of tegafur.

Insight into the Manipulation Mechanism of Polymorphic Transformation by Polymers: A Case of Cimetidine.

PURPOSE: Employing polymer additives is an effective strategy to realize the manipulation of polymorphic transformation. However, the manipulation mechanism is still not clear, which limit the precise selection of polymeric excipients and the development of pharmaceutical formulations. METHODS: The solubility of cimetidine (CIM) in acetonitrile/water mixtures were measured. And the polymorphic transformation from CIM form A to form B with the addition of different polymers was monitored by Raman spectroscopy. Furthermore, the manipulation effect of polymers was determined based on the results of experiments and molecular simulations. RESULTS: The solubility of form A is consistently higher than that of form B, which indicate that form B is the thermodynamically stable form within the examined temperature range. The presence of polyvinylpyrrolidone (PVP) of a shorter chain length could have a stronger inhibitory effect on the phase transformation process of metastable form, whereas polyethylene glycol (PEG) had almost no impact. The nucleation kinetics experiments and molecular dynamic simulation results showed that only PVP molecules could significantly decrease the nucleation rate of CIM, due to the ability of reducing solute molecular diffusion and solute-solute molecular interaction. A combination of crystal growth rate measurements and calculations of the interaction energies between PVP and the crystal faces of CIM indicate that smaller molecular weight PVP can suppress crystal growth more effectively. CONCLUSION: PVP K16-18 has more impact on the stabilization of CIM form A and inhibition of the phase transformation process. The manipulation mechanism of polymer additives in the polymorphic transformation of CIM was proposed.

Immune dysregulation is associated with symptom dimensions and cognitive deficits in schizophrenia: accessible evidence from complete blood count.

BACKGROUND: Schizophrenia (SCZ) is a psychotic disorder with an unknown pathogenesis accompanied by varying degrees of cognitive deficits. Recent studies have shown that immune dysregulation plays an important role in developing symptoms and cognitive deficits in SCZ. This study aimed to determine the complete blood count (CBC), including white blood cells, neutrophils, monocytes, lymphocytes, platelets, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR), in patients with SCZ and explore their correlations with SCZ symptom dimensions and cognitive function. METHODS: Seventy-four patients with SCZ and 57 age- and sex-matched healthy controls with available demographic and clinical information were recruited for this study. Blood samples were collected, and symptom dimensions and cognitive function were evaluated using the Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) separately. RESULTS: Our results demonstrate that SCZ patients showed higher monocyte counts, PLR, MLR, and worse performance in the total MCCB than healthy controls. Neutrophil and lymphocyte counts and NLR were positively related to symptom severity and negatively related to depressive symptoms. White blood cell (WBC) count, monocyte count, and MLR were positively correlated with cognitive performance in patients with SCZ. CONCLUSION: In summary, this study suggests that cognitive deficits and symptom severity in patients were associated with dysregulation of immunity. Moreover, we found that WBC could be used as a marker for symptom severity and cognitive deficits in SCZ and that neutrophils are more closely related to the former and monocytes to the latter. We hope that clinicians will pay more attention to dysregulated immunity in patients with SCZ in the future.

The bidirectional association between the disability in activities of daily living and depression: a longitudinal study in Chinese middle-aged and older adults.

AIM: Depression and disability in activities of daily living (ADL) are common in middle-aged and older adults. This study investigated the bidirectional relationship between depression and disability in ADL in Chinese middle-aged and older adults. METHODS: Data from a baseline study of 17,596 participants from the China Health and Retirement Longitudinal Study (CHARLS) and two follow-up visits at 4 and 7 years were included. We designed Study A and Study B to explore the interaction between depression and disability in ADL in middle-aged and older people. RESULTS: Individuals with disability in ADL at baseline had adjusted odds ratios (ORs) of 1.331 (1.118, 1.584) and 1.969 (1.585, 2.448) for developing depression compared with those without disability in ADL at the 4- and 7-year follow-ups, respectively. Individuals with depression at baseline had adjusted ORs of 1.353 (1.127, 1.625) and 1.347 (1.130, 1.604), respectively, for developing disability in ADL 4 and 7 years later. CONCLUSIONS: There was a bidirectional relationship between depression and disability in ADL. Depression increased the risk of disability in ADL, but this risk did not increase with time, whereas the effect of disability in ADL on depression increased with time.

Application of Chlorophyll Fluorescence Analysis Technique in Studying the Response of Lettuce (Lactuca sativa L.) to Cadmium Stress.

To reveal the impact of cadmium stress on the physiological mechanism of lettuce, simultaneous determination and correlation analyses of chlorophyll content and photosynthetic function were conducted using lettuce seedlings as the research subject. The changes in relative chlorophyll content, rapid chlorophyll fluorescence induction kinetics curve, and related chlorophyll fluorescence parameters of lettuce seedling leaves under cadmium stress were detected and analyzed. Furthermore, a model for estimating relative chlorophyll content was established. The results showed that cadmium stress at 1 mg/kg and 5 mg/kg had a promoting effect on the relative chlorophyll content, while cadmium stress at 10 mg/kg and 20 mg/kg had an inhibitory effect on the relative chlorophyll content. Moreover, with the extension of time, the inhibitory effect became more pronounced. Cadmium stress affects both the donor and acceptor sides of photosystem II in lettuce seedling leaves, damaging the electron transfer chain and reducing energy transfer in the photosynthetic system. It also inhibits water photolysis and decreases electron transfer efficiency, leading to a decline in photosynthesis. However, lettuce seedling leaves can mitigate photosystem II damage caused by cadmium stress through increased thermal dissipation. The model established based on the energy captured by a reaction center for electron transfer can effectively estimate the relative chlorophyll content of leaves. This study demonstrates that chlorophyll fluorescence techniques have great potential in elucidating the physiological mechanism of cadmium stress in lettuce, as well as in achieving synchronized determination and correlation analyses of chlorophyll content and photosynthetic function.

FGF12 restrains mitochondria-dependent ferroptosis in doxorubicin-induced cardiomyocytes through the activation of FGFR1/AMPK/NRF2 signaling.

Fibroblast growth factor-12 (FGF12) has been reported to play important role in regulating heart diseases. We aimed to explore the role of FGF12 in doxorubicin (DOX)-induced myocardial injury. DOX-induced mice and DOX-induced HL-1 cells were used as the myocardial injury in vivo and in vitro. Then, FGF12, Anp, Bnp, and Myh7 expression was detected. The pathological injury in myocardium tissue was observed by H&E staining. The levels of markers related to myocardial damage and oxidative stress were assessed. Then, immunohistochemistry and immunofluorescence staining were used to detect FGF12 and 4-HNE expression. Ferroptosis were detected by Prussian blue staining and western blot. The FGFR1/AMPK/NRF2 signaling was measured by western blot. FGF12 expression was downregulated in DOX-induced mice myocardium tissues. FGF12 overexpression alleviated DOX-induced myocardial tissue pathological injury and reduced Anp, Bnp, and Myh7 expression. Additionally, the levels of CK-MB, LDH and cTnT in serum were decreased after FGF12 upregulation in DOX-induced mice. Moreover, FGF12 overexpression reduced the levels of ROS, MDA, and 4-HNE but increased SOD and GSH-Px activities. Meanwhile, FGF12 led to less deposition of iron ion, decreased ACSL4, PTGS2 and increased GPX4, FTH1 expression. Additionally, FGF12 activated the expressions of FGFR1, p-AMPK, and NRF2. Moreover, FGFR1 silencing reversed the protective effects of FGF12 overexpression on cell viability, oxidative stress, ferroptosis, and FGFR1/AMPK/NRF2 pathway. To sum up, FGF12 inhibited mitochondria-dependent ferroptosis in cardiomyocytes induced by DOX through activation of FGFR1/AMPK/NRF2 signaling. These findings clarify a new mechanism of DOX-induced cardiac injury and provide a promising target to limit the disease development.

Annotation of Dipeptides and Tripeptides Derivatized via Dansylation Based on Liquid Chromatography-Mass Spectrometry and Iterative Quantitative Structure Retention Relationship.

Small peptides such as dipeptides and tripeptides show various biological activities in organisms. However, methods for identifying dipeptides/tripeptides from complex biological samples are lacking. Here, an annotation strategy involving the derivatization of dipeptides and tripeptides via dansylation was suggested based on liquid chromatography-mass spectrometry (LC-MS) and iterative quantitative structure retention relationship (QSRR) to choose dipeptides/tripeptides by using a small number of standards. First, the LC-autoMS/MS method and initial QSRR model were built based on 25 selected grid-dipeptides and 18 test-dipeptides. To achieve high-coverage detection, dipeptide/tripeptide pools containing abundant dipeptides/tripeptides were then obtained from four dansylated biological samples including serum, tissue, feces, and soybean paste by using the parameter-optimized LC-autoMS/MS method. The QSRR model was further optimized through an iterative train-by-pick strategy. Based on the specific fragments and tR tolerances, 198 dipeptides and 149 tripeptides were annotated. The dipeptides at lower annotation levels were verified by using authentic standards and grid-correlation analysis. Finally, variation in serum dipeptides/tripeptides of three different liver diseases including hepatitis B infection, liver cirrhosis, and hepatocellular carcinoma was characterized. Dipeptides with N-prolinyl, C-proline, N-glutamyl, and N-valinyl generally increased with disease severity. In conclusion, this study provides an efficient strategy for annotating dipeptides/tripeptides from complex samples.

A novel homozygous Y140X mutation of ISG15 causes diverse type I interferonopathies in sibling patients with cutaneous lesions or recurrent parenchymal pneumonia.

PURPOSE: Interferon-stimulated gene 15 (ISG15) deficiency, a rare human inborn error of immunity characterized by susceptibility to Bacillus Calmette-Guerin (BCG) diseases, neuropathic and dermatological manifestations. METHODS: The clinical and immunological features of two siblings with ISG15 deficiency combined with asymptomatic myeloperoxidase (MPO) mutations were analyzed, and their pathogenesis, as well as target therapeutic candidates, were explored. RESULTS: The manifestation in patient 2 was skin lesions, while those in patient 1 were intracranial calcification and recurrent pneumonia. Whole-exome identified novel, dual mutations in ISG15 and MPO. PBMCs and B cell lines derived from the patients showed hyper-activated JAK/STAT signaling. Normal neutrophil function excluded pathogenicity caused by the MPO mutation. RNA sequencing identified baricitinib as therapeutic candidate. CONCLUSIONS: We report two sibling patients harboring the same novel ISG15 mutation showing diverse clinical features, and one harbored a rare phenotype of pneumonia. These findings expand the clinical spectrum of ISG15 deficiency and identify baricitinib as therapeutic candidate.