PRRX1-fused mesenchymal neoplasm: A novel PRRX1::NCOA1 fusion transcript.

PRRX1-fused mesenchymal neoplasm is a recently identified, rare subcutaneous soft tissue neoplasm that is characterized by fusion of PRRX1 (exon 1) with NCOA1 (exon 13) in the majority of reported cases. Although initially considered to be fibroblastic, a possibility of neural or neuroectodermal differentiation has been suggested in a subset of cases. We report a 26-year-old female with a 4.0 cm painless mass located in the subcutis of the left thigh. Microscopically, the tumor was well-circumscribed and multinodular and was composed of relatively monomorphic ovoid to spindle cells arranged in loose fascicles, trabeculae, and cords within alternating myxoid and fibrous matrix, and vascularized stroma. Mitotic figures were scarce and necrosis was not observed. By immunohistochemistry, the neoplastic cells demonstrated focal co-expression of S100 protein and SOX10 and were negative for epithelial membrane antigen, smooth muscle actin, desmin, CD34, STAT6, HMB45, Melan-A, and MUC4. The expression of Rb1 was retained. Targeted RNA-sequencing identified a novel transcript fusion of PRRX1 (exon 1)::NCOA1 (exon 15), which was further confirmed by reverse transcription polymerase chain reaction and Sanger sequencing. The tumor was narrowly excised and no tumor recurrence or metastasis was identified after 13 months of follow-up. In summary, we report a new case of PRRX1-fused mesenchymal neoplasm, expanding the molecular genetic spectrum and providing further support for possible neural or neuroectodermal differentiation of this emerging soft tissue tumor entity.

Two new Cortinarius species in subgenus Leprocybe from Southwest China.

Two new Cortinarius species in subgenus Leprocybe, Cortinarius hengduanensis and C. yadingensis, are proposed based on a combination of morphological and molecular evidence. Cortinarius hengduanensis has distinct olive tinged basidiomata, a squamulose pileus, and small, subglobose to broadly ellipsoid basidiospores, the ITS sequence differs from that of C. flavifolium by at least 28 substitutions and independent positions. Cortinarius yadingensis has a squamulose pileus and subglobose to broadly ellipsoid coarsely verrucose basidiospores, the ITS sequence has at least 11 substitutions and index position deviations from the other members of the Leprocybe section. Both new species were found in mixed forests of southwest China.

[Lysine Succinylation:A New Perspective in the Treatment of Cardiovascular Diseases].

With the continuous development of identification technologies such as mass spectrometry,omics,and antibody technology,post-translational modification (PTM) has demonstrated increasing potential in medical research.PTM as a novel chemical modification method provides new perspectives for the research on diseases.Succinylation as a novel modification has aroused the interest of more and more researchers.The available studies about succinylation mainly focus on a desuccinylase named sirtuin 5.This enzyme plays a key role in modification and has been preliminarily explored in cardiovascular studies.This paper summarizes the influencing factors and regulatory roles of succinylation and the links between succinylation and other PTMs and reviews the research progress of PTMs in the cardiovascular field,aiming to deepen the understanding about the role of this modification and give new insights to the research in this field.

Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart against ischemia/reperfusion injury by limiting TNFα-induced mitochondrial injury in experimental diabetes.

AIMS: The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A, reduces myocardial ischemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments activity of HDAC6 and generation of tumor necrosis factor α (TNFα) and impairs mitochondrial complex I (mCI). Here we examined how HDAC6 regulates TNFα production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI. METHODS AND RESULTS: HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNFα, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of ATP. Importantly, genetic disruption of HDAC6 or tubastatin A decreased TNFα levels, mitochondrial fission, and myocardial mitochondrial NADH levels in ischemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or tubastatin A treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNFα levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown. CONCLUSIONS: HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNFα-induced mitochondrial injury in experimental diabetes.

Topical application of a BCL-2 inhibitor ameliorates imiquimod-induced psoriasiform dermatitis by eliminating senescent cells.

BACKGROUND: Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs. OBJECTIVE: To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis. METHODS: We explored the expression levels of p16INK4a and p21, classical markers of cellular senescence, in CD4+ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis. RESULTS: Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a and p21 in CD4+ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and ß chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model. CONCLUSION: We revealed the roles of senescent CD4+ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αß repertoire, and regulation of the TET2-Th17 cell pathway.

Multidimensional engineering of Saccharomyces cerevisiae for the efficient production of heme by exploring the cytotoxicity and tolerance of heme.

Heme has attracted considerable attention due to its indispensable biological roles and applications in healthcare and artificial foods. The development and utilization of edible microorganisms instead of animals to produce heme is the most promising method to promote the large-scale industrial production and safe application of heme. However, the cytotoxicity of heme severely restricts its efficient synthesis by microorganisms, and the cytotoxic mechanism is not fully understood. In this study, the effect of heme toxicity on Saccharomyces cerevisiae was evaluated by enhancing its synthesis using metabolic engineering. The results showed that the accumulation of heme after the disruption of heme homeostasis caused serious impairments in cell growth and metabolism, as demonstrated by significantly poor growth, mitochondrial damage, cell deformations, and chapped cell surfaces, and these features which were further associated with substantially elevated reactive oxygen species (ROS) levels within the cell (mainly H2O2 and superoxide anion radicals). To improve cellular tolerance to heme, 5 rounds of laboratory evolution were performed, increasing heme production by 7.3-fold and 4.2-fold in terms of the titer (38.9 mg/L) and specific production capacity (1.4 mg/L/OD600), respectively. Based on comparative transcriptomic analyses, 32 genes were identified as candidates that can be modified to enhance heme production by more than 20% in S. cerevisiae. The combined overexpression of 5 genes (SPS22, REE1, PHO84, HEM4 and CLB2) was shown to be an optimal method to enhance heme production. Therefore, a strain with enhanced heme tolerance and ROS quenching ability (R5-M) was developed that could generate 380.5 mg/L heme with a productivity of 4.2 mg/L/h in fed-batch fermentation, with S. cerevisiae strains being the highest producers reported to date. These findings highlight the importance of improving heme tolerance for the microbial production of heme and provide a solution for efficient heme production by engineered yeasts.

A Planar-Structured Dinuclear Cobalt(II) Complex with Indirect Synergy for Photocatalytic CO2-to-CO Conversion.

Dinuclear metal synergistic catalysis (DMSC) has been proved an effective approach to enhance catalytic efficiency in photocatalytic CO2 reduction reaction, while it remains challenge to design dinuclear metal complexes that can show DMSC effect. The main reason is that the influence of the microenvironment around dinuclear metal centres on catalytic activity has not been well recognized and revealed. Herein, we report a dinuclear cobalt complex featuring a planar structure, which displays outstanding catalytic efficiency for photochemical CO2-to-CO conversion. The turnover number (TON) and turnover frequency (TOF) values reach as high as 14457 and 0.40 s-1 respectively, 8.6 times higher than those of the corresponding mononuclear cobalt complex. Control experiments and DFT calculations revealed that the enhanced catalytic efficiency of the dinuclear cobalt complex is due to the indirect DMSC effect between two CoII ions, energetically feasible one step two-electron transfer process by Co2I,I intermediate to afford Co2II,II(CO22-) intermediate and fast mass transfer closely related with the planar structure.

Investigation on the contaminate of hand washing activities on the surface of environmental objects in intensive care unit.

To detect the contaminate of faucets in hospitals and the splash during hand washing, and to explore the reasonable layout of hand washing pools. Two faucets with roughly the same spatial layout in the ICU of a third-class first-class general hospital were selected, and the farthest splashing distance and specific splashing points were measured by color paper. Samples were detected by ATP detection technology and routine microbial detection method, and the contaminate of faucets was analyzed. After 72 h of daily hand-washing activities, the furthest distance to the splash point was about 100 cm around the faucet, and the place 40-110 cm around the faucet was contaminated seriously. The farthest distance that the splash point reached was about 80 cm around the faucet with the center of the circle, and the area 40-60 cm around the faucet was heavily contaminated. The distance from the water outlet of the long handle and the short handle faucet to the detection point had a high negative correlation (r = - 0.811, P < 0.001) and a moderate negative correlation (r = - 0.475, P = 0.001) with the number of splash points, respectively. The qualified rates of ATP detection and microbial culture were 25% and 15%, respectively. Pseudomonas aeruginosa, Staphylococcus epidermidis, and other pathogenic bacteria were detected in the water outlet of the faucet and the surrounding environment. Safe hand hygiene facilities are one of the important guarantees of hand hygiene effect. Clean objects and objects related to patients should not be placed within 1 m range near the water outlet of faucet. Anti-splash baffle should be installed as much as possible when conditions permit to reduce the contaminate caused by splash during hand washing.

Measurable residual disease testing by next generation sequencing is more accurate compared with multiparameter flow cytometry in adults with B-cell acute lymphoblastic leukemia.

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34-8.5; P = 0.01) and worse survival (HR = 4.87 [1.53-15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTROPC-14005546]).

One-to-Nine Single Spectroscopic Intelligent Probe for Risk Assessment of Multiple Metals in Drinking Water.

26% of the world's population lacks access to clean drinking water; clean water and sanitation are major global challenges highlighted by the UN Sustainable Development Goals, indicating water security in public water systems is at stake today. Water monitoring using precise instruments by skilled operators is one of the most promising solutions. Despite decades of research, the professionalism-convenience trade-off when monitoring ubiquitous metal ions remains the major challenge for public water safety. Thus, to overcome these disadvantages, an easy-to-use and highly sensitive visual method is desirable. Herein, an innovative strategy for one-to-nine metal detection is proposed, in which a novel thiourea spectroscopic probe with high 9-metal affinity is synthesized, acting as "one", and is detected based on the 9 metal-thiourea complexes within portable spectrometers in the public water field; this is accomplished by nonspecialized personnel as is also required. During the processing of multimetal analysis, issues arise due to signal overlap and reproducibility problems, leading to constrained sensitivity. In this innovative endeavor, machine learning (ML) algorithms were employed to extract key features from the composite spectral signature, addressing multipeak overlap, and completing the detection within 30-300 s, thus achieving a detection limit of 0.01 mg/L and meeting established conventional water quality standards. This method provides a convenient approach for public drinking water safety testing.

Physicochemical and Rheological Properties of Degraded Konjac Gum by Abalone (Haliotis discus hannai) Viscera Enzyme.

In the present study, a new degraded konjac glucomannan (DKGM) was prepared using a crude enzyme from abalone (Haliotis discus hannai) viscera, and its physicochemical properties were investigated. After enzymatic hydrolysis, the viscosity of KGM obviously decreased from 15,500 mPa·s to 398 mPa·s. The rheological properties analysis of KGM and DKGMs revealed that they were pseudoplastic fluids, and pseudoplasticity, viscoelasticity, melting temperature, and gelling temperature significantly decreased after enzymatic hydrolysis, especially for KGM-180 and KGM-240. In addition, the molecular weight of KGM decreased from 1.80 × 106 Da, to 0.45 × 106 Da and the polydispersity index increased from 1.17 to 1.83 after 240 min of degradation time. Compared with natural KGM, the smaller particle size distribution of DKGM further suggests enzyme hydrolysis reduces the aggregation of molecular chains with low molecular weight. FT-IR and FESEM analyses showed that the fragmented KMG chain did not affect the structural characteristics of molecular monomers; however, the dense three-dimensional network microstructure formed by intermolecular interaction changed to fragment microstructure after enzyme hydrolysis. These results revealed that the viscosity and rheological properties of KGM could be controlled and effectively changed using crude enzymes from abalone viscera. This work provides theoretical guidance for the promising application of DKGM in the food industry.

Optimal Treatment of Tumor in Upper Human Respiratory Tract Using Microaerosols.

Lung cancer is a frequently diagnosed respiratory disease caused by particulate matter in the environment, especially among older individuals. For its effective treatment, a promising approach involves administering drug particles through the inhalation route. Multiple studies have investigated the flow behavior of inhaled particles in the respiratory airways of healthy patients. However, the existing literature lacks studies on the precise understanding of the transportation and deposition (TD) of inhaled particles through age-specific, unhealthy respiratory tracts containing a tumor, which can potentially optimize lung cancer treatment. This study aims to investigate the TD of inhaled drug particles within a tumorous, age-specific human respiratory tract. The computational model reports that drug particles within the size range of 5-10 µm are inclined to deposit more on the tumor located in the upper airways of a 70-year-old lung. Conversely, for individuals aged 50 and 60 years, an optimal particle size range for achieving the highest degree of particle deposition onto upper airway tumor falls within the 11-20 µm range. Flow disturbances are found to be at a maximum in the airway downstream of the tumor. Additionally, the impact of varying inhalation flow rates on particle TD is examined. The obtained patterns of airflow distribution and deposition efficiency on the tumor wall for different ages and tumor locations in the upper tracheobronchial airways would be beneficial for developing an efficient and targeted drug delivery system.

Macrocarpal B blocks the binding between the phospholipase A2 receptor and its antibodies.

The pathogenic role of anti-phospholipase A2 receptor (PLA2R) antibodies in primary membranous nephropathy (MN) has been well-established. This study aimed to identify potential small-molecule inhibitors against the PLA2R-antibody interaction, offering potential therapeutic benefits. A comprehensive screening of over 4000 small-molecule compounds was conducted by ELISA to assess their inhibitory effects on the binding between the immobilized full-length extracellular PLA2R and its antibodies. The affinity of anti-PLA2R IgG from MN patients and the inhibitory efficacy of each compound were evaluated via surface plasmon resonance (SPR). Human podocyte injuries were analyzed using CCK-8 assay, wound healing assay, western blot analysis, and immunofluorescence, after exposure to MN plasma +/- blocking compound. Fifteen compounds were identified as potential inhibitors, demonstrating inhibition rates >20 % for the PLA2R-antibody interaction. Anti-PLA2R IgG exhibited a consistent affinity among patients (KD = 10-8 M). Macrocarpal B emerged as the most potent inhibitor, reducing the antigen-antibody interaction by nearly 30 % in a dose-dependent manner, comparable to the performance of the 31-mer peptide from the CysR domain. Macrocarpal B bound to the immobilized PLA2R with an affinity of 1.47 × 10-6 M, while showing no binding to anti-PLA2R IgG. Human podocytes exposed to MN plasma showed decreased podocin expression, impaired migration function, and reduced cell viability. Macrocarpal B inhibited the binding of anti-PLA2R IgG to podocytes and reduced the cellular injuries.

Brain Short-Chain Fatty Acids Induce ACSS2 to Ameliorate Depressive-Like Behavior via PPARγ-TPH2 Axis.

Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota-gut-brain axis. However, the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood. Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is a novel target of the rapid and long-lasting antidepressant responses. Here, we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2 (TPH2) promoter histone acetylation and its transcription in SH-SY5Y cells. In chronic-restraint-stress-induced depression mice, neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice, supporting that ACSS2 is required for SCFA-mediated antidepressant responses. Mechanistically, the peroxisome-proliferator-activated receptor gamma (PPARγ) is identified as a novel partner of ACSS2 to activate TPH2 transcription. Importantly, PPARγ is also responsible for SCFA-mediated antidepressant-like effects via ACSS2-TPH2 axis. To further support brain SCFAs as a therapeutic target for antidepressant effects, d-mannose, which is a naturally present hexose, can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2-PPARγ-TPH2 axis. In summary, brain SCFAs can activate ACSS2-PPARγ-TPH2 axis to play the antidepressive-like effects, and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.

The carbohydrate metabolism and expression of carbohydrate-active enzyme genes in Aspergillus luchuensis fermentation of tea leaves.

Introduction: Carbohydrates, which make up 20 to 25% of tea beverages, are responsible for their flavor and bioactivity. Carbohydrates of pu-erh tea change during microbial fermentation and require further research. In this study, we examined the carbohydrate metabolism and expression of carbohydrate-active enzyme genes during the fermentation of tea leaves with Aspergillus luchuensis. Methods: Widely targeted metabolomics analysis, high-performance anion-exchange chromatography measurements, and transcriptomics were used in this study. Results: After fermentation, the levels of soluble sugar, hemicellulose, lignin, eight monosaccharides, and seven sugar alcohols increased. Meanwhile, the relative contents of polysaccharides, D-sorbitol, D-glucose, and cellulose decreased. High expression of 40 genes encoding 16 carbohydrate enzymes was observed during fermentation (FPKM>10). These genes encode L-iditol 2-dehydrogenase, pectinesterase, polygalacturonase, α-amylase, glucoamylase, endoglucanase, ß-glucosidase, ß-galactosidase, α-galactosidase, α-glucosidase, and glucose-6-phosphate isomerase, among others. Discussion: These enzymes are known to break down polysaccharides and cell wall cellulose, increasing the content of monosaccharides and soluble sugars.